Wave Life Sciences Ltd. Aktie

Hello, and welcome to Wave's 2026 Research Day. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Good morning, everyone and welcome to Wave's 2026 Research Day. The slides accompanying today's presentation will be available following the event in the Investors section of our website at www.wavelifesciences.com.

Before we begin, I would like to remind you that management may make forward-looking statements during today's presentation. These statements are subject to risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in our SEC filings, including our most recent annual report on Form 10-K and our most recent quarterly report on Form 10-Q. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, you will hear from Paul Bolno, our President and Chief Executive Officer; Erik Ingelsson, our Chief Scientific Officer; and Chandra Vargeese, our Chief Technology Officer. We are also pleased to welcome Dr. Arun Sanyal, who will share his perspective on PNPLA3 I148M liver disease and the opportunity for an RNA editing correction approach. Following the presentations, our speakers will be available for Q&A as well as Chris Wright, our CMO.

With that, I'll turn the presentation over to Paul.

Thanks, Kate. Good morning, and thank you for joining us today. Today marks our Eighth Annual Research Day. Each year, we use this time to showcase emerging programs in our pipeline, our platform capabilities and our recent innovations. As an organization, we are relentlessly focused on our mission of unlocking the broad potential of RNA medicines to transform human health.

At Wave, we bring together deep genetic insights and our proprietary chemistry to rapidly advance a pipeline of transformational RNA medicines. There are thousands of known genetically defined diseases and understanding of how these genetic variations drive disease continues to deepen. At the same time, larger genetic studies and better tools for analyzing big data sets are rapidly expanding the number of strong genetic targets for common diseases.

With our multimodal platform, Wave is uniquely positioned to leverage these insights. For most of the field's history, oligonucleotide innovation has advanced through sugar and backbone modifications. And even today, traditional oligonucleotides are made of a serial random mixture with potentially up to 1 million unique isomers in a single dose. Wave's founding premise was to bring rational drug design to oligonucleotides to solve for this, resulting in improved distribution and pharmacologic and safety profiles.

With the introduction of controlling backbone stereochemistry, PN chemistry and modified bases, we've built the foundation for SpiNA design siRNAs and pioneered new modalities like RNA editing and bifunctionals. We've demonstrated clinical translation of our proprietary chemistry, RNA editing, allele selective silencing, and recently, our SpiNA design, further setting us apart in the field and demonstrating the differentiation of our platform.

We've been developing a way to extend these innovations beyond the liver. And today, we will provide an update on our PN conjugates. We have established an oligonucleotide center of excellence for accelerating these innovations into better RNA medicines. The process starts with selecting targets with strong human genetic support, and we've built in-house systems to integrate large data sets into our discovery engine.

Wave is uniquely situated to have options for choosing the right tool to silence, edit, or upregulate any given target, thereby enabling us to pair the modality that best addresses the target, including the ability to combine multiple modalities together.

As you'll hear later, PNPLA3 is a perfect example of where RNA editing enables distinct advantages over siRNA. Using PRISM, we can leverage predictive modeling and rational design to optimize favorable pharmacology and safety profiles for our therapeutics. We've been compounding these learnings for over a decade and continuously improve the platform. The result is that we develop clinical candidates rapidly at no additional cost to standard oligo development and reproducibly with scalable, cost-effective manufacturing behind them. The most recent example of this process is our WVE-007 INHBE siRNA, which was 18 months from our first in vitro experiment to first human dose.

Today we'll begin in RNA editing and highlight our PNPLA3 program. This program builds on our clinical success with WVE-006 for AATD. PNPLA3 liver disease is a similar story driven by a single base change and with strong human genetic support. We are pleased to be joined today by Dr. Arun Sanyal, who will discuss the unmet need for PNPLA3 I148M patients with liver disease and the opportunity for RNA editing.

Erik will then discuss our WVE-008 program, which is advancing towards the clinic. And Chandra will then cover the foundation of our RNAi portfolio and how our SpiNA designs are enabling dramatic improvements in potency and duration of activity and how they're translating in the clinic with WVE-007 with a safe and well-tolerated profile.

Next she'll speak about how we're using our chemistry to advance PN conjugates to unlock extrahepatic delivery and provide an update on our bifunctional modalities that provide the ability to silence, edit, and/or upregulate 2 distinct targets with a single construct.

Now joining from the Liver Meeting in Denver, I'm delighted to welcome one of the most influential figures in hepatology, Dr. Arun Sanyal. Dr. Sanyal is a Professor of Medicine and Physiology and Molecular Pathology at VCU and Director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health. He has chaired the NIH NASH Clinical Research Network, served as President of the American Association for the Study of Liver Diseases and authored more than 500 publications.

He's pioneered diagnostics and therapeutics for fatty liver and end-stage liver disease. And as recently as last week, he was awarded the American Liver Foundation's Leadership Award. Dr. Sanyal will share his perspective on PNPLA3 I148M liver disease and the opportunity for a genetic correction approach.

And so without further ado, I'll turn the call to Dr. Sanyal.

Thank you, Paul.

May I have the next slide, please? It's a real pleasure for me to give this talk. And we're going to talk today about PNPLA3, specifically a mutation at the 148 position that has been associated with more aggressive disease in the context of first steatotic liver disease, but now across a whole spectrum of chronic liver diseases.

The first identification of PNPLA3 as a potential gene mutation linked to hepatic steatosis came from epidemiological studies with the Dallas Heart Study in 2008. Since then, there have been a number of landmark findings which have provided insight into how this leads to disease, what are its clinical associations. And we are now poised to really talk about how the mutation itself can be modified to change the trajectory of the disease and that's really going to be the theme of what I'm going to talk about.

Next slide, please. Now one of the -- beyond linking this gene mutation to having excess fat in the liver, there are now data indicating that if you have this gene mutation, you are much more likely to have cirrhosis. So within cirrhotic populations, this gene mutation is enriched. And what is interesting is it is not just metabolic dysfunction-associated steatotic liver disease, but whether you talk about alcohol-related liver disease, even viral hepatitis, having this gene sets you up for liver trouble if your liver does get into trouble.

Next slide, please. So what has occurred is that now with PNPLA3 as the very first sort of gene that was identified, we have a slew of genes that have been linked to steatotic liver disease. But PNPLA3 I148M remains the clearest genotype-defined MASLD target, where whether you look at common polygenic susceptibility variants, it is a central anchor of all of those. There are other protective genes that have been identified, and I think this is important that there are gene interactions.

And so the evidence ladder, if you look on the lower right side of this slide, from starting with an association signal, we now know much more about the rare disease burden. We have understanding of disease biology, and we are getting ready to talk about functional and therapeutic validation of this as a target.

Next slide, please. The global prevalence of PNPLA3, and this is another way of describing the same mutation across the world is quite variable. But you can see certain areas where there are -- where it is particularly overrepresented. And so if you look at Latin America, it is very, very overrepresented. But there are other areas such as China. And here in the United States, it's estimated we have about 18 million people who have or who carry this gene mutation. And similarly, in Japan and Mexico, many million individuals actually carry this mutation.

So the public health relevance of today's conversation is underscored by the fact that there are many, many individuals, literally millions who actually carry this mutation. And when you think about the prevalence of steatotic liver disease in 1/3 or more of the general population and you layer these one on top of the other, that puts a lot of patients at risk from this mutation.

Next slide. It is also the strongest genetic risk factor for progressive scarring. It's not just cirrhosis, but along the way to cirrhosis, as the liver gets more scarred, PNPLA3, again, across multiple etiologies has been shown to be a very important genetic driver of accelerated progression of fibrosis and accelerated development of cirrhosis. And once you get there, it is one of the strongest genetic risk factors for the development of hepatocellular carcinoma, which is one of the cancers where we have still not tamed the beast. And so that creates another opportunity for prevention of hepatocellular carcinoma or to actually flatten that curve.

Next slide. Now if you look at individuals who already have established steatotic liver disease or MASLD, we see first that the impact of the mutation on the likelihood of developing a liver outcome is also age-related. So there is an interaction term with increasing age. Now if you look at our patients who already have advanced fibrosis, they are much older than people who have very early-stage disease. And so this is an important point.

Now on the right-hand side, when you look at the disease allele and the risk of a liver outcome, and these are -- if you -- related to having advanced fibrosis, and then you're already seeing the data for the subhazard ratio for age over 60, you're seeing that in diabetics, there is an interaction as well.

So all of these show that while there is a general impact on overall risk of liver outcomes, particularly in older diabetic patients, this is particularly relevant. And again, as you know, with more advanced fibrosis, there's an over enrichment of people with type 2 diabetes, which has been associated with accelerated disease progression also.

Next slide, please. And having this mutation is associated with poorer mortality. So if you look at liver disease mortality, these are Kaplan-Meier curves, the homozygous people clearly are separated or differentiated from the heterozygous state. And similarly, if you look at cirrhosis-free survival time in people who did not have advanced fibrosis at baseline, once again, having homozygous I148M mutation is associated with much poorer outcome.

So these provide a rationale that if you can convert somebody from a homozygous to a heterozygous state that you might actually improve their clinical outcomes, which would start looking like the curves at the top. So this is an important point. And so in this study, the gene mutation was associated with decompensation or composite endpoint after adjusting for age, gender, diabetes, and BMI, which we know are co-factors with which the gene interacts. And of course, these data are continuing to be analyzed.

Next slide, please. Now if you look at -- we talked about obesity. Here, we have data with obesity and with ongoing alcohol. And in both settings, for the same degree of obesity or same degree of alcohol consumption, you are seeing an amplification of the risk of development of hepatocellular carcinoma if you have this gene mutation.

Next, please. Now mechanistically, what is happening is that this -- the protein that is encoded by this gene sits at the surface of the lipid droplets. It's a triglyceride lipase. So it takes the triglyceride in the liver and modulates the function of how you break that triglyceride down to release fatty acids that can be used for cellular energy or for other functions or to be exported.

And so this is a loss of function mutation. So when you get decreased function, you cannot mobilize your triglycerides. So at any given degree of fatty acid triglyceride flux through the liver, you start accumulating triglycerides. Now PNPLA3 gene is also important in the stellate cells, where it -- if you have the mutation, it impairs retinyl ester hydrolysis and thus accelerates collagen production by the stellate cells. And it's believed this is an important additional mechanism by which it contributes to increased fibrosis. It also attenuates proteosome autophagy. And so it leads to more fat. And when you start accumulating more fat, you also drive lipids into other apparent pathways such as ceramides, et cetera, which are altered and which can also contribute to additional inflammation and fibrosis.

Next slide. Clinically, when you talk about treatment of NASH, there are data that NASH resolution with tirzepatide was weaker if you have the gene mutation. It's not that it's bad, it is just that less than what you would see in the CC carriers. And so this again provides an opportunity that if you can change a homozygous to a -- homozygous I148M mutation to a heterozygous state, you might be able to even improve the response to background GLP therapies.

Although I will note that with semaglutide and some of the others and survodutide, which data will be shown at AASLD, the PMP -- those drugs worked regardless of the presence or absence of this gene mutation. This has been really shown in the context of tirzepatide.

Next slide, please. So why is mutation correction really a cool solution for people who have this and have liver disease? One, that because it interacts with regulatory proteins and maintains lipid homeostasis, mutation correction, it would be expected to restore lipid homeostasis, reduce steatosis, and prevent liver injury. And because of its role through retinol homeostasis, mutation correction should be able to attenuate hepatic inflammation and oxidative stress and should be able to lower fibrosis and lead to NASH resolution.

So with that, I think this is my last slide. Can we have the next, please? So I will hand it back over to Paul. Thank you.

Thank you. I'll hand it to Erik.

Thank you, Dr. Sanyal. So as I think you will agree, Dr. Sanyal has made an excellent case for why PNPLA3, one of the strongest genetically defined targets in liver disease. I'll now walk through how we are addressing it with WVE-008, our wholly owned GalNAc-conjugated RNA editing candidate.

008 builds directly on what we have already demonstrated in the clinic with WVE-006 in AATD. With 006, we have shown efficient and consistent RNA editing. We have demonstrated increased M-protein and decreased Z-protein, the levels seen in MZ individuals as well as restore the dynamic pathological response to inflammatory stimuli, supporting that our RNA editing approach is not only showing target engagement, but intended downstream treatment effects.

The editing has been durable enough to support infrequent dosing and 006 has been generally safe and well tolerated. Together, these data establish Wave as a leading RNA editing company. They also give us a validated foundation to bring RNA editing to additional genetically defined diseases, starting with PNPLA3 I148M liver disease.

As you already heard from Dr. Sanyal, PNPLA3 is a compelling target with strong human genetic evidence and a clear path to early clinical proof of concept. There are over 9 million people in the U.S. and Europe who are homozygous for PNPLA3 I148M and are living with liver disease. Homozygous carriers have a significantly higher risk of a range of liver diseases. These include MAFLD, MASH, and alcohol-associated liver disease and the extensive cirrhosis and hepatocellular carcinoma.

As you can see in the survival curve to the right, homozygous I148M carriers have an approximately ninefold higher risk of liver-related death than noncarriers. Heterozygous carriers by contrast have about 80% of risk of liver-related death than homozygous carriers. This observation defines our therapeutic goal. We aim to edit at least 50% of PNPLA3 transcripts in the liver, restoring a functional heterozygous-like state that is associated with dramatically lower risk of liver complications.

Our GalNAc RNA editing approach is uniquely designed to restore PNPLA3 function and fully address the genetic driver of disease. We believe it will be superior not only to PNPLA3 silencing, but also to non-precision approaches in MASH.

Why edit rather than silence? The wild-type protein plays important roles in the liver to lipid and retinol metabolism. Multiple preclinical models highlight the potential liabilities of removing PNPLA3 altogether. To the left, in the iPSC-derived human liver organoids, silencing PNPLA3 worsens steatosis. In the middle, in primary human hepatocytes, silencing increases inflammation-induced liver cell death, and to the right, in hepatic stellate cells, a PNPLA3 siRNA worsens the fibrotic response. These findings are consistent with emerging clinical experience.

As Dr. Sanyal noted, the emerging data from trials with PNPLA3 silencing agents have been disappointing with a recent trial that even showed dose-dependent increases in liver enzymes. The message is that functional PNPLA3 is essential for liver health, both for sustained fat metabolism and to avoid inflammation and fibrosis.

This slide shows the mechanism. The I148M variant acts through a gain of function effect. The mutant protein builds up on lipid droplets and sequesters CGI-58, the co-factor of adipose triglyceride lipase, ATGL. This inhibits the lipase activity of ATGL, blocking lipid from being mobilized out of the liver. I148M also suppresses retinol metabolism, which worsens inflammation and fibrosis by promoting fat accumulation of fibrosis via activation of stellate cells. Silencing PNPLA3 can only partially address this biology, knockdown trades the PNPLA3 loss of function. ATGL activity is only partly rescued and retinol metabolism is not rescued.

As a result, silencing may partially address steatosis while inflammation, ballooning and fibrosis persists. By contrast, correcting I148M with RNA editing is expected to restore full PNPLA3 activity and lipid mobilization. That would reverse not only steatosis, but also inflammation, ballooning, and fibrosis, treating across the stages of liver disease. This is the key rationale for RNA editing over knockdown.

WVE-008 is a GalNAc-conjugated RNA editing oligonucleotide and AIMer. It incorporates Wave's proprietary chemistry and built on our learnings from 006. It is administered by subcutaneous injection with potential for infrequent dosing. In the left panel, you can see the dose response curve showing potent editing with 008. In the middle, you see results from RNA sequencing in 2 separate primary human hepatocyte lines, showing an ideal editing profile with strong on-target editing and no evidence of off-target editing elsewhere in the transcriptome, which gives us confidence in 008 specificity.

In the right panel, you can see high liver tissue exposure in preclinical studies supporting excellent delivery and feasibility of durable infrequent dosing. Together, these data provide a strong foundational -- translational foundation as we advance 008 towards the clinic, building on the clinical success of RNA editing capability with 006 for AATD.

Next, we looked at whether editing translates into a functional benefit on liver fat. We compared our PNPLA3 AIMer with a PNPLA3 siRNA using our best-in-class SpiNA format in 2 human hepatocyte models. In the upper world, you can see how PNPLA3 editing significantly decreased lipid accumulation in HEPATOPAC, 3D human liver cell culture model, homozygous for I148M.

At the bottom, you can see that 008, again, decreased liver fat, this time in a monolayer culture of primary hepatocytes. These results reinforce the biological importance of preserving wild-type PNPLA3 function and the rationale for correcting I148M rather than silencing PNPLA3.

For liver disease that progresses across the hepatic lobular cells, it's important that our oligonucleotide reaches all cells throughout the liver, not just in one region. Here, wild-type mice received a single subcutaneous dose of a surrogate PNPLA3 AIMer and liver tissue was examined a week after that single dose. The red signal shows the AIMer. You can see even distribution across all 3 zones of the liver, Zone 1, for periportal hepatocytes near the portal triad; Zone 2, intermediate hepatocytes; and Zone 3, pericentral hepatocytes around the central vein.

This broad uniform distribution is a critical finding, this supports our goal of editing PNPLA3 throughout the liver, which is important for treatment of MASH and other PNPLA3-driven liver diseases. This data is also encouraging for our other AIMer programs such as our 006 program as uniform distribution of the drug is important for all liver diseases.

Beyond hepatocytes, we also want you to understand whether our AIMers reach the hepatic stellate cells that drive fibrosis. Hepatocytes are only part of the story in PNPLA3 liver disease. As Dr. Sanyal described, the I148M variant also impairs retinyl ester hydrolysis in hepatic stellate cells or HSCs. HSCs are the main drivers of fibrosis in the liver, but it's important to know whether our AIMers reach these cells.

In this study, wild-type mice received our target PNPLA3 AIMer. Desmin shown in green, marks the stellate cells and AIMer is shown in red. For the 2 overlap, you see yellow, which confirms that our AIMers are inside HSCs. As you can see, a substantial fraction of HSCs shows uptake. We then asked whether the AIMer actually edits PNPLA3 inside stellate cells, not just reaches them. In the panel to the right, you can see that we observed over 60% RNA editing in stellate cells. This confirms that the AIMers are active in these cells, not just present.

These observations are critical because they suggest 008 could do more than correct PNPLA3 in hepatocytes. The data indicates that they also act directly in the cells to drive fibrosis, which gives us a direct antifibrotic mechanism on top of the expected benefit from reduced liver fat. To bring it all together, the PNPLA3 I148M variant is a well-established driver of steatosis, inflammation, ballooning, and fibrosis. Yet there are no approved medicines that directly address this biology.

Preclinical and clinical data increasingly suggests that simply knocking down PNPLA3 is not the answer. Losing PNPLA3 function can make the very features we're trying to treat worse. Our approach is different. With 008, we edit PNPLA3 rather than silencing. The goal is to correct the variant that causes the disease and restore normal PNPLA3 function in 2 key cell types: Hepatocytes and hepatic stellate cells. Continuing -- by contributing to restoration of lipid mobilization and reduction of liver fat as well as restoration of retinol metabolism, which directly counters inflammation and fibrosis.

Our preclinical data so far support each part of this approach with potent and highly specific editing with no bystander edits, reductions in liver fat in human hepatocyte models, even distribution across all 3 zones of the liver, presence and editing in hepatic stellate cells in addition to hepatocytes. Together, these data support 008's potential to reduce hepatic steatosis, inflammation, and fibrosis and to improve MASH resolution in people who are homozygous for PNPLA3 I148M.

008 also builds on our clinically validated RNA editing platform. If successful, it could be a first-in-class disease-modifying treatment for large genetically defined population with no targeted options today. In summary, 008 meets every criteria we set before advancing a program addressing PNPLA3 I148M liver disease into [indiscernible]. As we just outlined, there are strong supporting human genetics and a large addressable population of more than 9 million homozygous I148M individuals with no treatment options to directly target this driver of their disease.

Our preclinical data support each element of the approach. We've demonstrated substantial highly specific editing that exceeds the threshold expected to shift these individuals towards the lower-risk heterozygous phenotype. We've shown restoration of lipid regulation and decreases in liver fat in human hepatocyte models. And we've shown broad distribution across all 3 zones of the liver as well as uptake in editing in hepatic stellate cells, which supports a direct antifibrotic mechanism on top of the benefit we expect from reduced liver fat.

With strong preclinical data validating the translation of our best-in-class AIMer chemistry, we're excited to take 008 into the clinic. We will leverage previously genotype populations to efficiently identify homozygous I148M targets and accelerate enrollment, and we remain on track to file a CTA for 008 in the fourth quarter of this year.

Now I'd like to turn the call over to Chandra, who will discuss our latest platform innovations.

Thank you, Erik. I'll begin with the foundation of our SpiNA designs and how they have enabled significant improvements over industry-leading siRNAs while extending our delivery to both hepatic and extrahepatic tissues.

Next, I'll discuss how we are applying our best-in-class chemistry in RNA editing and RNAi to develop bifunctional oligonucleotides with the potential to address historically hard-to-target indications.

For more than a decade, Wave has advanced RNA medicines through innovations in nucleic acid chemistry. We began with novel proprietary backbone chemistry, enabling us to rationally design to oligonucleotides and to study structural activity relationships in single well-defined compounds. Since then, we have expanded our toolkit with novel-based sugar and backbone modifications, optimizing sequence, stereochemistry, pharmacological, and safety profiles altogether.

Our PN backbone modification improves cellular uptake, endosomal release, residency, nuclear uptake, and target engagement. Our novel base modifications such as N3U has dramatically increased RNA editing efficiency. Together, these advances have delivered step changes in potency, efficacy, durability, and delivery across hepatic and extrahepatic tissues. A hallmark of our platform is that insights from one modality informed others and helping us move quickly into new targets.

Today, I want to spend a moment on stereochemistry. Stereochemistry is a foundational aspect of chemistry relating to the 3-dimensional arrangements of atoms. It has long been recognized that molecules differing solely by their stereochemistry have radically different properties. Given this, stereochemistry has been a central feature from several Nobel Prize in both chemistry and medicine. And this year's Nobel Prize in chemistry recognized the foundational breakthrough in asymmetric organic synthesis and molecular chirality.

Critically, it should be noted that synthetic methods can be developed that overwhelmingly produce a single stereoisomers efficiently and without wasteful steps in separation, a principle we have built an entire company around. Chemically modified nucleic acids with chiral backbone, including RNA editing oligonucleotides and siRNAs exist as mixture of stereoisomers unless their stereochemistry is deliberately controlled.

Why does this matter? The case of thalidomide targets the importance of characterizing chirality decades ago. The middle of this slide shows 2 stereoisomers with identical target engagement can have markedly different tolerability profiles, the same sequence, the same chemistry, and the same knockdown, but different liver enzyme responses. The field has learned this lesson with small molecules, and it applies to oligonucleotides as well.

At Wave, we design and manufacture fully characterized single isomer RNA therapeutics. This capability is supported by a dominant IP portfolio and our unique ability to synthesize and screen stereopure oligonucleotides at scale.

Controlling stereochemistry also enables rational structure-based design. For example, our siRNAs that -- for our siRNAs that means positioning the guide strand with the mid and PV domain of Ago2 to maximize Ago2 loading. A mixture of hundreds and thousands of molecules does not offer the same precision. As a reminder, SpiNA is our stereopure interfering nucleic acid design.

By increasing Ago2 loading, it enhances RNA-mediated silencing, delivering greater potency and scalability than earlier designed siRNAs and industry benchmarks. The left panel here shows TTR mRNA silencing following a single dose of GalNAc siRNA. All constructs share the same sequence and 2 prime modification as the literature reference. Against this common background, SpiNA designs deliver substantially greater potency and durability of silencing than both the reference and our previously published constructs.

The right panel shows corresponding reductions in TTR protein following a single dose. Here, too, SpiNA designs deliver an unprecedented improvement in potency and duration of activity. So again, what drives this? In our nucleic acid research publication, we showed that our earlier designs gain potency and duration mainly from Ago2 loading. But with SpiNA design, the shift is even larger. It comes from several fold increases in both pharmacokinetics shown on the left as liver tissue levels and Ago2 loading shown on the right.

SpiNA delivers more than tenfold improvement in Ago2 loading versus the referenced siRNA. The SpiNA advantage extends even beyond TTR. Here, we evaluated PCSK9, our clinically validated cardiovascular target comparing 2 SpiNA designs with a construct based on the Inclisiran sequence and chemistry. Both SpiNA designs showed durable reduction in circulating PCSK9 protein compared to the reference siRNA at least through day 56 after a single dose.

On the right, we also saw a corresponding increase in liver LDLR protein, which is a downstream effect that lowers LDL cholesterol. Together, these results give us confidence that SpiNA's gain in efficacy and durability reflect the impact of our chemistry rather than an effect specific to a single target.

We will now describe applying our SpiNA design to a clinical target, INHBE. Our approach with the INHBE program relies on starting with the target with strong human genetics. What distinguishes our molecule 007 from others pursuing their biology is our SpiNA design, proprietary chemistry, and PN chemistry that enhance interactions with Ago2, stabilize the loaded RISC complex and improve liver exposure.

As we just shared, these designs achieved greater than tenfold improvement in the Ago2 loading versus a reference siRNA. And we'll discuss momentarily, this approach has translated in the clinic. While our INLIGHT trial is investigating in other ways, healthy participants with a markedly lower BMI compared to other obesity trials, no diet and no exercise modification, this study provided us with a strong proof-of-concept approach.

We demonstrated potent dose-dependent suppression of serum Activin E sustained through at least 7 months after a single dose, supporting once or twice a year dosing as seen on the left. The potent reductions translated to substantial reductions in total and visceral fat, reduction in waist circumference, stabilization of lean mass, all with favorable safety. Both our clinical data I just described as well as the preclinical data provide us with strong conviction for approach and our ongoing Phase II clinical trial.

We can look to our preclinical data to demonstrate specifically the importance of baseline adiposity to this mechanism. As we shared previously, our INHBE SpiNA demonstrated substantial reduction in both total and visceral fat with the prevention of muscle -- with the preservation of muscle in DIO mice.

In these DIO mice, in other words, mice with greater adiposity following a single dose of SpiNA, we also observed weight loss on par with semaglutide. However, when we looked at the impact of INHBE siRNA in lean mice, we see no effect on weight loss, as you can see on the graph on the right. These preclinical data support the potential to deliver an even more pronounced improvement in body composition in Phase IIa portion of INLIGHT, which includes individuals with higher adiposity or excess fat at baseline.

In addition to our ongoing Phase IIa INLIGHT monotherapy trial, we are also making strong progress on our strategy to evaluate 007 in the combination and maintenance setting. We believe 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle, and favorable safety profile are well suited to both approaches. And we have shared compelling preclinical data, which supports both use cases.

As shown on the left, we have observed approximately twofold greater weight loss as an add-on to incretins versus incretin alone. And on the right, they have demonstrated the ability to curtail weight regain following cessation of incretin. We believe the translation of SpiNA designs in the clinic unlocks opportunities for 007 across treatment settings and provide strong validation for our emerging pipeline.

While GalNAc has transformed delivery to hepatocytes, reaching tissues beyond the liver has remained a major challenge for RNAi for more than a decade. Our approach starts with backbone. By modifying PN linkages to create what we call PN conjugates, we can tune the physical chemical properties of the whole molecule and in turn its tissue distribution. The heat map on the right illustrates this flexibility. We evaluated the same sequence with 15 different PN conjugates, measuring knockdown in kidney, liver, and white adipose tissues.

Each conjugate produced a distinct silencing profile determined entirely by backbone chemistry. This flexibility lets us steer distributions to our different tissues and tune target engagement in each tissue. Rather than relying on a single fixed conjugate, we have a library of different conjugates and can match the design to the biology of the target.

This slide illustrates how we put the flexibility into practice with results from an 8-week mouse study following a single dose. The far left panel shows the well-established activity of GalNAc, which delivers oligonucleotides to hepatocytes. It also illustrates the constraints of its cell and tissue-specific delivery. GalNAc does not enable silencing in other tissues of interest such as adipose tissue. The middle and the right panels show how non-GalNAc designs in PN conjugates enable silencing of up to 90% in adipose alone or in both liver and adipose tissue together. We achieved this by tuning physical chemical properties, allowing us to select a design that best fits the target and indication.

Now I'll share how we have applied this to a historically elusive target, Target A. Target A is a cardiometabolic target supported by human genetics. Carriers of loss of function variants have a lower risk of both coronary artery disease and insulin resistance. This follows the same genetics first approach for INHBE. The unmet need is substantial. Insulin resistance drives type 2 diabetes, yet available insulin sensitizers offer either modest efficacy or meaningful safety concerns.

Because this target acts in both liver and adipose tissue, our goal is to silence it in both tissues. That's what we observed. Deep knockdown in liver and comparably deep knockdown in both epididymal and renal white adipose tissues sustained for at least up to 3 months after a single dose. Durable silencing across multiple tissues with a single subcutaneous dose, a profile no one else in the field has demonstrated. And we have replicated similar data sets for other cardiometabolic targets requiring dual tissue targeting of liver and adipose.

As we shared before, we have also extended SpiNA into kidney. Most oligonucleotides that reach the kidney go to the proximal tubule cells as a part of reabsorption, but that delivery usually does not affect the target. So through structural activity studies, we identified SpiNA variants with PN conjugate. That achieved 75% SOD1 mRNA knockdown in mice and a 50% reduction was sustained up to 3 months after a single 5 or 10 mg per kg dose.

The images on the right confirm both broad oligo distributions and reduced protein, mainly in the cortex and outer medulla. They have also confirmed knockdown across many cell types, including proximal tubule, distal tubule, endothelial cells, and podocytes.

Now let me turn to how we are using our best-in-class SpiNA capabilities to open up new ways of building RNA medicines. As highlighted earlier in the presentation, our GalNAc-conjugated SpiNAs achieved robust and durable silencing across multiple targets, including TTR, INHBE, and PCSK9. Using our unique chemistry design, we have built a single bifunctional SpiNA construct that silences 2 different transcripts at the same time in the same cell.

This could unlock complex indications that require engaging more than one target. It also has practical advantages over combining 2 separate drugs. One molecule to manufacture with the potential to reduce cost of goods, 1 drug through development rather than 2 drugs and delivery to the same cell, so both targets are modulated together. Here, that approach is in action with 2 well-validated cardiovascular targets, LPA and PCSK9.

In transgenic mice, a single bifunctional LPA/PCSK9 construct produced robust, durable reduction in both serum LPA and serum PCSK9 with activity comparable to each corresponding mono-SpiNA alone. Other dual siRNA approaches have sometimes shown reduced activity or durability compared with single target counterparts. Our chemistry preserves the activity of both arms, delivering performance on par with the current industry-leading designs and supporting potential once or twice a year dosing. And we continue to generate additional data with our bifunctional SpiNAs and look forward to presenting more data in 2027.

As we shared last year, we're also using PRISM to combine SpiNA silencing and AIMer editing or upregulation into one oligonucleotide. The single construct engages both endogenous Ago2 and ADAR. It can silence one target while editing or upregulating a different target, which opens up complex indications that needs more than one target engaged. And because the construct loads up into Ago2, we believe it may extend how the longer editing compared to the AIMer alone.

We confirmed this in vivo with a GalNAc-conjugated construct designed to edit UGP2 and silence TTR. Mice received a single subcutaneous dose at equimolar levels. On left, in mouse liver, the bifunctional construct achieved higher, more durable UGP2 editing than the UGP2 AIMer alone. As I noted earlier, we believe Ago2 loading may explain this. On the right, in the same mice, the construct silence TTR mRNA as robustly as the TTR SpiNA alone.

Before turning to our bifunctional silencing and upregulating oligonucleotides, let me briefly explain what we aim to achieve with upregulation. Many gene transcripts contain regulatory motives that acts as built-in brakes. These motives recruit Decay machinery, shortening the life of the mRNA and limiting how much protein it produces. The gene is active, but its output is constrained.

Our upregulators recruit ADAR to make a single A-to-I edit with the regulatory -- within the regulatory motive, destructing the break on the edited transcript. This stabilizes the mRNA, allowing it to persist longer and produce substantially more protein. Remember, we are not introducing a transgene, delivering a protein, or altering DNA. Instead, we remove a specific regulatory constraint to increase protein production from the genes' own transcripts while retaining endogenous localization and processing.

For diseases driven by insufficient proteins rather than excess, this offers a novel way to address the underlying deficit. Here, we revisited our application of this approach to hypercholesterolemia by silencing PCSK9 while upregulating LDLR. These targets act within the same pathway. The goal is to increase the LDL receptor levels on the hepatocyte surface while reducing PCSK9-mediated receptor degradation.

As we have shown previously, in primary human hepatocytes, our bifunctional constructs increased the LDLR protein to a level comparable to LDLR upregulator alone. In the same experiment, it achieved PCSK9 silencing comparable to PCSK9 silencer alone. Together, these results demonstrate the potential to address complex indications by engaging multiple targets with a single construct.

Finally, we have brought silencing and upregulation together in vivo with results that demonstrate the potential for synergy. Using an undisclosed pair of targets, the bifunctional constructs maintained potent Ago2-mediated silencing of target X as shown on the right. Notably, the target X silencer or the target Y upregulator alone produced only a modest upregulation of target Y by themselves as shown on the left.

However, the bifunctional construct, while effectively silencing target X on the right, also achieved a greater than fivefold upregulation of target Y, substantially more potent than either component alone. These findings illustrate the synergy we can achieve by pairing appropriate targeting targets in a single bifunctional construct, engaging 2 different modalities.

Beyond the examples I've shared today, we continue to expand what is possible with RNA medicines with the goal of bringing innovative therapies to patients in need.

With that, I'll turn it back to Paul for closing remarks.

Thank you, Chandra. As we reviewed today, Wave brings together deep genetic insights and proprietary chemistry to rapidly advance transformational RNA medicines. Our oligonucleotide center of excellence integrates large datasets in-house and applies rational design and combines a multimodal platform with our own manufacturing. We're advancing WVE-008 for PNPLA3 liver disease, an approach with strong support from human genetics and advantages over siRNA.

Our SpiNA design is translating in the clinic and our novel PN conjugates are enabling extrahepatic delivery with potential to unlock new therapeutic targets.

Finally, with our bifunctional modalities, we can simultaneously silence, edit, or upregulate 2 unique targets with a single oligonucleotide construct with potential to drive efficiencies in development and deliver value to patients, providers, and payers.

Looking ahead, we continue to expect to deliver multiple milestones this year, including filing a CTA on 008, initiating a maintenance trial for 007, and for sharing data from the 600 milligram cohort of our Phase I INLIGHT trial as well as sharing data from our 600 milligram cohort of our RestorAATion-2 clinical trial of 006.

I'd like to close by thanking Dr. Sanyal for joining us today and by thanking our team for their continued commitment and to our mission of reimagining what's possible for patients.

And with that, I'll turn the call over to the operator for Q&A. And as a reminder, Dr. Sanyal has stayed on with us for Q&A.

[Operator Instructions] Our first question comes from Yun Zhong with Wedbush.

So it's a very interesting concept and very interesting data, of course. But my question to both Dr. Sanyal and maybe to the company is that for the clinical development plan, is that going to be a -- well, this is talking about the liver indication. Is it going to be the standard anti-MASH therapy targeting the typical MASH patients that have been enrolled in previous studies? Because theoretically, this is really should be preventive given the fact that the mutation increases patients' risk for MASH. And is preventive therapy, I know it's very challenging possibility at all. And also another question is, what's the current status of genotyping, please?

Yes. Perhaps I'll start with our approach and then Dr. Sanyal, I'll hand it over to you to talk about the biology more. But our general approach, to your point, I'll take the last part first, which is how available is genotyping for patients. And I think what's really important here, and we've had some of the foundations come in very recently, this is a mutation that's in 23andMe and is commercially available for genetic testing.

So to Dr. Sanyal's point, this is a very prevalent mutation. And oftentimes, people don't or are unaware that they actually are walking around with it. And with the improvement in access to genetic testing, that number is continuing not just to grow, but people are actually coming and saying, to your point, what should I do with this mutation? Nonetheless, for drug development and while prevention is interesting, meaning correct the enzyme over time and prevent the chronicity of damage and the evolution of disease, there is the ability to develop this in a standard MASH way where you could look at improvement in steatosis and fibrosis.

However, we'll also plan to use these genotype patients and establish a homogeneous population for the purpose of a clinical trial to evaluate it, but always have that ability to look at the broader market.

Dr. Sanyal, I don't know if you have anything you'd like to add.

Yes. Maybe just a couple of points to build on what you said, Paul. First, that a drug -- this is a new area in the NASH space that we are entering. If you go into prevention, it takes a long time to show clinical outcomes and, therefore, you're creating a very long pathway. So the low-hanging fruit really are taking people who have established disease, but who are also carrying the mutation and, therefore, at higher risk of progression to cirrhosis as well as clinical outcomes.

Despite the availability of GLPs, as you know, there are still a lot of nonresponders in terms of fibrosis. There are people who are intolerant. All of these, particularly if you have this particular gene mutation, may not get the kind of benefit that one might hope just with the existing drugs that are out there. And that creates, one, an opportunity to build on what is already out there and further enhance for this particular subpopulation. And then for those who are nonresponders, this really gives an entirely new way of managing these patients because if you looked at those Kaplan-Meier curves that we showed, if we can reduce the -- if you can bring the survival curve up to what you see with the heterozygotes, that's actually a substantial improvement in both liver outcomes and liver-related mortality.

So that creates the rationale for why that probably should be the first thing to tackle and then deal with the more long-term issues of prevention. Also if you are otherwise healthy, having the mutation, the clinical impact of that may not be as significant as if you have underlying obesity and insulin resistance.

I'll turn to Chris for a couple of comments.

I'm just going to add to what Dr. Sanyal said was, is that preclinically, we have seen that we can reduce the levels of fat in hepatocytes. So we know that it has a direct effect there as well as on fibrosis and inflammation. And the other clinical studies of knockdown, you do see effects -- direct effects on fat levels. So I think it's not just that it's preventative, but that could be therapeutic as well.

Which is, by the way, consistent with the genetics, like the genetics is there across all stages of disease. It's not only to develop MASH or MAFLD in the first place or in liver disease, it's also in relation to survival. Dr. Sanyal showed those curves already.

Our next question comes from Joon Lee with UBS.

Just a quick clarifying question on Yun's question. Like so people with PNPLA3 mutation are born with it and get MASH and other complications. But can editing it as an adult be enough to reverse MASH? And how does PNPLA3 mutation actually rank compared to maybe other targets for MASH? And then just a follow-up question on INHBE. Is there a range of DIO models to test your hypothesis that higher BMI would indeed drive greater weight loss? In other words, would it be possible to generate mice with degrees of obesity by controlling for their diet to test for hypothesis that higher BMI in humans would indeed lead to greater weight loss for your INHBE program?

Yes, I'll take the last one first, Joon, and then hand it to Erik to follow-up on the PNPLA3 question and can also follow-up on the other one. But I think this is compelling where we know, and we've seen this now in human, even looking at 400 milligram, looking at a differentiation in humans with different levels of adiposity is it's very clear with increasing adiposity, you get increasing driver for fat reduction. That's something that we've always said is a core driver in achieving the weight loss off of fat loss.

And I think what was interesting about these models is that's exactly what we've seen preclinically, correct, right? The DIO is an obese mouse model with high adiposity, and you can achieve weight loss similar to GLP-1s with that fat to lose. And in very lean mice, that lean diets, there is no effect.

And so you do need that increasing adiposity. And again, it's translating in the Phase I where these patients do have increased adiposity versus a completely lean low BMI patient population, and we see an effect on 14%, 15% reduction in visceral fat, 5% reduction in subcutaneous fat, 3.3% reduction in waist circumference.

So even in the human subjects, we're seeing that this change comes out with the increasing adiposity. I think will be compelling it. We've got a 2a study running in, as Chris mentioned in earnings, that are achieving those higher levels of adiposity. So we are going to be able to evaluate this in humans. [indiscernible].

Yes. So thanks, Joon. I think in terms of the editing as an adult and if it's enough to reverse MASH, I think we have evidence that, that would be the case across a couple of different levels, starting with human genetics, as we've talked about already, we know it is associated not only with developing MASH in the first place, but also survival in MASH and progression to cirrhosis and cancer, as Dr. Sanyal already pointed out. So genetics would support that it could be a reversible situation.

The second thing is the preclinical. We've presented data today and before, both reversal of fat and of fibrosis, inflammation and fibrosis. I think that's also a second layer of evidence that it would be reversible in adults. And the third layer is the clinical data that already exists. You actually do see some reversal of the steatosis side of MASH. It's just the fibrosis that hasn't been possible to do with the total knockdown of PNPLA3.

But we also think that actually restoring it back to wild type will be more efficient for the fat as well. So we think it's a superior modality, but there is some clinical evidence as well. So I think this is across both genetic, preclinical, and clinical data is pretty strong evidence that, that is reversible in MASH in adults.

And then your second question was about how this variant ranks among different MASH targets. And I think Dr. Sanyal showed very nice overviews of that where this is that strong association. It was the first one really to be established through GWAS back in like around 20 years ago now. So it's like definitely the strongest genetically, and those are attractive because it's such a large population. It really allows for a precision medicine approach in a very large population of carriers.

Our next question comes from Alethia Young with William Blair.

Thanks for putting all this together today and having Dr. Sanyal on the phone. A couple of questions. One, the subgroup data, it seems to show a stronger risk association in patients with advanced fibrosis and diabetes. Do you think this suggests a greater dependence on the PNPLA3 biology? Or is it just kind of suggest that they're kind of identify high-risk patients? And can you use this for trial selection?

And then my second question is, I'm just curious how much SpiNA like design carries over from one target to the next when you're kind of thinking about across TTR, PCSK9, or the same stereochemical pattern is working? Or do you need to kind of reoptimize as you go through each sequence?

Great. Maybe for the first question, Dr. Sanyal, would you like to take that?

Yes. I think there's no question there is an interaction between increasing age and type 2 diabetes and having the PNPLA3 mutation. Now there could be 2 potential sort of scenarios over here. One, that the PNPLA3 that when you have diabetes, you already have more severe insulin resistance, more severe lipotoxicity and already more aggressive fibrogenesis.

And in that setting, having this, you could argue which one is the sub fire and which one is the catalyst. But the 2 together, they sort of synergize. And so if you take one of these away, you return things to sort of more of a baseline situation. And certainly, these could be used as enrichment factors for clinical outcomes. But I would suspect that based on the biology that the benefits of fixing the mutations would not be restricted only to those who have diabetes or are over the age of 60, although one could imagine stratification just if you had to show that there were differences in clinical outcomes that would help enrich for the clinical outcomes. I hope that makes sense.

Thank you, Dr. Sanyal. Chandra, do you want to do the SpiNA question?

Yes. So the SpiNA question you asked us about the sequence dependency. So the chemistry that we have developed, as I said, it's mainly looking at how the sequences dock onto the Ago2. And so this is actually sequence independent phenomenon. And we have translated our learnings from our TTR through our INHBE. And remember, we also have a clinical candidate declared for GSK. They're developing -- they have taken it for development. And so all this actually shows us that our technology is not sequence dependent at all [indiscernible].

Our next question comes from Samantha Semenkow with Citi.

Thanks for putting this together today. My question is with correcting this I148M mutation with 008. Is the therapeutic goal here reversal of disease? Or would prevention of further progression be enough for this market? And I guess what I'm getting at is, what do you need to show competitively in the clinic here to be used over some of the other obesity drugs, GLP-1s, and others that are in development?

Thank you, and I'll start and I'll let Erik. I think the short answer is both. And I think the opportunity we have on both the steatosis side and the fibrosis side give us a point of differentiation. As we've seen, there was a substantial investment in siRNA silencing to try to approach the disease with early data on the steatosis side, but again, not -- without being able to address the fibrosis side.

So I think there is a strong therapeutic component to this, not just preventive. And to that point, a lot of the other mechanisms are out to really address and focus on the steatosis side by taking down that path. So again, mechanistically, and again, in patients that have this specific mutation, both is [indiscernible].

Yes, I'm not sure if I have so much more to add. I think, again, yes, both. And I think it would be a great drug if it could entirely stop progression because, typically, individuals with MASH and they do die more from the cirrhosis stuff. So even if it, within quotation marks, only put a break on it, it would be great. But we do think based on the biology and what we know at this point that there is also a potential to actually reverse and push it backwards in this basis. So both.

Our next question comes from Rick Bienkowski with Ladenburg.

This has been a really informative presentation. For Dr. Sanyal, you showed some evidence earlier that MASH resolution with tirzepatide is weaker in PNPLA3 carriers than in wild-type patients. I was curious to get your opinion on the RNA editing mechanism of action here. Would you expect to see resolution of MASH with an RNA editing monotherapy in heterozygous and homozygous patients? Or do you think the mechanism would really shine brighter here in a combination setting?

Dr. Sanyal?

So I think my answer would have to be a little bit speculative. So in that -- this kind of setting, first of all, these findings from the Phase IIb study have to be confirmed and validated in larger studies. But assuming that is so, I would imagine this could really potentially -- if there is a causal basis for those with mutation to have less of a response, then there could be a way to enhance the MASH resolution. And the MASH resolution over time would be expected to reduce progression to cirrhosis because the fibrosis progression does not occur in a vacuum. It is the disease activity or the steatohepatitic activity that drives the fibrosis progression. So to that extent, I think it could enhance the therapeutic benefits of a molecule like tirzepatide. And remind me again, there was a second part to your question as well, wasn't there?

I guess the second part of the question was about preclinically we've seen between 50% and 60% correction of the PNPLA3 transcripts. So do you think that would be sufficient for heterozygous and homozygous patients? Or is this one of those populations?

Well, I think if we can -- if you saw the survival curves, the heterozygote and the completely normal individuals with or the CC phenotype, they're not really that differentiated. But that is the premise, that when you switch this from a homozygous mutation to a heterozygous state, it's sort of the PNPLA3, you have to remember, one thing is a little bit weird and it's hard to wrap your head around that on the one hand, it's a triglyceride lipase, and having the mutation decreases triglyceride lipase activity.

On the other hand, you need increased expression of the gene for the phenotype to develop. So that's a sort of interesting construct over there. And so, that has to be taken into consideration in terms of trying to understand whether a 50%, 60%, or more would be sufficient.

You probably don't want to completely wipe out all triglyceride lipase activity because then you have no way to mobilize your triglycerides. So then you will essentially start accumulating triglycerides. And so more is not always better. And this is a little bit of a Goldilocks situation, I think, where you just want to hit it just right, not too much, not too little, get it right in the middle.

And gene editing gives you that opportunity as opposed to gene silencing, which will wipe out all your triglyceride lipase activity, so then you cannot mobilize triglycerides or substantially impairs your triglyceride mobilization capabilities, which can have other unintended consequences.

And maybe if I could just add one thing. Thanks, Dr. Sanyal. I agree with all of that. And that's also why we set out 50% as kind of our bar for this development. Now just for the record, the 60% we showed today is that's in stellate cells and it's also for a surrogate AIMer for the mouse studies.

Now in our human with the compound that we're taking into clinic, we've seen up to 85% editing in hepatocyte, just for the record.

Our next question comes from Amine Chaherli with B. Riley Securities.

Thank you so much for the comprehensive update and for bringing on Dr. Sanyal today. I just had a question with regards to 008. I guess, if you could talk about how you're thinking about demonstrating target engagement. And I guess, like how that kind of interacts with that genotype first enrollment approach that you've described?

And then I just had a question about basically if you could just inform about the time course once the editing is established and whether clearance of the preexisting protein pool is kind of the rate-limiting step of the efficacy versus like just the editing itself?

No, it's a wonderful question. We'll obviously give more updates on the trial design as the CTA submitted and the trial initiates. But I think the premise really takes 2 approaches. One, because we can enrich and this is a study in PNPLA3 patients, the ability we have to start identifying those patients, right, and creating those relationships starts before the study goes. So we can actually start identifying patients with PNPLA3 mutations.

Second, to your point on evaluating efficacy, there are biomarkers, and we've spoken this briefly in the past that we can identify to look at target engagement as well as other measurements we can use to look at editing and then have other approaches that we can look on physiology. I don't know, Chris, if there's anything you'd like to add to that.

You covered most of it. We're planning to ensure that we have a number of patients that are prescreened that have the actual genotype that we're looking for so that we can enroll them rapidly into the study. So I think just to cover from that perspective.

And as Paul mentioned, and you can look at other sponsors trials where they looked at various lipid components to show that they were hitting their target. So it's possible to do that from a biochemical perspective or from biopsies, as you mentioned.

Our next question comes from [ Tessa Young ] with Jefferies.

This is [ Chacha ] on for Roger. So my question is for 008. My understanding for the ADAR-mediated RNA editing is that for the ADAR edit, you would generate the I148V (sic) [ I148M ] substitution rather than converting to wild-type isoleucine. So can you just share with us more data or how we're thinking about the functional activity of the edited protein with the valine in that position versus the wild-type isoleucine?

Yes, I can take this. So we actually looked at a lot of -- these genotypes actually naturally exist. There's a lot of species that have the valine substitution -- substituted for isoleucine. And so this is where we think that it's actually -- structurally, they're also very related. And so this helps us to get that, of course, we are not converting back to the wild-type, but we are actually making it to valine, which is actually a good substitution for isoleucine. So that's where this is coming from. Again, it's supported by genetic data in lots of different species, in monkeys and even in bovine, this is where it exists.

And maybe, so if I can add, so that was the starting point, both structure and conservation across species, et cetera. Now that was a little bit of a bet, but now I think we've shown in a lot of preclinical studies that it actually that's reverted back to a functional protein as we expected based on the conservation of the protein at the structure.

To that point, where we could look at it in comparison with other substrates like siRNAs to look at comparable effects on the control side. So yes, it was a great exercise both in understanding basic biology and translating that into a therapeutic.

Our next question comes from Catherine Novack with JonesTrading.

Just wanted to get a little clarity on the road and the time line to proof of mechanism data in humans for PNPLA3. The first-in-human data, I know you're focusing on genotyping, but will these patients also have clinically significant MAFLD? And in what percent liver fat reduction would be considered meaningful? And then from a timing standpoint, the duration of dosing, how many weeks do you expect to first efficacious data in the Phase I trial?

No, thank you. And I think once again, once we're file initiated, we'll give more definition of where we're going to get to on the various side of the trial. I think the thing to step back from, if I think about the 30,000-foot view is the goal initiation is to look at this in an expeditious experimental way of unlocking the potential here, meaning how quickly can we identify in these patients with mutations and underlying disease, the ability to show high degree of editing, distribution, durability, change of biomarkers, change in physiology, all of which are going to allow us to derisk the mechanism and then continue on the study.

So I think to step back, speed and efficiency, coupled with the ability to differentiate in this space will be the focus of the clinical trial. And I think interestingly enough, too, in terms of population enrichment, I think as Dr. Sanyal presented, there are ways to think about populations that have large numbers of patients. And so it's not just a screening strategy. There's areas where we can run these studies where we can get access to a substantial number of patients to be able to run those studies.

Our next question comes from Ananda Ghosh with H.C. Wainwright & Co.

I think, the first few questions are directed to Dr. Sanyal. So I wanted to know how well are these patients diagnosed currently? And with respect to the trial design, what is the sweet spot one should think about when one is thinking about the inclusion criteria for a POC trial and also from the comorbidity point of view? So is there a way to kind of enrich homogeneous patient population if one has to design a POC trial?

The other question is what is a good animal model to study steatosis in this disease? And strategically, this is for the company. Strategically, how are you thinking about the developmental plan given the long time lines one sees in MASH trials?

Dr. Sanyal, do you want to take the question to start?

Sure, sure. So I think the proof-of-concept trial design, we use individuals who have established steatotic liver disease and with criteria where they already have started scarring down their liver. So we have a well-defined natural history. So you can actually model how many patients you will need and how long you have to follow them to first show less progression to cirrhosis.

If you win that battle, almost certainly in the long term, the clinical outcome will improve because without cirrhosis, you don't really get clinical outcome. That's one of the basic clinical tenets of hepatology.

Your second part of that question was how many of these patients are currently diagnosed. But right now, probably a very small minority, but it's a self-fulfilling prophecy because the reason nobody is looking for them is what are you going to do with that information? How will it change your therapeutics?

And so third-party payers are not willing to pay for extra testing just to satisfy one's curiosity. Now if it would modify your therapeutic approach, then there's a strong rationale for doing it. And the beauty is that we already have the technologies. These are widely available, commercially available, and to eventually, once the clinical benefit is established, the scale-up could happen almost in real time because doing genetic testing in other disease states is sort of routine practice, for example, heart failure, lipodystrophy, other kind of situations.

So I think given that infrastructure already exists, this would be just another place to send a test. So I do not perceive that as any kind of a real significant barrier. And the proof-of-concept, of course, would be demonstration of improvement in steatosis, but we look at steatosis in multiple ways. It's not like there is one magic threshold that tells you yay or nay, and it's a thumbs up or thumbs down. So you look at people who have more than 30% improvement in steatosis, but it also depends where you start.

Number two would be the proportion of people who drop below 5% steatosis, who completely wipe out their fat. And we know that 30% is good, but 50% improvement is better, and 70% is even more and completely refatting the liver is probably ideal. So I think we'll look at the totality of the data and to make go-no-go decisions for further things. If it was my molecule, I'm, of course, only a consultant to Wave. But I would look at the totality of the data.

And of course, we are going into fibrosis patients who have already started scarring down their liver. I would like to see some improvement in biomarkers of fibrogenesis to show that fibrogenic drive is also improving. That gives me the confidence that I'll hit all my clinical endpoints in a larger, bigger study.

So I mean, the only other thing I would have to add is that from the recruitment perspective, as mentioned, we have -- there's a number of genetic databases for people that are already well characterized. And so you can leverage those to pre-identify patients and move them forward into your study.

And then maybe just to cover from the MASH perspective, I mean, I think it's very well described kind of what an approval pathway looks for MASH, like for MASH, and it's like a year, 1.5 years long study, and you can use surrogate endpoints to start with and get an accelerated approval. So you can move forward pretty quickly from that perspective and then follow-up with a pivotal confirmatory trial following that.

Our next question comes from Alec Stranahan with Bank of America.

Maybe just on the endpoints from the Phase I, I guess, which of the noninvasive liver measures, if you are measuring these liver fat, cT1, ALT, et cetera, should we focus on in the early data? And I guess how quickly would you expect those markers to move after dosing? And then just quickly, sorry if I missed this, but just the rationale pursuing the CTA route versus the IND route. Any color there would be great.

Yes. So I think as Paul mentioned earlier, we will be looking at a number of measures, including MRI, but we'll -- as we file our CTA and initiate the study, we'll provide more of the details around the assessments and the timing from that perspective.

Dr. Sanyal's point, the ability to look at these other biomarkers in conjunction also enriched in an early study, the ability to differentiate mechanism and derisk. And the last question.

CTA [indiscernible]. This is something that, I know a number of you, we have this conversation. We use CTA, I always say, in the broadest sense possible in that these studies can be U.S. and ex-U.S. And so we'll provide a filing sequence, but we use CTA just in general to mean the initiation of the trial.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

Interesting data on the INHBE knockdown in lean mice. And my question is actually about the clinical study. I'm curious, in the high BMI cohort of INLIGHT, are you protocolizing diet and exercise? And if so, how are you doing that? And if not, do you think it's sort of not important with this mechanism? I'm just curious if any of the preclinical data that you've sort of generated recently has sort of informed that at all as well.

Yes. So I think as we also mentioned at earnings, not only are we having a protocol for diet and exercise, it's very standard approach and other anti-obesity medicines used. We're also evaluating measures upfront from the MRI perspective to ensure that the participants have increased levels of adiposity, and that's what we're seeing.

So that's really how we're managing that upfront to ensure the best -- the highest likelihood of success and kind of reproducing what we're seeing in the preclinical data in these higher -- individuals with higher adiposity.

I think the other piece to add to that, to your second part of the question, Steve, which is really interesting because we have run extensive models, multiple models across settings. And I think the fact that caloric consumption is not a driver mechanistically for this, I think, is an important notion.

So again, standardizing things as part of these studies is always important to be able to compare and to run these clinical trials in a way that is benchmarked to well how others have done it. But across all of the preclinical studies, that caloric consumption piece has not played a role. And I'll say that in kind of 2 veins.

One, if we look at the DIO mouse model, just the comparison with GLP-1, I think what's kind of astonishing is that, that is all -- that weight loss, if you look at the 2 curves, the slope of GLP-1, where now we know looking at, I believe, early data with semaglutide, 40% of that early initial weight loss is driven off of lean mass loss.

So there's a very good mechanistic rationale when we look at the body composition in the DIO mouse that we're actually losing potentially even more fat, right, to get to that equivalent rate in weight loss. So I think that's encouraging and, again, independent of caloric consumption.

The other place where we see that directly, which I think is probably going to be one of the most interesting opportunities long term as we think about maintenance opportunity for this mechanism, which is completely orthogonal to this weight loss component that I know folks are indexed on.

But in maintenance, that driver at that point where the incretin was stopped and because it is a preclinical experiment and you do measure caloric consumption in these mice, that we saw the opposite, right? These mice who were on incretin, who had real -- had a massive increase, right, in their caloric consumption and equivalently whether they were on INHBE or not. And yet those who were treated when the brake came off lipolysis didn't restore that excess energy in terms of fat.

So I think across multiple preclinical settings, and again, we're seeing that caloric consumption is not the driver here. So again, the study in the IIa monotherapy combination and maintenance, they're all going to recapitulate, I think, a lot of this degree of high adiposity is a requirement in terms of seeing those changes.

Our next question comes from Jenny Gonzalez-Armenta with Leerink Partners.

It's Jenny on for Joe. Maybe just another question on biomarkers and early data in PNPLA3 and [ PL3 ] maybe for the doctor and the team. Are there any other early insensitive markers that we could see in the Phase I data that would suggest or even definitively differentiate 008 on eventual fibrosis benefit, especially versus knockdown approaches since you were talking about that being a potential differentiator?

Yes. Thank you, Jenny. Dr. Sanyal, would you like to start?

Yes. I think the low-hanging fruit really is relates to quantification of the fat for a couple of reasons. One, it's directly in the biological pathway. So if fatty acids come into the liver, they are very toxic. So the liver cell packages it as triglyceride, which is sort of a storage form that is relatively safe.

And of course, when you accumulate that, it's easy to see with MRI and quantify, you can quantify with CAP score, et cetera, and you can see it under the microscope as well. So that is the obvious thing. And the ability to mobilize those triglyceride droplets is linked. That's where PNPLA3 comes in.

So if you facilitate the ability -- you open the release valve, if you will, then you should see a decrease in fat, and that should be an immediate readout. Now the improvement of improving throughput of fat through the liver should be reducing lipotoxicity to the liver. So you would expect less liver injury. And so the next thing I would look at are the liver enzymes, which are markers of liver injury and to see whether they are actually declining.

Then in addition to that, if you reduce these 2, remember that this represents disease activity and injury, the injury activates fibrogenic drive. So there are now biomarkers such as PRO-C3, et cetera, that are more reflective of fibrogenic drive rather than the fibrosis burden itself. It takes a while to shift the actual fibrosis itself, but the fibrogenic drive can be cooled off. And so I think you can capture that also with these biomarkers.

Another biomarker that is now sort of looking good and more data are coming is the NIS2+. So this is based on microRNA-34a and YKL-40. So it's again measuring a couple of things. 34a is very much linked to the metabolic disruption in the liver. So if you're restoring metabolic homeostasis, you might expect to see an improvement in 34a and YKL-40 is linked in the fibrogenic pathway. And there are now data showing that NIS2+ reflects -- it's a composite biomarker that tells you whether you have the kind of NASH that requires pharmacologic treatment.

So what we call at-risk MASH, it is a biomarker for at-risk MASH as a composite. And so there are some early data that with effective treatment, the NIS2+ drops below the threshold for having -- so more to come on this, but that's another potential biomarker. And as you know, this biomarker space is very, very mobile and active.

So everything I tell you today, there could be new biomarkers in play a year from now. But these are some of the best-in-class today that we can talk about.

Yes. And as Chris mentioned, we're embedding biomarker-driven studies in addition to being able to look at target engagement as a number of early signals as well.

Our next question comes from Michael King with Rodman & Renshaw.

I wanted to see if you could address the topic of CIDEB. It was a target that was found at the Regeneron Genetics Center and some Phase I data, I believe, was presented at the liver meeting, a single dose of an antibody reduced liver fat to about 70%. So I wonder how you think about that incorporated into your thinking about development of PNPLA3? And then I have a separate question, but I want to ask that one first.

Yes. I mean I think there's a number of movements of ways of reducing liver fat. We know INHBE in the clinic substantially reduces liver fat as well, and we're exploring that through MRI-PDFF based on the clinical trial. But I think a lot of that has to do, as Dr. Sanyal was saying earlier, with this steatosis side of the disease. And I think what's really important for these patients who have PNPLA3 mutations is the fibrosis and inflammation component of the enzyme.

So again, whether or not eventually patients who have a mutation need the mutation corrected and then also get the benefit of having these other therapies or in the case of the early data that we saw on tirzepatide that show those patients are less responsive. I think these are things that will all -- as this field continues to grow with therapeutic options, I think what's intriguing for us is the strong genetic correlation on the enzyme that it has this functionality on driving this kind of retinol inflammation pathway. I don't know, Erik, if there's anything to add.

Not really. Maybe not more than that these are different mechanisms. And as far as I know, there aren't interactions necessarily between the side of variants and PNPLA3 variants. So you would expect that -- interesting targets, but this is an independent mechanism.

And again, there are a very large number of homozygous carriers here where this is the exact right way to treat it because it's treating the direct cause of liver enduring the [indiscernible].

Our next question comes from Ben Burnett with Wells Fargo.

This is [indiscernible] on for Ben. In light of 008, your bifunctional platform and as you go into new indications, could you share what your thinking is when it comes to developing assets by yourself versus partnering? And specifically, what piece of the platform and at what stage would you be open to partnering?

Thank you. I mean, I think there's a variety of targets that have provoked conversations because they are interesting mechanistically and pathway-wise. And so I think the key is continuing to be able to bring interesting innovative programs and products to the clinic, derisk platforms, both on the RNA editing side as we've seen with alpha-1 antitrypsin and the applicability here.

As we've shared before, INHBE broadly is garnering interest and relative to what we can do with SpiNA, and particularly Chandra's point, the fact that we're seeing the translation of candidates to our partners at GSK means the platform is now validated from an engine.

So with Monika joining, one of the core focus has been how do we think about the balance of a portfolio program? And how do we think about the platform capability and capacity more broadly. And I think our view is to continue to drive optionality across the portfolio to optimize what's going to be best and most expedient for patients and an efficient use of our capital to derisk and accelerate programs.

Our next question comes from [ Kathy Ewan ] with RBC Capital Markets.

Dr. Sanyal and then maybe also Paul, on 008. Paul, you spoke of speed and efficiency in your clinical execution to bring therapy to patients. So if I may follow-up and ask about comparing the expected disease progression and disease prognosis between PNPLA3 patients in your prospective trial versus typical MASH or [indiscernible] patients.

As you touched on in MASH competitors liver fat reduction signals where the MRI detects within 24 weeks or maybe even 12 weeks, but fibrosis improvement on histology generally requires a year or multiple years. But where this PNPLA3 patients on this time line given, Dr. Sanyal, you've talked about wanting to see fibrogenesis improvement and also the prognosis differs among patients with different baseline and comorbidities. Any color there on that is much appreciated.

No, absolutely. And I'll start and then, Dr. Sanyal, I'll hand it over. I mean, I think the first path for us is how do we get as rapidly as possible to finding that dose and editing efficiency, right? How do we get to that ability to look at target engagement, change in biomarkers, and the medicine derisking from a biology perspective. And then there's derisking it from a pathology perspective. And so I think we're actively, in the efficiency side, again, because we can identify these patients that have the mutation, as Dr. Sanyal pointed out, there's things we can do to enrich on pathology too, to optimize signal.

I think we think about that study as having kind of 2 components to it to accelerate. And the first being as rapidly as possible kind of derisking the PNPLA3 targeting and then how do we unlock the potential as we think about then derisking the pathological changes. And I think that gives -- we roll out the trial design on the other side, I think that's something that you'll see is the ability for us to think about those 2 pieces so that we can be efficient in derisking the program. Dr. Sanyal, I don't know if you want to add on the pathology side and how we think about derisking that.

Yes. I think you -- no, I basically agree with you. And in the early phases, of course, you get a signal for reduction in liver fat. And fat is extremely mobile. So there's all kinds of data going back 50 years that fat can move in and move out of the liver within a matter of literally hours to days.

So certainly, within 12 weeks, one should expect to see a significant improvement in overall steatosis and markers of injury. And as we move forward, depending on how you select your population, that will determine the trajectory towards cirrhosis.

So it is based on the relative numbers of F2 versus F3 population in terms of likelihood of progression to cirrhosis. So with the F3 patients, you would expect 7% to 10% over a matter of a year or 2 would progress to cirrhosis. And then so if you were to do a 3- or 4-year study, you would have about almost 1/4 of these patients would have progressed to cirrhosis.

And again, I think we are in a little bit uncharted territory. But if you look at the Kaplan-Meier curves for the clinical outcomes, then you would be able to see that, first, we have to show less progression to cirrhosis. And you would want to see an effect size that would reduce the hazard ratio to at least 0.8 or greater.

Greater is better, but it's very hard given current data to be absolutely certain where you land. But I would project somewhere between 0.5 and 0.8 is where we hope to land with this type of approach.

Our last question comes from Danielle Brill with Truist Securities.

This is Alex on for Danielle. Just a qualitative one on 008. I believe you said you're going to be initially investigating the efficacy of 008 in previously identified and genotyped homozygous I148M patients. Is there anything about these patients that led them to get genotyped in the first place?

I'm just curious where on the bell curve do these patients fall versus a potential typical bucket of patients that you might recruit for future clinical trials as it pertains to disease severity, comorbidities, et cetera.

So what I would say just maybe to start from the last part of your question and move up is that we're designing the trial with inclusion -- actually some criteria that allow us to best be able to detect the types of differences we're looking for.

So obviously, not too far, not too mild, but in that sweet spot where you can actually see a change. And so that's kind of irrespective of where the patient comes from, they'll have to meet those criteria. So -- and then to your earlier point, I mean, there's lots of different genetic databases out there that you could imagine, either private or public where people just get tested and for different reasons, and it may not be for liver disease per se. But then you do have all that information and you can utilize that to pre-identify individuals.

And again, there may be other settings in liver clinics, hepatology clinics where people have been genotyped over time because of the interest of the individuals there. So that's another way that you could potentially accelerate the approach versus just taking all comers and hoping that they have the genotype of interest.

There are no further questions at this time. I will now turn the call over to Paul Bolno for closing remarks.

Thank you, everyone, for joining us today, and we look forward to connecting with many of you in the near future at the multiple upcoming conferences. Have a great day.

Hello, and welcome to Wave Life Sciences Third Quarter 2026 Earnings Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. And good morning to everyone on the call.

Earlier this morning, we issued a press release outlining our third quarter 2026 earnings update.

Joining me today with prepared remarks are Paul Bolno, President and Chief Executive Officer; Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. Also on the call are Chandra Vargeese, Chief Technology Officer; Erik Ingelsson, Chief Scientific Officer; as well as our new Chief Business Officer, Monika Vnuk, who joined Wave last month.

The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I'd like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason.

I'd now like to turn the call over to Paul.

Thanks, Kate. And good morning to everyone joining us on today's call.

At Wave, we are harnessing the convergence of deep genetic insights with our proprietary chemistry to rapidly advance the pipeline of transformational RNA medicines. Our broadly enabled oligonucleotide platform has leading capabilities in both siRNA and RNA editing that are now translating across both our wholly owned pipeline and in our collaboration with GSK.

In siRNA, our best-in-class SpiNA design is demonstrating the potency and durability that we believe are needed to unlock important genetically validated targets. We've seen this translate clinically with WVE-007 and during the third quarter, GSK selected an siRNA development candidate to transition to its pipeline.

Next week, at Research Day, we'll take a deeper look at these capabilities and how we are continuing to push the boundaries of our proprietary chemistry across hepatic and extra-hepatic siRNA, RNA editing and our emerging bifunctional modalities.

I'll begin today by discussing WVE-007, our INHBE siRNA for obesity before moving to WVE-006, our RNA editing therapeutic for AATD and other recent updates. INHBE target is strongly supported by human genetics. Individuals who have a protective loss of function variant and one copy of the INHBE gene have a healthier cardiometabolic profile, including less abdominal fat, less liver disease, lower triglycerides and lower risk of type 2 diabetes and cardiovascular disease.

With 007, the goal is to replicate this healthy metabolic profile by silencing INHBE and lowering serum Activin E, thereby taking the brakes off lipolysis or fat metabolism. 007 offers a distinct therapeutic approach from incretins by driving fat loss without muscle loss. This makes it a differentiated alternative to GLP-1s or other incretins, a potentially powerful combination with incretins.

And importantly, when we think about the challenges of sustaining chronic long-term incretin therapy, 007 offers new potential to prevent weight regain with just a once or twice a year dose. There are several reasons we chose to target INHBE mRNA directly and turn off Activin E production rather than the receptor of Active E ALK7.

Turning off protein production in hepatocytes, the upstream source with a GalNAc-siRNA is the most efficient and durable way to impact this pathway. Suppressing Activin E is a more selective approach with a lower risk of unintended consequences as compared to disabling a receptor that transduces signals via multiple ligands across different tissues. We believe this selectivity is especially important for long-term safety and clinical translation.

007's unique ability to durably suppress INHBE is enabled by our proprietary chemistry and SpiNA siRNA design, which distinguishes us from others in the field and has been shown to enhance interactions with Ago2, stabilize the loaded risk complex and improve liver exposure. Across INHBE and other targets, our proprietary chemistry has repeatedly delivered greater potency and more durable effects than industry-leading siRNA designs, setting us apart from others attempting similar silencing approaches.

With 007, we have now seen the compelling INHBE biology translate both preclinically and clinically with differentiated data from other approaches in the field. Preclinically, our INHBE silencing drove substantial visceral and subcutaneous fat loss with muscle preservation and GLP-1-like weight loss in the DIO mouse model. Our preclinical data also demonstrate INHBE silencing increases adipocyte lipolysis, shrinks adipocytes, reduces pro-inflammatory macrophages and fibrosis and improves insulin sensitivity, all key indicators of better cardiometabolic health, which further validate the human genetics.

And in the clinic, we're seeing this profile translate in our Phase I single-dose study with clinically meaningful reductions in visceral and total fat and prevention of lean mass. We have also observed a favorable tolerability profile and durable dose-dependent Activin E suppression supporting once or twice yearly dosing, further highlighting the advantages of our SpiNA siRNA design.

Our upcoming 600-milligram data from the Phase I portion of INLIGHT is expected this quarter and will help further characterize potency, duration as well as safety and tolerability. We continue to make significant progress advancing 007 across 3 distinct treatment settings: monotherapy, combination therapy and a post-incretin maintenance therapy to prevent weight recurrence.

With our ongoing Phase IIa monotherapy trial, we are now evaluating 007 in our target patient population, individuals with higher BMI and comorbidities. In other words, a typical population observed in Phase II and III obesity trials. These patients are expected to have greater excess fat at baseline and will receive multiple doses of 007. With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in our Phase IIa higher BMI participants.

Clinical experience also highlights the importance of baseline adiposity. Leaner individuals without comorbidities typically show more modest fat reductions versus individuals with higher baseline adiposity. Collectively, these factors support the potential of this Phase IIa study to cross the 1 year regulatory threshold of 5% weight loss. This monotherapy trial will also include multiple assessments of cardiometabolic biomarkers, including liver fat, which have the ability to derisk development pathways in NASH and other cardiometabolic diseases.

The second part of our strategy is to evaluate 007 as a combination therapy with incretins, which has the potential to deepen weight loss and enhance metabolic benefits. During the quarter, we made strong progress on this initiative with the initiation of our Phase IIa combination trial, which is evaluating 007 in combination with weekly doses of tirzepatide in individuals with BMIs between 35 and 50 and type 2 diabetes. We believe that 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle and favorable safety profile are well suited to a combination approach.

Despite the commercial success of incretins, there remains a clear opportunity for orthogonal approaches. Incretins reduce body weight through both fat loss and muscle loss, and they carry high discontinuation rates due to GI side effects, limiting the potential for long-term health benefits. Muscle loss associated with current standard of care therapies is substantial, representing upwards of 40% of the total weight loss. The consequence of muscle loss is particularly notable as skeletal muscle plays an important role in both metabolism and weight maintenance.

We believe 007 could enable GLP-1 down titration and help patients achieve fat loss with a more favorable tolerability profile and less muscle loss. In addition to mitigating muscle loss and improving tolerability, 007 also garners the potential to help patients achieve further fat loss on top of incretins as up to 40% of patients don't reach treatment goals. Our preclinical data provide compelling support for 007's ability to help these patients as we've observed approximately twofold greater weight loss as an add-on to incretins versus incretins alone.

Lastly, and perhaps one of the most exciting and unique opportunities, we plan to evaluate 007 in the maintenance setting to enable an off-ramp for GLP-1s. We often hear from patients about the fear of weight regain post-cessation of incretins. Up to 70% of patients discontinued GLP-1 therapy within the first year of treatment. And for many, it's due to the challenges that 007 may address, including treatment burden and tolerability issues.

Notably, following discontinuation of GLP-1 treatment, upwards of 70% of lost weight is regained and driven by increase in total fat, not muscle regain. In this maintenance setting, 007 would have the potential to enable individuals and payers to realize the sustained health benefits of fat loss and improve metabolic health for the long-term. We remain on track to initiate a trial investigating 007 as post-incretin maintenance in the fourth quarter.

Collectively, we believe 007 development program can redefine the treatment landscape in obesity and are working expeditiously to examine its potential across treatment setting. We look forward to engaging with key opinion leaders and the community to present and discuss 007's differentiated approach at Obesity Week.

In RNA editing, we're advancing WVE-006, our GalNAc RNA editing candidate for AATD towards a potentially registrational study. Our clinical data support 006's potential to offer a new standard of care for individuals living with AATD by treating both lung and liver manifestations of the disease and restoring dynamic AAT response with convenient, infrequent, subcutaneous dosing and would offer a potentially differentiated value proposition for both health care providers and payers.

As a reminder, current IV augmentation standard of care does not have any impact on liver manifestations of the disease. And importantly, those augmented protein levels are depleted during acute inflammatory events, leaving the lung unprotected and potentially prone to damage. Investigational DNA editing, a different therapeutic approach carries with it both safety concerns and just as notably, payer challenges for a onetime very costly therapy with uncertain durability. This leaves RNA editing well suited as a first-line therapy.

As Chris will speak to in further detail momentarily, following our recent meeting with FDA, planning is now underway for a single registrational trial of 006 for AATD, offering an efficient path to full as well as potentially accelerated approval without the need for a separate confirmatory trial.

Building on our RNA editing success, we also continue to advance our second RNA editing candidate, WVE-008 for PNPLA3 liver disease towards the clinic this year. 008 aims to address an area of high unmet need with 9 million individuals living with PNPLA3 I148M liver disease. At our Research Day next week, we look forward to having Dr. Arun Sanyal, a leading hepatologist, join us to share additional perspectives on PNPLA3 I148M and liver disease and the opportunity for an RNA editing correction approach. We will also provide further updates on how we are continuing to push the boundaries of innovation with a proprietary chemistry across our hepatic and extra-hepatic RNAi, RNA editing and bifunctional modalities.

Beyond our internal pipeline, our PRISM platform and proprietary chemistry continue to demonstrate their value as evidenced by GSK's recent development candidate selection. The transition of this development candidate to GSK provides further validation of our best-in-class phenodesign siRNA.

We have also welcomed Monika Vnuk to Wave as Chief Business Officer. Monika brings extensive corporate development experience and joins Wave from Sanofi. Monika will leverage her background to further capitalize on and expand the potential of our platform and support Wave's next phase of growth.

Now I'd like to turn the call over to Chris, who will discuss our clinical development plans for WVE-007, 006 and 008. Chris?

Thank you, Paul. We continue to make strong progress on our WVE-007 clinical development plan.

Let's start with our Phase IIa monotherapy trial. This is a global placebo-controlled trial enrolling individuals living with obesity with BMI of 35 to 50 and comorbidities. There is a total of 4 cohorts with up to 40 participants each across 2 doses, 240 and 400 milligrams and 2 study populations with and without type 2 diabetes. Participants received 2 doses of 007, one on day 1 and one on day 85 and are followed for up to 12 months.

To date, with dosing underway, we're observing that participants have baseline levels of adiposity that are substantially higher than the Phase I portion in line with Phase II and III obesity trials. Given 007's mechanism of action, we believe this population is well suited to demonstrate 007's potential to deliver meaningful improvements in body composition and healthy weight loss. This trial also specifically includes measurements of liver fat content by MRI-PDFF to inform 007's potential in NASH. Our preclinical data and a growing body of clinical evidence support the potential for substantial reductions in liver fat.

In parallel with this progress, we remain actively involved with the patient community, key opinion leaders and foundations. Together, we're working to engage with regulators on the importance of improving body composition, including reducing excess fat and preserving muscle consistent with recent guidance.

Turning to combination therapy. In the third quarter, we initiated our Phase IIa combination trial. This portion of INLIGHT has a randomized controlled design that will evaluate 240 and 400-milligram doses of WVE-007 in combination with weekly tirzepatide versus tirzepatide alone in individuals living with obesity with a range of BMIs from 35 to 50 and type 2 diabetes.

For our third treatment opportunity, we remain on track to initiate a clinical trial of 007 in the fourth quarter as a maintenance therapy to preserve weight loss following discontinuation of incretin treatment.

In addition, we look forward to sharing 600-milligram data from the Phase I single ascending dose portion of INLIGHT in the fourth quarter. This will help us further characterize potency, duration as well as safety and tolerability.

Turning to WVE-006 for AATD. WVE-006 is our investigational RNA editing therapy with the potential to address both lung and liver manifestations of AATD. We continue to make excellent progress advancing WVE-006 for patients in need and following a productive meeting with the FDA are now planning our registration trial. Our discussions with the agency, key opinion leaders and the alpha-1 community underscore the high unmet need and limitations of current standard of care.

As a reminder, the only currently approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there is no restoration of the dynamic response, leaving individuals with alpha-1 at risk if AAT protein levels fall too low during an infectious or inflammatory event. IV therapy is time-consuming and often requires inpatient visits and does nothing to lower the Z-AAT to address the risk of liver disease.

While DNA base editing approaches target both lung and liver disease in AATD, they introduce permanent DNA modifications, carry bystander editing risk and rely on LNP delivery, which is associated with liver enzyme elevations. The risk of irreversible off-target effects is particularly notable as genomic DNA editing in cancer-associated genes has been reported in preclinical studies. In addition, treatment with DNA editing therapies may render patients ineligible for future base editing, RNA editing or other new therapies.

SiRNA approaches reducing Z-AAT are also in development for AATD liver disease. However, this approach does not restore M-AAT and even worse, it leaves the lung unprotected due to the chronic AAT knockdown. AATD is a uniquely compelling disease for RNA editing. It is a monogenic disorder caused by a single, well-characterized genetic variant in the SERPINA1 gene. This leads to misfolded in Z-AAT protein and an absence of healthy circulating M-AAT protein, which normally protects the lung during inflammatory or infectious events.

Without dynamic production of functional AAT protein, individuals with alpha-1 are at risk for lung damage, ultimately developing emphysema and bronchiectasis, characterized by chronic cough, recurrent infections and shortness of breath. In parallel, misfolded Z accumulates in hepatocytes and causes progressive liver injury and increased risk of liver disease.

With 006, which targets the underlying causes of AATD, we've generated a growing body of data supporting its potential as a new standard of care for individuals living with alpha-1 by restoring an MZ-like phenotype, which has a low risk of lung and liver disease.

In our ongoing RestorAATion-2 clinical trial, 006 delivered substantially reduced levels of Z-AAT, protective basal levels of total AAT with a percent of wild-type M-AAT well into the MZ range as well as a restored dynamic physiologic response to inflammatory events. Enrollment and dosing are complete in the 200, 400 and 600-milligram cohorts of RestorAATion-2. We remain on track to share data from the 600-milligram monthly dosing cohort in the fourth quarter, which will help inform an optimal dosing regimen.

With the compelling profile of 006 we've observed to date and following our FDA meeting, we're planning for a single 2-year registrational trial with a one-year interim analysis for potential accelerated approval based on AATD biomarkers. We believe the single trial design without the need for a separate confirmatory study offers an efficient path for full approval, bringing 006 to patients in need as quickly as possible. In addition, we're encouraged that the agency supported the use of our LCMS assay to measure M-AAT and Z-AAT proteins.

We also continue to make strong progress advancing our second RNA editing candidate, WVE-006 for homozygous PNPLA3 I148M liver disease. Similar to 006 and 007, our approach for 008 is strongly rooted in human genetics. There are an estimated 9 million homozygous PNPLA3 I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from liver disease as compared with noncarriers.

The PNPLA3 variant is a well-established driver of NASH and liver diseases more generally, if there are no approved medicines that directly address this underlying disease mechanism. Currently, the only treatment options are non-precision medicines aimed at reducing liver steatosis and early fibrosis, which have limited efficacy for these I148M carriers.

Silencing PNPLA3 can only partially address this disease biology and is likely to leave residual pathology as it knocks down all PNPLA3 protein without restoring healthy wild-type protein, which has several important physiologic functions in the liver. As a result, silencing may partially address steatosis, but inflammation and fibrosis may remain unaddressed or worse. Recent clinical trials of PNPLA3 silencing support this notion. A dose-dependent increases in liver enzymes were observed.

By contrast, with WVE-008, we aim to correct the I148M variant using our leading RNA editing platform with the goal of restoring normal PNPLA3 function. This is expected to enhance lipid mobilization from the liver, reverse steatosis, reduce inflammation and fibrosis and ultimately improve overall liver health.

In our upcoming first-in-human study of 008, we plan to leverage previously genotyped populations to efficiently identify homozygous I148M carriers and accelerate enrollment. We will evaluate target engagement with circulating biomarkers and assess early signs of efficacy using noninvasive liver imaging. We remain on track for a CTA submission in 2026.

With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris.

Our revenue for the third quarter of 2026 was $13.2 million compared to $7.6 million in the prior year quarter, and this relates to our ongoing collaboration agreement with GSK.

Research and development expenses were $53.8 million in the third quarter of 2026 as compared to $45.9 million in the same period in 2025. The increase primarily reflects continued investment in our advancing clinical programs, including the Phase II portion of INLIGHT and progress across our RNA editing pipeline.

Our G&A expenses were $25.4 million in the third quarter of 2026 as compared to $18.1 million in the prior year quarter. The increase primarily reflects costs associated with supporting our advancing pipeline and preparing for the next stages of development.

Our net loss was $61.9 million for the third quarter of 2026 as compared to a net loss of $53.9 million in the prior year quarter.

We ended the third quarter with $431 million in cash, cash equivalents and marketable securities, which we expect to be sufficient to fund operations into the third quarter of 2028.

We are also due to receive an incremental $12 million milestone payment from GSK in the fourth quarter of this year following their candidate selection. As a reminder, GSK has 3 additional programs advancing towards development candidate. Any potential future milestone and other payments to us under our collaboration are not included in our cash runway.

I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle.

Our strong execution and progress throughout the year leave us well positioned to unlock value across our pipeline. With WVE-007, we're actively advancing our Phase IIa monotherapy and combination trials towards key data in our target patient population and remain on track to initiate our post-incretin maintenance trial later this year.

We're advancing 006 towards a potentially registrational trial and building on our success in RNA editing with 008, which remains on track for CTA this year. We look forward to connecting with many of you next week for our Annual Research Day.

Before turning to questions, I want to thank our team for the progress we've made and for their continued commitment to reimagining what's possible for patients.

I'll now turn the call to the operator for questions. Operator?

[Operator Instructions] We'll take our first question from Rick Bienkowski with Ladenburg.

Now that you have clarity from the FDA on the accelerated approval pathway for WVE-006, do you have any insight on how large of a trial you might need to run for the pivotal study?

And also, I know you shared in the press release that you've aligned on the accelerated approval based on biomarkers. But I was curious if the full approval would also be based on these biomarkers? Or has the FDA asked for evidence of improved functional outcome for the full approval?

Yes, I'll start the question, and then I'll let Chris join in. But I think it's important as you laid out this kind of the first into your second, the second part of that first question that went into what's required for the full approval. I think that was stepping back, I think what was impressive for the team. I was excited that the team came back with a really innovative design that was efficient for patients, efficient from a capital standpoint and could get us to a potential full approval in a 2-year time point with the interim analysis being available for the accelerated approval. So the predicated design is for that single study without the need for a separate confirmatory study.

As it relates to the individual biomarkers that we're going to use, I think, we've been pretty clear that we're not going to competitively disadvantage ourselves as others are still going through processes of laying out what's required for those analysis for both full approval and for accelerated approval. But I think as Chris alluded to, it's nice to see that we've got validated LCMS assays that we can use to quantify.

Sure. So I would say we had a really excellent meeting with the FDA. The Pulmonary Division in CEDAR doesn't always have an opportunity to review genetic medicines. And so they were particularly, I think, excited about our approach and really saw that we were hitting our target as intended in terms of hitting the underlying cause of the disease with increasing M, decreasing Z.

And then also, they actually picked up quite quickly on the acute phase response as being one of the more relevant things in terms of treating the disease so that you are increasing the level into the event to protect the tissue when it needs it the most. And they also appreciated that from the protein replacement perspective, you kind of highest when you start and that kind of goes down over time. And so if you get an event as that's going down, you may end up being unprotected. And so they were, I think, quite understanding of that and getting it quickly and we're highly supportive of us moving forward for patients.

Our next question comes from Joon Lee with UBS.

Great to be following you guys again.

This year's Nobel Prize in Chemistry, how validating is that to your stereochemistry platform? And how do you think it helps you differentiate from your competitors? And are you able to provide some examples?

And just a quick follow-up, a question for Dr. Monika Vnuk she's on. What is your first order business update? And what is your midterm and long-term goals at Wave?

It's great to have you back. And I'll take the first part and then I think Monika will join. Obviously, she's sitting back to me for the second part, and we're excited to have her.

But first, I mean, I think it's nice to see the recognition on chirality. As you point out, it's not just an award for a prize, but it's the recognition of just how important chirality and stereochemistry is the fundamental biology. We've often talked about it in the context of other therapeutic examples like thalidomide and others and that specificity matters and stereochemistry matters.

But if we think about what happens on every enzymatic structure we work with, whether that's AGo2, whether we see it with ADAR, whether we saw it with [ RNA ], antisense, whether we see it with the innate immune system recognizing various patterns, biology recognizes single structures. And I think the most important piece in drug development is being able to optimize from a mixture.

And I think if we look back over a decade now, we're able to do this in a highly consistent programmable way, meaning if you think about, again, INHBE, it was 18 months from mouse data to human data. So it's efficient. It doesn't cost any additional features, so this isn't separation. So we've been able to build the platform capability to drive that to manufacturing where our costs are not different to unlock that potential.

And I think having that clarity of understanding of medicines lets us understand in preclinical studies why something is working or not. And frankly, in clinical studies lets us understand what needs to continue to be optimized as we watch the evolution. So I think it's fundamental, and it's nice to see it widely recognized.

I'll turn to Monika to answer. She has dove in with both feet or I guess, yes, that's jumping. But yes, go for it.

I'm very excited to be joining Wave and this highly accomplished team. I have been following Wave for over a decade, and it has been on my radar for partnering as it matured to emerge as the leading siRNA and RNA editing company.

When I reflect on the portfolio that we have, I see a lot of opportunity to create value through partnering both on the clinical side as well as our preclinical portfolio and of course, the platform. In the immediate term, what I'm doing is jumping straight in into the ongoing partnering discussions and working on the mid- and longer-term plans.

A lot of work to be done, but it's great to have you back.

Our next question comes from Amer Ahmad with William Blair.

This is [ Rema ]on for Alethia. We have 2.

First one on 007 for INHBE. Good to see that Phase IIa baseline adiposity is coming in much higher than Phase I and in line with Phase II/III obesity studies. Given that and what you've seen on body composition so far, do you still feel confident you can get to the 5% weight loss at 12 months?

And second, on AATD, how do you think about enrollment relative to competitors? How does your population differ from what other programs are enrolling like Arrowhead and Takeda? And if there are any comparable studies we should look at for time lines?

Yes. I mean, first, thank you for recognizing. I think Chris' statement on the baseline adiposity. I mean I think it's good. I would say some of these things are -- they're planning and you should be expecting them because Phase II/III studies in obesity as we've laid out, have that. But to your point, it's nice to see when that's recognized. And I think to that point, that's exactly just like we said going into a Phase II/III study would yield patients with higher baseline adiposity, meaning more fat to lose.

I think it's very consistent with the analysis and modeling we're doing that point us to a path to potential 5% weight loss after on therapy, which is the regulatory bar, meaning this mechanism should drive more fat, which is, I think, us back to preclinical data translating to clinical data, the DIO obese mice models lost substantial weight. It takes a little bit longer for that to happen because the weight loss in the DIO mouse in the sema arm is coming off of predominantly muscle initially, which is why the curve moves more quickly. But we do see substantial fat loss in the DIO mouse model. So again, all aligned with our preclinical clinical data in the Phase I moving into our IIa data. So we're excited about that.

And as for 006, I'll let Chris speak to the study specifically, but I think it's important as you point out the siRNAs because you pointed out the Arrowhead, Takeda, that's a liver-driven study. So we're not specifically looking at a, we're going to take lung and liver patients holistically. Augmentation isn't approved outside the United States. So as we think about a global study, we don't see any challenges with enrollment, but I'll let Chris answer that.

Yes, sure. Thanks, Paul. So we are engaged with a number of foundations and societies in Alpha-1, and they have these large registries. And so working together with them and we're going to leverage those registries, which have actually several thousand patients in them for our trial. So I think that will really help us to accelerate enrollment.

The other thing that I think is notable is we've had a number of discussions with KOLs and actually with patients. And what we're hearing is that people are excited about like a convenient, easy to administer therapy that's reversible in the sense that like if you need to stop it for some reason, you can or if the environment changes, there's other options, you can use those.

So I think what we're hearing is that people are excited to have this be the first thing that they start with and to help us to move it forward and get it to the market.

And then the last thing, just to highlight what Paul said is that just like our other studies, we don't really have any liabilities from the hepatic perspective. And in fact, we've already enrolled a number of individuals with liver fibrosis. So we'll continue to study individuals that have lung disease and liver disease throughout our program, and we're interested in showing benefits in both of those.

[Operator Instructions] We'll take our next question from Samantha Semenkow with Citi.

Hi. This is [ Jean ] for Sam at Citi. And congratulations on the progress.

My first question is about, can you help frame the bar you will need to meet at the one-year interim analysis to support your accelerated approval? And based on what data you have right now, do you believe you have already demonstrated a proof-of-concept against that bar?

I'm assuming that the reflection is for AATD for the one year, just to make sure I would say it's multiple aspects important to confirm.

Right.

Yes, I mean, as we said at the beginning, we're not going to get into the specifics of this from a competitive standpoint. But what we can say is in the conversations that we went into saying that the premise around RNA editing in general is to restore an MZ-like phenotype and following discussions with the agency, the one-year interim analysis would be predicated on delivering an MZ-like result.

And so I think I'll let Chris add to that, but that's the premise of how we think about that interim assessment.

Yes. So as Paul mentioned, really, we're looking to restore the MZ-like phenotype where individuals would have increased M of 50% or greater or in the range of an MZ patient, decreased Z and then recapitulating the acute phase response so that M increases at the time that there's infections or lung inflammation at the time that the tissue most needs protection.

So I think if we're able to achieve all those 3 things, which we've been able to show already in our data for RestorAATion-2, we'll be in a very strong position.

Our next question comes from Ananda Ghosh with H.C. Wainwright UK.

Paul, recently, Endocrine Society published a review urging to move beyond weight loss. We get a lot of inbounds on regulatory clarity on monotherapy in terms of weight loss. So looking at other measures such as DEXA and the waist circumference were actually considered to be some of the important endpoints other than weight loss, and there was this push for regulatory agencies to kind of accept it.

So from a sponsor point of view, have you engaged with the FDA on similar ideas?

Yes. As we said, this is an engagement that we expect this quarter and not just for once, but on an ongoing basis. And not just weight, very much to your point, when we met with the obesity patient advocacy organizations, they're having their own conversations with the agency around a similar approach. And I think getting this beyond weight loss to what is healthy weight loss, meaning there is a reduction of moving beyond just scale weight on pounds where a good majority of that is coming off of muscle to really focus on fat and importantly, visceral fat, which is dangerous. And so the best measurement of that, as you point out, I mean, we have already in our Phase I healthy volunteer comorbidity patient population have seen substantial fat reduction, visceral fat reduction, weight circumference changes.

So differences that we've seen with the profile of 007 that are distinctly different than other even INHBE siRNAs that have generated data. So I think we're compelled by that data that the medicine is working like it should. And we're moving forward at a time where I think we're seeing the holistic narrative from clinicians and as you point out, regulators shift towards what does healthy weight loss look like and really that being driven off of body composition.

So we're very much aligned with that. The profile demonstrates that. Our preclinical data shows that. But I think it is important because we know there's a number of folks who listen on the call and hear all of that and the importance of body composition improvement being driven and say, but is there still a regulatory pathway for that? And if we go back to the regulatory draft guidance, this one-year time point with greater than 5% change in body weight does emphasize the body composition improvement.

So we're very much set up to how do we deliver on a regulatory threshold and get to build on the labeling with what's going to be meaningful for patients in the long term, which is this improvement in body composition, all of which are captured across the clinical trials that we're running. So these are all measurements that we're already capturing as part of those clinical trials.

Our next question comes from Salim Syed with Mizuho.

Paul, Chris, maybe just one on 006. Could you just clarify for us when you guys were in discussion with the FDA on getting this single trial design for both accelerated and full approval, obviously, that contrasts to Beam where I think there's still an ongoing dialogue to get a confirmatory trial design.

Is your view here that the FDA has drawn a line now between RNA and DNA medicines? Or was this kind of Wave suggesting to them, hey, look, we think this makes sense and we may see at some point later, where the Beam trial starts to converge more like into the Wave trial single trial instead of separate confirmatory trial design?

I'm going to hand it to Chris. But I think at the general level to that last point you're making, I do think that there's an attempt now for better harmonization, and we're seeing that in a number of reports coming out of the FDA, starting with the Rare Disease Hub and then thinking about how the Rare Disease Hub helps orchestrate between CBER and CDER to get better alignment across endpoints.

And so I think we'll continue -- I very much believe, based on what we're hearing, too, that there will be even more of that to come, which I think is just great for the industry at large and rare disease at large.

Stepping back from that to the very specific point of why that you see differences coming out from these companies relative to this is, and I'll hand this to Chris, is I really want to give the team a lot of credit for thinking differently in rare disease. I think too often the standard, which is kind of what you're seeing in coming out on other sides, which is people start with this idea to kind of getting to an accelerated approval and then you end up having to run by the time you file these longer studies without alignment, that ends up continuing to add to cost patients time.

And so I think the team's approach was to really approach it differently, which was not to forgo, again, feeding 2 birds one hand, not to forgo the conversation on what a pathway to accelerated approval could look like. But most importantly, lock down what a path to full approval could look like and work backwards.

And so I'll hand it over to Chris to kind of the thought process and the engagement.

Yes. I mean I think Paul covered it quite well. It really was our strategy and the thinking of the team that really brought us forward with the single trial design, which would enable us to get to a full approval as quickly as possible, but also have an accelerated approval on the table. So I think it's a great approach.

We had discussions with the FDA on that trial design, and we're moving forward with a single trial with the duration mentioned 2 years for the full approval and a year for accelerated approval.

Our next question comes from Joe Schwartz with Leerink Partners.

So following WVE-006 monthly data in the fourth quarter, once dose is blocked, when do you expect to enroll the first patient in the registrational trial?

And then is a 3-month look at data in the Phase IIa for WVE-007 still planned? And if so, when could that occur? Thank you.

And I'll take the last question in terms of cadence and timing on the IIa INLIGHT. And we said, well, we have the potential to deliver the IIa data could start coming as early as this year. I think we'll provide an update later this quarter as we do our analysis of whether we would cut the data and look at the 3-month time point, which we know will be a body composition time point. I think we've seen that in the past that at 3 months with 007, that initial fat loss comes with muscle or lean mass increase.

And so it's really an important, and to the question that came out earlier, important from a body composition standpoint, but not the time point for weight loss. And so we're going to do our analysis of whether we cut it at the 3 months or the 6 months and 6 months being a time where we can assess weight loss. More to come on that this quarter in terms of timing and updates.

Chris, do you want to take the first question?

Sure. So our RestorAATion-2 study is still ongoing, and we look forward to getting the 600-milligram data, multiple dose data. And once we have the 600-milligram multiple dose data, then we'll be able to have a better sense of what dose and what dose interval we'll be taking forward into the pivotal trial, and we'll provide updates at that time.

Our next question comes from Ben Burnett with Wells Fargo.

Just one on 006 and AATD. It's a registrational study that's being planned. Can you talk about what endpoints might support full approval? And I guess, are some of these endpoints easier to power for than others?

I mean I think in principle, this is a competitive space, and we're not disclosing the endpoints that we're moving forward with. But just generically speaking, there are certainly some that are a lot better than others, right?

So I think what we've heard and what we've seen and what our own analysis have shown and actually that of others is like FEV1 is not really a feasible endpoint for ATD in a reasonable time frame with a reasonable amount of patients. So that's one thing to say.

There's a number of other measures you can look at. You can look at exacerbations, you can look at a number of respiratory symptom questionnaires. Also up and coming that's quite interesting is CT densitometry. And so that's something that's been used for approvals in Europe. The FDA isn't quite there yet, but I think that's something that's quite interesting and is advancing and would be able to allow a shorter, well-powered trial with not as many individuals going forward for registration study.

So those are the things we're thinking about currently.

Our next question comes from Yun Zhong with Wedbush.

And on 007, monotherapy, I understand that you are confident to meet the bar of 5% for approval. But in reality, for market adoption, do you have a sense of the magnitude of weight reduction that you will have to achieve for obese population to be willing to try this therapy understanding that the benefit of muscle preservation.

And also for combination therapy, for the bar for approval, do you think incremental weight loss alone versus GLP will be sufficient, or do you have to show additional clinical benefit when compared with GLP?

I mean I think as we think about crossing the bar and as that grows, that's a weight loss bar on pounds. And if you think about the requirement of pounds of fat to lose relative to pounds of muscle, it's not equilibrated, right? You ultimately have to lose more fat in order to lose the equivalent pounds of what's being lost in muscle weight.

So as we think about what's going to be meaningful for patients and particularly to the prior question, which I think was spot on that there really is a shift to what's driving health benefits. And I know some people are saying, well, these medicines have both health benefits as well as potential aesthetic benefits. The benefits of losing fat and preserving muscle, I think, achieved both of those aims. They help on the health outcomes perspective and aesthetically by preserving muscle and losing fat. And so I think ultimately, the profile is going to be that.

And if we go back to the DIO mouse data where it took time, that mouse data, just to put this into perspective, it was equivalent weight loss from INHBE to GLP-1. I think if we think about what does that mean, it doesn't mean that, that was truly equivalent. In order for that DIO mouse to reach that same point, they actually had to lose more fat than the equivalent GLP-1 to achieve that same profile.

And so as we think about this over the course of a year, I think that profile could continue to enrich what happens when you substantially lose fat, what happens when you preserve muscle and ultimately, what that means from both patients and physicians and payers as we think about this medicine progressing.

As to what's going to be required on the combination side, I think, there's a variety of settings, which is why we're looking at that, meaning if we achieve the regulatory bar, then you don't need a separate approval for the combination. This is like other medicines where those examples will be giving physicians the tools to see how INHBE and in this case, tirzepatide, but you can think about that as incretins coexist. And so people would get the experience data set and how to use that.

If you think about and asking the regulatory question in the context of combination as the first approval, then there's obviously the additive effect and that's been demonstrated discussed around an approvability pathway of the impact of incretin alone plus the additive benefit of putting another medicine on top. But I think the key ultimately is the power of what happens when you can reduce fat and preserve lean mass.

Our next question comes from Whitney Ijem with Canaccord Genuity.

Just another one on 007. And I know you've talked about in the past kind of expectations for the 600 mg MAD data. But can you just refresh our memory? How should we be thinking about that? What should we expect to learn?

And I guess the related question is, is there a scenario where you move the 600 mg dose forward into the maintenance study? I know you've chosen the lower 2 doses for the combo study, but just kind of trying to get a sense of if there could be different doses in different settings.

And I think it's important to a SAD study still. So it's still the Phase I SAD 600 that's coming from, just to put it in context, the MAD part of the IIa study with the multidose.

But no, the upcoming data, if we think about it, it gives us another opportunity to that point. I mean, we know that the lowest dose, Activin E, was suppressed out at 7.5 months. So the ability to continue to see what the profile looks like at both higher doses from a PK/PD perspective, obviously, we'll be looking at body composition. We do reflect on the fact that there's no reason to believe that the baseline body compositions for that group cohort will be different than the other dose ranges. But we're going to learn about safety and PK/PD.

In terms of your question around different -- an interesting one on different doses for different settings. What's different potentially about maintenance versus the combination and monotherapy kind of reflect more of the other direction, which is that the maintenance setting is probably the setting where there exists the best data set, right? If we think about the human genetics is a 50% loss of function that is pretty much like a maintenance study over life in terms of preventing fat regain. So it makes sense. You take the break off lipolysis at that 50% threshold and you don't gain that adiposity that you see elsewhere, similar to what we saw in the animals versus induction where you're losing that more fat.

So what we may find over time is actually the need and balance and doses that's required for maintenance may not be as high as what's required, let's say, for a monotherapy weight loss.

And so thinking about that over time, both on an induction and maintenance becomes interesting. And like I said, it's nice to have the pathway. It's nice to have a potent on-target durable approach to being able to look at that and we can assess it.

I don't know, Chris, there's, any, your thoughts on that.

No, I think we just -- 600 milligrams is to get more information about the dose, the duration, the dose interval, what do we need to get to once yearly or twice yearly dosing with the optimal suppression and to learn about safety at higher doses. I mean it's part of the dose escalation, single ascending dose study. But as you can see from the data that we've already presented, we have substantial knockdown with the lower doses, 240 and 400 with a single dose. So we think that the regimen that we have for our Phase IIa study will also have substantial and durable knockdown at these lower doses.

Yes. I mean it's nice to see dose-dependent knockdown having the durability. And then to your point, we're able to look at that across longer time points to ultimately optimize for the regimen.

Our next question comes from Danielle Brill with Truist Securities.

Just a quick one on 006. Given that you've already demonstrated the MZ-like phenotype that the FDA is looking for, just curious what incremental benefit hoping to see with the 600-milligram dose. And since you said this data is going to inform dosing interval as well, what would give you confidence to take a less than monthly regimen forward when that interval hasn't been directly tested in the clinic?

So I'm stepping back, I got part of it. But if I'm stepping back and saying to your point of what the 600 for 006 could look like, given what we've already seen, I think to the point that Chris mentioned and that you mentioned, what we'll learn from 600 will inform the dose and frequency. And I think if we think about the prior doses, we had -- there's the 200 biweekly and the 400 monthly.

So those were looking at exposure over that, having 600 monthly will help us complete the modeling curve so that we can look at total exposure, duration of drug product on board and be able to optimize that regimen, as Chris mentioned, for the subsequent study.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

I was hoping if you could talk a little bit more about the dialogue you had with the FDA on the assay itself for AATD in Phase III. Just like how flexible were they? Do you think the assay is going to need to be standardized across companies and across the industry going forward? Or were they sort of flexible on what you could use?

Yes. So we had quite a bit of dialogue around the assay. They had a lot of questions, which the team did a great job at kind of answering to their satisfaction. And so on the basis of them really digging deeply into our assay, they were comfortable with us utilizing that as we move forward as part of our registration study.

So I think that they saw the value of -- I think if you have an assay that you've well characterized and done the appropriate work on, they're open for you to be able to use that all the way through your development program.

I mean, to add on to the work that Chris and the team have done, the ability to know that we can use the same asset in these early studies through, again, provides consistency for ourselves, clinicians and others to be able to look and cross compare data. And I think when you think about how you can validate that against samples, when you're looking and assessing Z and we've got human M, so we have no bystander on it. So we're not trying to assess non-native proteins.

The ability to take existing data sets of MZ patients, MM patients, ZZ patients and characterize those levels of M and Z in those patients, you don't need to redefine or try to characterize the non-native protein. So I think to Chris' point, we've got an assay that we can now use to make those assessments through the study and frankly, beyond.

Our next question comes from Catherine Novack with JonesTrading.

Just curious if you can give any additional expectations on what kind of dose response you would expect from 400 to 600 mg monthly based on prior modeling data and exposure and whether this is an opportunity that you can use to explore whether the MZ ratio can further improve with multi-dose regimen.

I mean, one, I mean, we're going to look at as well. I mean the wonderful thing about GalNAc is we know like it's distributing. So there's a question really on a function of time to continue to produce. I mean we saw that in early studies and translate that with time hepatocytes recover and start producing more protein more efficiently. So I think the ability to see that, whether or not you could see an impact on Z faster. I mean I think those will be opportunities.

But I always step back and kind of reflect that 2 weeks after the lowest single dose at 200, we could get over 20 micromolar of protein. And so the notion that even at that lower dose, we were seeing a pretty robust response across was very clear.

I think the other thing just to add to that is when we do look at the natural history cohort of MZ patients, we're right there on the percent of M there. So again, in terms of what one needs to achieve, and this gets back to some of the conversations that we were having in the profile of going into what needs to be achieved to deliver on an MZ-like phenotype, we're delivering right at the percent of M that's seen in the natural history cohorts of MZ.

So again, some of the other balance may be a function of what happens with protein over time, but we're already delivering on the profile with the existing data sets that we've had at the MZ ratio that you'd expect to see in an MZ cohort.

Our next question comes from Madison El-Saadi with B. Riley Securities.

Congrats on the progress. Regarding your 006 readout in 4Q, what would push you to a biweekly regimen versus a higher monthly dose for the pivotal?

And then with the 006 trial design that you discussed, do you think this could be sufficient for submission and potential approval in the EU? I mean it seems like you could reach the EU market fairly soon after the U.S. or I'm being a bit too optimistic there?

Sure. I think in terms of the 4Q data update, I mean, again, I think, to the prior question, I think, we're going to get to look at that modeling data and see. I think it's highly likely to stay monthly just because based on the 200 and 400 alone, I think we could model that.

So whether or not the 600 adds anything else to that in terms of what the dosing frequency could be even less if we look at the totality of exposure, I think, we're going to be able to make a number of those assessments.

But I'll let Chris speak to the registrational strategy.

So I mean that's a great point about the EU, and we definitely are having that in our overall registration plans. You might be aware that in the EU, they have accepted CT densitometry as a primary endpoint for a pivotal study in the past. So I think that opens up a great rapid path forward there.

Our next question comes from Luca Issi with RBC Capital Markets.

Maybe, Paul, maybe like a bigger picture question here on GSK. Can you maybe talk high level about how your relationship with them has evolved over time? Again, obviously, you signed the deal back in 2022, then they subsequently decided to return the rights for 006, which maybe was not what you were anticipating. But now they're obviously decided to opt in for these novel hepatic assets.

So I guess when you look at it from the outside, it may appear that their interest in Wave has been kind of somewhat waxing and waning, if you will, over time, maybe as a function of their leadership changes and whatnot.

But again, I'd love to hear kind of your thoughts on how your dialogue with them has evolved over time. And most importantly, where you think this relationship is going from here?

Yes. I mean I think as you point out, I mean, the decision around leadership change and we kind of step back and the decision of what assets are moving forward and frankly, what we're able to bring back into the portfolio really is a function of this kind of rare and we're not allowed to disclose liver -- or hepatic indications. But what I'd say is it's very much aligned, I think, with that similar profile.

So I think to see them move forward with the assets that they are is exciting for us. The team is heavily engaged. I mean there's a lot of work that we've done and was presented actually at a Research Day a little while ago on the work that we've done on unlocking cell types and targets with various modalities.

And so it was always kind of at its core and ability to access platform capability and be able to unlock targets. And so it's been nice for both sides. And I say that because it's been mutually beneficial in terms of the things that we've learned as well around looking at various cell types that we can get exposure to, and how do we open up targets in that space and how do we validate that with modalities.

And so yes, I think on both sides, I'd like to think that each of us are getting out of it what we went into it saying this is going to be aligned with our portfolio construction and with us now having full ownership of 006. And frankly, if you remember 007 with INHBE that we selected out of the genetic target database early on in the collaboration, I think the collaboration has been mutually beneficial.

Our next question comes from Alec Stranahan with Bank of America Securities.

Good to see the Phase IIa has higher adiposity. One thing we've heard from KOLs in the space is that, yes, like you said, Paul, more weight to lose, but these patients also often have more muscle to carry that weight, so maybe more muscle to lose as well. So just curious to hear your thoughts around your outlook on the lean mass preservation in these higher BMI patients. Obviously, having a higher BMI means that the delta on the weight overall could be greater.

And then just one quick one, if I may, on AATD. Any additional FDA meetings planned ahead of launching the pivotal? And I guess, when could those happen?

If we get back to the adiposity question and body composition improvements, I think, it's spot on by preserving lean mass. You actually could accelerate fat loss. So the notion that you accelerate fat loss, you preserve muscle, muscle itself as an endocrine organ helps continue to drive that metabolic rate and ultimately could lead to further fat loss. There's not a huge need to lose muscle. I think preserving that and actually sustaining that in the setting of fat reduction is crucial.

I do think, as you're pointing out, what we're continuing to hear on is that this BMI is kind of almost an antiquated way of doing these assessments. I mean on one hand, you could be a body builder with elevated BMI or you could be overweight. And so I think the notion of really getting into body composition as a function of subcu fat, visceral fat and lean mass is important. And I know we've said this before, but I do think it's wonderful to start seeing the fact that scales that people can have in their homes are now as almost inexpensive to be able to measure and characterize that.

So the only tool people kind of were able to use before was a scale where they could look at pounds, they can measure height and they could try to calculate what's happening in terms of BMI and say, okay, I need to lose weight. I think the discipline that we're able to see now where people are able to really quantify the characterization of what weight is being lost, the quality of that weight loss as a function of health is important and is very much tied to what we hear from the patients that we're speaking to and their advocates as well as the clinicians we're speaking to.

So I think it all goes net favorably with the direction of travel that this program is taking and hopefully, the conversations that continue to emerge within what is healthy weight loss.

As it relates to 006, we don't comment on individual regulatory interactions, but it's safe to assume that we'll be well prepared when we go into that trial to deliver.

Our last question comes from Cha Cha Yang with Jefferies.

This is Cha Cha on for Roger. I wanted to drill down on some of the expectations for 006 for your post-incretin maintenance trial. Can you speak to the magnitude of weight regain prevention that you consider clinically meaningful in the maintenance setting?

Yes. And just to be clear because I know it's 007 just for others dialing in just to make sure. So for INHBE-007, the maintenance study and the prevention of weight gain, we'll share more details when that study initiates on the design and how we think about the characterization.

But what I thought was if we go back to the DIO data where we demonstrated the ability to drive that prevention of weight regain, I think, it's important as we do look at that is to quantify it is we actually saw essentially what we saw when you use this mechanism, which is you get a slight bump, which comes from lean mass increases and then the fat stays solid, hence, why it stays flat.

So what you would expect to see when we provide that update is a requisite update on not just prevention of weight gain as a total poundage number, but also both as a function of how weight is being regained, right? Because the prevention will be of fat coming back, which is the principal driver. If you think about what happens when people come off their incretins, is what we saw in the DIO, the hedonic eating comes back, you take that signaling off. And when the weight regains, it comes back predominantly as fat, which is a less healthy state than when you started your therapy. And so the ability to curtail that fat regain, but to potentially regain some muscle, we see as advantageous, and we'll give the specifics when the study initiates.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning, and we appreciate your continued support. Have a great day.

This concludes the call for today. Thank you for joining. You may now disconnect.

Hi, everyone. Just wanted to come on to welcome everyone to this session of our SMID Cap Executive Insights Virtual Event. So I'm Jill Hall, head of Small and Mid-Cap Strategy here at Global Research. So we're very happy to host this event for another year. Great opportunity to hear from corporates across the small and mid-cap space. Our analysts have great coverage in the space, about 1,000 small and mid-cap companies in the U.S. So fortunate to hear from almost 20 of them between today and tomorrow. So feel free to reach out to me or to the Corporate Access team if you need help registering for any other sessions. We can definitely still add people and -- or if you need the schedule as well as if you need help connecting with any of our analysts afterward or getting on to distribution for their research, our small and mid-cap research, we also do a fundamental compilation of small and mid-cap research each day. So with that, I'll pass it over to Alec.

Awesome. Thanks, Jill. So my name is Alec Stranahan. I'm a senior analyst covering biotech here at BofA. I cover 29 companies ranging from $40 billion to $400 million on the market cap scale. And I'd say Wave is probably one of the more interesting stories in my coverage, and it's my pleasure to be joined today by Paul Bolno, who is the President and Chief Executive Officer of Wave Life Sciences. Paul has been with the company since just about the beginning and I know you'll be able to feel his passion about their RNA platform and opportunities in obesity and elsewhere. So Paul, thanks so much for doing this with us.

No, thank you, Alec. Excited to be here.

Yes. Great. Great. So I've got some questions to run through here to sort of lead the discussion. But for those dialed in, if you do have a question, you can utilize the raise hand feature via Zoom or you can e-mail me separately, I've already gotten a couple of questions come in, and I'll be sure to relay those on your behalf. So Paul, maybe just to start, Wave has clinical validation for the RNA interference and RNA editing aspects of your technology. But maybe just starting at a high level for those less familiar, with the story and the technology platform, maybe you can run through what Wave was created to do and sort of what's going on at the company currently?

No. It's a wonderful place to start because as you said, when we kind of look at where we are today, it's easy to become fixated on some programs and clinical validation, and we talk about RNAi as if it's almost commoditized and we talk about RNA editing as this innovation on the platform. But as you pointed out, if I reflect kind of back on now in over a decade investment that we've been making at Wave, it's fundamentally off of chemistry. And at the core essence of Wave has always been about how do we design differentiation on chemistry that can ultimately unlock the potential of RNA medicines. And I say this both on the investment we made in stereochemistry and so making single molecules where we could really understand the fundamental pharmacology of how these medicines work to the ability to extrapolate new modifications that continue to drive potency, durability and differentiation as we see with our obesity program INHBE.

And so when I step back and say, RNA medicines, we've got a ubiquitous chemistry capability across all RNA therapeutics across the different modalities. And what's really exciting about that, and I think this is the opportunity that sits ahead of us, both with the pipeline that we're currently developing. And as we have R&D Day later this year, really extrapolating on where we can take this forward is the convergence between what you can do when you have differentiated chemistry and how that translates to the intersection with novel genetic targets. And that's really enabling us to really approach new areas.

So case in point, INHBE, a novel genetic target in obesity that really addresses what we see as kind of the fundamental future of the next generation of obesity therapeutics. Alpha-1 antitrypsin, the first RNA editing program that's an important program for alpha-1 patients but also unlocking the power of RNA editing more broadly with PNPLA3 coming behind it. And again, here's an opportunity where silencing as we predicted a little over a year ago, where we were saying that if you knock down this enzyme, you could make the disease worse. The idea that in editing that could actually treat the underlying disease, we were seeing that play out with some of the recent clinical data updates on RNAi and PNPLA3.

And so again, differentiated target, differentiated approach. And I think as we think to the future, the opportunity we have in front of us beyond the existing pipeline to use the platform to unlock differentiated targets that really address new biology is pretty exciting.

Yes. No, definitely a lot going on at the company. And maybe just to level set here in the beginning, what's the benefit of RNA editing versus DNA editing, which I think is maybe a little bit more mainstream for generalist investors. And I mean you're also competing against some DNA editing companies [Cyagen and ACB]. So maybe you can just speak at a high level on kind of the benefits of editing the RNA.

Yes. I mean, I think when we step forward, we say what is the target product profile for these patients who are living with a disease. In this case, we're talking about alpha-1 antitrypsin deficiency and how do we best address that? And the opportunity we always say is, we have different modalities and different ways to address diseases. So if we don't think that that's the best way to do it. We don't have to be doing it. And so really, RNA editing came about because our view fundamentally is that a redoseable medicine that doesn't permanently mutate DNA and put patients at potential risk for off-target edits and separate, when we talk about this space, in particular, alpha-1 antitrypsin deficiency.

When we talk about off targets, people tend to immediately go to just, well, is it bystander editing? Can you address that through specificity? The real risk to off-target editing that could lead to editing of cancer-associated genes that could take decades to materialize. In addition to what happens when you get bystander edits that create different proteins. So specificity is important. So can you redose it and get an access to new cell types? Can you get specificity that is exquisite? And we've seen that in our preclinical characterization. We see that clinically, which is beautiful crossing of our M protein and Z protein.

So we know we're functionally converting that Z misfolded protein to M. And durability, so being able to do so in a way that's not putting a dosing burden on patients and then when we think about access and market access to these patients. On the other side, how accessible do we make it when you work with payers?

And when we think about the idea of -- and I don't think we've ever seen the concept of a true one and done therapy. But if you take durability you need over a decade of durability on a DNA editor with safe, durable like no loss of editing to just break even from a payer on what you would get in terms of treating a patient with an RNA editor. And so when we think about being able to provide that, so potency, safety, durability and access. We see RNA editing is providing those features. And it's not dissimilar to what we're seeing in other therapeutic spaces. I mean, I think TTR has just been another great example of watching where RNA medicines have really unlocked the potential for an indication and maintain a competitive position. So I think we see that same opportunity in front of us for alpha-1 antitrypsin deficiency.

Great. And Wave, I think, has a distinct advantage that within RNA, you can silence, you can edit, you could do a splicing. How do you decide which approach is best for a given disease? And I guess, where does your proprietary chemistry maybe create the clearest competitive advantage?

So I think the wonderful thing about the chemistry is we can see that advantage whether we're talking about editing or RNAi or splicing. So the opportunity that the chemistry provides gives us, to your point, and I think it's a very good one that we can think about to hammer everything as a nail, with the wonderful thing about having optionalities as we think about these tools as we can select, to your point, the right tool for the right job. And I think there's no better example of that, frankly, than the program that will be going into the clinic later this year, which is PNPLA3. So there's 9 million patients who have this genetic mutation. You can find it in 23andMe, so it's commercially available and people can find out that they have the PNPLA3 mutation. And those patients are at a substantial higher risk of all-cause liver disease mortality. So the ability to actually provide a fix to that is important.

I say a fix because for a while, people said, okay, there's this mutation. If you can silence it, you can treat the underlying disease. And as we, as to your point, we can make RNAi and we can make editor. So what do we do? And we shared some of these data last year at R&D Day. When we looked at the comparison between silencing the enzyme versus fixing the enzyme, there were differences in outcome measurements. We saw differences in the cell's ability to dispose of the fat that was inside as we think about MASH. We also saw differences, and we'll be sharing more on this on the inflammatory component of the disease. And so when we look back and said, well, do you want to silence or turn off this enzyme, but frankly, you need it, right?

This is a disease where a heterozygous phenotype. So 50% correction basically restores functionality back to those patients in terms of their survival advantage. The idea that we had was, well, yes, absolutely. Here's a case where actually the correction actually fixes the disease. And I think not only do we see that in our preclinical studies, but watching multiple clinical programs start to read out on the silencing front is conferring that same advantage that we've been seeing that there's actually the real advantage in fixing and correcting that underlying mutation back to a normal functioning enzyme as opposed to silencing and then taking that enzymatic function away. And so we're excited as that goes forward to be able to think about this really in redefining liver diseases. Here's a PNPLA3 mutation. We can look at it for these different indications, but really what underlies this is protecting these patients very early on from a substantial risk. And 9 million patients is not an insignificant number of patients that can be addressed.

Right, right. And you've mentioned a few of the internal pipeline assets, and I want to go through them one by one. But I think maybe a good question just to sort of lead into that is I think WVE-007, which is your obesity asset got a lot of attention or a lot of attention to the company when we saw the really encouraging early human data a few months ago. But I guess which program kind of has the best or the greatest potential to change how the market values Wave over the next 12 to 18 months?

Yes. I mean I think over the next year, I think it's the wonderful aspect of these 2 programs, right? I think they have -- if we think about alpha-1 antitrypsin and we think about 007, each has the ability to be transformative in its own way, right? I think in the case of the next near-term period on 007, I think a lot of the -- what people will say is the initial enthusiasm, I still think sustains our enthusiasm in the program. I think the biology is really well understood.

We have genetic data. We have human data, and we have the bridging between human genetics of patients. We have the bridging to treated patients, and we have the models in between. And the medicine is doing exactly what it's supposed to be doing in a way that's differentiated as we've watched other silencing programs come forward. That reinforces our differentiated chemistry. And we're still looking at durability as we think about a once to twice a year dosing.

We still see the only clinical data set in patients who are otherwise healthy, so Phase I patient population in low fat who sees substantial reductions in visceral fat that are clinically relevant, substantial reductions in total body fat. So we think about what's going to drive ultimately weight loss in general is total body fat and change in waist circumference, which is actually a measurably meaningful way of looking at the impact of this medicine. And so I think as we think about the early data from the Phase I population, and even that is being compared to Phase II/III. I think we're highly encouraged that with dosing underway in the IIa monotherapy in the patient population that is the intent to treat, right? These are patients with higher BMIs, higher levels of visceral fat, higher levels of total body fat, with and without diabetes. There's 2 other cohorts so that we can really elucidate kind of the broader cardiometabolic areas for treatment, meaning diabetes, MASH and others, it's pretty exciting. And I think we're poised now without running to be able to accelerate and deliver the new data.

And then shortly from now initiate the combination study and then where I think there's probably an underappreciated application because everybody is so focused on the frontline and how are we going to win a monotherapy, and I think the opportunity is very much there, and I think this is going to be a meaningful medicine in combination. Do you have to keep pushing incretins in order to get a benefit or the add-on? And I think we're seeing examples of add-on being really great opportunity. But I think the most underappreciated aspect long term for treatment of these patients who are living with obesity have been treated are at steady state on regardless of what therapy they came into treatment on. I think the conversation we hear time and again against clinicians and patients and payers, for that matter is, what does maintenance now start to look like in this population?

And to date, maintenance is really like a titrating back on incretin levels and how much regain can you stave off in order to kind of keep people on a level. And I think that really fascinating opportunity of maintenance for INHBE is actually just shifted of how do you lock in and prevent fat regain? That's the challenge, right? If you titrate back your incretin, the weight that comes back is actually fat. And as you come back, you imagine a patient going back to baseline actually has more fat than they actually started their therapy with.

So the idea that we could shift to a maintenance therapy that could be once to twice a year, prevent that regain of fat back and really stabilize patients now has us not segmenting a market, but really thinking about how do you take any incretin patient and actually think about a forward-looking vision where they don't have to sustain on that and run all of the complicating risks to being on a sustained injectable or frankly, oral. Where we'll see whether or not the oral is in a real-world setting, actually sustain the levels that they're seeing now. But we think maintenance is a really exciting way. And at this moment in time, I don't think it's still getting the attention that we think it should. And I think as we start that clinical study this half, I think that's going to be an exciting news part of the story. So that's kind of how we think about unlocking obesity. And we saw that there is a lot of value there.

On the other side, alpha-1 antitrypsin is we're poised to have regulatory feedback on a path to accelerated approval, I think, accelerates a different conversation with Wave, right, which is one of how do we move into a commercial stream for a substantial number of patients, 200,000 patients in U.S. and Europe. Would be the first RNA editing program, we think, as we laid out as your first question in a way that's differentiated, I think, from others and as we test that profile amongst the medical community, patient community and payers. We think that's an exciting component in Wave that gets unlocked again in the second half as we think about going into next year and having this pathway to potential accelerated approval.

And so I really do think we're in a position as we look forward that the next 12 months is incredibly exciting across both assets. And I don't think -- I think both have the potential to contribute substantially to a higher value than we're seeing today. With then PNPLA3 coming behind that as a supportive asset that will continue to generate data in the next 12 months that unlocks that opportunity and as people will learn at R&D Day. The opportunity we have with bispecifics and other targets that sustainably deliver on that pipeline beyond the existing 007 and 006, I think is a really strong foreseeable future.

Yes. Yes, great. Those tend to be the 2 assets that I get most focused on from investors as well. So maybe we can touch on those, and then I do hope we get time to talk about PNPL3 -- sorry, PNPLA3 as well at the end because I know that's a large unmet need as well. But maybe starting on 007 in obesity and cardiometabolic disease. And I think you kind of covered a lot of it. But maybe we could just talk a little bit about the lessons learned so far from the Phase I data.

I mean you showed reductions in total and visceral fat with muscle preservation, which is kind of the holy grail when you think about maintenance or even an upfront therapy, like a lot of the total weight loss is actually from muscle and not fat with incretins. So if you're able to strike that balance with convenient dosing, like it seems like a pretty actionable profile. But I guess how did investors sort of interpret those results through the dose escalation? I think we're going to get a higher dose as well later this year and what have you learned about baseline BMI, the relationship between Activin E reduction and clinical benefit that's sort of helping you inform next steps for your clinical program.

Yes. I mean I think one from -- and I think this is great from a platform perspective, from preclinical data to human data, I think we're seeing strong correlations and translations of target engagement editing. And as we predict our dose going forward, I mean the fact that we're seeing that once to twice a year sustained at the lowest dose that we're going into, I think, continues to speak to what we expect to see from where we think we would need to be from a dose. And we're seeing 88% to 85% reduction in Activin E. So we're -- knowing that we've seen preclinically that once you cross the 70% threshold and sustain it, you start to see that reduction. So we're well in excess of that.

I think that's an important nuance too because I think what it also affirms for us is this differentiation on chemistry. So what we have seen in our preclinical data is it's the only preclinical data set that's seen single dose reduction in body weight. Not prevention of weight gain or slowing of fat regain, but true reduction in body weight. And I think that was important because it does demonstrate that with sustained reduction, and it's important to remember that the DIO mouse is an obese mouse model with excess fat. So I think it's affirming for us that where there's fat that can be stored, you'll see that reduction and lipolysis occur. And I think that's exactly what we saw in the humans. And in fact, to your point on the dose response was really interesting.

And we have to go back to these data and remind ourselves because I also think people tend to become, let's say, fixated on BMI and forget you can be a body builder with a higher BMI and you can be overweight or obese with higher BMI. And the main difference there is the amount of fat. And so I think what we've seen, which has been affirming for the mechanism is where there's higher fat, we see higher rates of decline, right? And so that played out actually in the clinic.

If we think about the dose response, the update we provided at the 400 was actually probably one of the clearest data sets to prove this principle. Once patients had a higher level of visceral fat and total fat, those patients had reductions on par with where we saw the substantial decline in the 240-milligram dose. So I think what's key in this early study, and I think it's hard because obesity is an area. And I do appreciate that those who are evaluating these kind of from the other side are looking at kind of the incretin pathway, right?

People come out and they're like, here's our IIa data. Here's how it looks in the IIa population. And if we look at our peers who share data for INHBE around us, they're all looking at the IIa. We never saw the early Phase I data. I think it was compelling as our Phase I data was competitive where we were starting to benchmark our Phase I population with the IIa population. We were like, "Oh, look, Wave saw a 14-point whatever reduction in visceral fat that looks similar to these other companies reduction in visceral fat." And a reminder, when we kind of step back is, yes, but if you look at -- because these patients had different starting rates of fat, our patients only had 1 liter of fat to lose, and yet they could lose it remarkably in comparison to a comparator with 5 liters of fat because they were a much larger population, which, again, will speak to what's next and why we have conviction in the program.

But I think it really taught us that the medicine is doing exactly what we had modeled to do it. It targets the cells, it's durable. It's potent, it's safe, and I think that's really important as we think about durability and potency in this population. So safety and tolerability looks exquisite. So I think that opportunity on top of that is translating very well.

Now the next question that everybody has is what about 600? And I think we've been saying time and time again that, yes, 600 should see -- we're probably at the blunter end of the curve. It will probably be -- I would anticipate more Activin E reduction, but I wouldn't expect that the baseline characteristics of those patients would be any different. And we know we've already suppressed that.

So I think we'll see what we'll continue to see around PK/PD. I think the most exciting and we've been very clear on this, is now seeing what the medicines do in the patient population with higher BMI, higher total fat, higher visceral fat and comorbidities. And that's that comorbidities piece that allows that fat to be larger. And I think if we think about our modeling, and we've shared this with a number of folks, if you look at the baseline characteristics, which are pretty much good baseline surrogates for baseline characteristics of patients into obesity studies, they have much higher total fat, much higher visceral fat.

And if you look at where our studies started in relation to those studies, and I should kind of give that, I don't know, it's like, but we started at a body composition profile that looked like where those patients end after a year on therapy and still saw that we could continue to bring that down. So what's encouraging is, as soon as we go to that population where we get to a higher fat to lose with the comorbidities, we model that we're not in any way kind of going, do we think we're going to see greater than 5% changes in body weight.

I think what's most important, and you pointed it out, is being able to see that improvement in body composition. And I think that's an exciting conversation that's also happening this half, where we're going to engage regulators around that more broadly. We know the other obesity patient groups are as well. And I think there's a big conversation to be had really on starting to reframe a focus on body composition that irrespective of the 5%, and we're not trying to change the regulatory paradigm there. But we do think from a label perspective and a forward-looking perspective, that changing the narrative from pounds on the scale, as you point out, you can have up to 40% reduction in your muscle mass in that early time point that's really accounting for weight loss with incretins. That's not a benefit.

Those patients are losing an organ that has -- plays a big role in insulin sensitivity, further weight loss and muscle mass and stabilization. So the ability to really frame what long term is providing health benefits as we think about improvements in body composition, I think, is going to be an exciting part of the story as we go through this year and into next year.

Right. Yes. And we know that in patients with higher BMI that have been exposed to other INHBE assets. You do see better activity, which is probably not inherent to that -- those other compounds. It's probably just where you start determines where you can end up. And to your point, Paul, the Phase IIa INLIGHT study, I think that's a BMI of 35 to 50, right, with or without type 2 diabetes. And you're going to be measuring the whole gamut, body weight, body composition, visceral fat, liver fat, HbA1c, lipids. I guess which of these endpoints kind of matters the most for establishing 007 and which could actually open up expansion opportunities into say, MASH or even diabetes?

I think they're all important in their own way, right? I mean I think in general, looking at that continued shift in body composition, right? Reductions in total body fat, reductions in visceral fat are going to be very important. I think ultimately, that translates to body weight because by stabilizing muscle, you're going to see weight as a function of losing fat, right? And so I think that's going to be a surrogate to looking at what we're going to have in addition to the drivers of what's causing that, which we want to see the weight reduction, but coming off of total body fat.

Then to add to your point, I think what's really important about this mechanism and frankly, it was also driving, I think, the patient disposition at the beginning of the study is the concept that these patients can have comorbidities, right? And so when you start thinking about prediabetics and diabetics as 2 different cohorts, the ability to look and track hemoglobin A1c and we go back to these humans who are walking around with a protective loss of function, they have improvements in hemoglobin A1c. They have better type 2 diabetes outcomes and cardiovascular outcomes. Why? Well, because of this improvement, they have lower triglycerides, they have higher HDL, right, in addition to these improvements in hemoglobin A1c.

So I think we're going to look and be able to elucidate some of those cardiometabolic endpoints as we think about looking at those 2 different cohorts, and we'll have the biomarkers to measure that. And as you point out, by having MRI-PDFF in this study, particularly the diabetic patients that have comorbidities and higher BMI, the likelihood, right, of having higher levels of liver fat as we've seen in the other studies is quite substantial. And therefore, the improvements that we can see if we look at our peers who have looked at liver MRIs, 44% reduction in liver fat is consequential. I mean that's substantially as large as, if not actually larger than some of the MASH studies.

So I think the opportunity we're going to have here is there's the unlocking the obesity perspective in a differentiated program with a differentiated pharmacology and we're going to have the opportunity to open up the broader cardiometabolic endpoints that are all part of the study.

Okay. Great. And with the approval of oral incretins I'd say, the field is moving pretty quickly. Although we haven't seen maybe as much progress as the clinical pipeline would have led one to believe 2 or 3 years ago. I guess where do you expect 007 to kind of fit into this evolving landscape? Like do patients get an injectable and then oral maintenance or would INHBE asset compete against an oral or would it be complementary in combination? How are you sort of thinking about these kind of synergizing together ultimately 5,10 years down the road?

Yes. I think if we don't think about the method of delivery, then we know that incretins are compatible and orthogonal to INHBE, right? So the same features apply your point of whether it's monotherapy at the front end, in combination with the oral which is an interesting way of thinking about it because the whole goal is to minimize patient number of injections and you could be talking about 1 or 2 a year on INHBE and then on oral and that could take down the frequent -- injection frequency from a weekly injectable down to once or twice a year in combination with an oral.

As I start thinking about maintenance and where we are, I think the difference is you talk to patients where you go into your physician's office and you get a shot and then you don't have to think about it for the year without the tolerability challenges and frankly, you don't -- it doesn't negate all of the other safety and tolerability complications on the incretins, whether we're talking about oral or injectables. The idea that you still go to a once-a-year injectable, we think is highly competitive with that as we talk to, again, physicians, payers and patients.

I think what's going to be interesting as the data continues to evolve and looking at some of the orals is what the impact ultimately is, right? I mean here's a medicine that you got to take every day. Some, depending on time based, some take whenever you like. But we know from other orals that are required daily. I mean, I think cholesterol and statins are just a great example of what adherence looks like on a medicine that doesn't have the same tolerability challenges causing nausea and vomiting.

And you start thinking yourself in the real world setting, when somebody is not calling you, you don't have an app, you're not kind of in a trial where you're taking it on this frequent basis. The evolution of what real-world data looks like when people miss a dose or missed 2 doses to start adjusting their doses titratable versus how that looks in a maintenance concept versus you go in, you get your shot. And you know you're covered for the period of time that your Activin E is suppressed. We think that the INHBE profile is highly competitive against orals in that maintenance setting.

Yes. Okay. That makes sense. Maybe I'll pause for a moment. We're about 30 minutes in, and I'll see if anyone on the line has any questions on obesity and then we can shift to the AATD and the rest of the pipeline. Again, if you have a question, feel free to raise your hand. I can see it through our platform, and we can unmute you. Maybe while we wait, I did get an e-mail question here on obesity. And the question is kind of around the partnership opportunity, right? Obesity is a large market. There's a lot of potential here for you guys to go alone or to leverage kind of the capabilities to run some of these large studies. Pharma has been focused on post GLP-1 maintenance, and that's not just U.S. pharma, also in the EU and areas like Japan as well. So what's sort of your outlook on partnerships? And would you look to develop this on your own? Or would you want to be strategic to run it with a partner?

I think we always want to make good strategic decisions with any program that we're investing in. And I think near term, what we feel is, again, with a once to twice a year therapeutic study, I think there's value to be unlocked with the current data set, right? I mean, we've got the ability to show duration, safety and efficacy in the patient population. I think as we think long term and as you point out, and I think some of this to your earlier question about how do we think about the interplay between programs where AATD could be a program that has the potential pathway now to, let's say, accelerated approval in a commercial transition. How these assets start to interplay as we think over the next 12 months with data and value being able to think about those strategic decisions. We do have interesting opportunities after value becomes unlocked on this program.

There is, as you point out, continued strategic interest in this program. It's orthogonal. I think it's enticing when people think about combinations. And I think the fact that we don't have to add to the injection burden, we don't have to add to the safety and tolerability burden. So as people think about combinations, which we're seeing in the obesity space, it is critical that this program is not adding the burden both on the administration or on the safety tolerability profile and in fact, may actually improve that in combination if you can come down in lower doses of some of the other therapies. So we're seeing people kind of proactively come and have that conversation about how to think about combination.

We're having conversations with folks, particularly maintenance as well, where there are a number of companies that have been interested in obesity and their whole debate is always how to get in front of it. And having the ability to come in and say, "Well, you don't have to build the market, you just have to move the market," opens up a pretty attractive set of discussions. So I think INHBE does provide that. I think the focus is also not losing sight that accruing and accreting data is critical. And so the focus of the company is making sure that we can deliver the data sets that are going to deliver a differentiated profile against the current programs.

But I think equally important, and we're seeing this in a really nice way in our partnering discussions is, I think, a real recognition that with INHBE, people didn't think about Wave for years as an siRNA company, right? I mean just I think INHBE has opened up conversations about the access that we've had as an siRNA therapeutic company, where we've been years ahead of, I think, who people would view as a best-in-class siRNA company that's kind of defined the field. I think the ability that we accelerated a clinical program for a massive indication ahead in a way that's sustainably differentiated, I think, has really solidified our place as both an RNAi capability company platform or broadly in addition to what we can do with INHBE specifically.

Okay. Okay. So partnerships could, sort of reading between the lines, it could span the in-house pipeline and it could also be kind of a discovery platform type?

Exactly, particularly the work that we've already shown at Research Day last year on extrahepatic siRNA. And so I think we're already there on that with durability. And then continued share updates on bispecifics, the idea of like, can you dual target, and that's exciting as well.

Yes. Okay. Very good. I want to shift gears now and talk about alpha-1 for a little bit. Here with the rights wholly owned to the program, you guys can kind of run with it. You've shown some deepening data, acute phase response, both Z and M protein production, which is important. And I think we're expecting some additional data in the second half. So I guess how should investors sort of be thinking about this program and kind of the path to a pivotal study as you approach the regulator?

Yes. I mean I think the key for us is that the current data is supporting that. This is doing exactly what it's supposed to be doing. It's going to the right cell type. It's converting Z to M in a -- I think there's always times when you look at it and you're like, "Oh, wow, there isn't this kind of concern that some patients are better responders than others." And I think the clarity of really showing the data that every patient is seeing this really nice conversion, I think, is really important as we think about positioning this going forward. And then I think the opportunity that we've seen preclinically where we have longer follow-up and being able to really show what's happening, which, as we saw in the humans, not just this M to Z, but that reduction in Z is consequential, right?

We oftentimes are always in our minds thinking about alpha-1 antitrypsin in the lung side of the equation. Liver is really important. And I think when those data were also shared at EASL, we got a lot of interest from the hepatologists who are -- so as we think about kind of bringing together the alpha-1 treatment community on both the pulmonologists and the hepatologists who are thinking about reduction in liver burden and improvement in lung. I think both of those features become crucial.

And that's important because as you continue to treat, and this is the preclinical data we showed. And so you take that burden of that misfolded protein off the liver, you actually see liver regeneration. And the beauty of liver regeneration is now you've got fresh hepatocytes that you can continue to correct. And I think this is one of the underappreciated sides that repeat administration is actually a feature in this disease, right? Because as you begin to correct the liver and as the liver repairs itself and gets healthier, you've got the ability to continue to access new hepatocytes that are continuing to get fixed, continuing to be able to produce more protein. And over time, we saw that in the animal model where we often get the question of why do we think there's this kind of continued uptick as it gets later. And clearly, we went back and saw a reduction in that burden on those aggregates in the liver and that transition, you're seeing more protein get made. So I think that really longitudinal piece of continuing to treat these patients is important.

So what to expect? I think the key for us as we come through this kind of regulatory window, and we'll provide those updates when they come is really what we would imagine, and we wouldn't have any reason to believe otherwise, is that there's a path to potential accelerated approval based on biomarkers, that's how we foresee it. I think the opportunity, as you lay out ahead of us is how do we think about the design of that study. And I think we don't have to look to the design that others have because there's features we don't have to evaluate, right, that we don't have to concern ourselves with.

So can we do that whether it's with different number of patients or more importantly, a different time horizon with which we can look to evaluate that from what could be an interim endpoint for a biomarker-driven, but are there opportunities for us to run a larger, longer study over time so we don't have to run two studies, one confirmatory and one that's an accelerated registration that gets us to a potential pathway to full approval faster, but not forgoing that you can have that interim look to get to the market faster.

And I think that's where we want to be creative in our discussions and that will be part of an ongoing conversation. But I think that's what we look at as we think about the design and update to the next trial.

Okay. Okay. So powering for early success at an interim, but having like a longer tail on the follow-up for -- to check the box.

That's right. And so the discussions around, and we know the advocacy organizations have been having C-PATH discussions on CT densitometry. So as we think about kind of aligning on what those potential endpoints could be, I think there's really a unique opportunity to be thinking about that long term that ultimately could potentially contract the time to full approval.

Okay. Okay. And I think data from the 600 mg monthly multi-dose cohort is also expected here in the second half?

That's right.

I guess what should investors focus on from the update versus what we already know about the asset? And how would that cohort reading out kind of influence your study design either way?

Yes. I think our plan is we look at the kinetics of our current -- I mean, we're getting high potency than we could get -- if we think about over 20 micromolar protein, right, like shortly after the lowest single dose, right? Like 2 weeks after that dose a patient could get to 20 micromolar during an acute phase response. So what we do know is that editing happens, it's happening pretty quickly in terms of that response rate. It's potent. And as we look at PK, I don't know if there's much more on that potency side, we'll see. We'll have, as we said, the 400 and the 200 were similar in terms of total exposures because one was biweekly and one was monthly.

We'll be able to look at some of that PK, which will probably inform more for us how do we think about dosing intervals. So what do we think the infrequency of administration needs to be? But we'll learn more about the PK. And I think what we'll see in terms of the translation of more time once you have cells that are exposed, is the impact more on time to generating protein than necessarily more drug. But clearly, we're in the MZI phenotype. So we have what we believe we need to have for a biomarker discussion as we go into those discussions.

Okay. Okay. Great. Looking forward to that. And another update that you have in the second half will be putting 008 into the clinic. That's your PNPLA3 asset. And this is not one that I get a ton of questions on, but when I was making up our model, and we do have a build for this indication, it was actually kind of interesting to see what actually the prevalence of I148M variant is, and just how important this is and actually the genetic validation that's already there in the literature, like it's a pretty obvious application for your technology with a large end market.

So it feels like next year, this could actually become more part of the conversation as people look at Wave. So I guess, what are you sort of thinking about this program? How do you approach the initial clinical study here in the second half? And what is sort of the first in-human derisking that you'd be looking for from the study?

Yes. I think, one, to your point, I mean, it is -- we had liver patient come in recently and walk through her PNPLA3 journey. And so I think what's wonderful is it's an opportunity to grow. Like patients are finding out that they have the mutation. There were experimental therapeutics on silencing. And I think what we're seeing was particularly after EASL, a big shift from some of the clinicians that have been kind of the voices of the silencing community shifting and saying, well, actually, we need to shift our focus to editing.

And so I think it's a great opportunity for us to engage that community as we're getting this trial forward-looking ready. And with the patient population, as you point out, that can be diagnosed just based on genetics, and those tests are already readily available. So I think there's a lot that we can do in this case well before we get to the trial that actually gets things ready to go so that we can accelerate things pretty quickly.

We'll share more on the trial design typically when we start the study, but I think the opportunity ahead of us, given that we know the patients, there's physician engagement to get these sites up and running and they're excited about this potential opportunity is we'll have the ability to look at biomarkers in that study.

So to your point, being able to get early reads on that target engagement and profile well in advance of seeing as we think about a MASH study later, being able to look at more near-term endpoints that tell us that this is doing what it's supposed to be doing. And I think on the heels of alpha-1 and the pharmacology learnings, I think we're able to take this very quickly over to PNPLA3, where we know a 50% correction actually fixes the mutation and opportunity for these patients. So I think that's -- and we don't have this acute phase -- this is not an acute phase protein. So what's really nice is an enzyme, you correct it to 50%, you repair the disease.

So I think on some basis, it's a little bit more simplistic in its understanding of the disease biology. And I think as we design the study, we've designed it in a way that we can derisk it, we think, pretty quickly. So I think as we think about 2027, while it seems like it's on the horizon and farther out. As we think about the back half of this year, getting this into the clinic and getting ready so that 2027, I think, does become an unlocking period for this particular program.

Okay. And maybe last question, Paul, as we run up on time here. And I think this will kind of help wrap everything up as well. And it's just around the cash balance, right? And it takes money to make money, especially in biotech. So how are you thinking about capital allocation, your cash runway, which I think is into the second half of '28 and what does that sort of carry you through in terms of derisking for the pipeline?

Yes. I mean, as we said, we -- I mean, on our last earnings call, we have nearly $500 million in cash. So that capital takes us into Q3 of '28. But the most important thing is as you lay out, it takes us through these inflections, right? We're going to continue to drive 006 or alpha-1 into the clinic on that pathway. We're going to deliver important data across monotherapy in the high BMI with and without diabetes, that cash covers the combo study and data there that unlocks that potential value and maintenance. So we'll see that data set. In addition to all of that opens up, and I think it is important to your point on what are we going to see in the other biomarkers? I know there's a lot of questions that people always have about what about all the other cardiometabolic indications.

Those are all in that. And I think that's the wonderful thing about this IIa design that we did say, and as you mentioned, it's an investment, but we invested in those biomarkers so that we don't have to run separate studies to be able to look at liver fat reduction, hemoglobin A1c reductions, lipid profile shifts, insulin sensitivity. And so those will all be unlocked as part of the IIa study. And so I think as we think about those in addition to bringing PNPLA3 into the clinic and delivering that data set, that again differentiates that program.

I think we've made the right investments in a very focused and deliberate way, and we came into the year with a resolute focus that these would be the 3 programs that we would be allocating capital to. And I think we've stayed very disciplined on ensuring that we can deliver the data sets across each of those. So we're excited to deliver the data.

Yes. Great. We're looking forward to seeing the data. So thanks for the updates here and the great conversation. I think we'll have to end it there for the sake of time. But Paul, really appreciate you joining us here for our conference, and thanks, everyone, who dialed in for your interest.

Thank you for having me, and thank you, everybody, for dialing in.

Thank you. Take care.

Hello, and welcome to Wave Life Sciences Second Quarter 2026 Earnings Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning we issued a press release outlining our second quarter 2026 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Erik Ingelsson, Chief Scientific Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer.

The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statements for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. At Wave, we are focused on harnessing the convergence of deep genetic insights with our proprietary chemistry to rapidly advance the pipeline of transformational RNA medicines. Over the past decade, we have built the most sophisticated and broadly enabled oligonucleotide platform in the industry. Multiple clinical data sets now demonstrate our ability to rapidly advance programs from novel genetic target to proof of mechanism in the clinic. Our proprietary chemistry is what differentiates our pipeline and distinguishes our molecules from others in the field.

In the first half of 2026, we delivered multiple positive data sets across our RNAi and RNA editing pipeline, led by WVE-007 for obesity and WVE-006 for AATD, positioning us to advance both programs to the next stage of development. We also continue to progress our second RNA editing candidate, WVE-008 for PNPLA3 liver disease and remain on track for a CTA filing later this year.

In March, we shared positive data from the single-dose Phase I portion of the INLIGHT trial of 007 in obesity. These data fortified our conviction in a best-in-class siRNA design with robust and extremely durable silencing demonstrated in the clinic, supporting potential dosing of once or twice a year. Also, even in this otherwise healthy population, a single dose of 007 led to substantial reductions in visceral fat and subcutaneous fat without muscle loss or other adverse events associated with incretin therapy.

We have 3 opportunities to explore in the next phase of development for this program. First, evaluate WVE-007 in a Phase IIa population with higher BMI and comorbidities typical of other obesity trials to demonstrate 007's potential in obesity as well as evaluate biomarkers to unlock other cardiometabolic indications, including MASH and type 2 diabetes. Second, evaluate combination with incretin, which has the potential to deepen weight loss and enhance metabolic benefits. Third, and perhaps one of the most exciting and unique opportunities, evaluate maintenance therapy, which represents an entirely new commercial frontier, enabling patients an off-ramp for their GLP-1s.

We often hear from patients about the fear of weight regain post cessation of incretins. Up to 70% of patients discontinued GLP-1 therapy within the first year of treatment. And for many, it's due to challenges that WVE-007 may address, including tolerability issues, treatment burden or anhedonia, loss of joy, among others. In this maintenance setting, 007 would have the potential to enable individuals and payers to realize the sustained health benefits of fat loss and improve body composition for the long term.

Over the past quarter, the FDA accepted the Phase IIa INLIGHT trial amendment and dosing is now underway. The Phase IIa is enrolling individuals living with obesity with BMIs between 35 and 50 and comorbidities with and without diabetes. These patients are expected to have higher total body fat and higher levels of visceral fat than the Phase I otherwise healthy patients. With this multi-dose clinical trial, we are evaluating our target patient population and have the potential to deliver further improvements in body composition, meaning weight loss driven off of fat loss without muscle loss as well as other improvements in cardiometabolic biomarkers, including liver fat and HbA1c.

We are also working expeditiously to initiate the additional Phase II trials of 007 in combination and maintenance settings this year. Collectively, our development program has the potential to redefine the treatment landscape in obesity. In RNA editing, we delivered data supporting 006 potential to offer a new standard of care for individuals living with AATD by treating both lung and liver manifestations of the disease and restoring the dynamic AAT protein response with convenient, infrequent subcutaneous dosing.

We are planning to engage the FDA as the agency has granted our request for a meeting to discuss a potential accelerated approval pathway for WVE-006. This meeting is expected at the end of summer and will help inform our registrational plans and path toward bringing a much needed new treatment option to the 200,000 individuals in the U.S. and Europe living with homozygous ZZ AATD. As a scalable, infrequent subcutaneously dosed oligonucleotide therapy, 006 would offer a potentially differentiated value proposition for both health care providers and payers. Current IV augmentation standard of care does not have any impact on liver manifestations of the disease, while investigational DNA editing in addition to any safety concerns would be associated with payer challenges for onetime costly therapy with uncertain durability and multiyear enrollee retention.

Building on our RNA editing success, we are advancing our second RNA editing candidate, WVE-008 toward the clinic this year for PNPLA3 liver disease. 008 aims to address an area of high unmet need with 9 million individuals living with homozygous PNPLA3 I148M liver disease. Human genetic data demonstrates these homozygous individuals have about a ninefold higher risk of dying from liver disease as compared with noncarriers. The landscape of therapies and development for this target has been narrowed by recent clinical demonstration that silencing approaches do not address the disease and may actually exacerbate it. An RNA editing approach is the only way to restore the functional protein and offers a potential for a novel infrequently dosed therapy with strong support from human genetics.

Beyond our lead RNAi and RNA editing programs, we continue to push the boundaries of innovation with our proprietary chemistry. We are planning to host our Annual Investor Day in the fall to shed more light on our latest platform advancements and work on our bifunctional modality. At the start of the year, we outlined our pipeline priorities, WVE-007, 006 and 008, demonstrating our core focus on RNAi and RNA editing as well as our intent to seek partnership opportunities for HD and DMD. Given the evolving regulatory and commercial landscape in DMD, we are exploring potential partnerships in advance of filing an NDA for N531. We continue to believe in N531 and 003's potential as best-in-class treatment options and look forward to continuing our partnering discussions.

With our continued success in the clinic and robust balance sheet, we are well positioned and well capitalized to bring our pipeline of potential first and best-in-class candidates to the next stage of development as we reimagine what's possible for patients.

Now I'd like to turn the call over to Erik, who will discuss 007 and how we are leveraging our proprietary chemistry and human genetic insights to advance the transformative approach for obesity and other cardiometabolic diseases. Erik?

Thank you, Paul. I'll start today by discussing our INHBE GalNAc-siRNA, WVE-007, and how our program aims to fill a large unmet need with a differentiated approach grounded in human genetics. Today, there are over 1 billion individuals living with obesity globally, including 175 million in the U.S. and Europe alone. These individuals face markedly higher risks of a range of diseases such as MASH, type 2 diabetes and other cardiometabolic diseases. Excess body fat, in particular, visceral fat is a key driver behind this elevated risk of disease.

While there are several therapeutic options available for weight loss and countless more in clinical development with similar modes of action to those already on the market, these therapies come with several limitations. Current standard of care therapies reduce body weight through both fat loss and muscle loss, and they carry high discontinuation rates due to the GI side effects, limiting potential for long-term health benefits. The loss of muscle also with current weight loss therapies is substantial with up to 40% of the total weight loss. This has significant health implications as skeletal muscle in addition to muscle strength and function also plays a key role in metabolism by sustaining basal metabolic rate, glucose disposal and insulin sensitivity. Muscle also prevents weight regain, which occurs mostly from fat in a majority of individuals at discontinuing incretin therapies. Remember, as much as up to 70% of individuals discontinuing incretin within the first year of treatment.

An ideal obesity therapy should instead selectively reduce excess fat, including harmful visceral fat, the fat surrounding one's organs that is most strongly linked to MASH, type 2 diabetes and other cardiometabolic diseases, while also lowering subcutaneous fat and liver steatosis and critically preserve skeletal muscle. It's well established that a 5% to 10% reduction in visceral fat mass is associated with positive health outcomes by reducing risk of multiple preventable metabolic diseases and preserving patient function and quality of life.

All these benefits can be delivered by 007's mechanism of action. Rather than acting on appetite, 007 silences INHBE and lower serum Activin E, a liver-derived peptide that signals adipocytes to put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction without the muscle loss seen with incretin-based therapies. Our INHBE approach is strongly grounded in human genetics that carriers of heterozygous INHBE loss of function variant, nature's own knockdown experiment exhibit a healthier overall metabolic profile.

As Paul discussed earlier, 007's unique ability to durably suppress INHBE is driven by our proprietary chemistry and SpiNA sRNA design. Our next-generation SpiNA designs enhance interactions with AGO2, stabilize the loaded risk complex and improve liver exposure, all of which contribute to dramatically improved silence and potency and durability when compared with industry-leading sRNA designs, something we have shown repeatedly for INHBE and other targets.

While RNAi is a well-established therapeutic modality and there are extensive human genetics data supporting INHBE as a target, we believe our proprietary chemistry distinguishes us from others attending a similar approach.

Our interim Phase I INLIGHT data sets from lower BMI, otherwise healthy individuals confirm that this proprietary chemistry and the underlying human genetics are already translating in the clinic. We have observed consistent durable and dose-dependent serum Activin E reductions of up to 88%, which were sustained through at least 7.5 months, supporting 007's potential for once or twice yearly dosing. Notably, we observed the translation of target engagement to substantial improvements of cardiometabolic risk factors with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat and weight circumference after just a single dose.

To provide context for our results of this early development stage, we calculated the visceral fat-to-muscle ratio or VMR, which is a measure of body composition that integrates harmful visceral fat and beneficial lean mass into a single index. Lower VMR is associated with a decreased risk of MASH, type 2 diabetes and cardiometabolic disorders.

With a single dose of 007 in our Phase I population, we already observed a 16.5% improvement in VMR, which is more than 12.2% achieved with weekly semaglutide in the Phase II BELIEVE study and approached the 18.8% observed with bimagrumab.

We believe VMR has the potential to serve as a novel composite biomarker that captures body composition improvements more holistically than BMI and that may better predict long-term clinical benefits. Together with the patient community and KOLs, we're working to engage with the regulators on the importance of improving body composition, including decreasing excess fat and preserving muscle consistent with their recent guidance.

What makes the comparison with the BELIEVE study particularly exciting is that our INLIGHT participants had substantially lower baseline BMI, lower visceral fat and lower total fat compared to Phase II and Phase III obesity studies, including the BELIEVE study. Clinical experience also highlights the importance of baseline adiposity. Early Phase I studies in leaner individuals typically show more modest fat reductions, while studies of individuals with higher baseline obesity demonstrate substantially larger decreases in total and visceral fat mass. Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with low levels of body fat also confirmed that higher baseline visceral fat led to greater visceral fat reductions overall.

As Chris will speak to shortly, we've been working expeditiously to advance 007 into participants with higher BMI and comorbidities in the Phase IIa portion of INLIGHT, where existing science predicts a larger effect. Activin E binds to ALK7 on all adipocytes and visceral fat being more metabolically active and better perfused mobilizes first, exactly what we have observed in Phase I. With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher BMI participants in the IIa study. For further detail on our 007 development plans and our RNA editing programs, I'd now like to turn the call over to Chris.

Thanks, Erik. As we recently announced, we're excited to have advanced 007 to a population well suited to its mechanism of action. We would expect even more pronounced effects on visceral and subcutaneous fat loss. Dosing is currently underway in the Phase IIa multi-dose portion of INLIGHT. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across 2 dose levels, 240 milligrams and 400 milligrams and 2 study populations with and without type 2 diabetes for a total of 4 cohorts of 40 patients each.

Assessments in this multi-dose portion are like those in the single-dose portion with additional inclusion of body composition measured by MRI, liver fat content as measured by MRI-PDFF, HbA1c, lipid levels and other measures. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in MASH, type 2 diabetes and cardiometabolic diseases. Participants will be given 2 doses of 007, one at day 1 and at day 85 and followed for 12 months with the first key assessments occurring at day 85. We believe that 007's orthogonal mechanism, ability to drive fat reductions while preserving muscle and favorable safety profile are also aptly suited to combination and maintenance approaches.

Our preclinical data provides compelling support for both use cases. We've observed approximately twofold greater weight loss as an add-on to incretin versus incretin alone in obese mice and have demonstrated the ability to curtail weight regain following cessation of incretin. Planning is well underway for clinical studies addressing incretin combination and post- incretin maintenance and remain on track to initiate this year. We also expect to share additional data from the Phase I portion of INLIGHT this year, including data from our 600-milligram cohort, which will further inform the durability of 007.

Turning to our ongoing RestorAATion-2 clinical trial of WVE-006 for AATD. AATD is a uniquely compelling disease for RNA editing. It is a monogenic disorder caused by a single well-characterized genetic variant in the SERPINA1 gene. This leads to misfolded Z-AAT protein and an absence of healthy circulating M-AAT protein, which normally protects the lung during inflammation or infectious events. Without dynamic production of functional AAT protein, individuals with alpha-1 are at risk for lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections and shortness of breath. In parallel, misfolded Z-AAT accumulates in hepatocytes and causes progressive liver injury and increased risk of liver disease.

Approximately 200,000 individuals in the U.S. and Europe live with homozygous PiZZ-AATD. Currently, the only approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there's no restoration of dynamic response, leaving individuals with alpha-1 at risk if AAT protein levels fall too low during an infectious or inflammatory event. IV therapy is time-consuming and often requires inpatient visits and does nothing to lower Z-AAT to address the risk of liver disease.

Investigational therapies in development also come with several limitations. DNA-based editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk and rely on LNP delivery, which is associated with liver enzyme elevations. The risk of irreversible off-target effects is particularly notable as genomic DNA editing has been connected to editing in cancer-associated genes. Also in development are AAT siRNA approaches, which reduce Z-AAT. However, they do not restore M-AAT, potentially exacerbating lung disease through chronic AAT knockdown. 006 has the potential to be the first treatment for AATD that enables individuals with alpha-1 to produce protective AAT protein when needed most and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapy.

With 006, our goal is to recapitulate an MZ-like phenotype as it's well established that heterozygous individuals have low risk of both lung and liver disease. MZ individuals compared to ZZs have reduced levels of Z-AAT, which protects the liver from damage and are able to protect the lung with basal AAT levels above 11 micromolar, of which at least 50% is wild-type and AAT.

And most importantly, are able to mount a dynamic AAT response during an acute infection. That combination, Z-AAT reduction, protective basal levels with a meaningful proportion of wild-type M-AAT and a preserved acute phase response is the bar we set for 006. As we shared in May, this is exactly the profile we've consistently achieved. WVE-006 delivered a compelling therapeutic profile following only 3 months of treatment across both 200-milligram biweekly and 400-milligram monthly dosing.

Importantly, 006 RNA editing -- the 006 RNA editing approach produces only wild-type canonical MAAT and does not include bystander edited isoforms as seen with DNA editing. This specificity is crucial as bystander edits not only introduce functional activity risk, but may also render patients ineligible for future base editing or RNA editing therapies. Enrollment and dosing are now complete in the 200-milligram, 400-milligram and 600-milligram cohorts of RestorAATion-2, and we remain on track to share data from the 600-milligram monthly dosing cohort in the second half of this year, which will help inform an optimal dose regimen.

With the compelling profile of 006 we've observed to date, we're continuing to engage with the AATD community, key opinion leaders and advance our discussions with regulators. We're excited to announce today that the FDA granted our request for a meeting, which is planned for the end of this summer. During this, we intend to discuss a potential accelerated approval pathway for 006 in AATD. Feedback from this meeting will help inform our potential registration study design and our plans to efficiently advance 006 for ZZ individuals with alpha-1 who are in urgent need of new treatment options.

Building on our success with 006, we are advancing our second RNA editing clinical candidate, WVE-008 for homozygous PNPLA3 I148M liver disease. Similar to 006 and 007, our approach to 008 is deeply grounded in genetics. The PNPLA3 variant is a well-established driver of MASH and liver diseases more generally, yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3, I148M carriers across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers.

Currently, the only treatment options are nonprecision medicines aimed at reducing liver steatosis and early fibrosis with limited efficacy for these IL-48M carriers. Silencing PNPLA3 can only partially address disease biology. It's likely to leave residual pathology since it knocks down all PNPLA3 protein without restoring healthy wild-type protein, which has important physiologic functions in the liver. As a result, silencing partially addresses steatosis, but inflammation and fibrosis remain unaddressed or worse. Recent clinical trials of PNPLA3 silencing support this notion as dose-dependent increases in liver enzymes were observed. By contrast, with 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reversing steatosis and fibrosis and improving liver health.

In May, we shared preclinical data supporting our approach at EASL, the European Association for the Study of the Liver Congress. We demonstrated that our PNPLA3 AIMers delivered substantial editing of the I148M transcript, exceeding the 50% threshold expected to lower risk for liver disease, achieved concentrations in the liver expected to support substantial editing and decreased lipid droplet density more than siRNA. In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I148M carriers and accelerate enrollment. We will evaluate target engagement with circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026. With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the second quarter of 2026 was $2.3 million compared to $8.7 million in the prior year quarter and relates to our ongoing collaboration agreement with GSK. Research and development expenses were $51.3 million in the second quarter of 2026 as compared to $43.5 million in the same period in 2025. The increase particularly reflects -- primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT and continued progress on our RNA editing pipeline.

Our G&A expenses were $24.8 million for the second quarter of 2026 as compared to $18 million for the prior year quarter. The increase primarily reflects costs associated with supporting our expanding pipeline and preparing for the next stages of development. As a result, our net loss was $69.4 million for the second quarter of 2026 as compared to a net loss of $50.5 million in the prior year quarter. We ended the second quarter with $490.6 million in cash, cash equivalents and marketable securities, which we expect to be sufficient to fund operations into Q3 2028. While we expect to receive milestone payments from GSK in the second half of 2026, it's important to note the potential future milestones and other payments to us under our collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. As we look to the second half of 2026, we believe we are well positioned to unlock value across our pipeline. With 007, our Phase IIa trial in individuals with obesity is underway, and we are rapidly working to advance incretin combination and post- incretin maintenance studies later this year. With 006, we are on track to meet with regulators on a pathway to accelerated approval. And we are also working to bring our second RNA editing candidate into clinical development for PNPLA3 liver disease in the second half of this year. Before turning to questions, I want to thank our team for the progress we've made and for their continued commitment to reimagining what's possible for patients. I'll now turn the call over to the operator. Operator?

[Operator Instructions] We'll take our first question from Yun Zhong with Wedbush.

So the question is on the 007 program for obesity. And I wanted to confirm that for the ongoing Phase IIa portion, the goal is to confirm that you are able to achieve 5% weight loss as compared to placebo at 12 months to support the advancement for this program into the indication of obesity. And then on combination therapy, I believe other programs have reported or will report data. And given the same mechanism of action, what would be your expectation on data from your own program? Do you think you will potentially be able to show any differentiation? Thank you.

I'll start with the second question, then we'll work backwards to the first question because I think the answer to the second question is, we do believe that I think it's valuable to see what others have been generating in that space, not just for the potential for increasing fat loss. And remember, these other data sets that people have seen in combination were in Phase IIa, high BMI, high visceral fat, high total fat patient populations. And that we're able to see, as you point out, substantial reductions in both fat, visceral fat in particular, and liver fat, we should remind that the liver fat was pretty substantial. I think given that in comparison, both on preclinical ED50, where we're about threefold more potent and in our preclinical data where we've seen increased potency, I think we would expect to see those data as affirming and that we would continue to expect to see with greater, more durable knockdown, potentially better data. So I think it's great to see that the field sees that in the combination setting.

I think we're also excited about maintenance because I think where we've generated data there and where the human genetics outlie, I think maintenance is an incredibly interesting opportunity for us in differentiation. Getting back to your first question, which I think is critical for people to hear, the Phase IIa is designed, as you point out, to be able to elicit that regulatory and cross that regulatory threshold of 5%.

I think as we've been pretty consistent with looking at other studies like BELIEVE trial of bimagrumab, where there was less fat loss in this healthy population than we saw out there. Actually, those that medicine had a greater lean mass gain than what we have. If we think about that equation and put our medicine into this population, we would expect to see no different, we should see weight loss. I mean, bimagrumab had greater than 5% weight loss in that treatment setting.

I think it's also important to point out that the Phase IIa design is more consequential than just looking and hitting that target. Remember, we built into the study intentionally by looking at diabetics and nondiabetics adding MRI-PDFF, the opportunity to expand this more broadly in cardiometabolic disease beyond just the obesity threshold in terms of looking at the treatment of MASH, where, again, we look at the comparators in this population, that ability to see substantial liver fat reduction is consequential in the field of MASH. And so we want to see that data. We'd want to see the data on hemoglobin A1c. And we also want to see the data on lipid. So I think in the totality of this is a cardiometabolic drug, including obesity. I think this study is designed and poised to unlock that opportunity.

We'll take our next question from Samantha Semenkow with Citi.

This is Ben on for Sam. I guess maybe following up on the first question. In the Phase IIa INLIGHT trial, what metrics are you focused on? And what magnitude of improvement do you need to see to support specific expansion into MASH or type 2 diabetes or the other cardiometabolic diseases?

Thank you. And I'll let Chris talk about the endpoints that we're looking at and then can affirm. Chris, can you talk about, the what we're evaluating.

Sure, sure. So we're looking at MRI-PDFF, so looking at liver fat in the Phase IIa study. And so I know that there are other compounds in the same mechanism in the same area that have shown substantial decreases in liver fat that really are highly competitive with what's out there in the MASH space. And then we'll also be looking at hemoglobin A1c. We are looking at both nondiabetics and diabetics, and that's a measure that can change over a relatively short time frame and can be utilized as a registration endpoint. So we're excited to see what types of benefits you would have there.

And then lastly, we'll be looking at a number of different lipid profiles to understand if there's a potential there as well for -- to move forward into a lipid registration type study since there's very tight connections between lipid levels and cardiovascular outcomes.

Just to add on, I mean, that in connection additionally with the other measurements. So being able to look at both depth and MRI, which will give us that opportunity to assess visceral fat volume and total fat. That's important because if we -- I know a lot of people want to always step back and kind of put these data sets of our Phase I up against other Phase II, III data sets and create tables.

And I appreciate the need for folks to do that. I think what is important is to remember in that low fat, low BMI, low visceral fat population that even when we do compare that against comparator studies where people said, oh, your visceral fat reductions look relatively similar. Our visceral fat compartment was a liter versus 5 liters, almost 5x as much visceral fat where we're seeing that reduction. So the ability that we've seen in this Phase I otherwise healthy population is highly encouraging. And so we do want to be able to -- for that comparator work, have MRI imaging to be able to set the comparators up where we have a high-resolution imaging system to be able to do that.

In addition, we'll look at other measurements like grip strength and others and be able to look at muscle retention because I do think when we do step back and think about this therapy in the context from a particular payer perspective and a patient perspective, yes, we want the cardiometabolic health benefits associated with that disease. But this muscle retention, as Erik pointed out, is critically important. I think we oftentimes think about muscle strength. We can be able to assess that, but muscle is also a metabolic organ. And so the ability to look at that ability to retain and sustain muscle in the setting of that fat reduction are endpoints we'll look at as well, like weight circumference and total body weight. So again, there's a number of endpoints that we'll be assessing as part of the study broadly that encompass both obesity and cardiometabolic indications in totality.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

This is Nick on for Steve. We just wanted to clarify in the FDA meeting end of summer. Have you already received some feedback on an accelerated approval pathway and subsequently requested a meeting to discuss? Or do you not yet have any feedback yet on a proposed accelerated pathway and this meeting in the end of summer will constitute the first feedback from the FDA?

Thank you for the question. This would be the first meeting with the FDA. So when we submitted for the meeting, they granted that, and this is when it's scheduled. So we would expect after that meeting to provide an update after we have written feedback. So we do appreciate the clarifying question that this is the first request for meeting. And we're excited that instead of a written response, the FDA granted a face-to-face discussion on an accelerated approval pathway.

Our next question comes from Joe Schwartz with Leerink Partners.

I was wondering if you could give us some more insight into how enrollment is progressing in the higher BMI Phase IIa cohorts for 007 and what you're seeing in terms of screen failure rates and baseline characteristics? And when investors should expect the first meaningful data from these cohorts?

Yes. So we're currently making really great progress on enrollment. We're in the process of opening additional sites. And once we have everything up and running well, we'll be able to comment more on kind of the timing. But so far, it's been -- there's been really great interest in the study, and it's enrolling extremely well.

Yes. Just I mean, echo Chris' sentiment like momentum coming off the last data set high, both ex U.S. but also importantly on this study, U.S. So as we think about this study having actually the expansion for -- expand the number of sites and accelerate it. Also to Chris' point, remember, this study has 3-month time points and other assessments. We'll continue to look at the rate of enrollment to guide. While the potential is there for 2026, we have to see how we're progressing in the study ultimately to provide that guidance.

Our next question comes from Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. So maybe just another one on 007. Looking at the human genetic data, INHBE loss of function does demonstrate the improved fat distribution as you've discussed, but not necessarily correlated with BMI as we understand it. So I guess like what gives you confidence that we'll be able to see BMI improvement with monotherapy in the Phase IIa?

Yes. I think the correlation, and it's interesting, and I'll move back and forth with Erik on this one. But I think what's interesting when we go back, there was a poster that we shared and actually, Alnylam has done the work on a large -- I think it was 300 patients is kind of a natural history cohort in nondiabetics. And actually showed Activin E, if we think about the actual ligand itself, actually a strong correlation with BMI, insulin sensitivity and truncal fat. So the data and correlation between the ligand and BMI is well correlated. I think the challenge in trying to -- and I think you bring up a very good point on the assessment and why BMI in itself is not a great indicator of body composition is you could be a body builder and have higher BMI.

So I think the context of really thinking about the addition of comorbidities where you get higher subcutaneous fat, higher visceral fat in addition to that becomes an important criteria and characteristic as we think about improvements in body composition. But I think what's encouraging is, again, even in the setting in the Phase I otherwise healthy patients, we did see substantial reductions in subcutaneous fat, visceral fat 3.3% reduction of waste circumference. And so I do think the ability to see those changes even in the lower BMI setting sets us up for encouraging changes to move to high BMI.

But again, with comorbidity, those patients, when you look at their characteristics and disposition are also high subcu fat, high visceral fat. And obviously, that's mechanistically what we've seen in reduction in the animal models. Erik, I don't know if there's anything or if you want to just add additional comments to that.

Yes. I think you covered most of it, but maybe just to add a few things. So the phenotype in the genetic studies were adjusted for BMI. So just to design when we set that up now 20 years ago, those type of phenotypes look at body composition. We wanted to adjust out like an overall body size. So just by design, it won't be associated with BMI. That's the first thing.

The second thing is that human genetic carriers, they have 50% reduction, and we think we need to get to kind of over 70% based on what we see in our animal data, where we definitely do see total weight loss. And then I guess the last thing is that we already see total body fat reduction with one single dose at the 240-milligram cohort. So we're pretty confident about that now as we're rolling into higher BMI with much more excess fat to use and multiple doses that we will get to the real weight loss as well, just based on the total fat loss that will accumulate in the Phase II.

Our next question comes from Salim Syed with Mizuho.

Paul, maybe just one from us on the DMD side. Can you just provide a little bit more color exactly what caused the shift here to, I guess, now evaluate potential partnerships in advance of filing the NDA for 531? And if you don't get the partnership, is there any scenario here where you still plan to file the NDA?

Thank you. I think we've been clear at the start of this year that we were going to seek a partnership for N531. And I think we remain consistent in discussions on partnering with N531. I think to the point of -- and the last part of the question of would we file absent the partner and advance file in advance of a partnership, I think we're going to continue to evaluate the space. I think what's evolved in this space, particularly with the update that the existing PMO 53 Golodirsen is going to file for potential full approval early in the year, and there'll be regulatory feedback around that, I think, in advance of recognizing that you need to fully enroll or have well underway a confirmatory study in advance wouldn't be prudent at this point in time until we understand that pathway and continue to have the discussions that are ongoing around potential partnerships and collaborations. So I think we've just evaluated all of that relative to where the current funds are invested and that was the decision we made.

Our next question comes from Alec Stranahan with Bank of America.

Maybe one for Paul. Curious if after regaining the rights to 006, whether the pace or the nature of the FDA interactions have changed within AATD. And I guess looking ahead to the meeting this summer, is your expectation kind of in line with endpoints and study size based on recent precedents or any sort of unique aspects of your data set that could warrant say, an even smaller study, for example?

No, thank you for the question. And I think the short answer to your first part of your question is yes. Obviously, by regaining the rights means that we can control the pace of regulatory interactions and with that, could obviously accelerate them. So that's obviously wonderful. I think to the second point, we wouldn't expect differences in terms of biomarker-driven approaches for potential pathway, but I think it's again incumbent upon us and which is why we want to have a face-to-face meeting to get alignment, not just on that biomarker-driven pathway to potential accelerated approval. But as you point out, just because others have requirements in terms of duration of study and numbers of patients, may not be equivalent for us. If we're doing a repeat administration, it may not have to run as long a period of time. And one of the other nature of the conversation that we're interested in is being able to open and explore what the full approval pathway looks like and how we might be able to more efficiently design a study that could have an interim analysis for a biomarker-driven accelerated approval with the potential to sustain those patients on for full approval. So we expedite the time and pathway to get there. So all of this will be the nature of the discussions with the agency, and we're excited to have that.

Our next question comes from Madison El-Saadi with B. Riley.

So what MRI-PDFF liver fat reduction would the team consider a meaningful cross read to MASH? Is this something we would benchmark against Rezdiffra, which I think was around a 30% relevant reduction? Or is there a population difference we should be aware of? And then maybe if you could just touch on your fall Investor Day, this is something that's really anchored by 006 regulatory update, obesity progress? Or is this really more about the broader earlier-stage platform?

Thanks, Madison. I think at a high level, I mean, look, as you point out, we've already seen from others in the field in a high BMI, high fat setting that they could achieve 44% reduction. So greater than existing therapies and products that are approved in MASH. So I think the potential is out there. I think the signals, I think we're going to look for similar signals and potentially the opportunity for more robust signals that we have a more potent drug, but also the ability to have a therapy to achieve that, which could potentially be, as a reminder, we have still the potential for once a year dosing.

So as we think about the opportunity in the field for once or twice a year dosing to be able to achieve that alongside beyond just the treatment of liver fat, all of the other potential cardiometabolic benefits that come with INHBE silencing, we think there's a tremendous opportunity in it as a differentiated product for the treatment of MASH, but we need to generate that data.

And I think it's important, as Chris outlined, that the current Phase IIa study beyond obesity is designed to elicit these signals so that we can look at the data, evaluate that and evaluate a potential path forward. As it relates to our fall research Day or Investor Day as it's evolved to, that's pretty consistent. I think you all have attended, we've done these now for nearly a decade. And so we try to do that consistent piece of understanding what's coming. I mean, if you think about the history over the last couple of years, it was INHBE introduction and then pass the clinic. Last year PNPLA3 passed the clinic. So I think there's an opportunity to learn about future programs. I think as we talked about, bispecific is an important deal that we're opening up and so the opportunity to continue to see more there.

We'll always guide if that's the best place for where data is coming or where updates are coming. As you also know, historically, if there's a meaningful update, we'll provide that absent having an intent to hold that for. So again, it's always been an opportunity for us to share whether that's data preclinically or clinically, we have that opportunity coming up. And we'll share more on what's going to be that schedule in the very near future.

Our next question comes from Catherine Novack with JonesTrading.

I just wanted to drill down on expectations for monotherapy body weight loss for 007 in patients with type 2 diabetes. We've seen combination data with incretins showing INHBE knockdown might help some size patients to therapy. But what do you exactly expect to see with monotherapy in type 2 diabetes relative to what you've seen in the healthy overweight patients?

Yes. No, thank you for the question because I think early on there were a lot of discussions that I think confounded this field into diabetic, nondiabetics and that, that would be different around thinking about combinations. And I think it's important as we think about how we bifurcated it. And again, as we shared on the prior question, the work that's encouraging is that there doesn't appear to be for INHBE in BMI and insulin sensitivity and truncal fat. That observational study that was run was in nondiabetics. So this correlation is not tied to a diabetic subcohort of population. It's the whole population that would be amenable to that.

So when we step back and look at it, we're not going to miss an opportunity. If there's a signal either in one versus the other, we'll have both. The real opportunity we have in bifurcating and studying the diabetic population is because we have hemoglobin A1c, we'll be able to look at what's seen in human genetics and the ability of INHBE or Activin E reduction to actually improve insulin sensitivity and improve hemoglobin A1c levels potentially. So we'll be able to see that signal.

But the study design, as we said, is designed to capture body weight reduction in a total -- in a patient population that has higher BMI, higher subcu fat, higher visceral fat, look for those cardiometabolic improvements more broadly. But again, not tied specifically to a subpopulation. And I think that was kind of a red herring like a year ago that I know spiraled into this being a diabetic subpopulation for effect. But actually, the data in human genetics and in the population studies that have been run don't demonstrate that to be an effect, but we'll have the study elicit that.

Our next question comes from Ben Burnett with Wells Fargo.

I wanted to ask about the 008 program as this is now moving towards the clinic, the PNPLA3 liver disease program. I think you mentioned that a 50% editing, you would expect to see sort of a positive clinical effect. How did you arrive at that threshold? And is that the threshold that you might expect in patients?

Erik, you want to speak to the genetics and the driver?

Yes. Thanks for the question. So this is anchored on the human genetics observations where it's known that individuals that are homozygous for this variant, they have a 9x higher risk of dying from liver disease during follow-up versus the heterozygous that are just mildly increased risk. And so the risk reduction, if you go from homozygous state to heterozygous state is more than 80%. So that's kind of what drives this 50%. That's the bar that we want to try to achieve. Getting higher than 50% is also better, but at 50%, we would expect to have the therapeutic effect. So that's kind of at the center of what. And yes.

And then just to follow on to that because I think as we spend more time on this program, I do think it's an exciting one. I think the confounding data too that's coming out on the siRNA silencing of that enzyme is equivalently important, right? So we're talking about now fixing it and repairing it and bringing it up to 50%. I think the human experiments that have shown that decreasing that continually actually leads to potential worsening in liver disease. And we just to think about this not just in the fat accumulation, but in the inflammatory aspect and fibrotic aspect, which is actually this particular enzyme works on both where the fat is located and on that anti-inflammatory antifibrotic effect. And so I think on both sides, the data continues on human genetics, why 50%, but also why silencing it is potentially detrimental.

Next question comes from Cha Cha Yang with Jefferies.

This is Cha Cha on for Roger. Mostly just a question on timing for your Phase II. Can you just let us know what we can expect for your data releases? Are you still going to be doing updates for 3 months, 6 months, 9 months, et cetera? And then just a sense on timing for that.

Thanks. As we've said previously, the study is initiating. Recruitment is going extraordinarily well, all things moving. And so once we have a cadence for when we can expect that we don't have to provide multiple updates on guidance, we'll have a good sense of patients and timing, and we'll provide that updated guidance as soon as we have a sense of the enrollment. Chris, is there anything you want to add to that?

No I think you covered it. We're just bringing on some new sites and just trying to accelerate it as much as possible, and there's a lot of interest. And so once that's kind of at a steady state, we'll be able to provide guidance.

Our next question comes from Danielle Brill with Truist Securities.

This is Alex on for Danielle. Question on AATD. I know it's a little bit early to talking about the potential commercial question. But as we think about the opportunity, any initial market research or anecdotes about physician or patient preference for a mechanism that is not a gene therapy, whether that's hesitation or awareness of off-target permanent editing potential of gene therapeutics. Just curious what your current temperature checks are from patients and clinicians.

Thank you, Alex. And yes, I mean, we're doing our market research and analysis, obviously, in preparation for feedback from the agency on potential pathways to accelerated approval. And they include not just as you outlined, patients and clinicians, but also payers. And I think as we're engaging around this, I think we're seeing a lot of support across all 3 constituencies. To your point, hesitancy on permanent genetic mutations with the potential for editing cancer-associated genes and what that risk factor looks like to be discharged over time, the risk that maybe you might not be able to get -- be amenable to other editing therapies if you were to come on, not to mention, as you point out, the potential safety risk. So as we're seeing that, we're seeing a lot of support for RNA medicines and not dissimilar to other therapeutic spaces like TTR, where people are seeing if you can get through a redosable durable. So pushing potential monthly dosing or less frequent, that ability to see that play out with correction, we're seeing a lot of support for that.

And as we think about the payer conversations, I think the idea that you need like over a decade of safe durability to breakeven on an RNA medicine, we're seeing a lot of support on that side. So again, as we're testing the constituencies, we're continuing to see a lot of support for RNA medicine approach to ATP.

Our next question comes from Ananda Ghosh with H.C. Wainwright & Co.

Continuing on the diabetic question, historically, the impact of incretins on the body weight in T2D patients has been always lower compared to pure obese patients. So given the differentiated MOA of incretins, what are your thoughts? Like what do you think the 007 might have an impact on in the diabetic patients differentially? And then I have 2 follow-up questions.

Yes, Erik, I'll let you start, and then I'll join.

Yes. So I think that's a great question. It's actually kind of at the center of why we think it's important to look at diabetics and nondiabetics separately because we know that weight loss mechanisms are different mechanistically. For a mechanism like this that is directly driving weight loss through fat loss, we do think it has a lot of potential for diabetics. But to Paul's point, we also know based on both human genetics and observational studies that this effect is also important in nondiabetics. So that's why we're going to study both in the Phase IIa trial.

I don't have anything to add to that.

Our next question comes from Cassie Yuan with RBC Capital Markets.

Maybe Chris, on your PNPLA3 program, can you just elaborate how RNA editing of I148M variant is expected to be superior to siRNA silencing. But meanwhile, Madrigal recently in-licensed an siRNA. You did mention preclinical data showing [ Amer ] reduced, is it accumulation more effectively than siRNA and given evidence that PNPLA3 silencing may also lead residual pathology in inflammation and fibrosis. So just curious how you would articulate the potential clinical differentiation of 008 to patients and potential partners and how you're thinking about patient enrichment and selection for first-in-human study.

No, thank you. And one, I think there's a lot to unpack there. I think on one hand, as you point out, it is a commonly detected mutation. So when we think about the ability for PNPLA3, it's in consumer genetic tests. So since we had a patient here even just a week ago kind of discussing the disease from one of the liver foundations and she found out to have PNPLA3 liver disease through one of her consumer genetic tests like that and her kind of starting to diagnosis, she knew she had liver disease, was getting evaluated.

And I think the drive to actually drive genetic testing there is increasing. So I think that's encouraging. And there's work that we're doing, obviously, in preparation for the clinic about enriching and identifying these patients in advance. So again, work that can be done that Chris and the development team are doing to enhance the enrollment and speed with which we can generate human data sets.

I think to your point, the growing body of evidence, both in preclinical and clinical data on silencing versus editing is continuing to accumulate. We shared at the last -- our Investor Day last year where we provided some of the preclinical data, yes, we see that there's a shift in terms of silencing where we can do SI, so we can knock it out if we wanted to. Editing was much more efficient in terms of driving not just that reduction, but also improvements in other inflammatory biomarkers. I think more we can end up sharing there as we think ahead.

I think what's encouraging as well as we think about this distinction is recent presentations at EASL on siRNA therapies that did show dose-dependent worsening in the liver disease. So I think the clinical data is continuing to accumulate on what happens if you knock out that important enzyme and the data is continuing to obviously amass preclinically and with us going into the clinic in June 1, we'll demonstrate human data, the ability to show that by restoring the function of this enzyme as the human genetics suggest we should be able to make efficiently not just the treatment for what happens with fat, but the reason that enzyme may be at the center of so many different liver diseases beyond just MASH is a function of its impact on this reactive oxygen system, kind of this pro-inflammatory system. And it's been seen time and time again that if you can increase this, you can improve the fibrotic side.

I don't know, Erik, if there's anything to add on the preclinical data and Chris, on the Erik, if there's anything to add on the preclinical.

No, I think you were very comprehensive. The bottom line is that you want to restore it to a function. It has an important wild-type function. So if you knock it out, you can exacerbate some aspects of the disease, and that's really where we -- by using an RNA editing approach, we're restoring it back to normal.

Our last question comes from Mara Goldstein with Clear Street.

I know it's late in the call, but I'm just curious if you can provide some color as you're thinking about sort of the cardiometabolic signals that you're looking for, for 007 in the trial, sort of how do you weigh that and -- or rank order what you'd be looking at and what the threshold might be?

Thank you. I'll step back from rank ordering. I think they're all important as we think about cardiometabolic diseases. They're all different, right? As we have elucidated like the ability, and I think this all stems as Erik shared during the remarks earlier, visceral fat drives -- we think about what's so important ultimately in this disease process is visceral fat as you go 5% to 10%, that difference, that increase in visceral fat, just 5% to 10% drives a whole bunch of different cardiometabolic output.

So this ability to see that substantial reduction in the output of that becomes important as we think improvement, as we said, we've already seen 14% reduction, 15% reduction in visceral fat. So we're consequentially changing that now in an otherwise healthy population. And again, being able to evaluate that in the IIa population is interesting for us, right, because it's going to allow us to look at each of these markers, what happens with hemoglobin A1c as a function, not just in stratifying patients, diabetic not, but really the impact on hemoglobin A1c, which by itself is a marker for registration in type 2 diabetes. What's happening with lipid levels and improvement in lipid levels as seen in the human genetics, but also potentially for insulin sensitivity as we think about HDL triglyceride ratios.

And then the ability to look at that in its compendium of obviously, fat loss and weight loss and obesity in more general. So I think -- and MASH with liver fat. So I think we're looking at all of these independently and in their global association with each other in the context of obesity and cardiometabolic disease. I don't know, Chris or Erik, if there's anything to add to that.

No, I would just say we'll look at the data and see where we're best differentiated and where we can move forward the fastest. And you can think about MASH, for example, where you can get an accelerated approval, that could be attractive if we're seeing strong effects on lipids there in the liver. So that's sort of how we're looking at it, just following the data and taking the best things forward into the most accelerated path we can to get this approved, yes.

Erik, anything to add?

No, I think you covered it. I think they're all -- I guess the only thing I would add is that it all comes back to the mechanism as in driving fat loss and decreasing visceral fat and that mechanism is really linked to all of these outcomes. So there are a lot of opportunities here.

Thank you. There are no further questions at this time. I'll now hand the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We appreciate your continued support. Have a great day.

This concludes today's call. Thank you, everyone, for joining. You may now disconnect.

Welcome.

Thanks, Rob.

Welcome to the inaugural session of the 47th Annual Goldman Sachs Healthcare Research Conference. Pleased to be joined by Wave Life Sciences, and Paul.

So first, Paul, for those in audience and listening, who may be less familiar with Wave today specifically, what do you think is the most important thing for investors to understand about the company and where it stands today?

Well, thanks for having us. And it's a great time to be connecting as we kind of hit the midpoint of 2026. We're kind of at, what I would call, a strategic inflection point on operating against what we set out as a strategy as we began 2026, which is: one, we see our platform chemistry translating into potentially meaningful therapies, starting with WVE-007 for Inhibin E coming off of our initial clinical data seeing again in the siRNA space, our chemistry uniquely translate to a meaningful improvement in body composition in a Phase I healthy volunteer study and excited for the updates as we transition to the Phase IIa high BMI study, which should be starting shortly, so we'll spend more time, I'm sure, talking about that, but that's obviously a very critical component in our evolution.

Second is the growth of our RNA editing platform, which is exciting, led by alpha-1 antitrypsin deficiency and the work we have there. And this summer being a key inflection as we engage with regulators and a potential pathway to accelerated approval, being able to differentiate that program in the RNA editing field from other therapies for alpha-1 antitrypsin deficiency and critically unlocking the platform capability for RNA editing, where we'll have WVE-008, the first RNA editing program for PNPLA3, so a disease of 9 million patients, that will come into the clinic as we end this year.

So again, lots of progress across siRNA, RNA editing. And we're excited to continue to do the work on the platform, and we're well resourced to execute on those clinical trials.

That's great. We'll get into individual programs here in a sec, but maybe before doing so, investors often debate the value of a platform in breadth versus depth. You obviously have a few different RNA modalities. How do you think about the benefit of having RNAi or any editing, splicing and emerging by functional modalities all under one roof?

Yes. I think when we step back and say -- I think there's lots of different ways to define platform companies, right? You can become a platform company off of biology. When you build a platform company off of chemistry, the main value there is to really demonstrate that, that capability is translatable. And so when we think about building an RNA medicines company, the goal and the premise has always been how do you unlock the power of emerging clinical genetics, right? How can you find? Because I do think, for our field and our industry, the biggest challenge is how do you find high-value, high-impact targets to make medicines for patients. The value of a chemistry platform is how do you unlock those genetics so that when those interesting, compelling, high-impact, high-value targets become accessible that you can be poised to translate those innovations. So case in point, Inhibin E going after a validated genetic target in the UK Biobank for obesity and cardiometabolic disease is intriguing on the RNAi side and we'll talk about our differentiation on chemistry where we're seeing that not just translate preclinically, but now in the clinic given our unique and proprietary chemistry.

Equally important, as we think about alpha-1 antitrypsin deficiency, PNPLA3-driven mutations for disease and liver, these are all opportunities not on the silencing side, but where actually -- and we'll talk about PNPLA3 specifically given some of the presentations at EASL that are reaffirming that siRNA is not the approach to take down the mutation, but correction is to be poised to have a platform that can correct an enzyme, lets us jump on that opportunity for those 9 million patients and have a potential therapy.

So I think the key on the platform is really how do you drive differentiation. I'll step back and say, when we talk about Inhibin E, I think the uniqueness of, again, the work that the team has done in that is special, and we'll see that later R&D Day this year as we talk more about, to your point, this bifunctional capability, which is how do we interplay these modalities of either dual silencing targets or silencing and upregulation editing in one molecule.

That's great. Maybe now turning to 007, before getting into study design data, can you talk more broadly about biological rationale of Inhibin E as a target in cardiometabolic, and maybe also what you've learned about it over the course of the last little bit?

Yes. I mean, one of the very important points as we said is, we like targets where there is human clinical validation for those entrants so that when we're working on a program that there is clinical support that if you interrogate that target with a medicine that you have a higher probability of that medicine translating in the clinic for patients. Inhibin E is a wonderful example of that. It's kind of like the PCSK9 for obesity in the sense that the UK Biobank data set has shown that there is very good translation of this target. People walking around with a 50% loss of function of this target have low abdominal visceral obesity. They have more lean mass. They have lower lipid levels, so lower triglyceride levels, higher HDL levels. And most importantly, the human outcome study has been run. They have a low risk of cardiovascular disease and a lower risk of type 2 diabetes.

So if we think about the totality of the evidence that says this is an important medicine for cardiometabolic disease, including obesity, the clinical genetics tell us that. I think stepping back and saying the translation from human clinical genetics to a medicine often entails the pathway of not having to be born with it, which is a great maintenance study, but ultimately, how do you create a therapeutic. And so this was our opportunity to really start to say, can we answer a fundamental question on our platform capability, opening up an opportunity unique to Wave, meaning can we take advantage of a target that the body has just a little bit of more biology of the target is a target that's the ligand is produced in the liver and hepatocytes and uniquely targets a receptor on adipocytes, ALK-7, and we can talk more because there's always a lot of conversations around ALK-7, but the unique mechanism is actually the ligand communicating with that receptor. So the target is the ligand.

What it does is it actually kind of puts the brake on lipolysis. So evolution was always about fat storage when calories were not plenty, and so therefore, the desire was how do you build and store fat. When you take the breakoff lipolysis, you see that breaking down, oftentimes starting with highly vascularized fat like visceral fat and then proceeding into the subcutaneous compartment, and we'll talk more about the ability of this in both subcutaneous and visceral fat.

So the key when you're developing a therapy is always will this translate? Can we uniquely translate this? And so far, we've been unique in the sense that our chemistry has translated to the only single dose reduction in body weight in the I/O animal model so we could give a single injection of drug. We could see weight loss comparable to the GLP-1s all driven off of fat, so preserving lean mass. And I think that's important as we talk, not just about the importance of muscle as a stabilizer, a functional component of muscle, but muscle is an insulin sensitizing organ. So as we talk about cardiometabolics, this idea of fat reduction, lean mass preservation then ultimately translate into healthier outcomes.

So we demonstrated that in the mouse model monotherapy can show monotherapy reduction in fat leading to weight loss. We did a combination study, and we know with the evolution, and we'll talk more about that clinically, but the idea that you could get even more weight loss when you combine these with GLP-1s with that weight loss coming off of just fat. So it gives you the opportunity to think about how do you preserve muscle sparing in the context of incretins.

And the last, which we think is a very compelling opportunity that we've demonstrated preclinically is maintenance. And as I said, that's also the compelling opportunity that's been seen in the UK Biobank clinical genetics, which is that if you knock the target out prior to cessation of incretins, you prevent rebound weight gain even in the setting of higher caloric consumption. So this idea that if you want to transition from incretins onto a muscle preservation, but not lose or drive that weight regain, and remember, that weight regain that patients experience where the body weight comes back usually 2 or above where they started is driven off of fat. So these patients, from a health standpoint, actually accrete more fat after they stop than they had at the beginning of the study.

So the ability to think about this is a therapy where you can give a once to twice a year injection that sustains patients. And I think when we think about these 3 use cases, it's a prime opportunity that we've been able to see that chemistry platform that you were referring to uniquely translate to Wave in seeing that. And we've seen these data both in the preclinical studies now translate to humans, where a single dose in a Phase I healthy volunteer study we could recapitulate that biology with a substantial reduction of visceral fat, about 15%, reduction in subcutaneous fat, about over 5.4%, and most importantly, a reduction in waist circumference of 3.3%, which is tightening of belt loop. When we think about that in the healthy setting, which is a very different setting than people historically look at obesity studies, that data was, in our minds, very compelling in the translation of moving into obesity studies that look like other larger obesity studies.

Makes sense. Maybe on -- you mentioned a little bit about this, but the unique chemistry platform that you have, this is a target that many others, including some of the largest names in RNA, have tried and frankly, haven't even been able to get a molecule into the clinic let alone continue through clinical development. Maybe just briefly in terms of what allowed you to bring something potentially very compelling to the clinic.

Absolutely. I mean getting back to that concept of platform chemistry, and it's -- we appreciate the question because oftentimes, as portfolios mature, we spend more time saying, what's unique about the clinical data and driving the clinical opportunities in it, forgetting that probably one of the most fundamental criteria of Wave is an oligonucleotide chemistry company. And I would say Inhibin E is giving us the opportunity to truly say that we have the potential of best-in-class in siRNA in this category is Wave's unique chemistry, meaning with the phosphoryl guanidine and our stereochemistry and control, the ability that -- and we published this paper probably about 3.5 years ago in NAR, we were able to compare it to, as you pointed out, some of the best oligonucleotides that are translating in the clinic and do head-to-head comparisons where we could see improvements in potency and improvements in durability.

I think at the time where we were generating that work in the target space, a lot of the targets we're kind of exploring of what more would you gain? You could gain more in terms of decreasing dosing frequency. And those are all -- I'm not discounting that, those are important and interesting. But it was really when we saw Inhibin E where we said, here's a target that is under pressure, to your point, is eluding others because it needs that suppression. This would be a wonderful target actually to translate those chemistry innovations into strong differentiation in the clinic. And so this is a target that needs to be suppressed.

And so again, to your point, the ability to suppress that target didn't just translate into preclinical animal obese models, but translated well even in the healthy volunteer studies and recapitulating that fat reduction, lean muscle sparing and durability to the point where, again, in this space, it's competitive now where we can have a once to twice a year subcutaneous injection that can drive really meaningful improvements in body composition.

Yes. Makes sense. Maybe on the data you've generated to date, obviously, reduction in lean mass, stabilization, there's a lot of focus on overall body weight. Like how do you interpret the data that you've had today, and maybe a little bit more detail than you've given as well as what do you think it means moving forward for the molecule?

Yes, I think when we step back and really say, what does it mean? What does it mean in obesity treatment? I think we are seeing an evolution. We actually just came to this conference from our time at ADA. And I think in the meetings there and in the settings before it, I think there's a real fundamental shift in how we talk about therapies for obesity. So we have had this compelling discussion about what does healthy weight loss mean? It means improving body composition. It means sustaining lean muscle mass, which does weigh more than fat, and shifting the narrative to pounds on a scale to what does improvement in body composition look like overall in terms of improving human health.

And so when we think about that, and I'm often reminded -- many people have heard this, but I just think it's the right way to visualize this. One of the key opinion leaders in this space, I'll give her credit, Angela Fitch, she has a very great analogy in her clinics where patients who come in, they may weigh 250 or more pounds and they come in and they say, I want to lose weight. I want to be 170 pounds. She is like, why? What is it about? And I think it's because, for a long time, that's the only way we had to measure what's happening to our bodies, right? You stand on a scale and you watch the weights on pounds go down. And remember, those pounds are often driven by lean muscle mass loss. And we saw that when we analyzed the BELIEVE data on the incretin comparator arm, in 3 months, 50% of that reduction was lean mass loss. So that's the tool people have to see that.

And so when these patients come in and say, I want to be 170 and she'll hold up a picture of Michael Phelps and say, if I told you, you're going to be over 200 pounds, but this is what you were going to look like, would you want that? They go yes. And I think it really changes the narrative visually of what people are really looking for and how important that lean muscle mass preservation is ultimately to human health.

So we moved the conversation past pounds on a scale driven off of weight loss and really reframed the discussion to what does healthy weight loss look like? It is substantial. It means you need to lose substantial amounts of fat to drive that body composition. And I think -- hands down, I think the tools for that are getting better and more distributed. I mean we're seeing scales now that people have in their homes that cost as much as body weight scales that actually enable people to measure their body composition. And it will be really interesting in the evolution of some of the incretins as people watch on that scale and see not the weight go down, but the lean mass changes that correspond to that, I think it will allow us to kind of reframe and refocus the narrative on what's important, which is fat reduction.

So to your point, coming into that framing, recognizing that the clinical trial that we delivered first was healthy volunteers. So I think it is important we oftentimes use BMI, and coming out of ADA, I can say BMI is uniformly viewed as not an ideal way to be talking about this space because you can be a bodybuilder with a high BMI or you could be obese with -- an unhealthy with high BMI. And so it is important to think about not just high BMI, but our study excluded patients with comorbidities. And it's the comorbidities that drive increase in fat, visceral fat and subcu fat. And that is what you ultimately want to see.

So in the Phase I, even in these healthy patients, we saw substantial reductions in visceral fat, 15%, just to put that in context because I think we always talk about numbers. An increase in 5% to 7% in visceral fat drives a number of diseases. So we can talk about cardiovascular disease risk, risk of diabetes. And as you kind of cross up to that like near 10%, you're talking about MASH. And so if we think about that change and seeing a 15% reduction in visceral fat in a healthy population, that is a really consequential shift for human health.

We also saw, and I think it's important when we get beyond what drives health outcomes is the reduction in subcutaneous fat and recognizing that, that's what drives change in body weight. That's the larger compartment. We saw a shift in declining subcutaneous fat by 5.4%, and again, in these patients who did not have a substantial amount of fat to lose. And that translated -- I always say, what does that translate to as we think about what's meaningful to patients is that 3.3% reduction in waist circumference, meaning this was translating.

Additionally and very important in the obesity therapeutics landscape is, this came with a safety profile that was extraordinarily clean. So for these medicines, the only AEs were mild irritations at the injection site in some patients without dose dependency. So again, the important piece is safe and driving these meaningful changes in body composition. And again, reinforcing for us, I mean, the lowest dose, 7.5 months after that injection, we were still suppressing Activin E. So the notion that you've got durability and then frequency, safety, but most importantly, those improvement in body composition in this Phase I population, I think is incredible as we kind of make that transition to the Phase II high BMI patients with comorbidities, with and without diabetes, where the setting is more fat and will look more similar to other trials that have been run in this space, and I think we're poised there to see meaningful differentiation.

Yes. Maybe along those lines, and as you're going into that patient population, any expectations for what you're going to further learn about the program in terms of dose optimization, et cetera., as well as kind of key differences in overall study design versus your Phase I?

Yes. So I mean first is very different in terms of Phase I. So this shift is a shift in the population. So this will be high BMI patients with comorbidities with and without diabetes. And as we model what that delivers and with all the waist circumference parameters that other studies have, that sets up the population where we would expect substantially increased levels of visceral fat and substantially a level -- increased levels of subcutaneous fat. And we've put it in baseline characteristics with other obesity trials. This study does have MRI and MRI-PDFF, and we'll talk shortly about liver fat reduction. But by having MRI in the study does give us a way to ascertain a baseline, whether or not we're meeting the body composition similarity. So again, the study will be poised to deliver that change.

I think with and without diabetes is equally important. So what do we want to see in this study, we'll have 2 different doses that we'll be looking at, the 240 and the 400. So that will let us have the ability to discern how do we optimize that infrequency of administration in those settings. We'll be able to explore that on the PK side. But on the PD side, one of the opportunities we have, so if we think about endpoints in this study, beyond just obesity and weight loss. So we're obviously going to measure body weight reduction, body composition by DEXA and MRI, but we're going to have other endpoints in this study with which we can evaluate other opportunities given that obesity is a metabolic disease, but what are the other cardiometabolic diseases that are approached with this mechanism.

So one, the reduction in fat, which we've seen from others who have developed their assets. We still think we have a threefold improvement in ED50, but it was highly encouraging to see in this setting post a number of about a 44% reduction in liver fat. I mean, that's substantial compared to other MASH drugs. So the ability to have that opportunity in the study to discern our own data set and what we can see is compelling as an end point. Two, hemoglobin A1c. So again, looking at the diabetic patients, let us evaluate what the impact would be on other biomarkers. Hemoglobin A1c is an endpoint that doesn't require an outcome study in diabetes. So we'll have that. And we'll also be able to look at lipid levels, which, again, the human genetics shows those improvements. So we'll be able to discern those endpoints in addition to things like insulin sensitivity looking at HDL triglyceride ratio.

So I think in totality, this monotherapy study is really poised to unlock the potential for Inhibin E in obesity and other cardiometabolic diseases as a single agent, realizing that there's 30 million patients in the U.S. who are at risk of lean mass loss that need an approach to body composition improvement and fat loss and is uniquely poised to do that.

I think the settings that will start beyond this, so there's 3 trials that will start on the heels of that, so this study will initiate this quarter, next study will be the combination study. So this will give us the opportunity to really look at directly with an incretin, and it's safe to say, given that others have looked at the combination with tirzepatide that, that would be a fair way to view this combination study. And the ability there is really not to drive weight maxing at the risk of lean mass, but ultimately, how do these 2 features intertwine. So the ability potentially is something like the low clinical dose of tirzepatide to see that you can maximize fat loss without having to push the incretin from a tolerability perspective and a lean mass loss perspective. And if we think about the idea that 70% of patients are intolerable to their incretin beyond a year, how do we think about these as keeping patients on meaningful medicines and maximizing body composition improvements.

The third opportunity, which we're excited about is maintenance, and that's recapitulating exactly what we did in the animal model and showing that we could dose Inhibin E prior to cessation of the incretin and be able to have a way to sustain that weight reduction that patients have achieved, but do so without continuing the incretin to suppress lean mass, again, tolerability and have, I think, a unique way to drive adherence, which is we speak to. Payers is something that everybody is focused on is the investment to get to a certain body composition, and what's the risk to staying there? We know patients, they're investing financially and trying to stay there. And so the ability to work with patients on maintenance to be able to have an off-ramp to incretins is pretty exciting.

Great. Maybe just briefly, you talked liver fat reduction, obviously, looking at in T2D, but potential outside of just obesity [indiscernible] of broader cardiometabolic opportunities?

[indiscernible] broader metabolic opportunities, in particular, as you mentioned, diabetes, MASH, what was formerly called PCOS and going through evolution, there's lots of ways to think about metabolically driven diseases that are driven off of importantly, visceral fat. And so the opportunity where we have a potent reduction of visceral fat drives a whole host of cardiometabolic inflammatory diseases. And so again, a unique approach where we're doing that, where the biomarkers are part of the study. And I can't emphasize that enough that when one runs studies in obesity, people kind of have in their mind the classic body composition, DEXA and weight. And I think the ability that we haven't missed the opportunity as part of the study to embed these other biomarkers and tools of measurement are going to give us that opportunity to unlock that potential as part of the study that's initiating. So that will continue to generate data over time in a number of indications that we can unlock.

Great. Turning to 006, several different approaches for AATD. I guess, maybe briefly before getting the data and what you've seen to date, why do you think RNA editing is a compelling approach here? And maybe also briefly on your RNA editing platform?

Yes. So I mean, RNA editing in general, we think, is an interesting platform. It's compelling in that we don't have to work at the DNA level with permanent mutation. So the ability to have a way to either correct a transcript or upregulate a transcript opens up the potential to explore a number of therapeutic opportunities. AATD is the unique one in the context of correction, meaning you've got a single mutation on the transcript that if you can correct you can restore the production meaningfully of healthy wild-type protein. Focusing on the ZZ patients, which is where we do, these patients make no N proteins. So it gives you [indiscernible] to evaluate how your medicine works, whether it's [indiscernible] one. And first and foremost is reducing the Z protein, right? These patients may have 2 copies of Z protein, and that's what's produced. That protein gets stuck in the liver, it's also secreted, but it's the toxic folding of that protein, which damages the liver, and therefore, by reducing that toxic protein, you ultimately enable liver repair.

And I say this because as we talk about editing versus other approaches, protein replacement therapy, we have to remember that alpha-1 antitrypsin patients are both lung and liver patients. So these patients have both higher risk of liver disease as well as lung disease. When we think about lung disease, and we'll talk about this shortly, it is a chronic disease of acute exacerbation. So what happens are, we all have kind of steady-state levels because it's an acute reactive protein that sit in the background. What really happens when we're exposed to an irritant is that UC or pneumonia, cold, kidney stone, that the body increases IL-6 and CRP, that's the acute inflammatory response. That increases the transcripts that produce the protein, the protein then gets produced to protect damage from occurring. And it's that chronic damage that happens over those acute exacerbations that injures tissues.

So the approach that editing has actually is to recapitulate changing these patients. So if we think about patients on the spectrum of ZZ to SC to MZ to healthy MM, as these patients have less Z and the ability to produce more M, they are protected in their various tissues. So that's exactly what we saw preclinically, and that's exactly what we saw in the clinic is that as we treated with 006, we saw, and it was actually really beautiful when you think about the curves that all patients were responding and you could look at an individualized patient level and actually see that their Z protein substantially reduced and they end up producing more M protein. And we expect that, as the liver continues to get better, those can continue to increase to higher levels.

What's nice is we can recapitulate getting to that MZ like phenotype, meaning reduction of Z, production of M, and importantly, having that acute phase response. So for example, we did see that when patients had an acute phase response, they could produce total protein levels greater than 20 micromolar. And so this idea that you could generate that protection when you need it is really the fundamental aspect of what editing is supposed to do, do that safely in a way that you could redose it. And as we know from clinicians and patients, reverse it, that if you stop the medicine, you haven't permanently altered the DNA of those patients.

I think it's important because sitting on the other side, as you asked the question on replacement, there is the replacement concept, which is really focused on just the lung. So that's infusing a protein in the background setting [ still ] of a ZZ patients to try to be there to protect that tissue. The challenge there is, these patients, when they have those events, it's consumptive proteins. So that protein goes away. So I guess the best way to think about these 2 as we do in either end of the pendulum is one is depleting the protein during the event, the other is producing the protein into the event, which we think is a core advantage of editing in general. And it's nice to see other editors also demonstrating those same features and phenomena. So I think that's a core component of editing.

We think about DNA editing versus RNA editing, again, I do emphasize that the idea in liver patients to not have to use LNPs that can be pro-inflammatory in liver is an advantage. And we saw that as clinicians reporting patients with more advanced liver disease, F1s, F2s on the studies as the study progressed is important. And as I said, not being able to off-target edit. That's not about bystander editing. There's a whole concept still around creating the M protein versus bystander M protein, which is kind of thinking about that as an on-target, off-target, but then there's also the risk of permanent off-target editing that's irreversible, and that's a very real risk. And so as we think about this balance having a reversible approach in RNA editing, we think, is highly compelling.

Great. Over the course of RestorAATion-1 and 2, what have you learned about PK/PD profile of the molecule and how it informs kind of go-forward plan here?

Yes. I think as we know and said in the last trial, the 200 biweekly was looking at that dosing versus 400 monthly. And so it did give us the potential for, as we said, monthly dosing in this. I think what we'll continue to look for is whether or not there are opportunities on that dosing regimen. And if you look at the curves at the end of these studies, we do see duration. So as it's loaded on to cells and as we're continuing to see that activity, the potential for less frequent administration or other dosing regimens is in the evaluation. I think the key for us right now is staying focused on this potential for monthly dosing and whether or not -- where that sits in, generate those data and continue to evaluate it.

Great. You mentioned 008 earlier. What initially drew you to PNPLA3 as a target? And why do you think RNA editing is the right approach here?

Yes. So PNPLA3 mutation, this is -- as we said, we like targets that have validation. So it's got very strong genetics on the mutation of this enzyme drives an increase of disease. There's also very good genetic epidemiology data that shows that if you can correct it back to 50%, you improve the survival of some of these patients, so their risk of volatile liver disease goes down. So very strong genetics in shifting these patients from the homozygous state to the heterozygous state.

The question is, and there's been a number of RNAi approaches, we demonstrated this work. We shared it in an R&D Day in the past that if you take this enzyme away, you can actually increase the risk of disease in these patients, meaning you could see increases in potential for liver fat, you could see increases in inflammatory response that aren't addressed, and that's really the ability of correcting the enzymes so they can do its' function, expel fat, improve the inflammatory response.

So when we did our own comparisons between these 2, and I think we're pretty good at making siRNAs given what we did with Inhibin E, we could really do that kind of cross comparison and modality to say, well, what's the right modality to treat this? I think recently and coming off of EASL very shortly ago, I think what we're continuing to see is that the siRNAs are doing that. They are actually, as they're dose-dependent, potentially worsening of the disease. So really shifting and reaffirming, frankly, from the human clinical data on the RNAi front, that correction is the right way to pursue this. And so we're excited to bring that data from our preclinical data that shows that potential now to the clinic where we can address this. And it is a very consequential size. And it's all for liver disease, while we're starting and looking at things like MASH and others are doing that, there's a whole variety of diseases that these patients are exposed to. And oftentimes, it goes undiagnosed in the context that these patients go on to have liver diseases for other consequences, whether it's alcoholic cirrhosis and hepatitis to other liver diseases from infection that they just have an exacerbated response. And this is an identifiable mutation, it's in 23andMe. So this is not an exotic mutation to look for and evaluate.

Great. Maybe in our final minute, what do you think is the most underappreciated aspect of Wave today?

Yes. I think when we go back, within each of these diseases we're talking about, there is that desire to see the next step. So I think what's underappreciated is how important body composition is ultimately to the obesity landscape, and we're -- how we believe we're best poised to address that with Inhibin E both with our existing human data, again, remembering that the underappreciated fact is that was a Phase I study and delivered results that very meaningfully should translate into the Phase IIa, and we're going to do that.

We're resourced to deliver that IIa study and the subsequent combo and maintenance. Additionally, AATD is an asset. We'll deliver those data and then with the upcoming regulatory discussions for that pathway and continue with PNPLA3 to unlock a very broad indication in the editing space. So I think collectively, we're resourced to deliver a portfolio that's translating across platforms, across mechanisms to deliver high-impact, high-value diseases.

Great. Well, that concludes our time today. Thank you, Paul. Thank you for coming. Great to have you.

Thank you very much. We appreciate it. Thanks.

Hello, and welcome to the Wave Life Sciences RestorAATion-2 Clinical Data Update Conference Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. This afternoon, we issued a press release announcing a positive update from our ongoing RestorAation-2 trial of WVE-006 in alpha-1 antitrypsin deficiency. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2025. We undertake no obligation to update or revise any forward-looking statements for any reason.

Joining me today in Orlando is Dr. Paul Bolno, President and Chief Executive Officer, who will begin with opening remarks. Next, Dr. Kyle Hogarth, Professor of Medicine and Director of the Alpha-1 Clinical Research Center, University of Chicago will provide an overview of the current AATD landscape and unmet need for PIDV individuals. Dr. Chris Wright, Chief Medical Officer, will then present the RestorAATion-2 clinical data update before turning the call back over to Paul for closing remarks. Dr. Erik Ingelsson, Chief Scientific Officer, is also here with us today and will be available to answer questions.

I'd now like to turn the call over to Paul.

Thanks, Kate. Good afternoon, and thank you for joining us for an update on RestorAATion-2, our clinical program for WVE-006, the first GalNAc-conjugated subcutaneously delivered RNA editing oligonucleotide for AATD. We're excited to be speaking to you from the ATS conference, where there is a significant appreciation for the limited treatment options available for the hundreds of thousands of individuals living with TIZZ-AATD.

Through our engagement with the Alpha-1 community, we have heard many accounts of the challenges of living with AATD. One individual described it as a full-time, full body and full life disorder. Every set of stairs, every fragrance candle store, every emptying a vacuum bag is uncomfortable and potentially dangerous. Our discussions with KOLs and advocacy groups have also shed light on their work to improve detection of AATD liver disease, which can ultimately lead to cirrhosis in these patients.

Our work at Wave is to help these individuals breathe easier and reclaim their lives. There is a clear and urgent need for new therapies, which address both the liver and lung manifestations of AATD and restore dynamic AAT production with a convenient and safe regimen, recognizing these patients have underlying liver disease.

Earlier today, data from our RestorAATion-2 clinical trials were highlighted for the first time in a major medical meeting, and there is broad enthusiasm for the transformational potential of our RNA editing approach. By correcting the mutant transcript in the liver, 006 aims to address the root cause of both the lung and liver manifestations of the disease. RNA editing with 006 enables the production of endogenous native wild-type MAAC protein, which reaches the lung and protects against the protease damage that drives lung disease.

Importantly, with RNA editing, we avoid creating bystander edits, meaning unintended base edits in the target SERPINA-1 transcript that creates a nonnative protein and avoid permanent off-target edits like indels, which could silence the protein altogether or has potentially other severe consequences. Publicly available data on DNA editing approaches also confirms that these off-target edits risk changes that include cancer-associated genes.

Designed using our proprietary PRISM chemistry, which drives potency, specificity, stability, distribution and delivery, 006 has the potential to be the first treatment for AATD that enables patients to produce protective AAT protein when needed and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapeutic.

With 006, our goal is to recapitulate an MZ-like phenotype as it's well established that heterozygous PIMZ individuals has significantly lower risk of both lung and liver disease. And the individuals have reduced levels of Z-AAT, which protects the liver from damage and are able to protect the lung with basal AAT levels above 11 micromolar, of which at least 50% is wild-type M-AAT and most importantly, are able to mount a dynamic AAT response during an acute infection. That combination Z-AAT reduction, protective basal levels with a meaningful proportion of wild-type M-AAT and a preserved acute phase response is the bar we set for 006.

We are pleased to share today this is exactly the profile we consistently achieved. With only 3 months of treatment, 006 continues to deliver a compelling therapeutic profile, achieving all of our key treatment goals with both 200 milligrams biweekly and 400 milligrams monthly dosing. Z-AAT, the misfolded protein that drives liver pathology was reduced by approximately 70% with 200 milligrams biweekly dosing and 400 milligrams monthly dosing.

Total levels of AAT reached 11.9 micromolar with biweekly dosing and 13.6 micromolar with monthly dosing, both above the 11 micromolar bar that has historically defined the proceptive level. Wild-type M-AAT reached 64% of total protein with biweekly dosing and 59% with monthly dosing, which recapitulates the M-AAT proportion seen in MZ heterozygous. This wild-type M-AAT is all canonical M-AAT and does not include bystander edited isoforms as seen with DNA editing. And we continue to see MZ-like dynamic AAT production with now 3 acute phase responses observed and a strong correlation supporting that AAT rose dynamically with CRP even in minor elevations throughout the study.

006 continues to be generally safe and well tolerated with no liver toxicities. Durability of editing remains impressive and supports the potential for monthly self-administered subcutaneous dosing. As Chris will elaborate on later, we are on track for regulatory feedback on an accelerated approval pathway for 006 in mid-2026.

Now to speak more to the unmet need and treatment gaps remaining for individuals living with AATD, I would like to introduce Dr. Kyle Hogarth. Dr. Hogarth is a Professor of Medicine in the section of Pulmonary Critical Care Medicine at the University of Chicago. He is the Director of Bronchoscopy and is heavily involved in the field of advanced bronchoscopy and interventional pulmonology. He also runs the Alpha-1 antitrypsin deficiency Clinical Resource Center, one of the largest in the Midwest with over 250 patients and helps write the 2016 Alpha-1 antitrypsin deficiency clinical practice guidelines.

Without further ado, I'll turn the call to Dr. Hogarth.

Thanks so much. I really appreciate this opportunity and bring everyone kind of up to speed on the broad understanding of what this disease is about and why a therapy like this is so interesting. As you know, alpha-1 is part of the SERPINA-1 family and the mutation in this, in particular, the Z mutation, which is our focus, can lead to both liver disease and lung disease, but both like completely different mechanisms.

As the schematic that you are the drawings that you see on your slides, the healthy phenotype of M, you make plenty of alpha-1 protein. It leaves the liver with no difficulty. And the little scale picture on the side shows you make way more alpha than we need. It's actually the second most common protein the liver makes, implying its importance. And that's all to counter the amount of inflammation that goes on in the lungs from just your daily breathing.

Now the ZZ phenotype leads to a misfolded protein that polymerizes and accumulates within the liver. And over time, that puts patients at risk for both fibrosis and cirrhosis. And it's unclear as to specifically which double Zs will develop this. So it represents a profound unmet need because we have at the moment, 0 therapeutics for alpha-1-related double Z genes in the liver and a lifelong fear of these patients for what level of liver disease they're going to develop.

But because of that mutation and the accumulation in the liver, there's a reduction of the amount of alpha circulating and then you get flipped the scale, you get this balancing act problem of not nearly enough protection and then way too much destructive forces going on within the lung from the inflammation. And that manifests then as damage to all different parts of the lung, including the airways where you'll get more asthma COPD predominant phenotype, but then also, of course, emphysema with the direct parenchymal destruction.

So when we look, of course, there's actually about 260 described mutations and counting, but the M and the S and the D are the big players, M is the normal. So hopefully, everyone's double M who's on this call. But the double Zs where our focus are the ones that are obviously of most importance. And as you will note, as you get worsening mutations present, the level of alpha-1 continues to decline. It's a broad range of levels within these proteins or within these mutations. But the double Zs are obviously consistently well below normal, but also importantly, well below the protective threshold of 11 micromolar.

And that even in an acute phase response, the double Zs can never get into the normal level. This actually matters even less because the Z mutation has got a double problem of being less -- having less ability to bind to neutrophil elastase. So the Z protein by itself is a dysfunctional protein on top of being a low level and it further polymerizes in the lung is another additional risk. And when you look across survival curves, we move this little thing off to the side.

I can see the curve better. speaking to the people directly. You'll notice the survivals of MMCs versus MM versus SZs versus MMs and then, of course, you doubleZs. And so looking at these slides, I think it becomes very clear that being a carrier has a beyond mild risk, and that's usually associated only with smoking. So carriers who don't smoke really have little to no increased risk for lung disease as opposed to people that start to accumulate mutations and reduce levels.

And then, of course, looking at our double Zs, double Zs who have a much worse survival probability than our double Ms than normal population. This represents, obviously, from a disease perspective, the unmet need of trying to alter this natural history of this disorder. Now when you look again, there's lots of different ways to slice and dice this data looking at both MZs, SS, SCs and Zs. What I think you'll see on this -- this is obviously a slide with a lot of data -- but when you compare, obviously, everybody to MM and look at the risk for liver disease and the risk for chronic bronchitis and emphysema, and they're called out in the boxes, your MZs are barely above the odds ratio.

The majority of that, again, is related to external factors such as smoking, vaping, et cetera. And then look at your double Zs where everything is shifted to the right in regards to the odds ratio for risk of fibrosis cirrhosis, risk of obstructive lung disease and emphysema. Double Zs have a profound increased risk for the problem -- both these problems developing as opposed to the MZ population, which barely has an increased risk and in some cases, actually crosses over the a no risk.

And so this is all simplicity aside, this is what you remember from high school biology. Carriers are carriers. They're not interesting. It's only people that have 2 mutations that are going to be at increased risk. And of course, we've got both disorders. And by various estimates across the U.S. and Europe, there's about 200,000 people that are CZ, but less than 10%, that's roughly -- it's actually less than 10% are diagnosed and managed.

So there's a profound unmet need on the diagnostic side, some of which is held back because of a perception of inadequate therapeutics related to plasma-derived therapy. That's been one of the biggest holdups when you talk to a lot of physicians about why they don't test. They don't feel like there's a management. There's no way to treat. So why bother? That leads to a problem of people developing lung disease typically at a younger age and on average, having to see 8 different physicians -- or excuse me, 3 different physicians over 8 years.

And then because alphas as our COPD meds have gotten better are living a little bit longer, we are seeing an adult onset of liver disease now roughly at around 60 years, what has traditionally been a disease of children. And so there is an overlap. you look across the Alpha-1 International Registry, lung disease being the predominant phenomenon, but then obviously, liver disease, both in isolation and in the setting of lung disease being present. That is our problem. And it's a profound issue of both unmet need, like I already stated on the liver side with no therapeutics and then on the lung side, very limited treatment options.

And so to put it into context because you're on this call saying, this is just a rare disease, not a rare disease. If you put it into the same rate of, say, that 100,000 double disease that are estimated to be the American numbers, again, that's an underestimate, but we'll stick to it. It's actually more common in both sickle cell and cystic fibrosis diseases that are usually something that people are quite familiar with and have seen.

Now the key difference here is that both of those are extremely clinically obvious. They present in a very specific way, and then you draw the blood to determine that you are clinically correct. Alpha-1 presents is a disease that every lung doctor on earth sees every single day, which is COPD and asthma. So it's been hiding in the noise as part of the problem that it's had. There's been a lot of discussions about making sure people follow the guidelines appropriately and actually work up these lung diseases. This is not a rare disorder. It's just been rarely tested for.

And going back to the core of the Z mutation, these folks actually on one level, make plenty of alpha-1. It's just all stuck in the liver. This is a biopsy of the liver of built up accumulated polymerized gumming up the system, if you will, alpha-1 protein stuck there. And the fibrosis is very common and often asymptomatic and then progresses on from F0 through F3, which is the worst form and you'll see where then you get clinically associated liver disease, both liver function abnormalities as well as a particular damage to the liver. And of course, if there's an additional insult, an inability to recover and continue to manufacture all the other things that the liver also needs to take care of.

And this is, of course, by itself as a double Z regardless of any other external liver insults, whether that's various meds, whether that's alcohol, et cetera. And this obviously impacts quality of life. I don't think it should come as any surprise that having lung disease, I think it was already stated talking to patients who gave you very specific examples. But these are folks who do suffer from obstructive lung disease, asthma, emphysema, chronic bronchitis, bronchiectasis, basically the entire obstructive phenomenon. They get short of breath, they get winded doing exercise.

On the liver disease side, obviously, there is this ongoing damage to the liver and actually an increased risk for hepatocellular carcinoma. There's also a rare manifestation within the skin and also an associated vasculitis. The issue is, is that we, I guess, technically do have a therapy for alpha-1, and it involves for the patient's rest of their life, every week getting a needle put into their vein and having someone else's plasma infused, and that's it. And if you have liver disease, I got nothing for you.

And on the lung side, you just take inhalers and then every week forever, chain to an IV. And that's been the state ofthe-art for a very long time. And why do we do this? Because obviously, when we look at the 60 milligrams per kilogram dosing intravenously, it kept patients above the protective threshold. And this became the standard of care. This became what we treat currently.

There's 4 plasma-derived products currently available in the United States based off of this. That's great. imagine from a patient's perspective, desiring something maybe a little bit better. And of course, the idea of going back to that scale where there's this deficiency of alpha-1, the imbalance where you have a whole lot more destructive forces. The idea, of course, of replacing it makes sense, built the scale back, right? So it's all about not just increasing alpha-1 levels generically, but it's increasing the amount of M protein.

But you'll notice when you look at this little graph, you don't see anything reducing the Z protein, right? The Z protein is still the same levels, and it's still got its own issues of not being able to avidly bind to neutrophil elastase and it's still got its issues of polymerizing. So alpha-1, a huge component of the acute phase response. the bodily response to injury of any kind, whether that's an infection, whether that's a kidney stone, it doesn't matter.

You get multiple elevations across multiple different proteins to essentially think about it as rallying the forces, if you will, if you want to make it very humanized. And obviously, lots of different things go up. But if you track the C-reactive protein is there in the red box, you'll obviously see that goes way up. That is a measure of inflammation. And you'll notice that alpha-1 also shoots up dramatically to help regulate all the inflammation going on because neutrophil elastase is one of the main responses to any amount of damage inside the lung.

And as the name implies, elastin, elastase, the lung is made of elastin, you now have unregulated enzymes quite literally digesting the lung. Through multiple other inflammatory markers. And of course, this is why you have this acute phase response. Now what you'll see right here is that's in a normal person. if I'm an alpha-1 patient who was infused on a Monday and I, Friday afternoon have pneumonia, true pneumonia and have a ridiculous amount of inflammation going on in my lung, I'm depleting the alpha-1 that I got on Monday rapidly. And I have no ability to respond. I only got a meager amount of Z protein as a response. That's not good for our patients. And that's seen right here in this schematic.

Again, when we give IV dosing, the levels go up, they come back down, they go up, they go back down. This is why it's weekly, and we've got lung protection. But now when I have that acute phase problem, I've already gotten rid of it, and I have this gap of time where I don't have any protection. This is also important. I mean, I used the example of the infused Monday and pneumonia on Friday, but alpha-1 is broken down in a one-to-one capacity to take down neutrophil elastase.

So if there's a ton of neutrophil elastase, I said pneumonia, but even an exacerbation is going to increase neutrophil elastase. You're going to have this profound and rapid imbalance. And while the liver is trying to churn out a little bit more Z protein, which again isn't very good at binding and is also going to continue to do potentially more damage to the lung. These people are literally getting kicked while they're down. And the problem is there's a 0 indication to give extra infusions. So this has been our problem.

And again, this represents state-of-the-art, the best we've had historically. So this is, of course, where other options come in. And this is where, of course, the excitement from today's data for people like me who are busy reviewing it and thinking about how we're going to be dealing with our patients, unbelievably excited. Now there's a lot happening across this whole space, as you're aware.

On the lung side, there's a recombinant form of augmentation therapy, less infusions, higher levels, but conceptually the same as what we're already doing. There's a liver-only therapy, except to shut down that Z mutation are going to essentially make our patients a double null. And so yes, you'll help the liver, blood, you're going to leave the lungs completely naked. And then, of course, on the genetic-based side and potentially 2 birds stone here, our ability to modify the RNA and as the data is obviously was presented, ability to do it easily and monthly and subcutaneously.

And then obviously, the potential for DNA-based editing, which has raises both some concerns and excitement all at the same time from a clinician's perspective. But I think this represents, obviously, for us in the alpha-1 world, an exciting time that people are finally interested in our disease. So thanks.

Let me turn it back over to Chris.

Thanks, Dr. Hogarth. We appreciate you joining and sharing your perspectives today and truly grateful for all the work that you do for the alpha-1 community. As a reminder, WVE-006 is a subcutaneously dosed GalNAc-conjugated A toy editing oligonucleotide or AIMer, designed to correct the single G2A mutation in the SERPINA-1 transcript that causes ZZ-AATD. The corrected transcript translates into the healthy wild-type M-AAT protein, the same protein the cell would have produced if the patient did not carry the Z mutation.

Two benefits follow. First, the cell makes less Z-AAT, allowing clearance of the misfolded protein aggregates that drive liver pathology. Second, the cell produces wild-type M-AAT, which is secreted into circulation and reaches the lungs where it performs its physiological role, inhibiting neutrophil elastase and related proteases that could otherwise damage lung tissue. Here, you can see serum AAT levels across the 4 major AATD genotypes. ZZ individuals, the people we hope to treat, produce only mutant Z-AAT and no M-AAT.

Their serum AAT sits below the 11 micromolar threshold and they are at high risk for both lung and liver disease. Notably, levels of misfolded Z-AAT for ZZ individuals are underrepresented by turbidimetry assays, which have lower limits of quantification as high as 6 micromolar. In our RestorAATion-2 trial, we use a highly specific LC-MS assay with lower limits of quantification of 0.03 micromolar. With 006, our goal is to shift these ZZ individuals towards an MZ range with reduced Z-AAT, production of wild-type M-AAT and a dynamic acute phase response.

Heterozygous MZ-AATD individuals have low risk of lung or liver disease and circulating M-AAT levels ranging from 57% to 71% of total with a mean of 64% based on an analysis of natural history study samples measured using the same validated assay as RestorAATion-2. Here, you can see the impact of RNA editing visualized. On the left is the same population we're treating in RestorAation-2, the ZZ genotype, producing exclusively Z-AAT, accumulating Z aggregates in the liver and not mounting a meaningful AAT response in the lung.

On the right is the MZ-like profile we are aiming to achieve with greater than 50% M-AAT as a proportion of total, AAT levels that rise in response to acute inflammatory events and CRP elevations and with the potential for higher serum AAT over time as Z aggregates resolve and hepatocyte health improves. When a ZZ individual, as shown on the left, encounters an inflammatory stimulus, CRP levels rise. However, these individuals have a limited ability to increase circulating AAT levels when it's most needed. The result is that lung damage accumulates during exacerbations, the moments when protection is most critical.

When an MZ individual, as shown on the right, encounters an inflammatory stimulus like a respiratory infection, 2 things happen in concert. CRP rises sharply and in close approximation, circulating AAT protein levels also substantially increase. That coordinated rise is one of the body's natural defense mechanisms, yielding more circulating AAT precisely when neutrophil elastase activity is highest.

One of the best ways to limit exacerbations and the associated damage that drives disease progression would be to enable ZZ individuals to respond like an MZ or healthy individual, increasing circulating protective AAT protein when it's needed most. Even with augmentation therapy, individuals with ZZ-AATD experienced acute exacerbations on an average of 1 or 2 times per year. When this occurs, a rapid increase in AAT is needed to maintain a healthy protease activity balance.

Healthy individuals, including MZ, mount that response within 24 to 72 hours of the stimulus. ZZ individuals on augmentation therapy may not be able to mount this response as they receive exogenous AAT on a fixed schedule. Between doses, levels decline and exacerbations further deplete tissue AAT. The result is that patients on augmentation therapy may be left at risk from the very events that drive lung damage over time. WVEs 006 mechanism allows the dynamic regulation of AAT. Endogenous AAT levels can rise during the acute phase response without the need for additional dosing, restoring the natural protective rhythm that healthy individuals exhibit.

Now turning to the clinical results. RestorAATion-2 is our ongoing Phase I/II trial of WVE-006 in adults with ZZ-AATD. Our restoration program began with healthy volunteers in RestorAATion-1. This was a safety, tolerability and PK dose escalation study that proceeded through single and multiple ascending dose phases, ultimately evaluating up to 3 600-milligram doses of WVE-006 administered every other week. These data informed the starting dose of RestorAATion-2, our open-label dose escalation study of individuals with AATD who have the homozygous ZZ genotype.

In RestorAATion-2, each cohort was designed to enroll 8 participants who began with a single dose of WVE-006 and then continued into a multi-dose cohort. Today's update includes data from both the single and multi-dose portions of the 200-milligram and 400-milligram cohorts, which have completed dosing as well as data from the 600-milligram single-dose cohort. Our 600-milligram multi-dose cohort is ongoing and data is anticipated in the second half of this year.

Baseline characteristics in RestorAATion-2 were similar between cohorts with some minor differences in gender and liver fibrosis levels as reflected by elastography. Participants mostly had no or mild evidence of liver or lung disease as required by protocol with 1 participant having moderate liver disease. All participants were required to be between 18 and 70 have a ZZ genotype and be non-smokers for at least 1 year prior to screening. WVE-006 continues to be generally safe and well tolerated across all dose cohorts. There were no serious adverse events.

All treatment-emergent adverse events were mild to moderate in severity. There were no treatment-related clinically relevant changes in laboratory parameters, including liver function tests and no clinically relevant changes in ECG or vital signs. This absence of treatment-related changes in liver function test is particularly notable as it is a key differentiator from approaches requiring LNPs for delivery.

One participant in the 400-milligram cohort completed the single-dose portion and withdrew prior to the multiple dose phase. This individual experienced a moderate injection site reaction and had a history of multiple allergies. There were no other discontinuations due to TEAEs across the study. Before walking through the biomarker data, it's important to reflect on what we set out to achieve with 006.

As we've discussed today, AATD is a multifaceted disease, impacting both the liver and the lung. An ideal AATD therapy should aim to address both manifestations of the disease, protecting the liver by reducing Z-AAT and protecting the lung by restoring M-AAT and its dynamic production during inflammation. Our results today support that these key program goals were achieved. Starting with the changes in M-AAT and Z-AAT at an individual level, you can see just how rapid and consistent the effects of 006 were across participants with everybody responding to treatment following just a single dose.

On the top, you see substantial increases in M-AAT protein with corresponding decreases in Z-AAT on the bottom of the slide, consistent with the presence of significant RNA editing. We also observed significant increases in neutrophil elastase inhibition or FAAT across all 3 cohorts. Here, we show the substantial mean reductions in Z-AAT across doses and regimens. On the left are mean maximum reductions of serum Z-AAT from baseline across 3 single-dose cohorts. Following a single dose, we achieved dose-dependent Z-AAT reductions of 47% at 200 milligrams, 50% at 400 milligrams and 59% at 600 milligrams.

With repeat dosing, these reductions deepened in the 200-milligram multi-dose cohort where participants received 7 total doses, 1 every other week. Z-AAT reductions reached 71%, up from 47% in the single-dose panel, as shown in the middle. Effects were similar with monthly dosing in the 400-milligram cohort where participants received 4 total monthly doses, Z-AAT reductions reached 68%, up from 50% following a single dose, as shown on the right.

These robust reductions in Z-AAT across dosing regimens are particularly notable as our preclinical data support that Z-AAT reductions of greater than 50% improve liver outcomes, including reductions in Z-protein aggregation in the liver, which is the central driver of ATV liver pathology.

Turning to mean M-AAT. We again see dose-dependent effects across our single-dose cohorts. On the left are mean maximum M-AAT percentages of total protein in the single-dose portion of our trial. Following a single dose, M-AAT as a percentage of total AAT reached 44% at 200 milligrams, 48% at 400 milligrams and 52% in 600 milligrams. In our multi-dose cohorts with just 3 months of treatment, we're delivering M-AAT as a percent of total AAT in the MZ range.

With extended dosing, both our biweekly 200-milligram and monthly 400-milligram delivered similar M-AAT levels that were within the MZ natural history cohort range of 57% to 71% as outlined earlier. Importantly, these are percentages of wild-type healthy M-AAT, which is not included bystander edits.

Looking at the individual responses and M-AAT percent of total on the top and the reduction of Z-AAT from baseline at the bottom, we again see consistent and durable responses. For the 200-milligram cohort, both single dose and biweekly on the left and for the 400-milligram cohort, both single dose and monthly on the right, we see editing sustained out to at least 3 months post dose. M-AAT as a percentage of total remains elevated and Z-AAT reductions persist well into the follow-up phase. This durability supports monthly dosing with data from our 600-milligram multi-dose cohort expected to further inform the dosing regimen.

A long-standing goal in the community has been to ensure individuals living with AATD are protected with sufficient circulating AAT during exacerbations. In September, we showed data demonstrating that we've already achieved these goals with 006 as we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar, just 2 weeks after a single dose. Encouragingly, the magnitude and the 4-week duration of this response are also proportional to the levels anticipated for an MZ individual based on natural history.

Today, we're excited to share a growing body of evidence supporting 006's ability to systemically restore dynamic production of AAT. In addition to the acute phase response we shared in September, we've observed 2 additional acute phase responses, which were driven by mild upper respiratory tract infections. These events once again resulted in dynamic elevations of AAT with proportional increases of 58% and 60% from pre-event. Furthermore, across our entire study, we see that CRP increases are strongly and statistically significantly correlated with AAT increases even in events of smaller magnitudes.

What's particularly important here is what these events represent. Not every inflammatory event escalates to clinical attention, but these events are happening in the background, consuming AAT protein and driving cumulative tissue damage over time. That is why a dynamic endogenous AAT response matters. It protects patients not only during major acute phase responses, but also during the minor inflammatory events that accumulate.

Collectively, our data support 006 as a differentiated potential new medicine for individuals living with AATD. We've observed robust RNA editing with Z-AAT reductions of up to 71% and restoration of M-AAT to an MZ-like range, potentially supporting both liver and lung health benefits with durability favoring a convenient monthly dosing regimen. We have a growing body of evidence supporting that 006 enables the natural inflammatory response with 3 acute phase responses observed and a strong correlation of CRP increases in circulating AAT increases.

Importantly, 006 continues to be safe and well tolerated across all doses with no clinically meaningful liver toxicities observed to date. With the urgent need for better treatment options for patients and the compelling profile we've observed to date with 006, we're excited to advance our discussions with regulators and expect feedback on an accelerated approval pathway for 006 in mid-2026.

We also plan to share data from the 600-milligram monthly cohort in the second half of this year. This will further help inform the optimal dosing regimen. In tandem with our clinical and regulatory progress, we're actively collaborating with global advocacy partners to increase awareness of AATD, shorten the diagnostic journey and incorporate community feedback in study protocols, consent forms and educational materials.

With that, I'll turn it back to Paul for closing remarks. Paul?

Thanks, Chris. With our update today, we are generating a growing body of data, which support 006 as a fundamentally differentiated treatment option for individuals living with PiZZ AATD. With the ability to reduce the midfolded Z-AAT driving liver disease, restore wild-type M-AAT to protect the lungs and enable dynamic AAT response with a favorable safety and convenience, 006 has the potential to offer a differentiated proposition for people living with alpha-1, the physicians who treat them and for the payers to reimburse their care.

AATD remains an area of high unmet need. Currently, only 10% of the 200,000 PiZZ individuals are diagnosed. Standard of care is weekly IV augmentation therapy, which only addresses lung disease and is not reimbursed in many markets outside the United States. And there are no therapies for liver disease. Despite the limitations of augmentation therapy and low diagnosis rates, the global AATD market today is approximately $1.7 billion.

This market is expanding and projected to grow to $5 billion globally by 2031, driven by increasing rates of diagnosis, broader treatment uptake, including earlier intervention and better ex U.S. access as more effective therapies become available. WVE-006 is positioned to be a meaningful driver of [indiscernible] addressing both lung and liver disease with a safe and more convenient administration profile that extends the addressable population.

Against the landscape of approved and investigational therapies for AATD, WVE-006 has the potential to be best-in-class. Approved augmentation protects the lung but requires weekly intravenous infusion does not address liver disease and cannot deliver a dynamic AAT response. Recombinant augmentation and development extends dosing intervals, but operates on the same protein replacement principle. Investigational therapies in development also come with several limitations.

DNA base editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk and rely on LNP delivery, which is associated with liver enzyme elevation. The risk of irreversible off-target effects is particularly notable as DNA editing has been connected to editing in cancer-associated genes. Also in development are AAT siRNA approaches, which reduce Z-AAT.

However, they do not restore M-AAT, potentially exacerbating lung disease through chronic AAT knockdown. 006 has the potential to offer individuals living with PiZZ AATD, a compelling treatment option, which addresses both lung and liver, restores dynamic AAT production, safe and well tolerated and is delivered subcutaneously with infrequent monthly dosing. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health.

Today's results accelerate the already strong momentum of our potentially best-in-class pipeline and strength and differentiation of our platform driven by our lead RNA editing and RNAi programs. Building on our success in RNA editing, we're advancing our next candidate, WVE-008 to the clinic this year, which has the potential to address the 9 million individuals living with PNPLA3 liver disease. In RNAi, we are rapidly advancing multiple studies of WVE-007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases.

This quarter, we expect to initiate our high BMI Phase IIa trial, followed shortly thereafter by trials investigating 007 in combination data. Beyond our lead RNAi and RNA editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or upregulate or edit to treat diseases with a single construct in a single dose. We're also advancing a growing pipeline of new hepatic and extrahepatic candidates.

With the substantial progress we've made, we believe we are well positioned and well capitalized to advance our pipeline of transformational therapies for patients. Before turning the call over to questions, I'd like to take a moment and thank all the individuals participating in our restoration clinical program, the clinicians involved in the study site staff. The Alpha-1 community inspires the work we do every day. And from everyone at Wave, we'd like to express our sincerest gratitude.

With that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] Our first question will come from Samantha Semenkow with Citi.

Congratulations on all the progress. My question is for Dr. Hogarth. I wanted to expand a little bit on perhaps the last slide you shared in your presentation, Dr. Hogarth. I'm wondering how you're thinking about the emerging efficacy and safety profile that we're seeing here today for WVE-006 and comparing that to the emerging data from DNA editing therapies and the recombinant AAT replacement therapies. Just wondering how you're thinking about potentially utilizing these for your patients.

Sam, it's a wonderful question. However, I must say Dr. Hogarth is in the middle of 2 other -- he's actually going to an alpha-1 back and just stepped out. We're trying to see if we can bring him back in for questions. But if not, we're happy to find him. I think he's already gone to the alpha-1 foundation recept but I apologize. But we'll get -- we'll connect him with you.

Your next question will come from Steve Seedhouse with Cantor.

Yes, I'll ask you a question then Paul in that case. So it looks to me like the biweekly dosing does, in fact, make a difference compared to monthly dosing. And my question is, do you agree? Is that what you see in the data? And do you think it's, therefore, worth exploring 600 mg biweekly to maximize efficacy and sort of close the efficacy gap with DNA editing? Or is there sort of a safety tolerability concern with doing that going forward?

Thank you for the question, Steven. So on one hand, the short answer to the last question is no. So if you think about the safety study we ran up through 600, there's no questions. So going up to 600 biweekly, which is what we studied in the Phase I portion of healthy volunteer study. So there's not a question of safety. What's interesting, and again, the 600-milligram monthly cohort will teach us a lot in terms of exposure is, to your point, there's -- on the dosing, we actually had a nice dose response as we gave doses to that kind of initial period of continuing to build and grow and see that shift from Z to M.

We also saw, and I think what you're looking at is a window early where biweekly looked that it was smoothing that line out and then continued. But when you stop and you look at the biweekly, it stays pretty relatively flat for well over a month and beyond after that period. So I think we're going to learn a lot about what happens on the monthly basis, particularly with what levels of exposure and how to balance those.

And I think the 600-milligram monthly data will teach us a lot. I think to the question of what does one need, I think we have to step back and realize 2 weeks after a single dose, we could get 20 micromolar protein. And even in -- as Chris pointed out, the cases now of what we call mild upper respiratory that's a common cold. And what we saw though is we could get up to 16 micromolar. So what we've seen even at these doses is the ability to mount an impressive response to meet the needs of the patient. So I think the question is ultimately going to be what's that optimized dosing regimen. And I think we're in a good position to explore that.

Your next question will come from Samantha Semenkow with Citi.

Apologies for the -- so based on the data, it seems like the 600-milligram single dose is tracking a little bit below what we saw for the 400-milligram single dose. So I'm wondering if you think that's going to be a plateauing effect in that 400 milligram is maybe the go-forward dose? Or do you think in the multi-dose when we see it, there's a possibility we could continue to see a dose-dependent effect ongoing?

Yes. I think the -- actually, it was really nice that we did see a dose-dependent effect. 600 was more in the reduction of Z and more M. So 600 was higher. So we did see a dose response at 600. I think the question ultimately comes down to once you reach a steady state inside the cell, how much more benefit is extracted from that. And I think that, again, as we look at the 600 monthly, where we'll be able to look at the 400 monthly and look at that exposure relationship.

Again, I think it will help us on that dosing regimen. I think as Steve pointed out earlier, 200 is interesting once it reaches a steady state, and it may very well be an interesting dose and frequency. But the last, I think, 600 monthly will be just one last piece in the puzzle in terms of modeling that dosing regimen. But we definitely infrequently is nice. And as we've been wonderful to be here at a conference and spend time with clinicians and as we've tested this thesis, this idea of really shifting these dosing intervals out has been well received.

Your next question will come from Yun Zhong with Wedbush.

And my question is also related to dosing. So while in the study, you only followed patients for 12 weeks. From the PD profile, do you think -- well, in reality, people will probably receive chronic treatment. Do you think more doses will eventually lead to higher editing efficiency and higher AAT -- total AAT protein being produced?

No, thank you. And it's a wonderful question because it's exactly what we saw both in preclinical models. It's well understood. To your point, this is only 3 months of dosing. And so as hepatocytes become healthier, they become more functional. We're actually rescuing hepatocytes and they'll continue to turn over and generate more protein. And with more protein and more editing comes the continued -- that sustained effect. I think that's coupled and importantly driven by, as both Chris and Dr. Hogarth mentioned, a profound reduction in Z protein.

So with the reduction in Z protein very quickly and removing those aggregates, those cells are now -- that toxic insult to hepatocytes is now removed, so these cells can become healthier and those cells turn over. I think that's a valuable component in RNA editing where we think about durability with the ability to continue to get access to these cells as they're turning over so that you can begin to capture them and again, be able to recruit more cells that can get healthier and generate that over time.

Your next question will come from Salim Syed with Mizuho.

Great. Congrats on the data. Paul or Chris, maybe just one for us on the 2 additional patients in the 400-milligram multi-dose cohort that saw an increase in AAT. Could you quantify the 57.8% and 59.8% increase? Could you quantify that in terms of total protein so that I believe you guys said 20.6 for the 200 milligram. Could you give us a similar number for the 2 patients? What was the M-AAT in those patients as well?

Yes. So that was the update that I gave, which is we see about a 16 micromolar increase. So those are the examples that we continue to see that increase in that relative proportion, as we said, of M and Z, is the same.

Your next question will come from Joe Schwartz with Leerink Partners.

Great. I guess I wanted to ask about the 3 dynamic response events. They look very compelling, but still anecdotal. So I was wondering how important is it to make this a labeled feature in your view? And if so, how might you do this? And then the CRP-AAT correlation is pretty strong with an R of 0.73, but I think this means that around half the variance is unexplained. Do you have any thoughts on what's driving the rest of this data?

Yes. break these into 2 parts. They're very much related in terms of the question of like anecdotal and continuing to look at what's happening. So I mean, to your point, I think we were the first to show it last year. I think there were a lot of questions of is it anecdotal. It was robust. It was exactly as we'd expect. I think what was encouraging in the interim is we saw that happen in DNA editing. So an editing approach as we think about protein replacement therapy and editing is driving this adaptive response. That's what's supposed to be happening.

And I think it's encouraging is we engage regulators as well on a path of, are you recapitulating an MZ-like phenotype with that responsiveness. That's a critical component across that because that is the response. Seeing 2 more, again, in the case of these were much more mild. These were cases of cold, and we see the 16 micromolar total. It had the same features to it. So again, the body of evidence is growing from an anecdotal response to it's behaving like it should.

I think to your point on the correlations, that was something we were looking for levels where patients weren't kind of at the level because when patients have a kidney stone, they're coming to their physician for an evaluation of that problem. Being able to look across the study for patients who aren't coming in and having those fluctuations, it's doing exactly essentially what Dr. Hogarth drew for everybody and where we should see that in those responses at a low level, when we see those correlations, it gives us the conviction and confidence that, again, the body is being restored to what it can do in a normal situation.

I mean there's always a degree of some variability to your point on that, which could be just around functional sampling. But I think when we step back and say, is it really achieving the key objective for these patients to mount the responses that they need to, to prevent lung injury. I think the answer is yes. And I think it gives us a lot of conviction going into the upcoming regulatory discussions around...

Your next question will come from Alec Stranahan with Bank of America.

Just a quick one for me. I guess as you're looking to gain regulatory alignment for the pivotal for 006, is your baseline expectation going in a biomarker-driven primary? And I guess, do you think functional AAT or total AAT would be more important here? And then maybe when you're thinking about future studies, given the good tolerability profile today, do you think there's room to go beyond the 600 mg dose, maybe to say, an 800 mg monthly or even bimonthly cohort?

Yes. So yes, I mean, the first question is a biomarker-driven approach principally driven as we think about that transition from M to Z, which is the hallmark of what an MZ phenotype is supposed to be with other biomarkers that will continue to look alongside. And to the last question that came up, the ability to see that relationship between CRP, AATD -- sorry, total AAT and AAT levels as it relates to those acute phase responses.

So again, putting together the picture and the totality of the biomarker data that really recapitulates the MZ phenotype. I think the question you're asking in terms of doses, there's a certain level of exposure that, again, we can get to 20 micromolar, which is like where we talk about with the IV protein replacement therapy trying to have somewhat of a native to protect. And as Dr. Hogarth said, deplete the protein when they have the event at 200 milligrams, 2 weeks post a single dose, we could get to 20 micromolar protein.

So I think we have to step out from the more phenomena that really is exemplifies what IV replacement therapy is supposed to do, right, pouring water into bucket with holes in the bottom and the hope that as you're depleting it, you're going to constantly fill it back up, versus editing where when you have that acute phase response, you mount the response that you need into the event for the period of time. And again, I think it's encouraging that when that's happened in places that we could mark in the study, we've actually seen the body rise to meet those occasions.

So I think that dynamic event is well within the dose cohorts that are already being studied. What we're really going to optimize is a couple of the other questions came up is what the dosing interval could be that we could push that out more conveniently to patients. And if we think about a convenient subcu potentially self-administered therapy for these patients, that's monumental in terms of transforming how we care for them. And if we can do that safely without causing liver injury in patients who are susceptible to liver injury and exposing them to other risks, I think we're putting together, I think, a very important proposition for patients and their caregivers.

Your next question will come from Catherine Novack with Jones.

Just wondering, is it possible for us to back into the mean max M-AAT using the percentages given? Or are the mean max total and the percentage of proportion of M to Z taken at, I guess, multiple different time points. How should we be thinking about that?

It's dynamic. I don't know if you could.

Yes. So because each individual has a sort of different time course, that's why the mean max makes sense in terms of trying to understand kind of the effects of the drug. So you can't really do the bowel calculation, as you mentioned, just because it's not at a specific time point. It's the max value for any individual subject over the course of the treatment duration.

But it's reasonable to think in totality about the percent M over time.

Your next question comes from Madison El-Saadi with BRS.

Congrats on the data. Just wondering, what do you think is new here that is most likely to incrementally influence the FDA on their conclusion on the accelerated regulatory requirements? And then somewhat related to that, is it -- do you think that the required frequency of administration of the drug could actually decrease over time, as you pointed out, as new hepatocytes are generated?

Yes. I think on the last question is, yes, with the caveat that we have to study that. But the data suggests like as we look at where -- that was what was interesting about the 200 biweekly where we stopped and you could see the durability continuing. It does suggest that there's some level of -- as drug gets on board and over time, you've got that exposure. And then to your point, as we get more cells that are healthier, but then are getting dosed that, that could continue to extend that range. And we'll continue to look at that dynamic range.

In terms of the agency and biomarkers, again, I think it's the range of biomarkers that support the MZ phenotype. So again, it will be that transition from showing we can move Z to M at the same levels that MZ patients have. And it will be this dynamic response. I think the dynamic response is so important in this because ultimately, that is the disease, right? It's a chronic disease of acute exacerbations. And so being able to mount those needs when patients have them at the appropriate levels that the patients need are great ways for us again to show that the biomarkers are doing kind of -- are possibly doing what they're supposed to do. And so I think relative to the approval pathway, I think we have the component there, and we're excited to engage.

Your next question will come from Cheng Li with OpCo.

Congrats on the results. So probably just going back to the dosing discussion. I'm just wondering if there's a scenario you can probably do like induction periods where you have slightly more frequent dosing followed by maintenance period where you can have like more extended dosing beyond monthly injection. Is that something like you can potentially consider for the pivotal study? And if I can just squeeze in one commercial question. I'm wondering how you're thinking about like patients already on like augmentation therapy and if you can encourage patients to switch to 006 once approved? And what is required for such like switching for patients?

Yes. No, thank you for the questions. And to the first question, I think the answer is yes. And I think the data suggests that. And as we think about that's something that's been done with other therapies, particularly in the siRNA space for a while to get to exposures. I think stepping back, I think this is where the 600 exposure question is going to get us a lot of learning in terms of those dynamics.

But you're absolutely right that, that opportunity, as we look at the modeling following the 600 monthly will give us opportunities to think about how infrequent. We maybe had to push it out actually substantially longer with a certain level of exposure. So that's going to help inform those dosing regimens. In terms of commercial, we spend a lot of time with that because I think as we think forward, and it was a good portion of a number of our meetings today with the community, physicians and others associated with alpha-1.

I think there's a lot of enthusiasm for thinking about kind of transforming this care from a hospital IV setting, to your point on augmentation to really transferring this back to patients where it could be self-administered and that they could have a subcu versus IV and now really thinking about how do you deploy that to patients with augmentation and Dr. Hogarth being a great example, but several other physicians who we've been working with do see this as a shift where augmentation protects you at that threshold, but we've got this ability to continue to provide that level of protection that's seen with augmentation in a way that's adapted.

And I think what's so critical, and we hear this a lot, we heard it a lot over the course of this meeting, is really the fact that these patients are all underlying liver patients. I mean it's interesting we're talking to the foundation today, and they brought up a really great point that as patients -- as hospitals started to do liver scans both patients who are coming in for pulmonary issues, the underdiagnosis rate of liver disease was astounding, the patients that were just being picked up on fibro scanning.

And so I think as we think about this as both a liver and a lung disease, it comes down and physicians are realizing that just because you infuse the protein, you're not protecting liver. In fact, you're keeping those patients exposing and making toxic Z protein. So the ability really to see physicians gravitate towards the shift in protecting both lung and liver is important. I will say to the prior question, there was a question on biomarkers. And I do think it's important as we do engage with the agency that the specificity of knowing that what we're calculating is truly wild-type M-AAT protein.

We know with others, particularly in the DNA space that the vast majority of protein being made is actually a variant of the native protein. So we think about being able to have those conversations about a wild-type protein and levels of editing that are exquisitely specific, I think that's going to factor in a lot to the discussion as well.

Your next question will come from Ben Burnett with Wells Fargo.

I wanted to ask about the discontinuation case that occurred. I think you mentioned that there was an injection site reaction that led to that discontinuation. Was that the only adverse event that the patient received? And any other color you can provide about that?

That's correct. So the person had the irritation at the injection site. And because they had a lot of allergies, the sense was that it was best for them not to proceed with the multiple injections. But -- so that was sort of the long and short of it. There wasn't really much more going on there.

Your next question will come from Whitney Ijem with Canaccord Genuity.

Sorry if I'm being dense here, but I just want to follow up and make sure I'm thinking about this correctly. I guess as we think about longer-term dosing, I understand that there is a potential for kind of higher total levers over time as the cells turn over. Is there also a potential for higher percent M over time? Or should we be thinking about that as kind of a fixed percentage, but with higher AAT levels? And then second part of that is just, are you continuing to dose the monthly doses for 7 doses to match the 7 doses and the biweekly? And should we expect longer-term updates from those cohorts?

So the next update will be the 600-milligram monthly cohort, and that will be our update. To your point on longer follow-up, it doesn't just clear total -- if you think about it, to your point, it will -- you should continue to see more M. So as you free up cells that can release more M protein and free out dose, you can continue to drive that. I think what's encouraging, and I know the question is so hard because we're in this mindset of augmentation therapy of like can you give out more?

Again, patients met 20 when they needed 20 micromolar total protein. And so I think we have to remember that so long as there's exposure inside the cell and to this point, if we push that frequency out as long, patients will be able to make protein that they need when they need it. And that's really, I think, probably the most important feature of editing in totality. And when we look at the levels that we're seeing, we're seeing levels that are in the MZ range.

So the ability to correct these patients both at their baseline, but also to see them meet those dynamic responses, again, as we go to regulators. So really a combination of the profile that we're excited to take forward.

Your next question comes from Cassie Yuan with RBC CM.

Congrats on the progress. And Paul, you have already nicely pointed out and other analysts have alluded to that going from flat to MAD at each level or going up on single dose escalation, circulating in serum constantly improve, but it's also notable that total AAT does not always increase. So how should we rationalize the biology there? Or is it mostly correlated with individual baseline level of so more of arithmetic experimentation than biological? And related to that, with Sanofi inhibit data update also at the conference is showing every 3-week IV can now get us to steady-state trough functional AAT above 24 micromolar. Does that raise the bar for any player in the editing space?

No, thank you. And I think the last question is, no, I think the challenge on this kind of where -- what is raising the bar is remember, that's the threshold with which patients now get exposed to Dr. Hogarth's important point seeing these patients is that's kind of the threshold where they had an event that they'd be depleting the protein. So again, being able to flip the narrative that actually with editing, and it's really a critical component to editing, you actually increase the exposure into those events.

Again, we could raise the 20 micromolar into the event, which is actually what the patient needed, right? And that could stay out over a month to provide that protective ability and then come back to baseline. And so the dynamic effect is really the underlying component of editing. I think as we think about the ability to do that infrequently, it also have the liver, right? So by pushing out the intervals so now it's, call it, monthly as a number of people have raised the potential for thinking about regimens that could be longer.

You have to remember that, that protein replacement doesn't raise the bar, as we said, not just because it's broken down, but because it's still not protecting the liver. These patients are still exposed and still during those acute events are actually producing Z protein into that event, which is causing further injury to the liver. So the ability really to shift to cascade, to shift, and that's really the driver of editing, to shift Z protein to M protein. That dynamic is the dynamic that you see in MZ is a shift from Z protein to M protein. That's the critical feature. That's what we do. And I think that's why it provides a really competitive differentiation from the protein replacement therapies.

Your next question will come from Michael King with Rex Biomed LLC.

It's Mike from Rodman. I don't know how we got signed in as Rex Biomed, apologies. Pretty much all of my questions -- sorry about that, Paul. I'm not trying to throw a curveball here. Most of my questions about the dosing and pharmacodynamics have been answered. I'm just curious from the animal modeling that you've done, do we know how long it would take to begin to either stabilize or even reverse liver or lung damage. Could you move patients from F3 to F2, could you reverse the lung damage, et cetera, over time?

Yes. I think -- I mean it's been interesting here to spend time with folks who've been looking at various ways of measuring lung injury. It's not easy to do in the animal model, but the levels of exposure and the levels of correction we get to, to the point on creating the MZ phenotype lead on lung. I think what is important to this pharmacodynamic modeling is we are able to look, as Chris alluded to on the call, at what level of Z protein reduction actually starts reversing aggregate damage where you see that reduction in liver aggregates and liver globules.

And in a 50% reduction in Z protein, we started to see that those dynamics shift in our preclinical models. So again, encouraging that we're seeing in excess of 70% reduction in Z. And so that ability both in the production of M, but really importantly for these patients because they're at risk of liver disease, being able to substantially reduce that Z protein should continue to shift that. And the advantage in that is, again, you now start making healthier hepatocytes, you start getting that turnover kinetics now with new hepatocytes that are corrected and aren't kind of saddled with decades of Z protein aggregation, you now get healthier cells that can make more protein.

So it's highly encouraging as we continue to think about this profile over a longer period of time. I think the other thing that was encouraging, too, in the liver baseline characteristics is that physicians were more comfortable putting patients on who were at more advanced stages of liver disease as the study progressed. And I think the notion that people were feeling comfortable versus, again, I think LNP background, patients with liver disease who occupy a substantial component of alpha-1 antitrypsin felt comfortable putting liver patients into the study. And I think it's important as we think about long-term treatment of both liver and lung patients.

Your next question will come from Cha Cha Yang with Jefferies.

This is Cha Cha on for Roger Song. Congrats on your update. I was hoping that you can share more about what we can expect from your FDA feedback update in mid-2026, assuming this is alignment on using AAT as a biomarker, but anything else we should expect there?

I think that's right. We're looking to have some agreement around using the biomarker to move forward. And again, it's not just total, but it's also how much M you have and how much Z you can decrease because you want to impact both liver and lung. And so we're excited to have those discussions with the agency.

Yes. I mean, I guess the key for us is much like others coming out with a very strong plan for what the path looks for the filing so that we could actually start guiding to the subsequent studies, right? I mean the goal for us is to think about this as a commercial program. So the goal is what's that path look like to commercialization, both on an accelerated approval pathway, but importantly, how we think about continuing to make sure that we address both lung and liver on the path forward. So I think this will be the beginning, and we're excited to provide that feedback.

Your next question comes from Alex Nackenoff with Truist Securities.

This is Alex on for Danielle. Congrats on the update. Just a detailed question from us. Can you explain the discrepancy in the reporting of the 400-milligram SAD data? I believe in the last cut, you reported the mean value was 12.8 micromolar. And today, you're indicating it's 14. Does that include additional patients, which drove the mean higher or removing the 400-milligram discontinuation? Just curious if these numbers were calculated differently and how to rectify those.

You've hit it because we've included a fuller data set with more patients for this particular analysis, everything up until the date of the data cut versus before.

So we didn't remove -- last part, we didn't take any -- just to be clear, we didn't take...

Yes, we didn't take any patients out. The one discontinuation completed their entire single ascending dose portion and then stop before the multiple ascending dose. So there was no patients that were removed. Go ahead.

Your next question will come from Michael King with Rex Biomed (sic) [ Rodman & Renshaw Research ].

Just a follow up on the previous question about the FDA interaction. Can you -- and it goes back to my question about the clinical benefit. The accelerated approval could come on the -- potentially on the biomarkers, but is there a clinical endpoint or endpoints that you think you might have to achieve over time to flip that to a full approval? Or do you think the biomarkers could allow for a full approval under the regs?

Yes. I think what's interesting, I mean, obviously, the focus right now is the accelerated approval based on biomarkers. I think the work that's happening around other tools in terms of CT densitometry, being able to do noninvasive imaging of liver, both give us opportunities. And you'd imagine that the discussions continue around those. And what's wonderful is those aren't just Wave having those discussions. So the clinical community, the alpha-1 community is engaged too through CPAP and other channels about really thinking about alternative endpoints that do and demonstrate benefits to long term.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you, everyone, for joining the call. I'm grateful to every employee for their dedication and focus on our mission and on the patients and families we serve. And thank you again to the ATD community for your continued support and partnership. Have a great night.

Hello, and welcome to Wave Life Sciences First Quarter 2026 Earnings Call. [Operator Instructions]. Also, as a reminder, this conference call is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our first quarter 2026 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Eric Ingelsson, Chief Scientific Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. Coming into the year, we outlined our key priorities for 2026, accelerating development of WVE-007, our INHIBNE GalNAc siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD and followed by WVE-008 for PNPLA3 liver disease.

Today, I'm pleased to share an update on the significant progress we've made towards these goals. We are rapidly advancing 007, which has the potential to be transformational in the treatment of cardiometabolic diseases, including obesity. Using our best-in-class chemistry, 007 continues to demonstrate a highly differentiated profile.

Clinical data, even in a Phase I population continues to demonstrate improvement in body composition with fat loss, importantly, visceral fat loss and muscle preservation, impressive durability with potential for once or twice a year dosing and a clean safety profile. We're accelerating 007 to the next stages of development where we have the opportunity to unlock its full potential across multiple treatment settings, beginning with our Phase IIa trial in participants with higher BMI and with and without diabetes.

We are preparing to initiate our Phase IIa trial this quarter as the FDA has recently accepted the multi-dose portion of INLIGHT. Closely following the initiation of our Phase IIa trial in higher BMI participants, we plan to initiate studies evaluating 007 in combination with incretins and maintenance post cessation of incretin treatment.

In RNA editing, we continue to lead the field with 006. Clinical data from our ongoing RestorA-2 trial has already demonstrated the potential for 006 to provide a much-needed novel therapeutic option to individuals living with AATD, including generating over 20 micromolar of AAT protein during an acute phase response. It's important to note that these acute phase responses are the drivers of lung damage in AATD. We look forward to highlighting these data during the ATS conference and hosting an investor webcast to share our monthly 400-milligram multiple dose as well as single-dose 600-milligram data.

Having already achieved therapeutically relevant AAT restoration with our interim data, we are on track to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. We're also building on our success in RNA editing to advance our next candidate, WVE-008 towards the clinic this year, which has the potential to address the 9 million individuals living with PNPLA3 liver disease.

Beyond our lead RNAi and RNA editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or edit to treat diseases with a single construct at a single dose. We're also advancing a growing pipeline of new hepatic and extrahepatic candidates. With the substantial progress we've made, we believe we are well positioned and well capitalized to advance our pipeline of transformational therapies for patients.

Now I'd like to turn the call over to Erik, who will discuss how we are leveraging our proprietary chemistry and human genetic insights to advance WVE-006 for AATD and WVE-007 for obesity. Erik?

Thank you, Paul, and thank you to everyone joining us on the call today. I'll start with WVE-006, our GalNAc-siRNA editing oligonucleotide or AIMer for alpha-1 antitrypsin deficiency. ATD is a uniquely compelling disease for RNA editing. It's a monogenic disorder caused by a single well-characterized genetic variant in the SERPinA1 gene, which leads to misfolded alpha-1 antitrypsin or AAT protein teredZ-AAT. Healthy circulating AAT turned MAAT protects the lungs during inflammatory or infectious events. ATD is sometimes referred to as genetic COPD for a reason.

Without dynamic production of functional AAT, patients are at risk of lung damage and ultimately developing emphysema and bronchiectasis, which is characterized by chronic cough, recurrent infections and shortness of breath. In parallel, Z-AAT accumulates in hepatocytes and causes progressive liver injury and risk of liver disease. By correcting the mutant transcript in the liver, RNA editing addresses the root cause of both the lung and liver manifestations of the disease.

Approximately 200,000 individuals in the U.S. and Europe live with homozygous PICV-AATD. It's a devastating disease, impacting the ability of patients to work, play with their children or even walk to the mailbox. Currently, the only approved treatment for AATD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there is no restoration of dynamic response, leaving patients at risk if AAT protein falls too low during an acute space reaction as a result of infectious or inflammatory events. IV therapy is time consuming and often required in patient visits and IV therapy does nothing to lower AAT to address development of liver disease in these patients.

RNA editing is designed to restore heterozygous emptT-like phenotype, including AAT production that drives to meet the demand during acute space response. This is a particularly important distinction between RNA editing and the current augmentation standard of care that we continue to hear echoed in our conversations with physicians and patients as there is uncertainty that there is adequate lung protection when patients experience infections between infusions. Such acute exacerbations, the sudden worsening of a patient's respiratory symptoms that often require urgent treatment occurs roughly twice per year on average, even on weekly augmentation therapy. 006 is a highly specific and efficient GalNAc AIMer.

Unlike DNA editing therapies in development, RNA editing does not modify DNA and 006 does not require delivery with lipid nanoparticles or LNPs that may be as with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. 006 also avoids reversible collateral bystander edits and inults, which are associated with DNA editing.

With 006, our goal is to recapsulate the emptylike phenotype as it is well established that heterozygous PINC individuals at significantly lower risk of both lung and liver disease. T individuals maintain basal AAT levels above the protective threshold of 11 micromolar, wild-type MAAT above 50% of total AAT and most importantly, they retain the ability to mount a dynamic AAT response during an acute infection. That combination, protected beta levels and meaningful proportion of authentic MAAT and a preserved acute face response is the bar we set for 006 and that we cleared in the interim readout of our RestorAATion-2 trial in the fall.

We demonstrated that 200-milligram biweekly dosing of 006 can restore endogenous MAAT protein to therapeutically meaningful levels and reduce mutant AAT correspond. This will lead to improved liver health and potentially even higher MAAT production over time, in line with what we have observed preclinically and ultimately lead to improved lung and liver outcomes in AAT.

Crucially, we have shown that 006 reestablishes the body's physiological response to inflammatory stress, something that is not possible with IV augmentation. Now with upcoming data from our 400-milligram multi-dose cohort, we look to continue to recapsulate the MC-like phenyat but at a more convenient monthly dosing interval. Moving on to our INHBE GalNAc-siRNA program for obesity WVE-007. Individuals living with obesity face markedly high risk of a range of diseases such as NASH, type 2 diabetes and cardiovascular disease.

Excess body fat, in particular, visceral fat is a key driver behind this elevated risk of disease. Current standard of care therapies reduce body weight through both fat and muscle loss and carry high discontinuation rates, limiting potential for long-term health benefits. An ideal obesity therapy would instead selectively reduce harmful visceral fat, the fat surrounding once organ that is most strongly linked to MASH type 2 diabetes and cardiovascular disease, while also lowering subcutaneous fat and liver steatosis and critically preserving skeletal muscle.

Muscle preservation matters. Why? Because muscle sustains based on metabolic rate, glucose disposal and insulin sensitivity. Also it prevents weight regain, mostly from fat, which occurs in the majority of individuals that discontinue increasing therapies. And remember, as much as up to 70% of individuals discontinue incretin within a year. Preserving muscle while decreasing total and in particular, visceral fat is the ideal profile for an obesity medicine and is well established at already a 5% to 10% reduction in visceral fat mass associated with direct health outcomes by reducing risk of multiple preventable metabolic diseases and preserving patient function and quality of life. All these benefits can be delivered by 007's mechanism of action.

Rather than acting on appetite, it silences in the knee and lower serum actin, a liver-derived hepatokine that signals adocytes put the brakes on lipolysis. Removing those brakes drives fat loss without calorie restriction and without the muscle loss seen with incretin-based therapies. This approach is also strongly grounded in human genetics as carriers of heterozygous in loss of function variants, nature's own knockdown experiments exhibit a healthier overall metabolic profile, driven by lower visceral fat as evidenced by lower waste-to-hip ratio and lower visceral lose volume as well as downstream effects with lower triglycerides, ApoB and HbA1c and higher HDL cholesterol.

These carriers also have favorable associations with liver traits such as ALT, a measure of liver damage and CT1, a measure of liver inflammation and fibrosis and importantly, lower risk of developing type 2 diabetes and coronary heart disease. And as we have said on prior calls, targets supported by human genetics carry a 2 to 4x higher probability of success in drug development. IvenE a textbook example of this opportunity.

We chose to target the activin E ligand through IBE silencing over its receptor ALK 7 for several reasons. Turning off protein production in hepatocytes to upstream source with GalNAc-siRNA is the most efficient and durable way to impact this pathway. Also suppressing activin E rather than disabling a receptor that induces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for long-term safety and for clinical translation. CER-07's unique ability to durably suppress IE is driven by our proprietary chemistry and SNAiRNAign.

While RNAi is a well-established therapeutic modality and there are extensive human genetic data supporting IBE as a target, we believe our proprietary chemistry distinguishes us from others attending a similar approach. 007 is highly differentiated by Wave's proprietary pheno design, including backbone serrochemistry and PN chemistry, which enhances interactions with AVO2, stabilizes the loaded risk complex and improves liver exposure. This contributes to dramatically improved potency and durability when compared with industry standard siRNA science. Our interim Phase I ENLIGHT data sets from lower BMI, otherwise healthy individuals confirm that this proprietary chemistry and the underlying human genetics are already translating with preservation of lean mass and clinically meaningful reductions in total fat, visceral fat and waster complement after just a single dose.

As Chris will discuss further in a moment, we're rapidly advancing 007 into patients with higher BMI and comorbidities in the Phase IIa portion of INLIGHT, where a scientific rationale predicts a larger effect. Activin E binds AP7 on allocytes and visceral fat being the more metabolically active and better pursued mobilizes first, exactly what we have observed in Phase I. Together, this means that we expect both visceral and total fat loss with 007 to be substantially more pronounced in higher BMI participants with more excess fat.

To review our clinical progress with 007 and our RNA editing programs in further detail, I'd now like to turn the call over to Chris.

Thanks, Erik. I'll begin by discussing our recent data and plans to accelerate development of WVE-007. In March, we shared interim data from the Phase I portion of our ongoing in-LI clinical program, placebo-controlled single ascending dose study designed to measure safety, tolerability and PK/PD. Participants were healthy individuals living with overweight or Class I obesity with an average BMI of 32, a population with less fat and lower BMI than those included in Phase II and Phase III obesity studies.

The safety and tolerability profile of WV007 remains encouraging, and we continue to observe robust, highly statically significant dose-dependent and durable active E reductions through at least 7 months. This combination of tolerability and durability supports a convenient dosing interval of once or twice a year that may allow for enhanced patient adherence, more persistent fat loss and better health outcomes.

Having reached 6 months of follow-up in our 240-milligram cohort, we observed further improvements in body composition following a single subcutaneous dose. This included placebo-adjusted visceral fat reductions of 14.3% well above the established threshold to deliver improved cardiovascular outcomes. Total fat reductions were 5.3% and lean mass was stable. There were also improvements across clinical measures, including a clinically meaningful 3.3% reduction in weight circumference. These results are particularly encouraging given this is a Phase I study of otherwise healthy participants with an average BMI of 32 and no dietary or exercise restrictions.

As Erik just spoke to, reducing fat, particularly harmful visceral fat while also preserving muscle is critically important for the treatment of obesity, including overall functional improvement and cardiometabolic health benefits. The current standard of care pushes the limits on high percentage weight reductions, but it comes at a cost of substantial muscle loss.

To provide context for our results at this early development stage, we calculated the visceral fat to muscle ratio or VMR, which is a measure of body composition that integrates harmful visceral fat and beneficial lean mass into a single index. Lower VMR is associated with decreased risk of NASH, type 2 diabetes and cardiometabolic disorders. We believe VMR has the potential to serve as a novel composite biomarker as compared to BMI alone that more holistically captures the body composition improvements driven by INHBE knockdown and that may better predict long-term clinical benefit.

With a single dose of 007 in our Phase I population, we've already observed a 16.5% improvement or greater reduction in BMR which was more than the 12.2% achieved with weekly semaglutide in BELIEVE and approached the 18.8% observed with vimanrimab. What makes this comparison particularly exciting is that our INLIGHT participants had substantially lower BMI, visceral fat and total fat compared to Phase II or Phase III obesity studies. Clinical experience highlights the importance of baseline adiposity.

Early Phase I studies in leaner subjects show modest fat reductions, while studies of individuals with higher baseline obesity demonstrate large clinically meaningful losses in total and visceral fat mass.

Early follow-up from our 400-milligram cohort, which included a substantially higher proportion of individuals with lower levels of visceral fat also confirmed that higher baseline visceral fat leads to greater visceral fat reductions overall.

Collectively, these data emphasize the impact of baseline body composition on therapeutic effect and support the potential to deliver even more pronounced improvements in body composition in the Phase IIa portion of INLIGHT, given participants higher excess fat at baseline and 007's mechanism of targeted lipolysis.

Following the FDA's recent acceptance of our protocol amendment, we remain on track to initiate the Phase IIa multiple dose portion of INLIGHT this quarter. This global placebo-controlled trial will enroll individuals with higher BMIs in the range of 35 to 50 and comorbidities across 2 dose levels, 240 milligrams and 400 milligrams and 2 study populations with and without type 2 diabetes for a total of 4 cohorts of 40 patients each.

Assessments in the multi-dose portion are similar to those in the SAD portion with additional inclusion of body composition measures by MRI, liver fat content measured by MRI-PDFF, HbA1c, lipid levels, CRP and muscle function. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in NASH, type 2 diabetes and cardiovascular disease.

Participants will be given 2 doses of 007 at day 1 and day 85 and followed for 12 months with the first main assessment occurring at day 85. As Paul discussed earlier, we are also planning to initiate trials evaluating 007 in combination with incretins and as maintenance post incretin this year. We believe that 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle and favorable safety profile are actively suited to combination and maintenance approaches.

Our preclinical data provides compelling support for both use cases. Planning is well underway for studies addressing incretin combination and post incretin maintenance, and these will initiate this year. We also expect to share additional data from the Phase I portion of INLIGHT this year, including data from our 600-milligram cohort, which will further inform the durability of 007.

Turning to our ongoing RestorAATion-2 clinical trial of WVE-006 for AATD. We continue to advance this study while engaging with key opinion leaders and patient organizations who are eager to be involved. As we speak to key opinion leaders, there are several aspects of our data that excite them. one, restoring a dynamic AAT response to address acute lung infections; two, decreasing harmful Z protein to address liver disease; and three, offering a safe, well-tolerated infrequent nonintravenous treatment for patients that avoids permanent genetic modifications.

We look forward to presenting an expanded data set during ATS on May 18, which includes data from the 400-milligram monthly cohort as well as the 600-milligram single-dose cohort. Continuing to recapitulate our prior interim results with a less frequent dose would strengthen the overall profile of 006 as a differentiated patient-friendly therapy for AATD. In addition, we plan to share from the 600-milligram multi-dose cohort in the second half of this year.

Now turning to our second RNA editing clinical candidate, WVE-008 for homozygous PNPLA3 I148M liver disease. This PNPLA3 variant is a well-established driver of NASH pathology. Yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3 I148M carriers across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers.

With 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid metabolism, reversing steatosis and fibrosis and improving liver health.

In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I148M carriers, evaluate target engagement with circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026.

With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the first quarter of 2026 was $38.2 million compared to $9.2 million in the prior year quarter. The year-over-year increase primarily relates to recognizing the full amount of revenue associated with WVE-006 as a result of regaining full rights to that program, along with the progression of work in our ongoing GSK collaboration.

Research and development expenses were $47.4 million in the first quarter of 2026 as compared to $40.6 million in the same period of 2025. The increase primarily reflects continued investment in advancing our clinical programs, including preparation for the Phase IIa portion of INLIGHT and continued progress across our RNA editing pipeline. Our G&A expenses were $22.1 million in the first quarter of 2026 as compared to $18.4 million in the prior year quarter. This increase primarily reflects costs associated with supporting our expanding pipeline and preparing for the next stages of development.

As a result, our net loss was $26.1 million for the first quarter of 2026 as compared to a net loss of $46.9 million in the prior year quarter. We ended the first quarter with $544.6 million in cash and cash equivalents, which we expect will be sufficient to fund operations into the third quarter of 2028.

I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. As we look ahead, we believe we are well positioned and well capitalized to continue delivering on our clinical development plans. We are rapidly advancing multiple studies of 007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases. We're delivering new 006 data in May that will continue to inform its potential to provide a differentiated treatment option to individuals living with AATD.

And we are progressing 008 towards the clinic for the 9 million individuals living with liver disease. With our proprietary chemistry translating in the clinic and an emerging pipeline of next-generation candidates, we are committed to translating powerful human genetic insights into potentially transformational RNA medicines for people who need them. We look forward to keeping you updated on our progress.

And with that, I will turn it over to the operator for Q&A. Operator?

[Operator Instructions]. We'll take our first question from Joe Schwartz from Leerink Partners.

Congrats on all the progress. It seems like a treatment approach targeting INHBE biology could be somewhat sensitive to baseline patient characteristics. So I was wondering, how are you thinking about optimizing for that in future trial design? Are there any screening or enrichment strategies you could implement to enhance signal detection?

Yes, Joe, and we appreciate the question. I think first and foremost, in the obesity study, as you point out, is particularly, as Chris mentioned on the study, a mechanism that's driven on hypolysis is excess fat, the requirement to have not just large BMI, but have fat to lose in order to have a reduction in fat, which is typical in most Phase I to Phase II transition. So if we look at the BELIEVE study, we actually haven't updated those who look at the 8-K today on the corporate deck on Slide 24, the realization that as you shift patients from a low BMI, low fat setting to a higher BMI, high fat setting, meaning the shift that you see from where our study started, which is where the BELIEVE patient ended to where the BELIEVE patient started both on semaglutide and bimagrumab.

There's an elevation not just in visceral fat, but on the left panel that slide, an increase in total fat. And so when we see those changes, we do expect, as you said, to see that reduction. Now what can we do to actually assure that as we enroll patients in that study that the patients exhibit the phenotype, meaning in an obese study are not just large in BMI, but large in visceral fat and in total fat.

And I think there, we've seen pretty consistently that if you use other metrics like weight circumference, allowing comorbidities, those patients do tend to fall into that range. One other opportunity we have to assure this as the study is enrolling is we are, as Chris mentioned, doing baseline MRI imaging on these patients as we start. So we will have the opportunity to look at baseline images to ensure that patients are collecting in that region.

We will take our next question from Steve Seedhouse.

I wanted to ask about the regulatory interactions in AATD and just get your thoughts on if the FDA -- or really just the discussions you've had, if the FDA is looking for specific MAAT levels, if that's part of the thinking here or if like the degree of MAAT increase that would support approval or accelerated approval is going to be more of a review issue. And then I'm also curious if you know yet if the primary analysis in a pivotal study here is going to be more of like a responder analysis on a certain threshold or if it's more of like a mean change in MAT or total AAT in the entire population?

Yes. No. Thanks, Steven. I'll start and then turn it over to Chris for further comments. But I think one is, obviously, we don't comment on individual interactions, but we will have feedback as we get to midyear. So it's safe to assume we're preparing and engaging in those conversations. I think in general, it's about the dynamic response, right? So it is this kind of shift from -- and based actually on comments that the FDA has made actually publicly, specifically as it relates to AATD and patient meetings, they did refer to AATD as an ideal example of a plausible mechanism pathway, meaning that there's the opportunity that we can see that editing translates these patients from a ZZ phenotype to an MZ phenotype.

So I think that we -- as we move past this kind of just threshold concept of what does it take to be an MZ patient, well, greater than 11. But we need to step back and remember that actually, the 11 micromolar, as people discuss that threshold level increasing is one of protein replacement therapy, this idea with a consumptive protein that you need to put more in, in order to have that when it gets depleted during an acute event be there. I think the context of not just Wave, but as we've seen B as well, seeing that when you do edit, you see this restoring of this dynamic response and what is the ability of that dynamic response to actually protect patients.

I think those are the best examples of the plausible mechanism meaning if you're at that greater than 11 micromolar and over 50% of that being N protein, then you're in the position that when you have a proportionate CRP or inflammatory response, you can mount that proportionate response in both total protein and in N protein. And that's exactly what we saw. We saw actually, if you model the CRP exposure that we saw, we saw an MZ level response both in total protein exceeding 20 micromolar and over 10 micromolar of protein in that individual. So that dynamic response is what's required being demonstrating the total both on threshold and percent M, we think is important. And those will be the nature of the conversations that we'll be having with the agents. And I'm sorry, the last -- you...

Last, I think responders versus me and the like. I think those are exactly the types of questions that we'll be engaging with the FDA on the pivotal studies. So more on that as we have those discussions.

Yes, it's important to note, remember that these patients are coming in with 0 and protein. So the idea that this is all de novo functional from editing to those responses is crucial. And I think the agency has been receptive...

We'll take our next question from Cheng Li with Opp &Co.

Congrats on the update. I'm just curious about the 007 like future clinical path, recognizing the body composition is an important feature for this mechanism. And also you mentioned several measures, including BMR. I'm just curious about which one you think can be incorporated into the clinical trial to support registration that you think has the best chance.

Yes. I mean I think as Chris mentioned, we're going to have a number of endpoints in this study that independently help us build the cardiometabolic profile. So obviously, we'll have body composition measures anddexXa looking at total fat, visceral fat. We'll have MRI imaging as well. And importantly, MRI-PDFF to look at liver fat. I mean I think that's going to be interesting as these patients would be expected to have increases.

In addition to that, as we think about just why when you have -- and I think about Phase I studies where you exclude comorbidities of why you end up seeing this lower level of total fat, but importantly, visceral fat, visceral fat is harmful fat, and it's responsible for a number of these other cardiometabolic risk factors, including diabetes and cardiovascular disease. So one of the opportunities we have in removing the cardiometabolic -- sorry, the comorbidities in addition to allowing patients with and without diabetes is we're going to have the ability to see what's played out in human genetics with reduction in IHIB-E, which is reductions in hemoglobin A1c.

Well, that's a registrational endpoint in the treatment of diabetes. We'll be able to look at ratios of triglycerides and HDL in terms of insulin sensitivity, and we'll be able to look at other measures like CRP from an inflammatory standpoint. So it really is important as we think about this study as being able to open up, one, how do we think about the treatment of obesity and what's really important, and we are seeing a big shift, particularly in the last quarter on finally discussions about body composition being what target and what should be targeted for these patients with an ability to tie that to an impactful measurement that will be in the appropriate Phase IIa.

And as Chris said, I mean, we'll have a 160-patient study across doses, across disease states that really will let us fully exploit the mechanism and shortly thereafter. So again, accreting the data to where I do think there's a substantial opportunity for INHBE which is in the maintenance setting. This idea that 70% of people can't stay on incretins. And if we think about the therapy for obesity with incretins being like the treatment of hypertension, we're seeing patients who need a lifelong treatment to stay in this range of body composition that they achieve.

I think we're also going to have the opportunity as we think about the Phase II studies that we will be initiating the concept of being able to have and lock in, in a maintenance setting an infrequent way of treating patients and preserving and locking in the benefits from a cardiometabolic outcome position that's been achieved with other weight loss therapies. So I think the totality of data that we'll be generating to unlock the full mechanism of is both in this Phase IIa study in the multi-dose, but also in the subsequent studies that we will be initiating.

We'll take our next question from Samantha Lynn Semenkow with Citi.

Just one for me on AATD. I think your explanation around the dynamic nature of the mechanism makes a lot of sense. I just wonder from a competitive landscape, we're seeing the DNA base editors get up to a mean of about 16 micromolar total in MAT. We've seen at least one patient from another competitor go up to 20. Do you think optically you need to achieve some sort of threshold in order to entice both patients and physicians to use an RNA editing approach? Or have you done any market research around this? Just curious your thoughts there on what the actual profile could end up being and how competitive that would be?

Thank you. And I mean this is where we spent a lot of time with clinicians as again, in preparation as we think about ATS coming. And I think there's a lot of enthusiasm from this community RNA editing. And I say that for a couple of reasons. I mean, one, the idea of being able to -- and we'll talk about kind of the thresholds and numbers in a minute. But I think the most important thing is that if we think about the ability to be able to infrequently redose patients, it's important because over time, the liver does regenerate.

And the idea that as these cells that are on a pathway to dying and becoming fibrotic are actually now rescued and saved because you're able to, through editing, deplete protein, take those toxic aggregates out of the liver, restore liver health, those cells are now right to be able to be dosed and have actually correction and actually become productive in their responses and producing healthy M protein.

And so as we talk to clinicians, that notion of infrequent repeat dosing is actually viewed as actually favorable as opposed to the risks and potential outcomes from permanent DNA mutations. I think the other thing that as we think about patients who have liver disease and ZZ patients, where they are on the spectrum will have liver disease is the notion of not using LNPs. We have to remember that LNPs activate IL-6 and the CRP immune response and in and of themselves are immunogenic.

And if we think about that as being a causing and inducing an acute phase response could also elevate 1 antitrypsin and a protective response to that. And so the notion that in patients with liver disease, we want to avoid things that are going to irritate the liver is also important as we think about the totality of the therapeutic modality that clinicians are thinking about in terms of their treatment of patients. Now while all of that is wonderful, at the same time, what we want to see is the ability to actually drive the correction. And so as we think about the production of protein and what RNA editing is designed to do is entirely specific.

So when we talk about protein and oftentimes, these things get inflated with numbers, when we say M protein numbers or M protein percentage, we are talking about purely the actual isoform of AATD. So this is the native M-AAT protein. And as the prior question suggested, that's something we're discussing as part of our regulatory interactions, which is that we make only the native M-AAT protein. We don't create bystanders. We don't create indels. But importantly, those bystander edited proteins have different ranges of function. So we can be assured that the protein we're creating behaves like the native natural protein.

So as we kind of shift back to the beginning of your question, which is what's going to be important as we think about this, I think where we've also seen clinicians is not being able to make that switch to thinking about. And actually at ATS, it's going to be interesting because it will be wave on presenting on editing and then there will be the updates on protein replacement therapy. It's really this shift from having to say, well, more is more to baseline because that is a protein replacement narrative that's you have to put more protein in because the patient can actually produce more.

And so therefore, it's a race to put more protein in that gets depleted. We'll have the opportunity to continue to say, with editing, you can now create that dynamic response. And as we said, we can create a dynamic response that's proportionate to a CRP response up to 20 when the patient needed 20 and could have easily generated more if the patients needed more.

So I think if we think about the range of both total and protein, we are very much convinced that we can create the baseline levels that serve as the biomarker to demonstrate that these patients are able to go out, live a healthy functional normal life and have the appropriate responses to these acute phase events as they happen. And I think one of the most interesting things when we went back and kind of looked at that initial patient wasn't just the spike the patient had that got up to 20, but it was the realization and every went back to those slides that are there on this dynamic response that over the multi-dose, these patients had small elevations in CRP.

And what was really compelling is every time they had those adjustments, they were generating an increased response to total protein that met that. So I think by restoring this dynamic response, that's ultimately how you prevent the chronic injury that happens for the 1 to 3 times a year that these patients needed.

Our next question comes from Alec Stranahan from Bank of America.

Just a couple of quick ones on the Phase IIa portion of INLIGHT. Could you walk us through how you're thinking about the dose selection given the Phase I portion is still ongoing? And will GLP-1 use be allowed in this population for enrollment? Or is this maybe a population you'll reserve for future studies? And in terms of cadence of data from the Phase IIa, is your plan to share regular interim updates like the Phase I, maybe, say, at the first 3-month assessment following the first dose?

I'll take the last question and then hand it over to Chris. But in terms of the cadence of data at this point, yes, it's possible that we could deliver the initial, as you pointed out, 3-month time point. We'll give a more concrete update on milestone cadence when the study initiates and as that study launch. But yes, there's a possibility of data as we think about this year. Chris, do you want to take the first question?

Sure. So in terms of the doses chosen, so this is really based on -- I mean, it is ongoing, but we clearly have interesting data on 240 as well as 400. And so based on the data that we've seen in terms of the level of knockdown, PK/PD modeling and the degree of efficacy that we saw even at 240, we felt that we could move forward in the multi-dose with the 240 and 400 and that these should be the range of doses that are expected to be efficacious also based on the modeling. So it kind of all falls together, modeling from preclinical. So it all kind of falls together from that perspective, and that's how those 2 initial doses were chosen.

In terms of incretin in this particular study amendment, it's a monotherapy amendment. So we're not allowing incretence. However, we're in the throes of combination study design, which would include incretN and we'll provide more information on that shortly as well.

Just to follow up on the last point. I mean, as Chris mentioned, I mean, we do see substantial reductions in the 2 dose cohorts that we're taking forward with very tight ranges between patients. And so I think a lot of what we're going to learn is not just getting more efficacy from that, but the impact of time, durability and which dose is going to allow for the most less frequent interval while not losing any efficacy signal.

Our next question comes from Yun Zhong with Wedbush.

So the question is on the Phase IIa portion of the obesity study. On the second dose, do you have any expectation on the potential impact on gene and protein expression? And in terms of the clinical outcome, would you expect the benefit to be on durability or the magnitude of fat reduction or both because you're changing the patient baseline characteristics. So I just wonder, will you be able to tell whether that's -- and any potential better outcome will be from repeat dosing or from the more higher BMI or both? Will you be able to tell the difference, please?

Yes.

I can just say our the way that it is designed and what we know about the pharmacokinetics and pharmacodynamics, we expect a very substantial knockdown with the 2 doses that would be very persistent over time. So we think that, that's a great approach to identify the right doses and understand the duration better and to optimize our likelihood of efficacy.

And then to that point, and you also mentioned it, the patient characteristics are different. And so the dose response could also be slightly different in people that have higher levels of obesity or higher BMIs. And so it's important to look at a number of doses in that context as well. But we would expect that we should see stronger results there, as we outlined earlier in the sense that this is a drug that increases fat metabolism. And so the more you have to metabolize the bigger the effect should be.

Just to add one more thing as well. The design here, the 0 and 3 months dosing is really to accelerate the Phase IIa trial. It's not because we do think we need to give the dose that frequent. So all of our PK modeling indicates that it's once a year or at most twice a year. So it's a way to kind of accelerate and facilitate data readouts fast.

And to that point, I mean, if you look at our 240, I mean, past 7 months, we're still seeing suppression of activin E. So again, with 400, we expect that to be larger. But you also bring up an interesting question on just -- and I heard you mention genetics. I mean I think we have to go back to the genetics and realize that activin E is a biomarker. Hence, we're able to look at the impact of the reduction on the actual protein biomarker over time. And when one looks at that interaction, there were the discussions that had come up a while ago about diabetes, nondiabetes.

And I think the data that has been shared to date doesn't demonstrate that these patients should be different in disposition, whether they have diabetes or not. Actually, the data that was run in that, I think it was an over 300-patient observational study from Alnylam clearly showed that acne correlated with high BMI, insulin sensitivity and truncal fat in nondiabetic patients. So I think the implication here is really that if you can dial back a protein that drives hypolysis, then you're going to see that impact.

Now we're going to be able to be in a position where we're going to look at that in different settings. So we'll have it in the nondiabetic setting, the diabetic setting will look at how that plays a role, particularly on endpoints like hemoglobin A1c. So if we think about the implications for broader cardiometabolic disease beyond obesity, we'll be able to look at what happens with insulin sensitivity, what happens with hemoglobin A1c for diabetes and other measurements in lipids and inflammatory markers as we think about cardiovascular disease.

So I think the study is really stepping back and letting us look at the broad range of cardiometabolic diseases in those different patient settings.

Our next question comes from Salim Syed with Mizuho.

Congrats on the progress, guys. Paul, Chris, maybe one for us on the data coming out on 006 and ATS. So is it possible to just kind of give us high level kind of what people should expect here or look out for? I mean, obviously, the data that was presented in September of last year, the 200 single and 200 multi, there wasn't much of a dose response or even got to the 40 milligram single that you guys continued progress here with the 400 multi and then we'll be getting 600 single and then I guess, in the second half of this year, 600 multi. So is there any reason here people should be expecting some sort of threshold effect as you break through the higher doses that we get more efficacy?

Yes. I mean... No, it's a great question. I think if we went back to September, there's actually a dose response if we think about M protein. It went from 0 to like 44% to 65%. So I mean, I think if we think about the context of where patients start and how that builds over time, I think editing can continue to grow. I think with the question of is more going to drive more in the absence of an acute phase response, that's really the distinction that we're separating, which is once you hit a point where you can catalytically edit, the transcripts that are necessary. It's really a function of time. You deplete Z protein, the Z protein continues to come down and clear from the liver, the cells get better. And you should, over time, as we've seen with MZ patients who actually don't have liver disease over their lifespan, they can actually generate more protein.

And so I think that notion of correction over time is important. But I think our guidance is we were able to mount a response that could generate a lot of proteins, 20 micromolar if you had the right event. So it's not substrate limited to the effect that people will say, is the enzyme exhausted or there is substrate limitation in the context that if you're not having an acute phase response and the body is not producing or needing to produce protein that it won't produce more. And so I think that's been the example we've seen and others have seen.

I think what we're able to do is look at this without the conflation of LNP irritation, which can also create kind of a inflationary signal of inflammation. In a signal where you have GalNAc, you can go directly to the target site, we do see that when you have these elevations of acute phase responses that you can meet those dynamics. So I think stepping back, if we could see that we could produce the same levels, meaning you could create stable levels of very micromolar, we were 13. So edited protein that's M that's above, again, the MZ threshold, so again, above 50% protein and be in a position where you can protect patients from a dynamic response, but now no longer have to deliver biweekly injections to get there, but demonstrate we can do it monthly or less frequently. I think that puts us in a very good position in terms of the regulatory context and ultimately, most importantly, to treat patients with alpha-1 antitrypsin.

Our next question comes from Roger Song with Jefferies.

Also on the INHBE. So understanding you will have a poster at the ADA. So just curious what kind of incremental data we will -- we should expect to see? And then regarding the FDA interaction, have you had any discussion around the 5% is coming to the total body weight reduction versus we can look at a total fat or even visceral fat reduction threshold moving away from the overall body weight given the novel mechanism?

Thank you, Roger. And I mean, to your first question, yes, we will have a poster at ADA. As it relates to new data cadence, we haven't provided any updates other than 2026, we'll be providing continued updates on 007. To your second question, as it relates to kind of regulatory thresholds and 007, I think it is important that there is a broader range of discussions beyond a flat 5% change in total body weight.

Nonetheless, it's why I think Slide 24 in the new corporate deck is important because I think the notion of -- and I know people were kind of trying to think about with visceral fat, it's kilogram.5 k and if you lose that, and everybody is trying to figure out where body weight reduction comes from. But if you look at the parallel side of what happens to total fat in that population, you've got about 48 kilos of total subcutaneous body fat that gets produced that ultimately delivers weight loss.

So I don't think we're needing to necessarily have a different conversation around how in a Phase II/III obesity study in patients with excess fat, how you can deliver on that 5% threshold. Nonetheless, I think there is a very robust conversation that we're preparing for with the agency, where I think there's a lot of alignment, particularly in this administration, thinking about the impact of pharmacovisceral fat. I mean there's 2 decades of literature on elevations of visceral fat driving NASH, driving cardiovascular disease, driving diabetes. quantitatively, meaning a 10% change in visceral fat changes outcomes that are clinically. And what do payers pay for? They pay for outcomes.

And so as we think about the endpoint of visceral fat reduction as actually being the driver of what makes patients unhealthy, that focus on being able to reduce visceral fat is important. As Chris pointed out, it doesn't -- there's not a lot of complicated mathematics to take BMR and look at the impact of visceral fat and lean mass preservation. There's literature around that. So this is not a new metric of identifying how you can change body composition in a positive way. And very much, we do plan to have a conversation with the agency that specifically focuses on looking at other metrics like BMR and visceral fat as an endpoint, not just to the exclusion of the 5%, but even in addition to that, being able to build in the real impact of improving body composition, which is what's required for the treatment of obesity is important.

And I think we all need to remember that obesity is a cardiometabolic disease. And so ultimately, a lot of the endpoints that we're measuring hemoglobin A1c, insulin sensitivity driven off of visceral fat reduction are going to be important. So yes, it will be very much a topic of conversation this year as we think about the path forward.

Our next question comes from Bill Maughan with Clear Street.

So I wanted to just mix things up and actually ask about your exon skipper program. While obviously not as massive a market as obesity, it is a fairly near-term opportunity and a potential significant revenue driver, yet there seems to be a bit of a lack of, I guess, emphasis just around discussions around Wave on the exon skipper. So I just wanted to get your most recent kind of thoughts on how big that could be commercially and whether or not there's potential for that to surprise a bit and get a little more credit than it's being given currently.

Yes. No, thank you for the question. As we think about DMD, I mean, we have delivered a differentiated approach with the clinical data update we gave. As we said, we were in the process of delivering and putting together that studies continuing to get to the monthly dosing regimen, which we believe would be, again, differentiated and required for an NDA filing. So that work continues to remain on track.

I think as you also point out, as we think about the opportunities of allocation of capital in terms of building out to commercialization, we have said that we do plan to engage in strategic partnering discussions as it relates to that transition and commercialization.

And we continue to look for several things evolving. One, the evolution of the commercial landscape as we look at the product dispositions that are out there and two, the regulatory environment. So I think over the course of this year, there's going to be a lot of opportunities for us to make those assessments in commercial landscape, the regulatory landscape as we can continue to deliver on that pathway.

Our next question comes from Ben Burnett with Wells Fargo.

Our next question comes from Danielle Brill with Truist Securities.

Our next question comes from Luca from RBC.

This is Cassie on for Luca. Congrats on all the progress and a quick one on the competitive landscape for obesity. Your competitor is moving into combination approaches relatively earlier on in development. Could you -- maybe could we take that as maybe signaling that monotherapy alone has inherent limitations in obesity treatment for INHBE? Paul, you already gave some color on this, but do you believe there's a feeling what INHBE alone can achieve? And are you concerned that waiting until Phase II or later to explore combinations may put you in a competitive disadvantage versus competitors already testing combo strategies? Sorry for the long question, but any color would appreciate.

I think it's a wonderful question because I do think already, if we look at where we were relative to just our Phase I population with our single-dose data, we are competing with visceral fat reductions that were in multi-dose of others, right? And as we think -- including combination. So I think if we think about what we have is differentiated, and I think Eric shared that during his update on the call, our chemistry is giving us a high degree of potency and durability. And if we think about the INHBE target itself, it requires not just potent reduction, but requires stable suppression.

And so this notion of being able to keep that target low despite any desire of the body to upregulate it is a key differentiator. We saw that in preclinical data that differentiated us from our competitors where they to do repeat dosing of a GalNAc siRNA to drive weight loss. Remember, these are obese mice. So the mice that we're all talking about in these studies were mice that would be much more representative of your Phase II/III high BMI mice. And what do we see? We saw that if we could give a single dose and suppress activin E, we could see weight loss in that model, driven off of fat reduction, visceral fat reduction, subcutaneous fat reduction.

So I think we're seeing strong clinical translation on potency and durability distinction from our competitors, such that absolutely, I think we will see continued fat loss substantially with muscle preservation in this high BMI setting. So I don't think that there's necessarily the ceiling effect as much as it is the treatment effect in the appropriate population.

As we said a number of times last year, it was always going to be about treating the patients with the right disease setting, meaning the Phase II/III population of obesity, high fat with the right dose over the right amount of time. So I think we're set up to see that. Nonetheless, I think the power, as you point out, in combinations is very real. So if we stay in the monotherapy, we do believe that, that's going to be a segmented marketplace. We think about the opportunity for -- I think there's nearly 30 million people in the U.S. who are at risk of lean mass reduction who need weight loss.

And so as we think about segmentation, I think there is a substantial population monotherapy that's going to need fat reduction without the risk of lean mass loss. Combination nonetheless is a very interesting place to be. I don't think we're losing our lead there.

As Chris alluded to, we're actually accelerating the combination studies. And so already at a monotherapy piece, we have a distinction from our competitors. And again, we believe that in combination, we should see a more robust effect by being able to add INHBE onto existing inreatment therapies. And so the opportunities there are twofold. I know on one hand, we tend to think about giving more and trying to drive even more weight loss, importantly, fat loss, which comes from INHBE.

I think we've got another distinction, which is the ability, frankly, not to have to kind of push incretin to the edge of tolerability, but being able to think about actually in this environment, particularly as we watch that space evolve, being able to actually have to give less incretin therapy in combination to exert a maximal effect. And so I think there's a big piece on titration where INHBE can add to that combination strategy to ultimately drive profound visceral fat loss, subcutaneous fat loss along and coincidentally with incretin.

And then ultimately, where we have generated data uniquely, I think for Wave with INHIBN-E, I think this maintenance setting is actually a wonderful place to be. We were just on calls recently where there's a lot of thought going into what does the evolving treatment landscape look like in a world where like antihypertensive, obesity treatment is now going into a place where you have patients who have BMI reductions.

And frankly, now you have payers saying, now that you're no longer meet the BMI criteria, you might need to come off therapy. And so there's actually now discussions on the payer side of saying, actually, you're going to lose those benefits and actually build a maintenance setting.

So as that maintenance concept evolves, so what does a lifelong therapy look like that preserved outcomes, I think this maintenance opportunity is pretty substantial for us that if people invest, payers invest in getting to that healthy, stable outcome, how do you sustain that in a way that's going to be tolerable is not going to help drive additional complication side effects, tolerability effects and the potential for now a once to twice a year maintenance therapy is consequential. So I think all 3 settings are set up for us to be uniquely differentiated. And as we said, all 3 studies are pulled into this year and being accelerated. So we'll be generating human data in the right population in all 3 of the settings.

Maybe just to add one more thing. So since this is new biology as well, I think it's important to really try to understand the potential across a lot of ways, and we have so many ways of winning this year, like we're going to look at the 5% threshold for weight loss. We're looking at body composition with a focus on fat loss. We're looking at potential cardiometabolic protection across lipids, HbA1c with diabetes and fat in liver for MASH.

And then in addition, the combo and maintenance. There are a lot of opportunities, and we're accelerating. So we're going to get all of that data and starting everything this year.

Our next question comes from Catherine Novack with Jones.

I just have one on the 006 multi-dose regimen. I guess knowing that successive dosing can push mean max AAT higher, how should we be thinking about mean max AAT achievable with monthly versus biweekly dosing that was used for a multi-dose regimen prior readout? And how do we think about the delta between the single dose and the multi-dose when we're switching to monthly?

Yes. I mean I think one -- and I'll take the second part first. I think that will be interesting, right, as we look about what's the difference in terms of the on rate, if we think about it between the 200 to 400 and the 600. So we'll have the opportunity to look at what do those kinetics look like as you point out. And then the difference between biweekly dosing versus again, monthly and then the impact on those rates. And I think, again, -- our framing today is that if we assume that we are getting a biweekly 200 to near steady state in the sense that it's not substrate limited, but in the absence of an acute phase response where you're producing more transcript that you're not going to necessarily get more without the benefit of time, right, the ability of cells to clear out the cells to get healthier producing hem. That's going to be the chief driver of seeing those increases. And so we'll be able to look at what happens on the repeat dosing of monthly versus biweekly.

But I think that's the big shift in the dosing regimen. I think 600, as Chris alluded to later this year, 600 monthly would give a better sense of keeping the kinetics and the timing of those dosing intervals coupled with dose to get better. But this is really to see can we see that we get to that same steady state, the ability to balance acute phase responses of as much protein as patients need, they can produce, but do that in a monthly I think that's going to be the driver for this next update.

Our next question comes from Whitney Ijem with Canaccord Genuity.

I think just to quickly follow up on the last question. I think you've answered it, but just to put a finer point on it, is what you're saying that given the time frame of the next update, we shouldn't necessarily expect to see a dose response on either total or M protein at steady state at ATS in particular, but that dose response could come over time or maybe in the setting of an acute phase response later. Is that the right way to think about it?

I think the way to see it is when we should -- it is going to be that. We'll see what the driver is of more. But again, I think our demonstration to date, even looking at the early data is we got to more, right? We got to 20 micromolar in the setting of an acute phase response where you actually generate more substrate, more transcript to be edited. So I think at a certain point, there's going to be this concept of steady-state editing where as much transcript is being edited, you can clear Z. I think that's going to be what we clearly want to see as Z protein continuing to come down. And then there's a function of time. And so I think it's more than thinking about dose at the time of what -- how much duration is there for the body over time to clear Z, get healthier hepatocytes that can produce more protein. I don't know if there's...

Our next question comes from Madison Wynne El-Saadi with B. Riley.

Just looking at the Phase IIa MAD design, I mean, it's certainly looking like a CV MAT versus, say, pure obesity study. I'm curious if -- did the FDA acceptance include any commentary on body comp as a kind of co-primary -- or was it more of a kind of protocol discussion?

And then relatedly, what's the magnitude of MRI-PDFF reduction in Phase IIa in lGHT that management would view as supporting a stand-alone MASH development versus, say, a subsegment of the obesity program?

Yes. I mean I think to your first point in general, I do think it's just important, we can't say this enough that obesity is a cardiometabolic disease. So running a study that fully interrogates the cardiometabolic implications of a target that comes out of human genetics that is a cardiometabolic target. So I think being able to fully extrapolate all of the value of what does that mean for a patient beyond just as you said, at classic obesity, which is the classic studies are looking at weight loss at the expense really of muscle and muscle drives the predominant early reduction in that body weight.

So being able to shift the narrative to not just reduction of fat that will be important in the treatment of obesity, but all of the other advantages that come to patients and frankly, are recognized by, again, what payers pay for, which is the cardiometabolic improvement is what this study is designed to elucidate.

So yes, we'll be able to look at body composition, and that's part of the endpoints as we said, as part of an obesity study in addition to body weight. But all the important metrics, as you point out, are critical for us because they are all part of the development paradigm here. The last piece is, I mean -- and we've seen this with others and competitors who've done monotherapy reduction of liver fat, and they saw consequential reductions in liver fat that pretty much surpassed other match programs and reduction of again, fat in the liver.

So given our potency, durability, given that we wouldn't expect this mechanism to be differentiated, we should see in terms of like reduction in liver fat because of what we're doing, we would expect to see substantial reductions and that target engagement there, reduction of fat on imaging would guide us to say that MASH would be a target to pursue a dependent.

Maybe I add one more thing, and that is that these cardiometabolic risk factors and liver fat are very strongly correlated with obesity and visceral fat. So it's not so much that we're not requiring -- it's not an inclusion criteria. It's more that we're removing the exclusion criteria from the Phase I, which hampered us in terms of looking at those things. So again, we -- just based on the normal distribution of liver fat in this obesity class, we expect that there is liver fat that we can look...

Our next question comes from Michael King with Rodman & Renshaw.

This is [indiscernible] on for Mike. Congrats on the updates. Just a quick question on the DMD program. So Novartis was just talking about the drugs they got from Avidity that they're using antibodies to deliver oligos to the muscle. Do you think you have the best tissue penetration you can get with N 531? And how are you thinking about the competitive dynamic as you head towards the NDA filing?

Yes. I mean I think in general, it's a wonderful question because, again, in the absence of conjugates, if you look at the muscle exposure, our muscle exposure was pretty extraordinary even in comparison to muscle targeted ligand. So when we think about distribution to the tissue without having to add that, that was consequential nonlimiting. And we saw for the first time actually real measurements of muscle regeneration.

So when we think about getting into stem cells and regenerating muscle and think about more broadly the platform implications for being able to treat the disease in the muscle, both with splicing oligonucleotide, siRNA and others, we talk about extrahepatic. I think there was not a requirement as we think to have to create the complexity of that to get exposure. So the landscape is something we continue to look at as it evolves. But in terms of being able to access the tissue and what would be required to do that, I think our platform delivers exquisitely muscle....

Our last question comes from Ananda Ghosh with H.C. Wainwright & Co.

When you look at the genetics of the actin and when you talk to the academic community, one aspect of the biology, which they all stress about is that Iin probably works best in the negative energy balance, which you see when you add actin knockdown approach with GLP-1s, which also Arrowhead has already shown. The question is what happens when you take off the GLP-1s during the maintenance phase when probably the patient energy balance either neutralizes or probably goes to a positive energy balance. Then what happens to those liberated free fatty acids? Do you actually think that you will see a stability in the weight gain? And if you do see where does those 3 fatty acids go, which are liberated when you don't have GLP-1s, in which tissues do they accumulate?

And probably in the same as they did in the first point, right, when we saw it go to muscle. And if you actually a beautiful experiment that we had run in this was the preclinical data where when you stabilize these obese mice on GLP-1 exactly to your point, their caloric consumption declines dramatically, they lose weight, they hit their steady state. And interestingly enough, and I think it does speak to the mechanism of action when you predose and the timing of that was critical, not after you dose before the cessation to get the on-ramp of active suppression before turning off the GLP-1. When you stop the GLP-1, you actually saw caloric consumption increase in both arms of the study. the placebo arm and the INHBE treatment arm. So again, the energy balance while going up wasn't changed.

Now what you did do in advance of putting those excess calories on is actually turn off exactly what the body wants to do and actually what's really damaging in weight cycling with GLP-1s and it's a real problem in patients who chronically come on and off of them is that when the weights regain, it's regained its fat, fat is position in a variety of tissues, and that's unhealthy. And so what we did see is when you actually take the brakes off lipolysis, the body is now not able to store new fat. So you don't see that reaccumulation of fat.

What you do see is -- and we kind of see this slight -- much like probably what we saw in the slight increase in the monotherapy arm, which is it goes to muscle. So you end up with the free fatty acids and the muscle, muscle can then actually build. And so we don't expect -- that will be interesting to see whether or not that plays out that people who have actually been losing muscle over time might gain some muscle back when at the same time, but not restore that as fat and hence stay at steady state.

So again, as we said on the call, that study is going to initiate this year, we're going to be generating that human data to recapitulate what we saw in the animal model. But I do think if we think about what the best human genetic evidence is for INHBE, it's maintenance. These are people who go over a lifetime without thinking about their caloric consumption and have low abdominal visceral fat, have an improved metabolic profile in terms of risk of diabetes and cardiovascular disease and lipid profile. And so actually the setting where there's the most human genetic data for, and we're excited to run that human clinical trial.

There are no further questions at this time. I'll now turn the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We look forward to speaking with many of you later today and during the ATS conference next month. Have a great day.

Hello, and welcome to Wave Life Sciences Positive Interim Phase I Clinical Data from INLIGHT Trial of WVE-007 for Obesity Call. [Operator Instructions] Also, as a reminder, this conference is being recorded today.

I will now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. This morning, we issued a press release announcing Positive Interim Clinical Data from our ongoing Phase I INLIGHT Trial of WVE-007 in otherwise healthy individuals living overweight or obesity. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2025. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Erik Ingelsson, Chief Scientific Officer, will discuss WVE-007, our INHBE GalNAc-siRNA; and Dr. Chris Wright, Chief Medical Officer, will present the INLIGHT clinical trial interim data and Phase IIa update. Next, Paul will review next steps and anticipated milestones before turning it over to Q&A. Dr. [ Sandra Barges ], Chief Technology Officer, will also be available to answer questions.

I'd now like to turn the call to Paul.

Thank you, Kate. At Wave, our goal has been to harness the power of human genetics to develop transformational medicines, leveraging our best-in-class chemistry. Today, we're pleased to share with you significant progress towards this goal with the continued clinical translation of WVE-007, our GalNAc-siRNA for obesity. 007 is a potentially transformational treatment for obesity that improves body composition by reducing fat, in particular, harmful visceral fat while preserving muscle.

There are 3 key takeaways I'd like to highlight from today's update. First, our best-in-class siRNA for obesity continues to demonstrate an industry-leading and highly differentiated profile in the clinic. Potent, dose-dependent and durable reductions of active [indiscernible] and a very clean safety profile. Second, 007 continues to translate in the clinic and demonstrate its potential as a novel transformative therapy to deliver fat loss and muscle preservation. In a Phase I study with low BMI and a generally healthy population, we are already seeing substantial improvements in body composition, including a clinically meaningful 14% reduction in visceral fat and a 3.3% reduction in waist circumference in 6 months following just a single dose. The continued fat loss we're observing a concurrent stabilization of muscle also led to weight loss of 1%.

And third, as planned, we are quickly advancing 007 to the Phase IIa portion of INLIGHT in a higher BMI population that includes individuals with comorbidities, which is consistent with other Phase II or Phase III obesity studies. These study populations carry more excess fat and will enable demonstration of higher fat loss with continued muscle preservation leading to greater weight loss as well as demonstration of clinical biomarkers to inform development in MASH, type 2 diabetes and cardiovascular disease.

Today, Erik will first remind you of the unique and compelling biology and human genetic evidence that support 007, and Chris will then cover our Phase I Interim Data update and next steps for Phase IIa development. Erik?

Thank you, Paul. Before diving further into today's results, it's important to reflect on the current obesity treatment landscape and why we believe that 007 is well positioned to deliver a truly differentiated novel therapeutic approach. Individuals living with obesity face markedly higher risk of a range of diseases such as MASH, type 2 diabetes and cardiovascular disease. Excess body fat, in particular the dangerous visceral fat is a key driver behind this elevated risk of disease.

Current standard of care with GLP-1s and other incretins is focused on caloric restriction by reducing appetite and slowing gastric emptying and carry many limitations such as muscle loss, frequent dosing and tolerability challenges, resulting in high discontinuation rates as well as weight cycling due to individuals coming on and going off therapy. The consequence of muscle loss is particularly important to emphasize that skeletal muscle plays an important role in metabolism and weight maintenance.

Taken together, there is a large unmet need for therapies that leverage an orthogonal approach to induce fat loss while preserving muscle, enhance efficacy of incretins as an add-on and maintain weight loss and metabolic improvements after cessation of incretins. 007 improves body composition by decreasing excess fat through adipose lipolysis and retaining muscle and does not lead to or require caloric restriction to achieve these results. With a favorable safety profile that we have observed to date and the potential for infrequent once or twice yearly dosing, we believe that 007 could offer a transformational approach to obesity treatment.

007 is designed to silence Inhibin E to lower serum Activin E and compelling human genetic data support our confidence in this mechanism of action. In the UK [ Biobank ] and other population-based studies, heterozygous Inhibin E loss of function variant carriers, individuals living naturally with 50% less Inhibin E exhibited a healthier overall metabolic profile, driven by lower visceral fat as evidenced by lower waste-to-hip ratio and lower visceral adipose volume as well as downstream effects with lower triglycerides, [ ApoB ] and HbA1c and higher HDL cholesterol. These carriers also have favorable associations with liver traits, such as ALT, a measure of liver damage and CT1, a measure of liver inflammation and fibrosis and importantly, lower risk of developing type 2 diabetes and coronary heart disease.

By silencing Inhibin E mRNA, we aim to recaptulate the protective phenotype seen in these heterozygous loss of function carriers. Inhibin E is produced in the liver where it dimerizes as the [ hepatokine ] Activin E. Activin E is released into circulation where it binds to ALK7 receptors on adipocytes. This blocks adipose lipolysis to break down of triglycerides, promoting fat storage, increasing risk for obesity and cardiometabolic disease. By reducing hepatic Inhibin E mRNA with a GalNAc-siRNA, we lower circulating Activin E, leading to a decreased ALK7 signaling in adipose tissue and releasing the brake on lipolysis or in other words, increasing metabolism of excess fat, which is ultimately expected to lead to weight loss and lower cardiometabolic risk.

Although there is human genetic evidence for both Inhibin E and ALK 7, further supporting the importance of this mechanism in regulating body composition, we chose to target Activin E through Inhibin E silencing over its receptor ALK7 for several reasons. Turning off protein production in hepatocytes, the upstream source with the GalNAc-siRNA is the most efficient and durable way to address this mechanism. Further, suppressing the Activin E ligand rather than disabling the ALK7 receptor is a more selective approach with lower risk of unintended consequences since ALK7 has multiple ligands across different tissues, including reproductive organs. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation.

007 is highly differentiated by our proprietary chemistry, which makes us well positioned to deliver a potentially best-in-class approach. 007 is a GalNAc-siRNA using Wave's [indiscernible] design, including backbone [ serochemistry ] and [ PN ] chemistry, which enhances interaction with [ A02 ], stabilizes the loaded risk complex and improves liver exposure, all of which contributes to dramatically improved silencing potency and durability when compared with industry standard siRNA designs, something we have shown repeatedly for Inhibin E and other targets.

In addition to strong evidence from human genetics, there is also robust evidence showing that higher circulating Activin E levels are associated with a range of cardiometabolic measures, providing further evidence of the importance of this mechanism in development of obesity and cardiometabolic disease in humans. In an observational study of 324 nondiabetic participants, Activin E levels were strongly correlated with increased BMI, abdominal fat and fasting insulin. This, together with the genetic evidence from the general population, our preclinical data and our data from the INLIGHT study all support that the associations of Inhibin E and Activin E with body composition are not restricted to individuals with diabetes, but that Inhibin E suppression can result in fat loss regardless of diabetes status.

Importantly, the strong correlations of Activin E levels with BMI highlight the opportunity for larger effects of 007 when we move to higher BMI individuals in our Phase II studies, which Chris will speak to in more detail momentarily. 007 is designed to improve body composition while -- by decreasing fat while preserving muscle. We expect effects on both subcutaneous and visceral fat as Activin E binds to ALK 7 on all adipocytes. Generally, any weight loss regimen will have a proportionately larger effect on visceral fat, especially at the earlier time points since this type of fat is more metabolically active, better supplied with blood and more sensitive to fat mobilizing hormones. We expect this phenomenon to be even more pronounced with 007 as it acts directly on light policies. We expect both visceral and total fat loss with 007 to be substantially larger when studied in higher BMI populations with more excess fat.

Visceral fat, which is around your organs, is strongly linked to insulin resistance, MASH, type 2 diabetes and cardiovascular disease. There is robust evidence supporting that 5% to 10% lower visceral fat is associated with decreased risk of a number of cardiometabolic diseases. Wave's circumference is an easily accessible clinical proxy for visceral fat that has also been shown to be strongly associated with cardiometabolic diseases in many large studies. We are already observing more than 14% reduction in visceral fat and more than 3% reduction in weight circumference after 6 months in our 240-milligram dose despite low baseline levels of visceral fat and BMI.

While it tends to get less attention in obesity, muscle also plays a crucial role in metabolic health in addition to preserving strength, function, bone density and longevity and reducing risk of sarcopenia and frailty. For context, with incretin therapy, up to 40% of the weight loss is driven by muscle loss, meaning that the health benefits delivered from fat loss are partially offset by muscle loss. Skeletal muscle increases basal metabolic rate, the number of calories you burn as your body performs all basic life-sustaining functions, making up about 70% of the calories we burn. Further, higher muscle mass with higher glucose disposal, better insulin sensitivity and improved over energy balance which helps reducing visceral fat and preventing weight regain.

Visceral fat and skeletal muscle are the 2 components of body composition that are most important for cardiometabolic health. As most obesity treatments drive fat loss at the expense of muscle loss, using a metric such as visceral fat to muscle ratio or VMR is a good composite measure of body composition to integrate both the harmful visceral fat and the beneficial lean fat into a single index. This metric has been used in many scientific publications and a lower VMR has been shown to be strongly associated with the decreased risk of MASH, type 2 diabetes and cardiovascular diseases.

Our comprehensive preclinical studies underscore our conviction in our potentially best-in-class therapeutic approach that leverages a completely orthogonal mechanism from incretins by inducing fat loss with lean mass preservation. We have shown that our molecules reducing Inhibin E [ RNA ] and circulating Activin E levels, increase adipocyte like policies and lead to reduction of adipocyte sizes and fat loss, in particular, visceral fat. This, in turn, results in a reduction of inflammation and fibrosis in adipose tissue as well as improved insulin sensitivity, changes that are likely to contribute to a lower risk of cardiovascular disease in type 2 [ diabetes ].

In our studies in [ DIO ] mice, a model that represents severe obesity with an abundance of excess fat, weight loss within Inhibin E sRNA was similar in magnitude to semaglutide but occurred more gradually. A potential explanation for the initially slower weight loss could be that the preservation of lean mass is offsetting weight loss early on, but that over time, the substantial fat loss is translating to weight loss as the lean mass stabilizes.

The early clinical translation of 007 in INLIGHT fortifies our excitement in other treatment settings, such as add-on to incretins, where we have observed approximately twofold greater weight loss as an add-on to semaglutide versus semaglutide alone in DIO mice. We have also shown an ability to curtail weight regain upon cessation of semaglutide within Inhibin E, providing powerful data for its utility in the maintenance setting.

With that, I'll now turn it over to Chris to walk through the INLIGHT clinical data in more detail.

Thanks, Erik. Good morning to everybody on the call. As a reminder, the Phase I portion of INLIGHT is a placebo-controlled single ascending dose study, randomized 3:1 active placebo with potential to escalate up to 5 single dose cohorts. It's designed as a safety tolerability PK/PD study. Participants are healthy individuals living with overweight or Class I obesity with key inclusion criteria of HbA1c less than 5.9 and BMI between 28 and 35. The study does not require diet or exercise modifications or counseling.

In addition to safety, tolerability, PK and Activin E levels, the study has exploratory endpoints of body composition by DEXA, biomarkers and body weight. [indiscernible] is currently ongoing at multiple trial sites, including in the U.S. We began testing WVE-007 at our lowest subtherapeutic dose of 75 milligrams in 8 participants, which did not include DEXA. We next evaluated the 240, 400 and 600-milligram ascending dose cohorts, including DEXA and other measures. Today's update primarily covers 6-month follow-up data from our 240-milligram cohort as well as observations from our 400-milligram cohort.

In addition, further updates on safety and PK for the 75 through 600-milligram cohorts are provided. We will describe the design of our Phase IIa multiple dose amendment to INLIGHT in more detail as well. Participants were in their late 30s to early 40s on average with a mix of men and women in each cohort, with a somewhat higher proportion of females in the 75-milligram group and males in the 240 and 400-milligram cohorts. Mean baseline BMI was approximately 32 across the treatment cohorts, consistent with the participants having healthy overweight or Class I obesity. Baseline characteristics show differences between our 240 and 400-milligram cohorts with the 400-milligram cohort having lower baseline BMI, lower weight circumference, lower body weight, total fat and visceral fat with higher lean mass.

The difference in baseline visceral fat was particularly notable as it was 30% lower in the 400-milligram group compared to the 240-milligram group. Overall, the differences suggest that the 400-milligram cohort had a healthier baseline body composition relative to the 240-milligram cohort.

To put these baseline characteristics into perspective, here you see a graph showing the U.S. general population distribution of BMI on the X-axis and visceral fat on the Y-axis. The dark blue contour represents where 50% of the U.S. population falls for these measures and the light blue contour indicates 95% of the population. On this background, we show the baseline BMI and visceral fat levels for our 240 milligram, that's purple dot and 400 milligram in the pink dot Phase I INLIGHT cohorts. And the baseline BMI and visceral fat levels, the open dots typical for Phase II and III obesity studies using the BELIEVE study as an example.

As you can see, consistent with Phase I obesity studies, baseline BMI and visceral fat and INLIGHT are markedly lower than the baseline levels of Phase II and III studies. The Phase II BELIEVE study provides a good example of this with baseline BMI and visceral fat primarily outside of the 95% population contour in light blue, meaning that the baseline BMI and visceral fat are in the most extreme 5% of the population. Further, baseline levels in the 400-milligram cohort are even closer to a healthy population with average BMI and visceral fat levels near the 50% population dark blue contour.

We continue to observe a favorable safety profile across all cohorts, which is of critical importance for a potential new medicine designed to treat millions of people living with obesity. There were no treatment discontinuations, serious TEAEs or deaths. All study-related AEs were mild. There were no clinically meaningful changes in lipids, glucose or other clinical laboratory measurements, including liver function tests through 600 milligrams.

Following our update in December, we continue to see robust and durable reductions in Activin E. In this chart, the percentage reduction of Activin E from baseline is shown on the Y-axis with days on study on the X. We're pleased to show highly statistically significant dose-dependent active decreases across all 007 dose levels with a mean max reduction of up to 88%. Notably, over 70% suppression of Activin E was still observed out to at least 7 months, supporting a highly convenient dosing interval of once or twice a year. With this durable Activin E suppression, we're now excited to show a pronounced improvement in body composition observed over time following a single 240-milligram subcutaneous dose.

Visceral fat mass decreased from a 7.8% placebo-adjusted reduction at 3 months to a statistically significant 14.3% placebo-adjusted reduction at 6 months. Total fat reduction reached 5.3% at 6 months and lean mass stabilized. There were also improvements across clinical measures, including a 3.3% reduction in waste circumference and a 0.9% reduction in body weight. Overall, these data demonstrate that a single dose of WVE-007 can shift body composition towards best visceral and total fat while preserving muscle mass, consistent with our preclinical findings and the underlying human genetics. These results are encouraging as we're starting to see evidence of improvements in clinical measurements such as waste, circumference and weight at 6 months, even after a single dose of 007 in a Phase I study of otherwise healthy participants with an average BMI of 32 and no dietary or exercise restrictions.

As Erik previously discussed, we believe improvements in body composition will drive meaningful health outcomes. A key indicator of these improvements is the visceral fat to muscle ratio or VMR, which is an established measure of body composition. As Erik described, low VMR is associated with a wide range of health benefits, including increased risk of MASH -- sorry, decreased risk of MASH, type 2 diabetes and cardiometabolic disorders. To benchmark and contextualize our results at this early development stage, we calculated the change or improvement from baseline in BMR for our 240-milligram dose of 007 and estimated this for the treatment arms of the Phase II BELIEVE study investigating weekly semaglutide and [ IV bimaglimab ], a myostatin inhibitor in participants with a BMI of 37.

As you can see, a single 240-milligram dose of 007 is outperforming both high and low semaglutide at the 3-month and 6-month time points, even in the context of otherwise healthy participants with BMI of 32. This is due to the substantial reductions in lean mass by semaglutide, which adversely impacts its BMR score. The BMR 007 is on par with [ bamaglimab ] with convenience of potential once yearly dosing and favorable safety profile.

What's particularly impressive about these results is that we're able to achieve these improvements in body composition in a Phase I study of otherwise healthy participants with mean BMI of 32 compared to Phase II and III obesity studies with BMIs of 35 or higher in metabolic comorbidities. On this graphic, when we add the baseline and post-treatment BMI and visceral fat values from the BELIEVE Phase II trial, as shown in the green arrows. You see that the INLIGHT baseline BMI and visceral fat are at a level where the BELIEVE study ends after 48 weeks of treatment.

Turning to the 400-milligram cohort of INLIGHT. We observed placebo-adjusted changes from baseline that were lower than what we observed in the 240-milligram cohort at the 3-month time point. For example, the visceral fat reduction was 5%. As I previously shared, the 400-milligram cohort had a notably healthier body composition profile. To understand this impact, we performed a post-hoc analysis, categorizing participants by baseline visceral fat levels of greater or less than 500 grams. 500 grams is an established threshold for healthy levels of visceral fat. Importantly, we saw similar statistically significant reductions in visceral fat at 3 months in both cohorts where the baseline visceral fat was greater than 500 grams.

The key takeaway is this, these data are highly supportive that baseline BMI and excess visceral fat will drive treatment response magnitude and reinforce our expectation that with high BMI and visceral fat, effects of 007 on body composition and weight should be even greater.

Now I'd like to reorient you back to this chart and mention why the data I've just shared with you are encouraging when we think ahead to the Phase IIa portion of our ongoing INLIGHT trial. As this trial will enroll participants with BMI and visceral fat at levels comparable to other Phase II and III obesity studies, we expect greater fat loss and total weight loss like what is observed in other Phase II and III obesity studies.

Turning to the Phase II portion of the INLIGHT study. Our teams are actively working to initiate this study in the second quarter of 2026. This Phase IIa portion will enroll individuals with BMIs in the range of 35 to 50 and comorbidities with a 3:1 active placebo randomization. Assessments in this multi-dose portion are expected to be similar to those in the SAD portion with additional inclusion of body composition measured by MRI, liver fat content as measured by [ MRI-PDFF ], HbA1c, lipid levels, CRP and muscle function. The design and study population enables enhanced evaluation not only of improved body composition and weight loss, but also informs additional opportunities for 007 in MASH, type 2 diabetes and cardiovascular diseases.

The study will enroll 2 different populations with high BMI with and without type 2 diabetes, with the diabetic cohort initiating after the start of the first 2 high BMI cohorts. Participants will be given 2 doses of 007 at day 1 and at day 85 and follow-ups for 12 months, with the first major assessment occurring at day 85.

Finally, in addition to investigating 007 in individuals with high BMI and comorbidities, including diabetes, 007's favorable safety profile and ability to drive reductions in fat while preserving muscle with an orthogonal mechanism may support the use of 007 as an add-on to [indiscernible]. Within the community, there's excitement about 007's potential as a maintenance therapy, which would allow people to transition off infant therapies while at the same time preventing rebound weight gain, preserving muscle and sustaining cardiometabolic health. Planning for this new Phase II program is actively progressing, and we remain on track to initiate trials investigating 007 as an incretin add-on and as a post-incretin maintenance in 2026.

I'll now turn the call back to Paul.

Thanks, Chris. We are extremely excited about the profile we have observed with 007 in this study population with low BMI. We've demonstrated clinically meaningful improvements in body composition, favorable safety and tolerability and durability supporting once to twice a year dosing, and we're moving quickly to advance 007 into the next phase of development.

In addition to initiating new trials investigating 007's potential as an add-on and maintenance post incretin therapy in 2026, we're on track to initiate the Phase IIa MAD portion of our ongoing INLIGHT study next quarter in individuals with higher baseline BMI and comorbidities. Here, we'll have an opportunity to evaluate further improvements in body composition in a population with higher BMI, which is much more representative of typical Phase II and III obesity studies with participants having a lot of excess fat to lose. Therefore, we believe this study population will achieve even greater effects on body composition with substantial fat loss, lean mass retention leading to the regulatory threshold of at least 5% weight loss. In addition to measures of body composition, we'll also be evaluating improvements on imaging and clinical biomarkers, which will inform 007's potential to impact across additional indications.

As a reminder, reducing visceral fat by at least 5% is strongly associated with improving broader cardiometabolic diseases. Therefore, the over 14% reduction in visceral fat 6 months after a single dose of 007 is highly encouraging. We will be evaluating a number of measures in the Phase IIa portion of INLIGHT, including MRI-PDFF, hemoglobin A1c, lipid levels, CRP and muscle function, which will have the potential to unlock indications beyond obesity, including MASH, type 2 diabetes, cardiovascular disease, PCOS and more.

With 007's ability to improve body composition through reducing fat and preserving muscle, we believe 007 will offer a transformative approach for obesity in combination, maintenance and as monotherapy, particularly individuals who are not able to tolerate incretins or muscle loss as well as for a range of metabolic diseases. With over $600 million in year-end cash and cash equivalents, we are well capitalized and well positioned to deliver on multiple milestones with both WVE-007 and WVE-006. We remain on track to initiate the Phase IIa portion of INLIGHT in individuals with higher BMI next quarter as well as to initiate new trials of WVE-007 as an incretin add-on and as post-incretin maintenance in 2026.

Also this year, we plan on sharing additional data from INLIGHT, including data from the 600-milligram cohort of our Phase I study. In the second quarter, WVE-006 remains on track to deliver data from the 400-milligram multi-dose cohort and the 600-milligram single-dose cohort of [ Restoration-2 ] at the ATS conference in May, and we expect to receive regulatory feedback mid-2026 on a potential accelerated approval pathway.

Before turning the call over to questions, I would like to take a moment to thank everyone participating in INLIGHT, the clinicians involved and the study site staff. They continue to inspire the work we do every day. And from everyone at Wave, we'd like to express our sincerest gratitude.

With that, I will turn it over to the operator for Q&A. Operator?

[Operator Instructions] Our first question comes from Steve Seedhouse from Cantor Fitzgerald.

It's a multipart one on the dose selection going forward. I was just hoping you could expand on the rationale for the chosen doses given what you're seeing in this initial data set for the Phase IIa, including if you could clarify how frequent you're going to be dosing. It wasn't clear if the day 85 visit includes the second dose or if it's going to be less frequent.

And then last part of that question is just was the dose selection informed at all by any insight into the efficacy of the 600-milligram cohort?

No, thank you for the question. So the dose selection is informed by 2 important criteria. One is obviously Activin E reduction. So if we think about the dose response, the whole mechanism, as Erik laid out fundamentally at the beginning, is potent durable suppression of Activin E. So we see a dose-dependent suppression. But what's interesting is we get to the 240 and 400, the PK is looking incredible for 240. I mean, as we said, we're out now past 7 months with suppression. With 400 continuing to accrete behind it.

So we do believe we have the suppression we need to stay below that 70%, 75% threshold across both the 240 and 400. The biggest question is ultimately going to be what ultimately gives us the potential for once a year dosing. So we'll understand does 240 sustain that? Is it once a year or is it twice a year? And is 400 give us that opportunity for longer duration. So we do believe we've got the Activin E suppression necessary for the dose selection.

Safety as well. I mean, we're cleared through 600. So safety is clean across all of the dose cohorts. In terms of the dosing regimen, as you point out in the Phase IIa, with durability out past 12 months, we know we've been talking to a number of you about the fact of how long -- how can we accelerate this MAD study. So our view is we're actually truncating that at day 0, day 85. And so there'll be those 2 doses in that regimen.

So remember, the Phase I study, as we think about PK follow-up, follows these patients over a year. So we'll be continuing in this current Phase I INLIGHT to be monitoring Activin E levels over that period of time to look at durability, while in the MAD study, be able to truncate the distance between those 2 dose regimens. So the MAD will have that shorter interval. And that combined with the Phase I will inform the subsequent dosing regimen. But again, we continue to see active durable suppression. And I think to step back one other piece on dose selection to activity.

When we go back to the observational study in over 300 patients where there's a correlation between Activin E, BMI and truncal obesity, it informs us really well that if we stay at this level of suppression and go into, as Chris showed, that high BMI, higher excess visceral fat population, we do expect substantial continued decreases in both visceral fat from where we already are at over 14% total fat and importantly, body weight.

Sorry, 600. So we will have, as we said, we'll look at the 600 data later. But no, the dose selection is not informed by the 600. We will look at that data to see where that goes subsequently.

Our next question is from Joe Schwartz from Leerink Partners.

So I have a 2-part question. In a landscape where most therapies drive weight loss broadly, how confident are you that preferential visceral fat reduction will be valued by regulators, physicians and payers as a differentiated benefit?

And then is there a specific patient population such as high visceral adiposity, insulin resistance or sarcopenic obesity, where this mechanism and profile is particularly compelling if total weight loss remains more modest relative to visceral fat loss? And can you quantify any good base case opportunities for us, recognizing that most investors are not underwriting broader use at this point?

Yes. I mean I think to step back, as you just define the obesity population in the commercial setting, that's studied in patients with high abdominal adiposity and high excess visceral fat. If we go back to every 2, 3 study. And I think stepping back, we have to remember, we're all looking now, as Chris nicely laid out, at a Phase I population.

So to your point, the population that we'll be going into as we think about an obesity therapy has high abdominal adiposity, high visceral fat. And in that reduction, you'd expect to see continued drop in body weight, which is why, again, we've always said in the right dose at a year in the right population, meaning the obese population, we would expect to see the regulatory thresholds.

I think moving down the regulatory thresholds and thinking about reimbursement and what payers pay for, payers pay for outcomes. And so if we think about what's driving health benefits of obesity therapies, it's driven exactly, as Erik said, on the danger of visceral fat. Visceral fat is what drives cardiometabolic risk, diabetes risk. And so again, the fact that we're seeing levels in a Phase I study, low BMI, lower visceral fat than in Phase II obesity studies that are exceeding those like we should be able to have that health benefit play out as part of that therapeutic landscape.

That said, to your last question of are there unique populations as we think beyond monotherapy -- sorry, beyond combo maintenance, that for monotherapy, there's over 30 million people living with obesity who are at risk for muscle loss. So just as a distinct population within the monotherapy setting, there's people who can't afford to lose muscle from a metabolic standpoint in addition to frowsy. And so the ability to still achieve high levels of important reductions in fat with muscle preservation is unique to that. But I think it is really important to say that's assuming that locking in the profile currently on substantial visceral fat in the current study, which is not the study that you do in obesity, which will be in high abdominal fat. So again, we do anticipate in that higher population, the data suggests, the genetics suggest that we'll see substantially larger...

Just to add one more thing as well. As Paul said, when we move into the Phase II/III trial with a higher BMI population, we expect that both the visceral and the subcutaneous fat will continue to go down. The Inhibin E [indiscernible] binding is happening on all types of adipocytes, and we have already seen effects on both visceral and subcutaneous. We do see that both will continue to deepen in the larger BMI population with more fat excess.

Our next question is from Cheng Li from Oppenheimer.

Just maybe 2 parts. I'm just wondering what is the -- what may be the best predictor for 007 efficacy, whether it is like baseline visceral fat or is BMI or maybe baseline Activin E level? And just a follow-up question is, just wondering if BMR can be validated as like a predictor for a clinical outcome that can be used as part of the registration endpoint.

Thank you. And I think you pointed out the important access because if you actually look at the correlation, it's very nice between exactly what you laid out, which is that Activin E levels correlate with higher BMI. So the higher BMI as we move into, there are higher active levels. And I will say, we see very similar data to the population data in our study. Her BMI correlates to higher Activin E levels. So again, higher BMI, higher Activin E. And if you look at the -- that also correlates to higher abdominal truncal obesity and so higher visceral fat. And so again, when you put those metrics together and you look to where Phase II/III obesity studies run, you improve the metric that's hence the X and Y axis on both BMI. BMI is a reflection of abdominal adiposity, hence, visceral fat and in that setting of higher excess fat.

I do think it's just really important to level set coming into this study, which is why I think people kind of are going, how does this compare? Is that when we have the healthy Phase I study with patients living with obesity and overweight, the criteria that caps any of these other effects limits because visceral fat drives additional comorbidities, limits the ability to explore that. So I do think based on actually the response in the 400 and the 240 that this point on visceral fat thresholds and what an excess visceral fat threshold does is actually really validated. We see higher levels of visceral fat tied to those comorbidities driving larger effect size. And so again, going to the Phase II study in that higher BMI, higher visceral fat population would be expected to drive further efficacy.

Our next question is from Alec Stranahan from Bank of America.

This is Matthew on for Alec. Two from us. First, can you explain how you think about the kinetics of total fat loss, which remained relatively flat between month 3 and 6 and visceral fat loss, which doubled in that same time frame? Just maybe thinking about how we view that in the higher BMI population, whether we expect the kinetics or magnitude of these changes to be different?

And then maybe a second quick one, I guess, looking at HbA1c lipid levels, CRP muscle function, have you been tracking these in Phase I data? And any comments on how those have looked so far?

We'll take the last question first, and then we'll focus on the first. But the last one is those were actually part of the exclusion criteria to be a healthy overweight obese study. Patients had to be excluded with changes in hemoglobin A1c, serum lipids or not. So most -- there's not an ability to see a dynamic effect, hence, the subsequent study where we'll have patients with comorbidities where we will be able to see those dynamic effects. I think what's encouraging on the lipid profile on the safety side was despite the changes, there were changes in lipid profiles that would suggest any concern. So I think we could use that in that context in the Phase I study. But obviously, as we said, that's a core part of the Phase IIa assessment.

As we think about the dynamics on fat, as you point out, that's absolutely going to be driven on where you start from. the more excess fat you have subcutaneous or visceral, the larger the effect size and impact. And so if you shift the curve up, I would expect the continuation of that distribution, if you look at percentage of fat, the impact on visceral versus subcutaneous fat. That will continue to be and you imagine that ratio in an outsized effect percentage-wise on visceral fat. That said, subcutaneous fat, which is a larger proportion of the body, when you lose that will be responsible for further weight loss.

So if you imagine going up that curve from -- again, we started at the end of where the BELIEVE study was and saw these data. When you pull that back up to a starting BMI that's greater than 35 and that study, average BMIs in all of the recently reported studies in obesity around 37. So you go up to that BMI benchmarking to that level of visceral fat, we would expect to see the magnitude even on visceral fat, which is impressive as it is after a single dose now to actually get steeper and deeper.

Our next question is from Madison El-Saadi from B. Riley.

Maybe if you can comment, just curious what the percentage of treated patients in the 240 mg arm at 6 months may have reached, say, 3% body weight. Just trying to understand maybe what that distribution looks like behind that 0.9% number. And then if we could maybe take a step back and try to understand the path to 5% weight loss that we know investors want to see. What's the dose, the duration, the population BMI that can get us there? And then what is the earliest data set you think could demonstrate it?

Yes. I'll take the last question. I mean I do think this is why we're accelerating the IIa as we announced going into this year that from the beginning of the study, we've always said this is a Phase I safety PK/PD study to look at the impact of 007, Activin E levels, dose suppression. And then because we're going to be studying it in patients who are living with overweight and obesity, we'd be able to look and measure the impact of fat and reduction and obviously, body weight, but being able to look at DEXA. I think what these data continue to affirm is we've got a very powerful medicine that reduces fat and preserves muscle. I think to your point of where that efficacy is going to be drawn, and that's, again, the announcement we made coming into this year was that's going to be seen like every other obesity medicine in a II/III study where patients have high BMI, high visceral fat, and they're in a setting where they have excess fat to deplete.

And so I think, again, we're set up and we're poised to be able to see that. Within the individual weight metrics, I mean, that is the number for the cohort, and we haven't broken and looked at that into the dynamic range to be able to look at the placebo response. So that is the number. And I think what's encouraging, it's consistent. So if we look at the change as we think about fat reduction between 3 months and 6 months, there's continued progress. So it does speak to what we thought, which is going to be important as we go into the high BMI setting that the initial lean mass plateaus, so you hit that. And as long as you have excess fat to lose, we'll continue to remind you excess fat is what obesity is. This medicine's mechanism of action is reduction of excess fat, visceral or subcutaneous. So you need to put patients into a setting where they can have excess fat to lose, which is what's planned for the IIa study.

Our next question is from Roger Song from Jefferies.

I found this high visceral fat post-hoc analysis very interesting, maybe very informative. Just curious, you see higher visceral fat reduction in this high population. Did you look at the total fat and the weight between the high and the low visceral fat population? And then how should we think about the dose dependence here between 240 and 400, 2-part question.

Yes. No, thank you. And so we take the second part of the question. The challenge in any obesity study is always powering, having enough sample to look at. And the most sensitive measure on a medicine that reduces fat, as we know from all of it is visceral fat is the first index. So as you point out, 500 is not an arbitrary threshold. So just to be clear, 500 is the threshold of kind of what defined as excess visceral fat. So by crossing into the excess visceral fat threshold, i.e., having more excess fat to lose, that's where that separation occurs. But once you get past that, it's very hard to pull out with the noise, other signals beyond where we have sensitivity.

What it does tell us, and this again, forms the IIa study is if you look at that graph that we put out on BMI and visceral fat, once you get up to the BMIs and in that study, you'll see that it's well in excess of the 500-gram threshold of where you need to see to see a reduction in fat.

Yes. Maybe just to add, Roger, you mentioned that you found it interesting. We also found it very interesting and encouraging because it really emphasizes that this approach and this therapeutic really works as supposed to do, right? Like if you have excess fat, there is an opportunity to burn that through increased light policies. So it's highly encouraging as we now move into the IIa study with higher BMI and much more excess fat to act on.

And your question on dose dependency, I think we have to think about what -- how do we define dose dependency. So the first part of dose dependency on a medicine whose mechanism of action is the reduction of Activin E, right, the central ligand in all of this is we do see a dose-dependent reduction. What we see is that as you compress because of potent durable selection, we're right at that inflection point across doses. So we do see the dose dependency. But what we see is that the determination ultimately comes down to fat and the ability to have excess fat.

So therefore, if we think about the dose dependency on excess fat, the more excess fat you have to lose, the greater effect size you're going to see across the cohorts without having to necessarily push the dose. So I think, again, the benefit of the IIa study where we are going to take 240 and 400 both forward is we'll be able to look at that effect size on a duration construct between those 2.

Our next question is from Salim Syed from Mizuho Securities.

Apologies, he seems to have lowered his hand. We will go to Luca Issi from RBC Capital Markets.

Congrats on the progress. This is Cassie for Luca. For weight loss, could you help us characterize what's happened in the placebo arm just on the weight loss part? We know in other obesity trials, patients can be receiving lifestyle management instructions and that might help them lose weight there. Any color on how we see that is very helpful.

And if we can ask another one on the visceral fat, the impact of baseline body composition makes a lot of sense. And going forward, do you anticipate that sort of minimal visceral fat threshold in your inclusion criteria? And what is the thinking on the proportion of obese patients have visceral fat over 500 and above overall? Is the profile closer to the 60% that you see in your 400 mg or it can be higher? Any color there much appreciated.

No, thank you. I'm going to work backwards on that. So what's interesting is if we -- and it's a very good question because it's the one where we put our head on, on making sure that when we design the IIa study in a medicine that reduces fat, how sure are we going to be that we've captured that population. And actually, the data and the analysis we did on both BMI and waist circumference inclusion criteria will put us in the same box as others. So we do fully expect that the study will look like other Phase II/III studies. And when you look at the disposition of patients in those II/III studies, they're well in excess of that 500-gram of visceral fat. And again, it's why we kind of put the graph there because it's a nice way to get a sense visually of where we expect these patients to cluster on that study.

And if you imagine that patient population would high abdominal adiposity, there's a big impact for visceral fat reduction beyond the over 14% we're seeing. But importantly, on subcutaneous fat and ultimately, with muscle preservation, that leads to weight loss. So again, the conviction is high based on the patient population. That's -- we see across studies. We don't just -- there are no diet and exercise requirements in this study. So again, placebo that placebo-adjusted weight is the best way to visualize the study because there are dynamics in that. And again, it was important for us that we do see that weight loss is coming because I know there were a lot of questions coming up, what's happening with lean mass? Is lean mass going to stabilize and is fat loss going to eventually lead to weight loss, not just for this study, but importantly, how would we imagine the impact of that back in the Phase IIa study.

And absolutely, I mean, consistent with what we've been saying for a very long time now in the patient population, which is reflected in that right box of an obesity patient population where we can substantially reduce fat and preserve lean muscle, we would anticipate weight loss in the regulatory framework and lens. So I think we would expect the majority and not really all the patients in the obesity study when you look at baseline characteristics from other studies to have high degree of abdominal adiposity and visceral fat, where we would expect to see an effect size.

Our next question is from Salim Syed from Mizuho Securities.

Hopefully, you can hear me this time. Paul, just one from us. I know you're talking about the framework of the 5% that the regulators want to see, but I presume you're also speaking to the regulators about body composition and trying to get them to be perhaps more vocal about why that matters. And I think that would certainly help Wall Street with the body composition lens. Is that something that you're actively speaking to them on? And do you have any sense on the path and when they could perhaps get more vocal? What are they looking for to get more vocal?

So we don't comment on direct interactions with the agency, but I will say you are correct. I mean the agency is focused on body composition. Even in the most recent guidance that they put out last year, there was this reflection on weight loss with the caveat is the recognition that it's really body composition changes they want to see. I mean this race to the bottom where weight loss is driven off of lean mass is recognized to that. And there's a focus on building muscle building protein, and that's very important amongst the current administrators and health and human services. So I think there's a lot of alignment between what's driving benefit.

And I think it's super important to remember that visceral fat when we talk about obesity and the driver and obesity, it's visceral fat that drives the complications in health and health outcomes. And again, that's what payers are paying for. When CMS what do we pay for? It's paying for outcomes. And so the advantage that we expect to see where we already are in this low BMI, low setting, which is kind of incredible, a single dose, 240, 6 months later, we're taking visceral fat back down to levels that exceed kind of the 5% to 10% threshold that you'd want to see to see change in outcomes, we see that.

So we are encouraged to have those conversations with regulators on what's going to ultimately drive it, but also not having to concede the fact that with substantial reduction in visceral fat and on subcu fat in that Phase II population, greater than 5% weight loss to hit a weight loss threshold is not taken off the table, but where the conversation should be if we put weight loss aside, we know clinicians and patients want to see leaner, not lighter. Scale weight is less important than body composition. We're having a huge impact on the area that people are focused on and including the regulators. And we're excited to bring these data where, again, we're already exceeding what's in the literature for now over decades of 5% to 10% visceral fat being tied to bad outcomes, bring these data and have these discussions with them on subsequent studies.

Our next question is from [ Bill Mallon ] from Clear Street.

So just to put a finer point on that, how firm do you expect the 5% weight loss to be the eventual registrational endpoint? I know in your previous answer, you talked about what patients and regulators want to see, but could that convert into an actual registrational pivotal study endpoint?

And second, on the 3 use cases that you discussed, mono, add-on or maintenance, is monotherapy now probably the least likely eventual commercial presentation? Or do you still see that as sort of a beachhead in the market?

No, thank you. I mean I'll take the last question first because I just think it's really important. So I think the obvious, which is, I think, what you're reflecting on is combination and maintenance are 2 key aspects of this medicine, right? The ability to see, particularly given the safety profile, so you're not adding on additional safety on top of the existing therapies. So we don't see changes in good safety tolerability.

So I think those become obvious. We've had companies suggest maybe you start with Inhibin E and then you can actually titrate incretins depending on what patients need. And so there are a variety of ways of thinking about add-on maintenance, and we think that's interesting. I think as we pull back and say, what does mono mean? I think to understand where we're going to be is why we're running the Phase IIa monotherapy study. I think these data don't -- again, these are Phase I data. Everyone, including some of our peer companies in biotech who've shared recent Inhibin E data are sharing patients with BMIs of 37. So again, these data are low BMI patients in a healthy study, and this is an early obesity study.

So I think we need to wait and see what IIa obesity data looks like, where we do inspect larger impact on visceral subcu fat impact on weight loss to really define the profile. And within that profile, we do recognize within monotherapy, like I said, there's about 30 million patients who are living with obesity who are intolerant to or can't tolerate that potentially 40% reduction in muscle mass. So that population is already thought to be segmented at a certain point in time. And I think a profile with substantial fat reduction and particularly visceral fat will find a place in that monotherapy market. But I think we need to wait until we have IIa obesity data in order to define where that sits relative to other obesity products.

And on the registrational endpoint?

No. So that -- to Salim's question, I mean, that is an area that you would imagine that we're very focused on. So again, putting the 5% and not taking that off the table, I do think that that's an arbitrary number. The most important thing when you're -- and truly, I think part of the reason people are throwing up 5% is there's a back calculation of fat reduction that's tied to that, what the impact on these therapies might be to visceral fat.

And so this is where, as both Chris and Erik alluded to, the VMR and being able to look at an index that is correlated to cardiovascular management and diabetes, which really looks at the impact of both visceral fat, so bad fat, harmful fat, excess fat and lean mass preservation actually gives a tool, and we've had several clinicians that we've been speaking with recently who actually think that's a really viable way because it's not a complicated measurement to look at somebody's visceral fat, which is already calculated and their lean mass to determine some sort of comparable ratio of how patients are doing on a weight loss journey that ultimately protects body composition. And we think that conversation in the setting with supported in literature with regulators would actually be a really powerful way to actually codify and quantify the impact on body composition.

Our next question is from Michael King from Rodman & Renshaw.

I think we pretty much covered everything. But Paul, just in the answer to your last question, I think I know the answer to this, but just want to get confirmation from you, which is what are the gating factors or factor that you'll need to proceed past to get -- start combination studies with incretins?

Yes. I think we're already -- that planning is underway. And the way we've designed our submission protocol on the IIa will get us some feedback that will inform how quickly we can get that started. So I think our conviction is high, obviously, on the IIa study starting soon, but I also have good conviction on the combo maintenance study. And so I think all 3 of those this year become important components to really address the prior question, which is how to think about this in the 3 treatment settings, monotherapy, add-on combination where there's a powerful way of thinking about this given the impact on visceral fat and where we think the payers will be on that and maintenance.

And if I could just quickly follow up on that. Do you feel like you want to be sort of agnostic to which incretin you combine with? Or do you want to go with the most powerful one? Do you want to go with the orals, the injectables? There's a lot of different permutations that one could envision here.

We've been having that conversation internally, and there are a lot of folks who've been talking to us about ways of which incretins they would prefer us to work with. So I think in general, we're going to make that determination when we share the ultimate study. I think there's a lot of options, particularly on the injectable side. I mean I think that there's an opportunity there because I think they're well validated. So again, we run a study. We want to have the data to be able to be reflective on where the experience and particularly when you're looking at the effect of 2 medicines together, where there's a very good understanding of the impact of what you're combining with so that signals aren't overlapped and you can really discern the impact of your product. So again, you'd imagine we're spending a lot of time with folks on that.

Our next question is from Whitney Ijem from Canaccord Genuity.

Can you hear me?

Yes.

Just a couple of quick points of clarification. For the additional data we'll be getting later this year, should we be expecting like 9-month data from 240 and 6 months from 400, et cetera, like assuming every 3-month cadence? This is the first question.

And then the second question is, have you looked at the baseline characteristics for the 600 mg dose and have any comments, I guess, on BMI and visceral fat there relative to the 400 mg cohort?

Yes. So I'll take the last question. So again, we haven't evaluated the 600-milligram cohort yet. But given the inclusion criteria and how patients are dispositioned across the study, I wouldn't expect it to look differently than the current disposition across patients. So we'll see that data. So again, to your point on data updates and cadence, the 600-milligram data will come as will other updates. I think our guidance right now is these data continue to accrete, and we'll provide opportunities over the course of '26 to share those data because I think it will be informative to us and others.

The most important data, which is kind of where I don't want to reflect is we've just seen -- we're getting super high levels of fat reduction in patients who don't have a lot of fat to lose, right? These patients don't have excess fat. So the most informative data in INLIGHT is going to be the second portion of INLIGHT, which is the Phase IIa. And that's where we're going to be able to provide updates on when that study gets up and running to and when we expect data, again, in those higher BMI patients, which is going to be much more reflective of all of the great questions that we're being what happens in that setting, we're going to have the answers to those. And based on all of the modeling and prediction, it all net gets better when you have excess fat.

So I think we're going to have a lot of data over the course of 2026 that are going to continue to inform the profile of Inhibin E with the realization that we're talking about a potent durable medicine on Activin E. I think -- well, it's easy to kind of stay focused on, and I get it, we focus there a lot too on what the downstream effect is on fat. The most important starting point is, do you have a potent, durable suppression of the Activin E ligand with which to see that effect. And I think there were a lot of questions over a year ago is what does Activin E suppression look like? It's a challenging target for a number of companies to keep durably suppressed.

So I think we kind of go back to the most fundamental and foundational part of the data set. We've got safe, durable suppression of Activin E. So then we can look forward and say, what's the impact in this low BMI setting, that checks the box that we feel very confident about going to the high BMI setting, and that's where we should be able to create the comparisons to other obesity therapies.

Our next question is from Samantha Semenkow from Citi.

Just in the Phase IIa, with the addition of the second dose, is the expectation there to drive further reduction in Activin E with that dose? Or is it longer durability of that initial reduction? And then I guess you've already talked about the 70% to 75% that you want to stay under. Is there a target Activin E dose that you believe will maximize the fat and weight loss with this potential mechanism?

No, thank you. One, I think we're there. I mean I think the key here is getting to higher excess fat and then that's where we're going to see the change. I think the dosing regimen, as you're pointing out, is going to teach us just a lot about the suppression. I mean if you look at the curves, as soon as we give the single dose, that there's a rapid decline in Activin E levels. We'll see. I mean that it's going to -- I'd say any time you study something, you're going to have an opportunity to really look at the impact of that on Activin E suppression. But really, it's going to help us as we think about long-term dosing regimens and again, focus on the potential for once a year, what that ultimately looks like.

So between the continued 12-month follow-up of the current dose cohorts, we're going to learn a lot there, particularly on Activin E suppression. And then in the MAD, that will continue to inform us in between those 2 studies, that will ultimately define a dosing regimen for a Phase III registrational study.

Our next question is from Catherine Novack from JonesTrading.

Can you hear me now?

Yes.

All right. Sorry if I missed this, but can you just give us an explanation for the change between December reporting and today's reporting the 3-month reductions in visceral fat and total fat mass. Is that a change in the pool placebo comparator? And then just one more on timing. Do you anticipate that 3-month Phase IIa data could be achievable within 2026, given a 2Q '26 start?

I'll let Chris take the first, but the short answer is yes, to your full placebo, yes.

So it is the full placebo and also that goes into like an overall model of all the data. So we have all the data since December in the model, MMRM and which includes additional placebo participants that were recruited at that time. So that's the reason.

Which is an important way to do the statistics on the study as you treat new placebo patients to make sure they're incorporated.

To your last question, mean it's highly encouraging. So again, if we get the study up, as you noticed when Chris presented, we'll have that 3-month follow-up time. And so we do see that to the prior question on the dosing regimen, we do think that single dose initially is sufficient, right, as we think about potential once a year, twice a year therapy. So we will have an opportunity within the IIa study at an earlier time point to be able to assess the impact on higher BMI patients as it relates to body composition and weight.

Our final question comes from [ Melinda Ghosh ] from H.C. Wainwright & Co.

One question regarding the VMR comparison, I just wanted to know how comparable is the BELIEVE and INLIGHT Trial to do a head-to-head comparison?

Yes. It gets back to the -- and it's a wonderful way to, I think, to reflect back again on we've got BMIs of 32, right? If we think about where our patients are proportionately. Again, it's the direct comparison of where we're starting where those BELIEVE study patients are ending on their treatment. And when you compare our patients and where they're starting after treatment to the BELIEVE patients, recognizing that they have more abdominal visceral fat, they have more subcutaneous fat, they have higher BMIs. We're still outperforming semaglutide on the VMR index, right, which does speak to this improvement in body composition in a Phase I study in low BMI patients. And so -- and on par with [ bamagrimab ].

Again, hence, not the equivalency, we think, long term because when you take our patient population and you bring them back up to the top of the curve where there would be comparison, we'd expect to see even larger impacts on visceral fat and subcutaneous fat with that higher starting point. So it is really important that while these comparisons are done, they're being done from a different patient disposition. So our patients, lower BMI, healthy, no comorbidities, no diet exercise as part of the study. And again, I just kind of reflect on these patients got a single shot and in 6 months without a diet exercise regime that's put on them, lost visceral fat in a consequential way and began to lose body weight. So these patients and most importantly, the 3.3%, we spent a lot of time with questions on body circumference. I mean this is patients also able then to tighten the belt buckle.

So just to put the visualization into what's happening in this low BMI healthy population. Again, we're highly encouraged going into the IIa study, which everyone else is looking at to see an outsized effect.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you, everyone, for joining the call this morning. I'm grateful to every Wave employee for their dedication and focus on our mission and on the patients and families we serve. Have a great day.

Good morning, and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2025 Earnings Conference Call. [Operator Instructions] As a reminder, this call is being recorded and webcast.

I'll now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations. Please go ahead.

Thank you, Sophie, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our fourth quarter and full year 2025 earnings update. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Dr. Chris Wright, Chief Medical Officer; and Kyle Moran, Chief Financial Officer. Dr. Eric Ingelsson, Chief Scientific Officer, will be available for questions after the call. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason.

I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. 2025 was a tremendous year for Wave, marked by positive clinical data sets in obesity and AATD that further demonstrated the broad potential of our unique differentiated RNAi and RNA editing capabilities. Entering 2026, we are building on the strong momentum with a focus across two priorities: accelerating development of our WVE-007 and INHBE GalNAc siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD, followed closely by WVE-008 for PNPLA3 I148M liver disease.

Today, I will start with WVE-007, which is designed to address the substantial need for better next-generation treatment options for individuals living with obesity. While GLP-1s have clearly defined the market and raised awareness of the disease, they require frequent dosing, carry tolerability challenges, induce muscle loss and result in high discontinuation rates as well as weight cycling with patients coming on and off therapy. INHBE silencing with WVE-007 aims to lower serum activin E levels and improve body composition by reducing fat while preserving muscle. Compelling human genetic data support our confidence in this mechanism of action. Activin E is a liver-derived hepatokine that signals adipocytes to slow or put the brakes on lipolysis. By removing these brakes, 007 aims to unleash fat burning without calorie restriction and without concurrent muscle loss. The current obesity treatment paradigm is focused on total body weight loss, which is not the best way to improve overall health and longevity. An ideal obesity treatment should primarily focus on improvements in body composition, meaning decreasing metabolically harmful fat tissue and preserving healthy functional muscle tissue.

Next-generation obesity therapeutic strategies must first and foremost, reduce harmful visceral fat and also be able to decrease subcutaneous and liver fat while preserving muscle. This profile is exactly what 007 aims to achieve. Visceral fat is strongly linked to multiple metabolic disorders, including type 2 diabetes, cardiovascular disease, NASH and others. It is well documented that lowering the mass of visceral fat by more than 5% is associated with reduced risk of developing many metabolic diseases. Additionally, total fat loss has been shown to improve glucose tolerance, insulin sensitivity and overall lipid profile, while simultaneously attenuating adipose inflammatory state and decreasing hepatosteatosis, which is the first step in the development of NASH. Preservation of skeletal muscle is not just about strength. Rather, muscle plays a central role in maintaining basal metabolic rate through higher glucose disposal, better insulin sensitivity and improved overall energy balance. All of these benefits can be delivered by silencing of INHBE.

We chose to target the activin E ligand through INHBE silencing over its receptor ALK7 for several reasons. Turning off protein production in hepatocytes, the upstream source with a GalNAc siRNA is the most efficient and durable way to impact this pathway. Suppressing Activin E rather than disabling a receptor that transduces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation. 007's unique ability to durably suppress INHBE is driven by our proprietary chemistry and SpiNA siRNA design. While RNAi is a clinically and commercially proven mechanism, there are extensive human genetic data supporting INHBE as a target. We believe our proprietary SpiNA designs distinguish us from others attempting a similar approach. With SpiNA designs, we've demonstrated an unprecedented tenfold improvement in Ago2 loading and several fold increase in exposure versus industry benchmarks. Together, these improvements drove substantial increases in potency and duration of activity.

WVE-007 is our first SpiNA design and our preclinical data for WVE-007 remains differentiated from any other competitor. Most importantly, we are now seeing our preclinical data translate in the clinic. In December, we shared interim data from INLIGHT study. In our lowest therapeutic dose cohort just three months after a single dose of 007, we observed fat loss similar to semaglutide without the associated muscle loss. These improvements in body composition included substantial reductions in fat, including reductions in both total body fat and visceral fat and importantly, muscle preservation.

I want to remind you, this is a Phase I study in otherwise healthy individuals with overweight or obesity and average BMI of these participants was 32, meaning this population has less visceral fat and subcutaneous fat than typical obesity studies. The trial also didn't include any diet or exercise modification. Already at our single lowest therapeutic dose, we observed that 007 demonstrated robust and durable suppression of activin E, supporting once or twice a year dosing, and we shared a clean safety profile through our 600-milligram cohort. The INLIGHT study is fully dosed through the 600-milligram cohort, and we are on track to announce six-month follow-up data from the 240-milligram single-dose cohort as well as three-month follow-up data from the 400-milligram single-dose cohort later this quarter. With continued fat loss and with stabilization of muscle or lean mass, we are looking to see continued improvements in body composition and fat loss beginning to drive weight loss.

As mentioned earlier, the INLIGHT population has lower fat to begin with, versus typical obesity studies, and thus, a better comparison will be made of individuals with higher BMI who have greater fat mass, both visceral and subcutaneous, which is exactly what we will be looking at in the Phase IIa multi-dose portion of INLIGHT. This MAD portion will enroll patients with higher BMI and comorbidities and is on track to initiate in the first half of this year. Chris will speak more on that later.

We are also excited about the potential for this molecule as both an add-on to incretins as well as for maintenance post as an incretin offering. We have generated a compelling body of preclinical evidence supporting these use cases, and we remain on track to initiate new clinical trials evaluating 007 in these settings in 2026. There is widespread recognition of the need for novel obesity mechanisms and therapeutics beyond ingredients. A once to twice a year treatment, which can reduce fat and preserve muscle with a favorable safety and tolerability profile has the potential to shift the obesity landscape.

In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing because it is a single gene disorder where correcting the mutant RNA transcript in the liver directly addresses the root cause of both the lung and liver manifestations of the disease. There are approximately 200,000 individuals in U.S. and Europe living with homozygous ZZ AATD with high risk of disease. AATD is a debilitating disease that impacts multiple aspects of daily life from their ability to work and play with their children to even just walking to the mailbox. These individuals living with alpha-1 have been underserved and remain in urgent need of an effective therapeutic option. Current treatment options are limited to IV augmentation therapy that aims to address the lung with nothing currently approved for AATD liver disease. With our highly specific and efficient GalNAc AIMer design for RNA editing, we do not modify DNA, and we do not require delivery with lipid nanoparticles or LNPs that may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. We also avoid the irreversible collateral bystander edits and indels, which are associated with DNA editing.

With 006, we have shown that RNA editing can restore endogenous M-AAT protein to therapeutically meaningful levels, reduce mutant Z-AAT and reestablish the body's normal physiologic response to inflammatory stress, something that is not possible with the current standard of care. Remember, AAT protein plays a protective role during inflammation or acute phase responses when it's rapidly consumed. A patient on IV augmentation risk lung injury if AAT protein levels fall too low during an event. In contrast, RNA editing is designed to restore an MZ-like acute phase response where AAT production rises to meet the demand. With our data demonstrating already over 11 micromolar protein greater than 50% editing and acute phase response at our lowest dose, we're advancing our regulatory engagement with full control of the program. We expect to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. Additionally, we are on track to report data from the 400-milligram multi-dose cohort of the ongoing RestorAATion-2 clinical trial this quarter and report single and multi-dose data from the 600-milligram cohort in 2026.

Building on our clinical success in RNA editing, we are advancing our second RNA editing clinical candidate, WVE-008, a GalNAc-conjugated AIMer for homozygous PNPLA3 I148M liver disease, and we are on track for CTA submission in 2026. In DMD, we remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In addition, our research collaboration with GSK continues to progress, and GSK has now selected a fourth program to advance the development candidate following achievement of target validation, which carries an associated milestone payment that was received in the first quarter. Under the collaboration, GSK can advance up to eight programs leveraging our PRISM platform with target validation work ongoing across multiple therapeutic areas. Wave is eligible for up to $2.8 billion in initiation, development, launch and commercialization milestones as well as tiered royalties, and we expect to continue to receive milestone payments in 2026 and beyond.

With that, I'd like to turn the call over to Chris to review our clinical progress with 007 and our RNA editing programs.

Thanks, Paul. Starting with our INLIGHT clinical trial of WVE-007. The ongoing portion of INLIGHT is a Phase I randomized placebo-controlled single-dose study in otherwise healthy individuals living with overweight or obesity. The study is active at multiple clinical trial sites, including in the U.S. and is fully enrolled through four dose levels. Our three therapeutic dose cohorts are fully expanded with 32 participants in each cohort. Individuals received a single dose of WVE-007 and are then followed for up to 12 months with key assessments, including safety, tolerability, PK, activin E, body composition as measured by DEXA, biomarkers and body weight. The average BMI in the study is low compared to what is observed in typical obesity studies, and there are no diet or exercise modifications.

With this backdrop, we are particularly excited with the positive interim data we shared last year. At three months in the lowest therapeutic cohort, a single 240-milligram dose of 007 led to an improvement in body composition, characterized by a placebo-adjusted 4% reduction in total fat, 9.2% reduction in visceral fat and preservation of muscle as evidenced by a 0.9% increase in lean mass. Notably, 007's placebo-adjusted reduction in total fat mass was on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat. The safety profile was favorable and there were durable reductions in serum activin E, supporting potentially once or twice yearly dosing.

Overall, these data demonstrate that a single dose of 007 can shift body composition towards less visceral and total fat while preserving muscle consistent with our preclinical findings and with the underlying human genetics. We look forward to evaluating the impact of this mechanism at a higher dose and over a longer duration later this quarter. With this data, we anticipate that the continued fat loss and stabilization of muscle mass will drive further improvements in body composition and weight loss.

We are preparing to initiate the Phase IIa multi-dose portion of INLIGHT in which we expect to enroll individuals with higher BMI and comorbidities. Assessments in this multi-dose portion are expected to be like those in the single-dose portion with additional inclusion of body composition measured by MRI and liver fat content as measured by MRI-PDFF. We're excited to evaluate not only body composition to demonstrate fat loss with lean mass preservation in the study, but also better understand the impact on liver fat, which could read positively for a NASH indication. Finally, we remain on track to initiate new clinical trials evaluating 007 as an incretin add-on and as a post-incretin maintenance therapy in 2026.

Now turning to our ongoing RestorAATion-2 clinical trial of 006 for AATD. Our goal is to achieve three criteria: one, keeping basal protein levels at or above 11 micromolar. Two, driving circulating M-AAT protein above the 50% heterozygous MZ threshold with corresponding decreases in the mutant Z-AAT protein and most importantly, three, restoring the physiologic response of serum AAT protein to acute inflammatory events.

Last September, we delivered data from our RestorAATion-2 trial, demonstrating that we have achieved these goals with 006. Most notably, we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with a total AAT levels of greater than 20 micromolar, just two weeks after a single dose of 006. We are accelerating our regulatory engagement time lines now that we have full control of the program. We anticipate receiving feedback mid-2026, which will guide our path towards an accelerated approval.

Now turning to our second RNA editing clinical candidate. We are advancing WVE-008 for homozygous PNPLA3 I148M liver disease. This PNPLA3 variant is a well-established driver of NASH pathology, yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA3 I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. With 008, we aim to correct the I148M variant using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reversing steatosis and fibrosis and improving liver health.

In our upcoming first-in-human study of 008, we plan to leverage previously genotype populations to efficiently identify homozygous I-148M carriers, evaluate target engagement of circulating biomarkers and assess early signs of efficacy using noninvasive imaging. We remain on track for a CTA submission in 2026.

With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the fourth quarter was $17.2 million compared to $83.7 million in the prior year quarter. For the full year 2025, revenue was $42.7 million as compared to $108.3 million in the prior year. The quarter-over-quarter and year-over-year decreases were attributable to revenue recognized upon the termination of the Takeda collaboration in October 2024. These decreases were partially offset by increases in revenue recognized under our collaboration agreement with GSK.

Research and development expenses were $52.8 million in the fourth quarter of 2025 as compared to $44.6 million for the same period in 2024. Research and development expenses for the full year of 2025 were $182.8 million as compared to $159.7 million in 2024. These increases were primarily driven by our rapidly advancing INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation.

Our G&A expenses were $20.9 million in the fourth quarter of 2025 as compared to $16.1 million in the prior year quarter, and $75.3 million for the full year of 2025 as compared to $59 million in 2024. These increases were primarily related to compensation-related expenses, including share-based compensation. Our net loss was $53.2 million for the fourth quarter of 2025 as compared to net income of $29.3 million in the prior year quarter. Net loss for the full year of 2025 was $204.4 million as compared to net loss of $97 million in 2024. We ended the year with $602.1 million in cash and cash equivalents, which we expect will be sufficient to fund the operations into the third quarter of 2028. It's important to note that potential future milestone and other payments to us under the GSK collaboration are not included in our cash runway.

I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. 2026 will be a year of strategic focus aimed at accelerating development of 007 for obesity and rapidly advancing our RNA editing portfolio. We are excited to build on our positive momentum and are energized now more than ever to unlock the full potential of our RNA medicines pipeline to transform human health. Looking ahead, we expect our next update to be data from our INLIGHT clinical trial of WVE-007 for obesity and additionally, expect this to be followed by data from our RestorAATion-2 clinical trial of WVE-006 in ATD. We look forward to keeping you updated on our progress. And with that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] We'll take our first question from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. I guess just one on AATD. One of your major competitors recently aligned with the FDA on their biomarker-based accelerated approval framework. How closely does your regulatory strategy mirror what they've laid out for their biomarker-driven path? And are there any key differences? And have you had comparable alignment discussions with the FDA?

No. Thank you, Jenny. And I think what we all heard in the feedback from one of our recent peer companies from the agency is very much aligned with our thought process in AATD in the beginning and frankly, fairly well aligned with the existing therapies that have been developed for AATD, which is a biomarker approach in a disease where the protein is the measurement therapeutically active substrate. And so we wouldn't anticipate a distinct or different conversation. I think for us, recognizing that the only protein we're making is the M-AAT protein, and we don't have to deal with bystander edited proteins and the functionality of that, I think we're in very good shape for a discussion on active protein and meeting the requirements that we see as the therapeutic threshold. So we are engaging with them. Obviously, we don't comment on individual conversations with the agency, but we do fully anticipate feedback by mid-2026 on a registrational pathway. I think it was also highly encouraging recently, and I'm sure many of you heard on the plausible mechanism pathway, comments made by the head of the FDA as well as CEDR on using those pathways specifically for ATV. So I think it's a very good time for us to be approaching regulators on a pathway for alpha-1.

Our next question comes from Salim Syed with Mizuho Securities.

Maybe just one for us on just the second quarter data. I think at JPMorgan, you guys mentioned that we should be expecting the 400-milligram multi and 600-milligram single in the second quarter of this year for INHBE. It doesn't seem like it's listed in the slide or the press release. Has there been a change? Are we going to get that data? Or what caused you to remove it from the catalyst slide?

Yes. No, the data is on track. I mean, as we always say, the beauty of a single-dose study with exquisite durability is all the patients are dosed. So data just continues to accrete. So we'll focus on the upcoming data, looking at the impact of time on 240 and the 400. And there's opportunities again for data cadence over the course of the year. We're not guiding to each individual update. But as you said, all these data time lines are all on track given that all the patients in the study have been dosed. I mean we have now over 100 patients on the study across multiple dose cohorts. So it does create a unique opportunity over the course of this year.

Okay. So we'll still get that data then, Paul, or something that we -- you're still sort of...

Data included by the next update in Q1, and then we'll provide subsequent updates on Catalysts at each time we provide the update. So the next update on INHBE is this quarter.

Our next question comes from Steve Seedhouse with Cantor Fitzgerald.

I wanted to actually expand on the alpha-1 antitrypsin deficiency expectations. So assuming you get alignment on an accelerated approval pathway and some AAT marker either M or total. What are you hoping that the confirmatory trial requirement will be there? Or what are you expecting? Do you already have sort of clarity on what the post-marketing requirements would be for full approval eventually?

It's a great question, Steve. I think that's the conversation that we want to have with the agency and align on. I think there's a number of ways of thinking about that, that can be efficient, particularly in the design of a subsequent studies that could roll into addressing some of those opportunities. And I think there's really two sets of development pathways. One is obviously respiratory. The other important feature of RNA editing, remember, is we see dramatic decreases in Z-AAT protein, which open up the opportunity for liver indications as well. So I think our goal is make sure that we focus on an accelerated approval pathway for AATD patients. These patients aren't liver and lung patients. These are AATD patients and then ultimately establish the right pathway as it relates for both labeling for lung and liver, and we'll align with the agency on those.

Our next question comes from Joon Lee with Truist Securities.

Do you have an internal weight loss bogey for the forthcoming six-month data for the 240 milligrams and three-month data for the 400 milligrams to feel confident on achieving the 5% weight loss bogey at 12 months? And what sorts of outcomes data are you planning to generate to minimize potential payer pushbacks?

Yes. Thanks for the question, Joon. I mean I think if we ultimately think about the pathway for a greater than 5% weight loss, remember, that threshold is after 12 months in patients that would be presumed to have an average BMI of 37 on an optimized treatment regimen. So in the low BMI Phase I otherwise healthy patient population at the doses we're in now, I think we'd like to see continued trajectory down on the weight loss curve. I mean we had about 0.9% decrease in body weight with increase in lean mass preservation and decrease -- substantial increase in fat. So with the expectation that total fat should continue to decline, we expect lean mass to stabilize, we would expect to see that change in total body mass. And that would just be a great indicator for us. And again, we continue to follow that, all of which would signal incredibly favorably that in the study, and as we mentioned on the call, I think this half of the year, getting that Phase IIa portion of the study in the MAD in patients with allowing for comorbidities, which means the expectation for higher BMIs that more aligned with other obesity studies would put us in a wonderful position to be able to have a regulatory pathway on weight loss.

I think the broader conversation that we all need to kind of be ready for, and I think this is what we're hearing too from our strategic partners as well, is that this addressing body composition piece is critically important. I mean what we hear time and time again, both from the clinicians, patient advocacy community and obesity, again, and strategic partners is scale weight versus body mass. And this notion that weight on a scale equating to actually healthy phenotype and actually what's driving obesity improvements in health outcomes is driven from fat reduction, lean mass preservation and ultimately seeing that forward. So I think it's important that we look at the benchmarking for weight loss to be, can we cross those criteria for an approval in obesity? And we do believe that we will use that pathway. But I think what's more important than that in terms of ultimately the therapeutic potential for INHBE in the obesity landscape is really driving this improvement of an overall body composition, and that's how you get healthy outcomes.

Our next question comes from Alec Stranahan with Bank of America Securities.

Good to see the progress. Maybe one on obesity. It was interesting to hear your thoughts on the various activin E strategies out there. Are there any specific AEs or other metrics you think we should pay attention to for, say, ALK7 or direct active modulators that you may be avoiding here with targeting INHBE? And I guess, longer term, given the better tolerability you're seeing so far, how does the duration of mass benefit that you could potentially achieve with 007 fit into your picture for addressing some of the comorbid conditions that these patients face.

No. Thank you. And I'll break the question into the first piece. I mean, as we think about, as you mentioned, some of the myostatin and other activin pathways. I think as we're looking at our safety profile versus safety profiles of other medicines in that space, I think they've been distinct. So I do think what we're seeing in terms of not just driving fat loss, and we'll talk about that in the context of your what's ultimately going to improve the outcome for patients in that status. I think we see a very differentiated safety profile and efficacy profile as it relates to fat loss.

As it relates to the -- as you pointed out, some of the potential risks and future looking at ALK7, I think we need to continue to watch those programs over time. I mean that's something that has to be evaluated is what is the downstream impact of this kind of multifaceted ligand strategy and what happens. And I think we'll be -- data will be accreting there and people will be able to observe what the impact of that is. I think it gets back to the very important point of why we selected INHBE, which is specificity. I think this has all learned over a long time in obesity that specificity and understanding pathways is important. And I think the INHBE access with ALK7 in terms of driving improvements in outcome is established both in genetics, following patients over time, so in clinical genetics and ultimately, as we're seeing translate in our human studies.

As you point out, and I think this is an incredible opportunity in thinking about areas for INHBE reduction and particularly active reduction. I do think this opportunity is it's very well established that a 5% or more change in visceral fat does change outcomes, cardiovascular outcomes, diabetic outcomes. And so when we do think long-term about what's actually driving the benefits of when people say weight loss, ultimately, what's driving those benefits is this reduction in visceral fat, which we've surpassed with now nearly 10% reduction in visceral fat at our lowest therapeutic dose at the earliest time point and reduction in total body fat. So I think with all of that, coupled with preservation of muscle, which ultimately as an endocrine organ is critical for sustaining, the profile of what's ultimately going to drive health outcomes is that benefit. And those outcomes are well established in the literature.

I think when people step back and say, what overall is important in medicine, I think those two things are really important. One, we have the health outcomes and for those who try to think about what's going to happen with that preservation. I don't think people raise their hand and say, I want a medicine that I'm going to lose 40% to 50% of my lean body mass at the expense of losing fat. And so I think ultimately, as an obesity therapy on health outcomes and other measurements, a reduction in substantial fat, particularly visceral fat and preservation of lean mass over time creates an optimal therapy in the space and with durability of once to twice a year as we think about the commercial prospects. You really can change the landscape in the current setting. So as we think about maintenance and the opportunity for once twice a year and the ease of administrating that. But we also think about the global 1 billion patients worldwide living with obesity and how they get access to therapies. And when you change that dynamic where patients aren't having to go in for a weekly or monthly injection of a protein or stay on a daily oral pill that has to be coincidental with eating and has all of the other tolerability challenges. We think it opens up the global obesity landscape, too.

Our next question comes from Madison El-Saadi with B. Riley Securities.

It's nice to see you're adding MRI-PDFF to your planned Phase II obesity trial. Just wondering what is the treatment delta you are expecting to get there, just recognizing that monotherapy semaglutide gets around 30% to 40%. So curious where you think you may land on that scale from, say, GLP-1 to the FGF21 mechanism.

Yes. I mean without at this point, running -- I mean, it was interesting in looking at comparator data, peer data on combinations where they were seeing nearly a 78% reduction in liver fat. I think there is a substantial opportunity, as Chris pointed out on the call, for MASH as a potential indication as a monotherapy. So I think by enrolling a study where we have patients that allow for comorbidities, I think there is going to be a substantial opportunity for us on imaging to look at monotherapy data by itself in recognizing that there really is a powerful signal that's been seen with INHBE reduction in weight loss. And I think it steps back into again, the overarching opportunity for an INHBE pathway and really thinking about the substantial active knee reduction and driving outcomes, both for MASH and reduction of liver fat. And as we were talking about the last call, as we think about just lipid levels in general, you should see with this reduction in these patients with comorbidity. And this is really, I think, again, speaking about long-term outcomes and benefits to patients in cardiovascular disease, reductions in lipid profile, meaning reductions in cholesterol, LDL, hemoglobin A1c and triglycerides.

Our next question comes from Catherine Novack with Jones Trading.

Just one for me on the dose response and relationship between activin E and fat loss. So clinically, you are seeing similar fat loss to a competitor with lower activin E knockdown. Is there anything we're missing or is it just small numbers? And then similarly, do you have preclinical modeling data that shows that going from 75% to 85% knockdown is going to lead to better fat loss?

Yes. I mean I think one of the things that we've seen, and as you pointed out, our study versus other studies that have come out is we actually have larger cohorts. So I think the dynamic effect that we're seeing with longer-term measurements of activin E, I think we feel really confident that both -- and we'll talk about the dose response second, that we do see really highly durable suppressed activin E levels over time. And I think that's the most important feature of speaking to activin E reduction is not just do you knock it down, it's keeping it chronically suppressed. And so we have the long-term data that, again, to your point, differentiates this from other programs in the space.

Secondly, going back to our preclinical data, yes, we have shared that we see a dose response on activin E reduction driving, again, with suppression, driving further weight loss. Remember, that was the measurements we were using in our preclinical experiments were reduction in weight loss and that weight loss driven by fat loss. So again, gives us continued support between the 240. And we've been consistent in saying the bookends that we think around the therapeutic activin E, we believe, are modeled into the 240 versus 400 as being opportunities to look at that dynamic range on weight loss as we saw preclinically and translate that into fat loss in the clinic. So yes, we would expect to see the impact of both time but also dose on fat reduction.

Our next question comes from Cheng Li with Oppenheimer.

Congrats on the quarter. Just wondering for the upcoming INLIGHT update, are you planning to share some additional like biomarker data for those like related to inflammation or maybe fibrosis? And also, are you planning to present the data at maybe a medical conference this year?

Yes. We haven't guided to where we're presenting. It will be this quarter. So I think that's the most important update for consistency. In terms of data, we'll present the data the expectation should be similar to last time in terms of looking at the key metrics of measurements. I think what's important and really where the opportunity sits, to Chris' point on the call for the IIa portion of the study is since these are otherwise healthy individuals, and that's really why the BMIs are in this range of around 32 is because we've cut out patients that have a lot of the other features that you're measuring because those wouldn't be considered otherwise healthy individuals, and they don't meet that criteria. And so therefore, being able to look at some of the other markers that one can see in the study does present more of a challenge because they're otherwise healthy. I think the opportunity as we get into the Phase IIa, where we allow patients with comorbidities being higher hemoglobin A1c, other lipid characteristics will give us more opportunity to be able to discern some of these other changes that are seen with INHBE in a clinical context, but that will be in the subsequent IIa portion of the study.

Our next question comes from Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. Can you just maybe help us set expectations into the upcoming obesity and AATD readout? So for 007, how should we all be thinking about what is good in terms of body count or fat reduction from the 240-milligram cohort at six months and then 400 at three months? And then similarly for 006 in terms of what AAT levels would you want to see from 400 MAD? Thank you.

I mean I think the key criteria for us is we're already on that curve with the 240, where we're seeing fat loss similar to GLP-1s increased visceral fat, higher fat visceral fat reduction than GLP-1s and lean mass preservation versus remember, at that three-month time point, there was nearly a 50% reduction in lean mass on the GLP-1. So I think continue to see the profile of an improvement in body composition with, I think, continue to see the impact of that fat reduction. So that should happen over time and lean mass should be stabilizing over time, which should be driving that lean -- the total body mass curve down, so weight down. I think that will be the opportunity of looking at the impact of time at 240. And then it was brought up by one of the other questions, which I think is an important one is we're going to be able to look at the establishment of this dose response context. So what's the impact of time on that curve and what's the impact of dose on that curve? And so the 400 will be equally as important looking at that early time point. So that will be at the three-month time point because, again, we can compare it to the GLP-1s on the dose response at that early time point with a higher dose and suppression of activin E and potential decreasing in fat and be able to set the stage for what does that look like modeled over time based on the 240 six months. So I think we've got an opportunity really to continue to watch those kinetics play out.

And if we go back to our preclinical data, that was really the slope of that weight loss curve was driven by exactly what we believe we're seeing in humans, which is mice have substantial reductions in total body fat. They had a slight increase in lean mass. And overall, the mice lost weight similar to GLP-1s and their curve was continuing. So I think the opportunity is to actually be able to model between our preclinical data and clinical data based on the human evidence coming forward in obesity.

For 006 in AATD, I mean, I think it's important to remember that the arms race for more and more protein isn't necessarily what the requirement is if you're not doing IV protein replacement therapy. So I think the idea in editing has been to establish do you have the therapeutic threshold to say that these patients are corrected to an MZ phenotype so that ultimately -- and it is really important when we talk about editing to step back and say, it's a chronic disease of acute exacerbations. And therefore, the whole premise of this is how do you prepare a patient so that when they have that exacerbation, they can rise to meet that need. And as we saw, 20 micromolar, the lowest single dose meant that those patients actually in the event are protected at levels that we're talking about for IV protein replacement to hopefully prevent that where that nadir could actually be lower in the IV protein replacement space. So I think we've already seen that we're at that threshold. I think the question going forward is going to be both durability, time, so opportunity to continue to see as liver gets healthier, are we producing potential for more M protein over time, which we think based on our preclinical experience should be seen, so you can continue to see that protein get released to see increases in, but ultimately continue to sustain the portfolio. I mean, the pattern of increased editing efficiency.

So I think that's the notion. We're going to be able to look at that at the 400 and see again, duration. So is this -- this will be monthly? Do we think about the opportunity to think about a medicine that could be quarterly or less frequently. Being able to model that is going to be important ultimately as we think about a therapy. And so I think we're set up to be able to distinguish this as delivering on the profile that we believe is going to be requisite for the regulatory interactions for a potential accelerated registrational pathway.

Our next question comes from Ben Burnett with Wells Fargo.

This is Craig on for Ben. I appreciate the opportunity to ask you all a question today. So appreciating the fact that 007 is a liver-directed agent, I guess, based on your understanding of the biodistribution of that agent, would you expect any of it to find itself to muscles? And maybe just a quick second one here. Given that now you're exploring the benefit of 007 on liver fat, how do you see that coexisting with 008 over longer periods of time?

Yes. I mean I think to address the first one very simply, it's a GalNAc conjugated siRNA. So it's an active receptor-mediated uptake in the liver. So that is the target organ for delivery. And based on our preclinical data, that's where the drug is distributed and exerts its impact on a simple basis. And the second question was -- sorry, if you want to...

008.

008. So, how do these work? Yes. I mean I think what we have to think about in 008, and it's important to kind of step back separately from just thinking about 007 and the impact on liver fat and 008 in the constituency, MASH is one indication for 008. If we step back and think about the PNPLA3 indication, these patients are at risk of all told liver disease. So the best way to think about PNPLA3. And maybe, Erik, you can share and we should double-click back on the indication because I think it is important to really think about this as a genetic mutation for the liver disease in general and all to liver disease, not just NASH and where the ability to identify the mutations found in 23andMe, it's a genetic mutation that can drive a whole variety of diseases, of which NASH is one. But Erik, I don't know if you want to...

Yes. Just to build on that, I think this is the first approach that is directly -- or rather, there are no approved drugs that are directly addressing the pathology in these carriers. So it's kind of -- it really corrects back the disease driving variant in these carriers. And to Paul's point, it's not only MASH, it's across a whole set of different liver diseases. So it addresses directly the causal variant. So therefore, it's kind of a unique approach, we think.

We think about this as having kind of and we shared some more on this. So it's a good opportunity for us to go back to Research Day. There's this concept on lipid trafficking and when we think about MASH and where that application is, but there's also an inflammatory component in these PNPLA3 patients, which is why their response to injury drives this fibrosis and liver injury in general. And so the real opportunity in correcting this, and this is again why you want to correct it and not silence it is restoring the functionality of this enzyme so that what you're able to do now for these cells is actually repair them. So not thinking about kind of symptomatic treatments that improve kind of one aspect of the disease, but actually fix the underlying pathology that allows these patients to go forward, not just focus on liver fat, but actually prevent fibrosis and downstream sequelae, where these patients who are homozygous are at very high increased risk of really progressing to cirrhosis and ultimately new transplantation. So I think the opportunity we really have in fixing this disease at the source.

This is separate from thinking about how do we think about the opportunities beyond treating body composition as it relates to obesity therapies with 007. So if we think about 007, there are a whole host of things we can think about as we think about visceral fat reduction and what the impact long-term is on visceral fat reduction, improving outcomes to patients, not just thinking about obesity in general, but thinking about visceral fat reduction downstream, thinking about MASH as another indication because of the increased impact on reduction in liver fat. And so I think these medicines are very different in how they approach things. INHBE really focused on a pathway around fat reduction and the ability of 008 to focus on a pathology that's very uniquely driven off of a genetic mutation.

Our next question comes from Roger Song with Jefferies.

This is Cha Cha Yang on for Roger. I had two questions. One is, can you speak more to what you expect to see for 007's kinetics based on some preclinical PK data? And what we should expect to see for the rate of fat loss, weight loss and lean muscle mass change over the next six to nine months? And then just second question really quickly. Can you just remind us what trials and programs your 2028 cash runway will include?

Yes. I mean I think what we see on the curves, if you look at the animal modeling data, so you can follow where the GLP-1 curve on weight loss is, where that's heavily predominantly driven on lean mass loss at the beginning and then continued fat reduction kind of gives you this that increased slope and plateauing and then where you see INHBE, where you see this acceleration kind of into that curve. And so I think we're right on that tracking with the rate. We're all learning about the pathology -- say we're all learning about the rates of that curve together. I think it is tracking actually very nicely to our preclinical experience. I would say mouse kinetics to human, there's always a separation. So we just have to continue to watch that play out. But I think we have a very good benchmark in looking at the GLP-1 versus INHBE, and they're tracking as to be expected. So again, high degree of conviction that with more time, you see more fat reduction. With higher doses, you'll continue to see more fat reduction. And then as you point out, we'll have these periods at six months, nine months and out to the patient study allows for a follow-up out to a year. We're going to get the opportunity to really follow that in this lower BMI setting.

I think what's going to be exciting about bringing on earlier now this higher BMI setting is going to be that we're going to be able to look at these things in tandem, right, be able to track these together and be able to see, again, in that higher setting, which is more akin to the animal model, does that happen faster? And so we'll be able to look at that and track that. But again, very good correlation between the DIO mouse and what we're already seeing in the clinic. So again, drive that conviction, remembering that we did see weight loss in the preclinical models.

Your other point within this 2028 envelope is exactly, as we point out, delivering on our four strategic priorities. We're going to deliver the 006 data. We'll have our regulatory interactions in the middle of this year. It was and why we said last year, it was important for us to accelerate INHBE. It funds the Phase IIa studies so that we can continue to deliver the study in patients with a higher BMI. And it's inclusive of accelerating, as we said this year, the study on both add-on and maintenance. And what's been interesting in some of our strategic conversations is we are getting -- there are good conversations happening with the ability to access various incretin and various designs and studies. And so that isn't incorporated into those savings in those studies, but there's opportunities that exist as we think about those collaborations ways of thinking about retaining the asset, but ultimately continuing to drive clinical data sets off of that. So again, delivering in our runway, as we said at the beginning of this year, the core strategic principles of 007 in obesity, 006 for alpha-1 antitrypsin deficiency and bringing also forward the CTA submission and the clinical trial for 008. So that's in the envelope.

The next question comes from Michael King with [indiscernible].

I just want to maybe reflect more on 007. We're talking in very scientific terms. But if you think about the trajectory of the obesity space, I look at it as kind of a war of one upmanship that started between Lilly and Novo and then it's going to be, I think, joined by the likes of Pfizer and others just trying to focus on body mass index or loss of body weight. You see the consumerism aspect of it with Serena Williams and Charles Barkley losing 30-plus pounds or 50-plus pounds, respectively, of weight. So how does one communicate maybe -- and this may not be your problem to solve. It may be your strategic partner, but how does one communicate the benefit of loss of visceral fat and preservation of muscle apart from body weight when so much of the light in the obesity ecosystem is focused on body weight loss.

No, it's where we spend a lot of time, and it's frankly why we're extraordinarily excited about where INHBE fits into this because I think athletes is not aside, call it you're a normal person, right, who is going and wants to your point, there's a need or requirement in their minds, they're saying, I need to lose weight, right? They're worried about either being obese or overweight and they want to take a therapy. And if you look at this, I don't know anybody who is going to raise their hand and say, you know what, I wouldn't mind losing 30%, 40%, 50% of my lean body mass because I'm going to look at a scale and it's going to go down. When you could look -- and actually, I'm reminded this because I was actually talking to a KOL yesterday. And what she was reminding me of is we need patients who are leaner, not lighter. And the notion that she has patients to come into the office and she remind them, she's like, don't look at your scale. But if I told you, they're coming in because they're saying, look, I want to lose like 40 pounds. I want to lose this. And then she puts up a picture actually like Michael Phelps. And she's like, if I told you could be 200 pounds and look like that versus 150 pounds but have no lean mass, what would you -- and inevitably, when people think about it in real-world context, what they're really saying is they want to be leaner. They want to have high lean body mass low subcutaneous and visceral fat, but they don't want to do it at the expense of muscle, and they're thinking about it.

They can get their back.

It's just as important. And now -- but it doesn't mean -- so like -- and I don't want to take us into the swirly of, it doesn't mean you're not going to lose weight. If you lose subcutaneous fat and you preserve muscle, you will lose weight. So this notion that all of that has to not coexist with the regulatory pathway, I think, is a false pretense. So you can completely exist within the regulatory paradigm. But if I actually see where regulators are going as well, they're indexing this, right? The guidance last year was on body composition, bring us weight loss, but bring us body composition. Don't come where this race. You pointed out, the race that's happening in this other kind of or call it on the incretins. It's just like incremental loss of -- it's at the expense of muscle. There's tolerability, there's weight cycling. There's this notion of a whole generation of people who are on a therapy and it's switching from saying, well, we should think about this like hypertension, keep people on it for a long time. 70% of people can't stay on the incretins for a full year, right, with all of the other complications to it. So I think the notion of really reminding ourselves why are we doing this? A once to twice a year medicine that can drive substantial fat reduction, preserve lean mass. So you get that opportunity on both, as you said, the perception side, what do I look like kind of question. But most importantly, what's going to drive health outcomes benefit is the profile of what INHBE and activin E reduction brings, but does so at a scale where, again, safety, tolerability, I think, is highly differentiated from the growing incretin class. I think maintenance will be a really fundamental opportunity here, the idea of what does the off-ramp for a chronic therapy look like where somebody now has to look at the potential lifetime of sustaining themselves on an incretin therapy. It's why we're excited this year to get the maintenance study, which is give patients an off-ramp. You can have the sustained reduction in fat, you can prevent continued sustained loss of muscle. You can have a once to twice a year maintenance therapy. And so I think there's an enormous opportunity on the maintenance setting. And I think we're hearing this echoed by all of the strategics that we're talking about that truly recognize that this INHBE body composition, maintenance is crucial.

And not to be lost to realize that when we do talk about this as an obesity therapy, there are a substantial number of people who can achieve goal on the incretin therapy. They can't tolerate staying on. They can't tolerate being titrated up on it. And so we really do think about the therapeutic paradox. We have one strategic say, what would be really interesting is INHBE is the basal state and then titrate the incretins around it so that you can preserve better tolerability and safety. So I think this really does fit within this paradox. But as you point out, I think it really is important for people to remember in the real-world consequence, this really is delivering the profile that patients are looking for, reduction in fat, preservation of muscle, ultimately allowing patients to be leaner, not lighter.

We'll take our last question from Cassie Yuan with RBC Capital Markets.

On INHBE here, I appreciate that you're amongst the most advanced in clinic today for this target, but it also seems like some of your competitors are speeding up by following signals in comorbidities and subpopulations earlier in their studies. Could you maybe comment on how important is it to be the first pivotal data for INHBE? And ultimately, do you see activin E space accommodating multiple players? And what do you think is going to be the differentiating factors amongst the players here for activin E lowering therapies? Any color there on these dynamics is much appreciated.

Yes. I think, look, I mean, as you point out, obesity is a very large space, so it can accommodate multiple therapeutic companies. But as we've also seen in the space, it's helpful to be a leader. And I think within the INHBE access, I think Wave is well poised to be the leader for INHBE silencing. I think our chemistry is highly differentiated. We saw that from driving single-dose weight loss in our preclinical studies, which is the only preclinical data to date that's shown dramatic decreases in sustained activin E reduction tied to weight loss. So our chemistry translated to differentiated preclinical data, which ultimately, as we've seen, translate into the clinic in a highly differentiated way.

I think what we're seeing across the INHBE space with competitors are programs that look very similar across all of the peer companies. I mean if you look at all the posters that were sitting there on other INHBE programs at Obesity Week, they all looked remarkably similar. So I think there will be a separation between here's what Wave is bringing to the table in a highly differentiated way to look at INHBE with a once to twice a year therapy that drives a dramatic difference. And then there'll be everybody else. So I think it creates a very unique opportunity for us really to define the space and then sustain our leadership within that space. And I think it is important because I think we tend to think about siRNA as a commoditized space across indications. And I think we're hearing this from those who are experts in the field recognizing that what the team has done in driving new chemistries forward has created a very unique space for us here.

Now we need to sustain that leadership, really, as you pointed out, defining what success is going to look like. And so it's wonderful that we could see already this differentiation. Everybody is comparing us to GLP-1s at three months, other INHBE programs at these time points, that we're a little bit later. But we're doing this in a way where our BMI setting, to your point, we're looking at patients who are nondiabetics, right, who are low BMI, and we're already seeing these differences. We're excited to go into the higher BMI setting because I think that's going to give us the opportunity to see even greater weight loss and fat loss and then ultimately changes in other outcomes measurements. So I think we're really poised to not have to say we need to get into these settings to be able to see the efficacy. We can see it in this low setting and then only build on that from here, time, higher doses and also in patients with higher BMI and comorbidity. So the data should continue to mature as these studies move forward, both in the existing INLIGHT study, but also in the Phase III study.

Thank you. There are no further questions at this time. I will now hand the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning. We appreciate your continued support, and have a great day.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Wave Life Sciences and presenting on behalf of the company, we have President and CEO, Paul Bolno. Paul, over to you.

Thank you, Tess, and thank you, everybody, for joining us today. Before we start, we'll obviously be making some forward-looking statements during this call, so I'd please ask you to refer to our SEC filings for updates. Taking a pause and thinking about entering 2026, we are energized now more than ever to unlock the broad potential of RNA medicines and open up the opportunity to transform human health. And what this really reflects back on as a journey on building a leading RNA medicines company and at the foundation. And this is going to be important as we speak to the evolution of the clinical portfolio is the foundational bedrock of Wave is in our RNA chemistry. So when we talk about what we've been able to build and differentiate from, we should be thinking about a proprietary chemistry engine, and we'll share more on that later. That enables us to rapidly take deep genetic insights and translate those into impactful medicines. And I say this because the speed with which now we can take chemistry and translate that into medicines is incredibly rapid. So to put this in context for the obesity therapy. It was 18 months from the time we generated mouse stated human clinical data and about 24 months from the time we had identified a genetic sequence to delivered clinical data. So rapid insights into rapid medicines. This is all built off of a foundational broad IP estate and importantly translates to the building that we've done in manufacturing. So therefore -- and so with our own in-house GMP manufacturing we've been able to rapidly translate medicines forward. And we'll talk about how that's been important as we advance in the clinic.

Taking forward in the clinical portfolio, the dominant program that we'll spend a lot of time talking about today is our innovative GalNAc-conjugated Inhibin E siRNA program. We've been able to see highly differentiated approach to treating obesity that's driven off of an improvement in body composition, meaning reduction in fat and muscle preservation. In addition to the ground baking work we've been doing at RNAi, we've been leading the field of RNA editing. And then pioneering that with our alpha-1 antitrypsin program, and we'll share more data on that program later as well as the advancement of the next program on our RNA editing platform, PNPLA3 for liver disease. Beyond what we've been doing with GalNAc conjugation for liver with siRNA and RNA editing, we've been able to advance extrahepatic set of programs, both in RNA editing and in siRNA, delivering the adipose tissue, muscle as well as CNS. And we'll share a little bit of data that we've built beyond our R&D Day on the novel bifunctional modality. And this really lets us think about taking these 2 opportunities in siRNA editing into a single oligonucleotide construct, let's just have one drug that can both upregulate and edit as well as silence a second target. So a lot happening, but a core focus that we'll share on obesity and alpha-1 antitrypsin and editing.

We're well capitalized, and we entered this year with now $602 million of cash, which will take us into the third quarter of 2028. So as we talk and pause about our innovation on chemistry, and it's really important to take this as a foundation because as we think about this field, there's others in this approach, who are talking about RNAi. And we need to think about how these approaches are different. Why is the chemistry different? So on the left-hand panel and on the far left, you'll see data that's represented from one of our paper that we shared several years ago. This is an NAR paper. And we shared in the paper is that black line and that teal line. And when you look at the paper, what we showed is that the innovation that we see on our siRNA chemistry is giving us about a 10- to 15-fold improvement in Ago2 loading, yielding a more potent and durable knockdown in SI. What we've shared an update on at our R&D Day is that actually with the innovations that we continue to push forward on our chemistries that we're actually seeing much deeper knockdown. So again, enhanced Ago2 loading, leading to deeper knockdown to the target but even more durable suppression of that target. This is going to be critical as we talk about Inhibin E and the opportunity in obesity where we can differentiate based on our siRNA formats between our chemistry and that of others that are moving forward. I should say that, that black reference compound represents the state-of-the-art siRNA chemistry as it stands today. So we'll talk about this again in the context of obesity.

In addition to the work that we're doing in siRNA, these chemistry innovations also apply to new modalities. So new modalities like RNA editing. And as we shared what we're able to do in highly potent, highly specific base editing. So this is ADAR editing. We can see these chemistries transition to more potent, durable editing and that translating ultimately into the portfolio.

As we said at the beginning, while we've built a deep and broad portfolio chemistry translating across programs in the clinic across different modalities, 2026 is a year of strategic focus. When we talk about strategic focus, that really means an emphasis on 2 areas. The first area is accelerating the development plans for WVE-007 across multiple treatment settings within obesity. And rapidly advancing our RNA editing portfolio of WVE-006 for AATT as well as 008 for PNPLA3. What does that mean? So in obesity, it means moving as we announced yesterday, to the Phase IIa portion of the INLIGHT study. So this is the multi-dose portion where we'll be exploring the ability to knock down Inhibin E in patients with higher BMI and with and without comorbidities. And we'll share more on that later. In addition, it also means that we're going to initiate new clinical studies in both a combo and add-on study to incretins as well as maintenance. We think 2 very important opportunities to explore the 007 program.

In RNA editing, it means delivering the data from the 400 and 600-milligram cohorts this year, the 400-milligram editing data for WVE-006 is coming this quarter and as well as filing the CTA and transitioning WVE-008 for PNPLA3 for the 9 million patients living with liver disease into the clinic.

So looking forward to obesity, we do believe that obesity is in need of a treatment paradigm shift. We know that the current standard of care for GLP-1s is limited by a loss of muscle mass, and this is consequential, and we'll share more on that later, not just in the case of thinking about frailty, but really thinking of muscle as an endocrine organ is character by frequent dosing, poor tolerability and discontinuation rates that are driven from that. When we think about the future of obesity therapy beyond in treatment therapies, we're thinking about what the possibility is when you can improve body composition. WVE-007 to flash forward ahead, we saw fat loss similar to GLP-1s at the 3-month time point. It preserves muscle mass. So very importantly, and we'll talk about the consequences of that preserving a muscle mass, has the potential for once to twice a year dosing, both in the preclinical data as well as our clinical data. And very importantly, for an obesity therapy was generally safe and well tolerated. And we say that, that was all the way through the 600-milligram dose cohort in the study. We believe that this principle of what we're bringing forward has the potential to change and improve body composition for the over 1 billion patients worldwide living with obesity. So we talk about body composition. There's often [indiscernible] what does that mean? How important is body composition. And we have to think about body composition as having 2 components. The first is a reduction in fat, in particular, visceral fat. That's critical to when we think about cardiovascular outcomes, inflammation, MASH and a number of diseases that are associated with obesity, those are driven by increasing levels of abdominal visceral fat. Inhibin E silencing does reduce subcutaneous fat, and that's obviously important as we think about the majority of body fat, which is tied to body weight reductions. So we will see a reduction in fat as well as a reduction in abdominal visceral fat. Equally important is thinking about muscle preservation. And we say this is important again beyond frailty because muscle is a very large endocrine organ that's responsible for improving insulin sensitivity. But as you maintain that and lose body weight, is also a feature in how you can continue to progress body weight reduction over time. So preserving muscle is crucial in a therapy for obesity. So how do we think about Inhibin E. Inhibin E Is a wonderful target in that it comes from the U.K. Biobank. So we like targets that have protective loss of function variants where essentially the human clinical trial has been run. This means that in the human population that's been studied in the U.K. Biobank, a 50% loss of function of Inhibin E has a genetic profile of low waste to hip ratio, so low abdominal visceral fat, has an improvement in lipid profiles, so low LDL, high HDL. And essentially, the clinical outcome experiment has been run, patients with a 50% reduction of Inhibin E have a low risk of Type 2 diabetes as well as cardiovascular disease. So an ideal way to come into a program is one where the human experiment has been run, the genetics are there. The question that always hums forward is can you induce a change in that phenotype? Well, how do we do that? So thinking about silencing Inhibin E. So this is a target that's produced in the liver. So an ideal target for a GalNAc siRNA construct, the liver target makes and forms a dimer of Inhibin E and that is the Activin E substrate. That is the protein of the ligand. We have assays that can measure activity in blood so that you actually have a great serum biomaker for efficacy, and you can measure the impact of silencing on that biomarker. Activin E binds to, and I'm sure people have heard of ALK7 is a receptor that's on the adipocyte so the fat cell, so this is highly characterized communication of a hepatokine from the liver that cross talks with receptors that are on the adipocytes. And if you silence that, so in a normal environment, I'd say before we silence, Activin E binds to ALK7, and that's actually the body's mechanism for storing energy, storing fat. And evolutionarily, that's how humans protected themselves. You store fat, you store energy and that protects you during times of famine. If you knock out Activin E, you remove the brakes on lipolysis from that receptor and you see a shrinkage of adipocyte fat cells and it goes through lipolysis and you lose that. So that's the mechanism between the 2. The efficiency and the reason we chose Inhibin E is the efficiency of taking a catalytic siRNA with GalNAc to a specific cell type that produces the ligand hepatocyte and being able to turn off the spigot and prevent Activin E from engaging with the receptor is a highly efficient way to target this pathway. Now there are other approaches of looking at Activin E in the periphery around the adipocytes, we do believe that targeting GalNAc the hepatocyte is the most efficient way to drive this process. Now this activin E is in circulation. And recently, there's been some discussions of whether or not Type 2 diabetes has a role to play in weight loss with Inhibin E therapies and others. We'll say that a very large prospective or I should say, observational study in 250 patients was presented in a poster at Obesity Week. And in this study of 250 nondiabetic patients, it was seen that Activin E levels correlated with increase in BMI, increase in truncal and abdominal fat and increasing in [indiscernible] insulin, all suggesting similar to the data that we'll share soon in our healthy overweight population without Type 2 diabetes that type 2 diabetes is not connected with the Inhibin E, Activin E pathway in terms of weight loss. But actually, BMI is highly correlated, and we'll talk about that in the context of moving into high BMI patients in the next study. So what did we see preclinically that drove our enthusiasm around this target is that we did see that with our chemistry being able to take a single dose and silence Inhibin E, it led to a potent durable reduction of Activin E levels. That reduction of Activin E below our threshold of 70 caused a reduction in fat, particularly visceral fat, preserved muscle and there was a slight increase in lean mass that we saw preclinically, and we'll talk about that in the context of the human data and ultimately resulted in body weight reduction in the DIO mouse at a similar level of weight reduction to GLP-1s. What you'll notice in that line on the far right, in terms of the Inhibin E weight loss curve versus the semaglutide weight loss curve is there's a shift in that rate of weight loss and weight decline. Originally, before our clinical data, it was thought that maybe lipolysis takes longer, and that might be accounting for that -- the change in that slope even though we reached the same standpoint and that sema moves pretty rapidly. I think what we're seeing both on our preclinical data and ultimately, as we'll share in our clinical data is that rapid weight decline in semaglutide is principally driven through a decline in loss of lean muscle mass. We'll share the 12-week data from the sema from the BELIEVE study. But at the 12-week time point, it's actually about 50% in humans lean mass loss at that early time point. And hence, why we think the steepness of that curve moves pretty rapidly. What's interesting with Inhibin E is we actually see that this weight loss while slower is principally driven because you have stabilization of lean body mass and then continued reduction in subcutaneous fat. And that continuous reduction in subcutaneous fat drives weight loss. And so that's an important characteristic as we think about the profile as we move forward.

Importantly, beyond monotherapy, so the idea that can you take down Inhibin E and does that drive weight loss similar to GLP-1s, we also saw the potential for combination. We've had a number of discussions with a variety of folks who've got differentiates across the treatment landscape of different ways to be thinking about how to drive the study as we think about our clinical study. But what was important is these approaches are completely orthogonal. So the idea that Inhibin E and its pathway is non-calorically driven, and we'll talk about that in the next slide when we look at the caloric comparisons on the maintenance study. But given that you have a throne approach of 1 being calorically driven or hedonically driven, which is the GLP pathway, one that's driven on lipolysis and the pathway for Inhibin E, they are combinable and synergistic, and we can think about approaches of titrating between GLP-1s as well as Inhibin E to drive weight loss. And what was really exciting to think beyond the combination is the opportunity for maintenance. And so this study, which we ran, where we track both calories and weight, what we could see is as you induce on a GLP-1 you see weight loss very similar. You have that anhedonic behavior, mice lose weight, both in the scope of muscle, lean muscle mass as well as in fat. And what we showed is if you pre-dose prior to cessation of GLP-1s, you curtail the rebound weight gain. This is independent from the fact that in both arms, the placebo arm and the treatment arm, caloric consumption resumed back above baseline. So essentially, what happened is that starvation phenotype of now eating and storing calories drove an increase in weight, all fat. But if you pretreat and took the brakes off lipolysis, you see a steady state of maintenance therapy. So these are the 3 treatment settings, mono, combo and maintenance that we've been looking at for Inhibin E preclinical data.

Transitioning to our clinical data. We ran a healthy overweight volunteer study. This Is a Phase I study. The criteria, while the BMI, as you could see, had a larger range, the criteria that restricted that was that these had to be healthy patients. So no comorbidities. And in that, the average BMI on the study was 32%. So substantially lower than that seen in other obesity trials. Additionally, there was no diet or exercise modifications required as part of the study. So this gave us a real-world setting where we could treat and see how patients actually low BMIs behaved on treatment. Cohort 1, because this was a Phase I healthy volunteer study, was a subtherapeutic dose and then the subsequent cohorts 240, 400 and 600 were at or above therapeutic expected threshold. I should say at the current time, all cohorts have been dosed. We've been cleared by the DSMB to go higher than 600, but as you'll see in the data, we don't believe that that's necessary. But it was important from us from a safety assessment when we did our first data cut, that the Safety Assessment included all cohorts on the study. So what do we see? We saw a highly durable reduction in Activin E levels. And I think this was incredibly important when we think about it in comparison to other Inhibin E programs that have been in development. We see an ED50 that's nearly threefold higher than other programs. So we're seeing potent, durable reduction of Activin E. Even at the subtherapeutic level, we're seeing that, that's sustained out months. And we believe, looking at the 240 and the 400 that, that should continue to support the once a twice-a-year dosing regimen. I will say that the time of the data cut, the 400 is still going down, and we'll share that we'll expect that data this quarter where we'll have the follow-up data on the 400 milligram. But we see that we're in the threshold, it's stable and it's durable. I'll also say that there's really good distribution into hepatocytes. So if we look at the error bars between the 6 patients that were on the 400 at the time of the cut and the 6 patients that were in the 75-milligram as we get that higher level of exposure, we're not concerned that there is lack of variability or distribution across patients. So again, highly encouraging as we think about therapeutic profile continuing to mature.

As we think about the clinical data, we saw much the recapitulation of that same data. So from human genetics to DIO mice. Now to humans with a substantial reduction in visceral fat, nearly 9.5%, a substantial reduction in total fat mass and a slight increase above placebo and lean mass, again, consistent with what we saw in our preclinical data. When we take these data and compare them to the only now published data, on 12 weeks with GLP-1s that include DEXA, so we can do points of comparison. We see that and have to recognize that the semaglutide study at this point had a BMI of 36. So it's nice that we're comparing from a BMI of 32 with no diet and exercise to study with a BMI 36 with diet and exercise. But in that study, we still see substantially decreased abdominal visceral fat when we compare that to GLP-1. We see about equivalent reduction in total body fat. So again, similar body fat reduction to GLP-1s at that time point. But importantly, that slight increase in lean mass versus substantial decrease. And what's interesting there is we said earlier, is at that time point, there's about a 50% reduction in lean body mass. So again, very important that what we're seeing at this time point is fat reduction and importantly, visceral fat reduction as well as retention of lean body mass. We do expect this study as it continues over time to continue to see like we saw preclinically, continued sustained reduction in fat, preservation and muscle. And when you put those 2 parameters together, that continued to drive reduction in total body weight. That's important because what we believe and continue to focus on is a regulatory pathway that follows the obesity guidance, which is a 12-month study looking at greater than 5% change in total body weight with an emphasis on body composition. So we do believe that these data continue to put us in the direction of an obesity study driven off of fat loss with muscle sparing.

One of the other things we can look beyond just generalized fat loss, driving subcu and ultimately, weight loss is the impact on visceral fat. And I think this is an important point of differentiation because what is seen is that a 7% to 10% decrease in visceral fat. Ultimately, you can play a role in cardiovascular outcomes. So as these studies continue, the ability to think about not just the impact on body weight through a reduction in subcutaneous fat as the dominant reducer, but actually visceral fat should point to an improvement in cardiometabolic outcomes.

So what's next for INLIGHT. Beyond the [indiscernible] INLIGHT Phase I portion, which will continue to accrete over time. This study allows 12-month follow-up at each cohort. So we'll continue, as I said, all patients have been dosed. So we'll continue to follow these patients out over time. The goal as we announced yesterday is to accelerate the Phase IIa portion, the multi-dose portion of the study. And that's going to enable us to change the criteria to have higher BMI individuals where we can then look in addition to having comorbidities, we do expect a larger impact on fat reduction with higher BMI, and therefore, a bigger impact in overall changes. And then, therefore, can look at that in comparison with similar BMI studies that have been done. We plan to initiate this study in the first half of this year. So focus on that study being the monotherapy. So building on our single dose, we do see a monotherapy application for weight loss with a once to twice a year drug that loses fat and preserves muscle. We do see the ability and we'll initiate this year at the combination study to look at the add-on effect. And I think as we've seen from other studies that have reported out recently, the power of the combination, particularly the liver fat reduction has been pretty consequential. And so we see Inhibin E in combination with incretin having a big impact on reduction of liver fat. So that's an important thesis to think about as we go forward. And then ultimately, where we see a very substantial portion and utilization of this is in maintenance. The idea that we can transition patients from a life of chronic incretin therapy to a once to twice a year maintenance drug. And the key that's there is thinking about -- as we think about the over 1 billion patients living worldwide with obesity, how can we move this beyond the United States and think about patients worldwide where you can get better access, better distribution if you only have to treat patients 1 to 2 times a year. So exciting. The value of this program continuing to go forward is now we'll continue to create data over time. And that data will really answer a question of how much does time play a role in continuation of body weight? How much is driven based on dose and Activin E reduction, and the study is already poised to deliver on both of these features as we look at data over the course of this year.

Beyond obesity, WVE-006, which is the first RNA editing program to go in the clinic, is moving forward and a quick update on that. For those who aren't familiar, AATD rare disease focused on about 200,000 patients in the U.S. and Europe who have a ZZ mutation. So these patients have 2 bad copies of a gene. This creates a misfolded protein. That protein is unable to be expressed and protect the lung and those patients go on to have lung injury, but also because of that protein is folding, go on to have liver injury due to the accumulation of that protein in the liver. There's no approved therapies that treat both the lung and liver manifestations of the disease. There is IV protein replacement therapy that's been approved to treat the lung conditions and to try to provide protein to protect that lung during periods of injury. There's no approved therapies yet to deplete the liver protein. So the approach that we have is grounded in genetics, Therefore, looking at the heterozygous patients. So these patients have 50% corrected M protein. So they are able to make a good copy of that protein. And when you look at these patients, they have greater than 11 micromolar protein that's able to circulate and protect the lung. They have 50% edited and protein. This is important because they're able to have a dynamic effect that can actually rise to meet that injury signal. And so these patients go on to have low risk of lung and liver injury. So the principal guiding feature in developing the AATD program is developing in a corrector that can correct over 50% of the transcript and therefore, deliver the restoration of this healthy phenotype. The other key dynamic effect, and this is important as the data came out, is thinking about augmentation therapy. So this replacement versus correction. And I think what's interesting, and you have to reframe a thought of what happens to these patients. So what happens in the case of AATD patients is it a chronic disease, but there's acute exacerbation. So these patients go through these intervals where they'll have a stimulus of inflammation that drives an increased protein response of damage. And normally, these patients would make alpha-1 antitrypsin protein to protect their organ in the lung. In the case of not having that, you get augmentation therapy, the challenge of augmentation therapy is you do this peak infusion. And then over time, as you can see on the graph, it's a consumptive protein, it declines. And actually, during that period of injury, patients are actually more exposed to that injury signal than they would be. So nobody knows kind of what happens in that interval as the protein is consumed, how much risk of injury there are. And it's a concern for clinicians. The difference of editing and correcting is actually the protein rises to meet the need of the body. So you reach a steady state at that heterozygous level that protects the body, and during that injury period where that stimulus is there, you actually see the increase in transcriptional activity and through correction can actually increase the expression of protein to protect an individual during that period of time, therefore, preventing the exacerbation from driving injury. The current design of the study had a healthy volunteer component that's been completed. We reported data from the 200 single and multi-dose study last year. We shared the single-dose data from the 400 last year, and the data this quarter will be from the 400 multi-dose cohort, looking at M-AAT levels, total AAT levels. What's important from the last time we repeated data is exactly what one would expect or want to see in that heterozygous genotype. We saw the lowest single dose of the study. We saw 13 micromolar protein at a steady state. We could see the actual correction and it was highly tight across patients in terms of that switch from Z protein to M protein. So we saw over 64, so well over 50% edited protein that could meet the need of that correction. And very importantly, we actually saw during the acute phase response when the patient needs it, they could produce over 20 micromolar proteins. So a patient had an actual event during the study. We could look at the CRP level during the study, it was a modest level but we could actually see that they could generate over 20 micromolar protein during the event. That's essentially where people are talking about where IV protein replacement should start before it actually starts to deplete. So when we think about the profile of delivering the heterozygous like phenotype, we were seeing that at the early parts of the study. As we said, we'll have the 400-milligram data in Q1.

Building off of this program and very quickly, a lot of the principles of editing and can we get to this 50% editing, highly efficiency, GalNac-conjugated subcu, a lot of the features that we like to see, coupled with generally being safe and well tolerated was, could we apply this to another indication. There's often a question that gets asked are, what are other large indications beyond alpha-1 antitrypsin. PNPLA3 is actually -- that mutation is a very interesting mutation. There's a strong foundation in human genetics. There's over 9 million patients that have in the U.S. and Europe that have this mutation, and it drives an increased incidence in liver disease. It's an enzyme, so it also has an approach where the 50% correction doesn't have this dynamic response event. So it's -- should I say, nothing is ever easy, but you can measure this and say that actually, you're just measuring can you correct this protein and allow it to restore its function. And the function really is about processing lipids as well as retinol, so be involved in fibrotic cascade. So when you think about that, given that it's involved in both lipid metabolism as well as fibrosis, you imagine that if you have that mutation, you can get a whole variety of liver diseases that come from this. So it's not restricted to MASH as an indication, although several companies talk about silencing in that approach. [ ALT or ] liver disease for PNPLA3 is how we think about this. And with that mutation, you have about -- if you can correct that to the heterozygous level, you have about an 80% risk reduction of disease. So very similarly, 50% correction drives an improvement ultimately in outcomes.

Why silence versus edit, it's been known that this is an enzyme that's really important again in lipid metabolism in fibrosis. So what we see in the control of the green -- the blue highlights or the nuclei of cells, the green is liver fat. And what you can see is if you can correct that protein and actually restores physiologic function to 50% or more, you actually see a better lipid traffic and you metabolize that fat, that's processed without the cell. We think this is why the siRNAs have had challenges, which is if you knock that enzyme out, you actually don't restore lipid metabolism. You don't [indiscernible] retinol metabolism, you can see fibrosis. So we think it's an ideal target. It's differentiated in the approach of why do editing and also attack disease that's consequential. We see continued and potent editing. We have the experience of translation from our preclinical models to clinical with alpha-1 antitrypsin. We see highly potent durable editing in our preclinical studies, highly specific, and this is a good point of differentiation as we think about the DNA editing constructs is that this editing is highly specific with no bystander edits, no off-target edits. And we see really strong tissue distribution, delivery and durability and expect to file a CTA in 2026.

Lastly, being able to put these 2 pieces together, we are working on bifunctional conjugates, we actually take the best of what we can do in RNA editing, the best of what we can do in siRNA and rather than making 2 molecules to drive therapeutics can actually create a single oligonucleotide construct that can do both editing and upregulation, coupled with silencing and have shown data preclinically at our last research day that you can think about targets like LDLR upregulation with PCSK9 silencing and think about applications where you wouldn't want to have 2 independent development plans, 2 commercial products to be co-administered. But think about it as 1 clinical trial with 1 product to transition to the market. So the key focus for Wave going forward is an emphasis in RNAi driven by obesity with 007 for Inhibin E, 006 in AATD and PNPLA3, with the ability to continue to drive those platforms and formats forward. Anticipated milestones, multiple data sets accruing on obesity over the course of this year with the next inflection being Q1, the 400-milligram 3-month data and the 240-milligram 6-month data. Additionally, 006, first quarter, we'll have the 400-milligram data, 008 moves into the clinic. We do expect to submit the NDA for N531 this year. However, we've been very clear on our strategic focus that we will look to find commercial distribution partners for that as opposed to invest the capital that we currently have allocated for advancing our siRNA program, particularly running those 3 trials that we mentioned in obesity, that we'll use those partnerships to drive the N531 study forward.

And with that, thank you for your time.

Great. Great. Thank you, Paul, for that presentation. So I thought I would just dive right in, in the time that we had and start with obesity. Can you speak in a little bit more detail to the size and the scope of the Phase 1 additional INLIGHT trial data that we will get this year? What is the type of profile you're looking to deliver in this trial overall? And what level of that loss and body composition results would you like to see with longer-term follow-up and higher doses?

Yes. That's we'll unpack that in a variety of ways. I think first and foremost, kind of stepping back to INLIGHT. INLIGHT right now has over 100 patients currently dosed in the study. So when we think about the magnitude of effect and being able to observe that over time, we have substantial number of patients that we can look at across the study over -- for both Activin E reduction and correlating that ultimately to therapeutic effect. So we do care about sample size and powering as we think about being able identify impact and effects from the study. In terms of what we want to see is we'd expect to see continuation of what we currently see, meaning we saw that if we potently and durably reduce Activin E, it translates to a reduction in fat. Emphasis on visceral fab, but that's not to say that we don't see substantial reduction in subcutaneous fat, which should continue to drive the potential for weight loss as well. So we see fat reduction and we see lean mass preservation. The profile that we'd expect to continue over time, both at that dose and then we'll talk about what happens as we go higher, is that we would expect to see that fat continue to decrease, but we would expect lean mass to stay stable. So again, when we think about what would drive the ultimate -- this is kind of the calculation for how to think about body weight reduction is that if you change body composition in that reduction in fat and you keep lean mass stable, you will lose body weight. And I think the important observational medicine to see that. And it was in the BELIEVE study is bimagrumab. So a totally different pathway, that's a myostatin medicine that makes lean mass go higher and actually has less an impact on fat, still sees weight loss over time. So again, we expect that profile of focus on fat reduction, lean mass sparing to drive that. I think what we're going to have the opportunity with this quarter is to see the impact of dose on the rate of change? Does a higher dose actually drive that transition faster? And ultimately, does it allow that to continue out longer. So we'll be able to look at both dose response as well as time response on body composition as the study continues to progress. And then the opportunity with the higher BMI Phase IIa portion is going to be able to see the impact of higher BMI on that rate of change.

Great. And you talked a little bit about the number of different treatment settings you can go -- could go into here. How do you think about overall Phase II development? And which of the pathways do you think are most derisked at this point versus where there may be a little bit more risk?

Well, derisking has 2 different components to it. I think on 1 hand, we do see on the monotherapy side, a derisking event that substantial reduction of Activin E causes substantial reduction in fat, which is tied mechanistically to both the animal model where we saw fat reduction similar to --- weight reduction similar to GLP-1 as well as the human clinical genetics. I think on the other side of the equation beyond monotherapy is actually there's substantial data on maintenance because if we think about the human heterozygous phenotype, there's a lifetime of maintenance essentially with a 50% reduction in the genotype that ultimately leads to an improved phenotype over time on maintenance therapy of what happens when you reduce Activin E, those patients don't gain weight. So when we think about the maintenance setting where persons at a set body weight from an incretin and you're dosing and withdrawing the incretin, that's probably the most correlative to when we think about the human clinical genetics but we'll be running that study as well.

And any further comments you want to make on kind of overall where you see this asset fitting into the treatment paradigm here? And also just how you see the evolving development landscape in the kind of the area that you're in?

Yes. There's a lot to discuss there. I think in each treatment setting, we see high need and impact. And if we work from the maintenance setting forward, I think in maintenance, keeping patients on a lifetime of a multi-dose incretin therapy has challenges. And I think we hear that from a number of individuals we talk to clinicians, patients, even strategic partners thinking about how do you continue to keep patients on incretins for a very long period of time. I think 1 approach that has been suggested is why we see the shift to oral medicines. But as we've learned from the statin community, trying to stay on an oral daily statin that actually has very low instant side effects, it's very hard to do consistently and compliance is a very difficult problem in keeping patients on therapy. Flash forward to an oral medicine that drives nausea, vomiting, and my guess is that, that real-world data as it emerges, we'll see how that continues to drive a maintenance therapy. So I think the idea of rapidly transition patients to a once to twice a year therapy that allows for sustained fat reduction, preservation of lean mass, and as a safety tolerability profile as we do, I think, is an ideal way of thinking long term about that opportunity. And we know what the current opportunity sits with that transitioning of those patients forward. Combination is real. We know patients who come in and talk about their journey with us and remind us that they could be looking at an advertisement on television that shows what the weight loss opportunity is in combination and says, even if they achieve that, they still wouldn't be at a treatment goal of healthy weight loss. And so therefore, the additional setting of being able to add this on to existing incretins to continue that weight loss journey is important because, again, because of the safety tolerability profile, the combination actually is not adding additional safety or tolerability events. We also have seen and had a number of [ strategics ] have discussions about how do we think about these interacting in terms of titrating back incretins and finding an optimized schedule between incretin therapy along with the combination. So that's intriguing. And I think there's a number of different ways to explore that. And then we're working our way back to monotherapy. And I think this is one of what is that rate of weight loss. And I think when people can have the conversation move from this being a pound for pound weight of weight reduction, which is principally driven off of lean mass. And I don't know many people are saying, I want to lose like 50% of my lean mass within 3 months have given an opportunity. The opportunity to reimagine what that looks like when you can have a monotherapy that you preserve your lean mass, you lose fat, weight loss will occur. But in terms of improved body composition, we think that is ideal. And as we talk to clinicians were saying, look, I've got patients who, I'll tell them, they've got to eat protein, but the anti-hedonic activity of the GLP-1s is having them not consume the protein that they need to retain that muscle. I think the treatment paradigm in monotherapy is ripe for migration. But we realize that, that with time for the community to adapt. And so I think all 3 treatment settings are an opportunity.

Okay. And I know it's such a tight amount of time here. So I'll just ask kind of an overall question to end us. Are there any other data milestones that you think matter most for Wave in 2026 that you would draw people's attention to?

I think the upcoming data, as we think about the continuation of 007 and driving improved body composition, again, is a paradigm shifting, it's probably the most watched, the most focused on opportunity. And the benefit we have is, as we roll forward, we're going to have ample opportunities to see that data continue to accrete both at each dose level over time, but also at the higher doses to see the continued improvement in body weight reduction.

Okay. Okay. Great. Thank you so much, Paul, and the entire Wave Life. Thank you.

Thank you. Appreciate it.

Hello, and welcome to Wave Life Sciences Positive Interim Clinical Data from INLIGHT Trial of WVE-007 and Obesity call. [Operator Instructions]. Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. This morning, we issued a press release announcing positive interim clinical data from our ongoing Phase I INLIGHT trial of WVE-007 in individuals living with overweight or obesity. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks.

Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2024. We undertake no obligation to update or revise any forward-looking statement for any reason.

Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Erik Ingelsson, Chief Scientific Officer, will highlight WVE-007 our INHBE GalNAc-siRNA, and Dr. Chris Wright, Chief Medical Officer, will present the interim INLIGHT clinical data. Last, Paul will conclude with next steps and anticipated milestones before turning it to Q&A. Dr. Chandra Vargeese, Chief Technology Officer, will also be available to answer questions. I'd now like to turn the call over to Paul.

Thank you, Kate. At Wave, our goal is to translate powerful human genetic insights into transformational medicines. And with WVE-007, we are addressing a significant unmet need individuals living with obesity. In particular, our focus has been on meaningfully improving body composition by reducing fat, in particular, harmful visceral fat and preserving muscle. And as you'll see, that's exactly what we did.

Today, we are excited to share a significant milestone towards this goal with the first clinical translation of 007 in our Phase I INLIGHT study, which has exceeded our expectations. We've long stated that our goal with a 3-month data from our 240-milligram cohort was to demonstrate that we are on the curve to deliver meaningful backlogs. And with today's update, after only 3 months, we're excited to be observing fat loss similar to GLP-1s without their associated impact on muscle. What was particularly remarkable was that this was despite in light investigating healthier participants without diet or exercise modifications.

Just 3 months after a single dose, 007 led to dramatic improvements in body composition, with substantial reductions in fact, including a 4.5% reduction in total body fat and a 9.4% reduction in visceral fat. Importantly, we observed clear evidence of muscle preservation with a 3.2% increase in lean mass. Our best-in-class SpiNA design is leading to robust and durable suppression of Activin E, supporting once or twice per year dosing, and we're seeing remarkably clean safety profile through our fourth 600-milligram cohort. As you'll hear today, these results support a potentially transformative profile and drive our excitement in advancing INLIGHT and further development of 007 across multiple settings. Now to provide further background on 007's differentiated approach and strong biological foundation. I'd like to turn the call over to Erik.

Thank you, Paul. Before diving further into today's results, it's important to reflect on the current obesity treatment landscape and why we believe WVE-007 is positioned to deliver a truly transformative novel therapeutic approach. Individuals living with obesity face markedly higher risks of a range of serious conditions, including cardiovascular disease, type 2 diabetes and several cancers. The key driver of this elevated disease risk is unhealthy body composition, with an excess of body fat in relation to lean mass.

While GLP-1 receptor agonist and other incretins have transformed obesity care, their impact is often limited by a substantial loss of muscle mass as well as tolerability challenges, especially GI side effects, frequent dosing and high discontinuation rates. The loss of muscle with incretins is particularly important to emphasize in this context due to the important role of muscle in metabolism and weight maintenance. We believe that an improved body composition is the key goal of any effective obese treatment strategy.

Body fat, in particular, excess of visceral fats, including fat around internal organs, is strongly linked to diseases like type 2 diabetes, fatty liver and cardiovascular disease, acting through chronic inflammation and insulin resistance. Additionally, skeletal muscle, which is the main component of lean mass is important for improved insulin sensitivity for sustaining a higher basal metabolic rates, which is critical for long-term weight maintenance, as well as for preservation of muscle strength and function and to reduce the risk of sarcopenia and frailty.

There's a lot of literature from over the last few decades, demonstrating the strong links of increased visceral fat with insulin assistance, MASH, type 2 diabetes and cardiovascular disease. As shown on the left, decreases of 5% to 10% visceral fat leads to substantial and clinically meaningful improvements across the number of cardio-metabolic disorders. As shown on the right, you can see that increasing levels of visceral fat are associated with the dramatically increased number of cardiovascular events. For these reasons, we're excited about the approach we're taking with 007 that leverages the completely orthogonal mechanism from gut, brain signaling and appetite suppression by inducing fat loss through lipolysis, breakdown of triglycerides, directly in adipocytes.

007 aims to improve body composition by reducing body fat, in particular visceral fat while preserving muscle to deliver a healthier cardiometabolic profile. 007 targets INHBE or Inhibin Subunit Beta E with a strong foundation in human genetics, which has been shown to increase the probability of successful drug development by up to two to fourfold, with coding variant evidence in the upper part of that range. In the U.K. Biobank and other cohorts, heterozygous Inhibin E loss of function variant carriers exhibited healthier metabolic profile with lower abdominal obesity by Waist-to-Hip ratio and lower visceral adipose volume, lower triglycerides, ApoB and fasting glucose and higher HDL cholesterol.

We also have favorable associations with liver trades, such as ALT and CT1, a measure of liver inflammation and fibrosis and lower risk of type 2 diabetes and coronary heart disease. Our therapeutic hypothesis is straightforward. By silencing INHBE mRNA, we aim to recapitulate to protect phenotype seen in these heterocycles loss-of-function variant carriers. Inhibin E is produced in the liver, where two of the subunits dimerize to form the hepatokine Activin E.

Activin E gets released into circulation where it binds in a specific manner to alpha-7 receptors on adipocytes. The resulting signaling blocks adipose like policies, promoting abdominal varicosity and increasing risk for cardio-vascular disease and type 2 diabetes. By reducing hepatic Inhibin E mRNA with a GalNAc-siRNA with lower circulating Activin E decrease ALK7 signaling adipose tissue and release the brake on life policies, which is expected to shrink adipocytes and reduce abdominal adiposity, thereby lowering cardiometabolic risk.

In addition to Inhibin's E, strong foundation in human genetics, we believe 007 is differentiated by our proprietary chemistry, which makes us well positioned to deliver a potentially best-in-class approach. 007 is a GalNAc-siRNA using Wave's SpiNA design, including backbone stereochemistry and [ PM ] chemistry to enhance interactions with Ago2 and to improve silencing potent and durability. We have demonstrated the dramatic improvement of Ago2 loading, which is a critical differentiator when trying to silence Inhibin E, a target that is hard to keep sufficiently and durably suppressed, presumably due to evolutionary pressure for the need to store energy efficiently. Based on observations from human genetics studies, we would expect that Inhibin E silencing and Activin E reductions should lead to meaningful improvements in body composition as well as cardio-metabolic health, which should be the main objectives of any obesity medication.

As we have shared in a number of previous presentations, our preclinical studies show that by reducing Inhibin E mRNA and circulating Activin E levels, increased adipocyte life policies leads to reduction of adipocytes sizes and fat loss, in particular, visceral fat. This, in turn, results in a shift from pro-inflammatory to anti-inflammatory macrophages and less fibrosis in visceral adipose tissue, as well as improved insulin sensitivity, changes that can contribute to lower risk of cardiovascular disease and type 2 diabetes.

As we also shared previously, our preclinical data in diet-induced obesity mice strongly support 007s ability to both potently and durably knockdown Inhibin E and reduce circulating Activin E, leading to substantial changes to body composition, with fat loss, in particular visceral fat while sparing muscle. Based on our preclinical data, we would expect reductions of Activin E levels of at least 70% to translate to improvements of body composition in clinical trial. As observed in the right figure when comparing the kinetics, weight loss within Inhibin E siRNA was similar in magnitude to Semaglutide, but occurred more gradually, potential explanation for the initially slower weight loss could be that the preservation of lean mass is offsetting weight loss early on.

But that over time, the substantial fat loss is translating to weight loss as lean mass stabilizes. As Chris will share in further detail momentarily, our results with 007 represent the first clinical data linking durable Inhibin silencing to meaningful changes in body composition in humans. With the clinical translation of 007, strong human genetics foundation and our robust preclinical data, we're incredibly excited to continue to evaluate 007 across cohorts and with longer follow-up in human light, where we expect to continue to see the loss of total and visceral fat with muscle preservation. With that, I'll now turn it over to Chris to walk through the INLIGHT clinical data in more detail.

Thanks, Erik. Good morning to everybody on the call. As a reminder, INLIGHT is a placebo-controlled single ascending dose study, randomized 3:1 active to placebo, with potential to escalate up to 5 single dose cohorts and plans for additional multiple dose cohorts. It's designed as a safety tolerability PK study. Participants are healthy individuals living with overweight and mild obesity.

With key inclusion criteria of HBA1c less than 5.9 and BMI between 28 and 35. The study does not require diet or exercise modifications or counseling. In addition to safety, tolerability, PK and Activin E levels, the study has exploratory endpoints of body composition by DEXA, biomarkers and body weight. INLIGHT is currently ongoing at multiple clinical trial sites, including in the U.S. We began testing WVE-007 at our lowest subtherapeutic dose of 75 milligrams in 8 participants, which did not include DEXA and was primarily to a firm early safety in PK/PD.

We next evaluated the 240 milligram, 400-milligram and 600-milligram ascending dose cohort, which are expected to be at or above our therapeutic threshold. We have expanded 2 and fully dosed 32 subjects in each of these cohorts based on the favorable safety profile. Today's update primarily covers 3-month follow-up data from our first potentially therapeutic 240-milligram cohort and equals 32. In addition, further updates on safety for the 75 through 600-milligram cohorts and PK from 75 milligrams to 400-milligram cohorts are provided. Baseline characteristics were generally well balanced across the treatment arms. Participants were in their late 30s to early 40s on average with a mix of men and women in each cohort, with a somewhat higher proportion of females in the 75-milligram group and males in the 240-milligram group compared to placebo.

Mean baseline BMI was approximately 32 kilograms per square meter in the treatment cohorts consistent with the participants having healthy overweight or mild obesity. In our cohorts from doses of 75 milligrams to 600 milligrams, including placebo, there were no discontinuations, serious TEAEs or deaths. All study drug-related AEs were mild. There were no clinically meaningful changes in lipids, glucose or other clinical laboratory measurements including liver function tests through 600 milligrams. Overall, we are very pleased with the favorable safety profile that WVE-007 continues to exhibit across a wide range of doses and our first-in-human trial to date.

Following our updated Research Day, we continue to see robust and durable reductions of Activin E. In this chart, we show the dose-dependent Activin E decreases over time across 3 single dose levels of WVE-007 and placebo. The percentage reduction of Activin E from baseline is shown on the Y-axis, with days on the study on the X-axis. As a reminder, at Research Day, we reported that at day 29, we saw statistically significant mean Activin E reductions of 56% at 75 milligrams, 75% at 240 milligrams and 85% at 400 milligrams. Activin E reductions in the 75-milligram cohort were sustained out to 6 months and reached a maximum reduction of 59%. Both the 240-milligram and 400-milligram dose levels still appear to be trending downward at day 29.

We are now pleased to show that these statistically significant reductions are enhanced and persist in the 240-milligram cohort at later time points with up to a 78% mean reduction in Activin E at day 43 and sustained [indiscernible] uses of greater than 75% out to day 85, which is approximately 3 months. These data continue to support a highly convenient dosing interval of once or twice a year. So what do these durable and robust reductions in Activin E translate into?

As I will now cover, we are seeing significant fat loss and meaningful improvements in body composition. Even at our initial 3-month time-point in our lowest therapeutic 240-milligram single-dose cohort, if you look from left to right, we observed significant reductions from baseline in visceral fat of 9.4%, total fat mass loss of 4.5% with increases in lean mass of 3.2% from baseline as measured by DEXA. Importantly, these changes were observed in otherwise healthy individuals with mild obesity and without any protocol mandated diet or exercise modifications. No significant changes from baseline were observed on any DEXA measure in the placebo arm. Overall, these data demonstrate that a single dose of WVE-007 can shift body composition towards less visceral and total fat, while preserving muscle consistent with our preclinical findings and with the underlying human genetics.

With this important and unique clinical proof of principle, we are looking forward to evaluating the impact of this mechanism with higher doses and over longer durations throughout 2026.

To help contextualize these body composition changes at the 3-month time point, we evaluated our results and examine those of the BELIEVE Phase II study, evaluating semaglutide and the myostatin inhibitor, bimagrumab, where DEXA scans were available at the 12-week time point. On the left are the placebo-adjusted changes from our INLIGHT study, with a single 240-milligram dose of WVE-007 at 3 months and participants with a mean BMI of around 32.

A 9.2% treatment effect was observed on visceral fat as well as on a 4% decrease in total fat mass. There were also small improvements in lean mass and decreases in total mass of 0.9%. In the center and on the right are the estimated placebo-adjusted changes from the BELIEVE Phase II trial, which investigated weekly semaglutide and intravenous bimagrumab and participants with BMIs around 36.5%. The total placebo-adjusted fat mass reductions for semaglutide were of a similar magnitude as for 007 at 4.2%, but there was substantial lean mass reduction of 3.5% or approximately 4.5 pounds. Visceral fat reduction was 5.7% and total mass reduction was 3.8%. Notably, 007 showed a placebo-adjusted reduction in total fat mass on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat.

When evaluating bimagrumab, which increases lean mass with reported safety limitations, there are modest reductions in visceral and total fat mass, along with increases in lean mass leading to small increases in total mass. It is particularly encouraging to see 007 driving total fat reductions on par with semaglutide or greater at the 3 month time point even in a lower BMI healthier population without diet or exercise modifications. Coupled with the convenience of once or twice yearly dosing, lean mass preservation and a favorable safety profile, we believe 007 has the potential to transform the obesity treatment paradigm. And we look forward to keeping you updated on our progress in INLIGHT. I'll now turn the call back to Paul.

Thanks, Chris. WVE-007 has demonstrated a potentially transformative therapeutic profile by improving body composition, specifically a loss of fat, including harmful visceral fat with muscle preservation. All of this is delivered with a single subcutaneous injection given only once or twice a year and a favorable safety and tolerability profile. Taken together, 007 has the potential to address the significant unmet needs that remain in obesity.

The clinical translation of WVE-007 in INLIGHT fortifies our excitement in other treatment settings, where we've demonstrated compelling preclinical evidence. As shown on the left, in mice, we've observed approximately twofold greater weight loss as an add-on to semaglutide versus semaglutide alone, and on the right, the ability of WVE-007 to curtail rebound weight gain following cessation of semaglutide, providing powerful data for its utility and maintenance setting. This translation now unlocks opportunities to investigate 007 in multiple treatment settings.

While INLIGHT is currently investigating otherwise healthy participants with a markedly lower BMI compared to other obesity trials, and no diet or exercise modifications, we believe 007's favorable safety profile and ability to drive reductions in fat while preserving muscle also support investigating 007 as a monotherapy in higher BMI populations with cardio-metabolic comorbidities. With it's orthogonal mechanism, we also see an opportunity to use 007 as an add-on to incretins -- and within the community, there is particular excitement about 007's potential as a maintenance therapy, which would allow people to transition off incretin therapies while at the same time preventing rebound weight gain, preserving muscle and sustaining cardio-metabolic health. Planning for these Phase II trials in these settings are now underway.

The substantial reductions in fat mass we've observed at this 3-month time point are already on par with semaglutide. And as we look ahead to the coming quarters, we have multiple opportunities to assess the impact of duration and dose on the continued improvement in body composition. Next quarter, we'll have 6 months of follow-up data from the 240-milligram cohort as well as 3 months of follow-up data from the 400-milligram cohort. And in the second quarter of 2026, we'll have 6-month follow-up data from the 400-milligram quarter as well as 3-month data from the 600-milligram quarter.

Before turning the call over to questions, I would like to take a moment to thank all the individuals participating in our INLIGHT clinical trial, the clinicians involved and the study site staff. They inspire the work we do every day and from everyone at Wave we'd like to express our sincerest gratitude. And with that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] Our first question comes from Joon Lee at Truist Securities.

Congrats on the great data. It looks like there was a net weight gain in the placebo arm, driven by increase in lean mass. How do you explain that given most weight loss trials placebo arm loses weight, not gain. And bigger picture down the road, how are you looking at the potential labeling differentiation to compete against GLP-1s, which now just $300 to $600 per month?

No, thank you, Joon. And as you see, there was a gain in the placebo arm as well as in the treatment arm from baseline. Remember that this did not require diet and exercise and yet we still saw a statistically significant increase in lean mass. But if you look at the placebo adjusted data sets, it was about 0.9% increase. And we also saw, as you pointed out, a 0.9% decrease in total mass. So I think ultimately, we have a medicine that's driving weight loss down by losing fat. And this is very consistent with our preclinical data that demonstrated strong fat reduction, and over time muscle stabilization, both of which led to a total body weight decrease compared to semaglutide. So again, I think it's really a powerful medicine in a world that's really looking for improvements in body composition, long term.

To your point on the evolution of the commercial landscape with the pricing pressures on GLP-1. There are over 1 billion patients worldwide living with obesity. And I think the power of what we've shown today is that with a once to twice a year subcutaneous administration, one that can open up monotherapy to maintenance. I think it creates a powerful disruptor to the marketplace. So we're excited to accelerate it and to generate those data. And I think lastly, I think it's very much tied to the direction that the FDA is moving to obesity therapies. While they say in guidance that there's a 5% weight loss requirement for approval, it is very clear from the FDA that they want to see weight loss driven from fat loss and not from muscle explicitly. So I think this product definitely delivers within the realm of what the agency is looking for.

Joon, if I also can add, you asked about other trials. Remember that placebo loses weight is mostly from the Phase II and III trials where individuals are under intense lifestyle intervention. In this case, we didn't give any diet or exercise modifications. So it's hard to compare it in that case.

Great. And just a follow-up. Is weight loss going to be the regulatory hurdle that you guys are going to loop, I mean jump over? Or are you looking at something else as an approvable end point down the road?

Yes. We're not focused on creating new end points. I think the goal is that weight loss remains an approvable endpoint, and it remains a focus of what we see with Inhibin E human genetics, in our mouse models and ultimately, what we believe will continue to occur in humans. So very much a focus. But again, I think we're seeing momentum across the clinical community, the patient community and the regulatory community to drive a focus on body composition and driving that weight loss and preserving the mass and losing that. I mean, as Chris mentioned on the call, this is sounding at the first 3-month time point that actually a lot of that predominant weight loss driven off of the GLP-1 is fat, it was almost 4.5 pounds of fat that were lost at that early point in muscle. And so by preserving that muscle, that a lot of muscle to lose very early. And so we do see it as critical to loose fat, which is what we saw.

Our next question comes from Steve Seedhouse at Cantor Fitzgerald.

I wanted to first ask if you could comment on the precision and accuracy of the DEXA methodology that you're using in the study. I think it has a pretty good reputation, but I just wanted to confirm how much variance across patients in the study you'd expect to be just biological versus actually technical margin of error from the measurement? And I have a couple of follow-ups.

So from the DEXA perspective, we used a standard methodology and had a group that made sure that it was standardized across all the sites and all the data was analyzed in detail to ensure quality across the board.

Just relatedly, what was the -- if you have it handy, what was the highest percent fat loss and highest percent total weight loss that you saw in like any individual patient in the treatment, if you have that?

I mean, obviously, it was tight. This is the data that we're sharing in the means. We'll have more data coming in meetings in the future. But I think what's really important and what drives weight loss. And this is something that if you look at the Activin E data early on between the 75 and as we got to the 240, it's how tight the knockdown got. So if you look at the error bars in Activin E at the 75-milligram cohort, there was a lot more variation. And as you moved into higher doses, the expression and knockdown got tighter and tighter, and that translated to good tight fat loss and muscle preservation.

Got it. I'm just trying to get it basically as you follow through 6 months, your level of conviction that the true effect of the drug here with increasing fat loss over time that would be expected would sort of easily reveal itself.

And then the other question I want to ask is [ bimekizumab ] has an adverse event profile that includes like diarrhea, muscle spasms, I think, acne as well. Are you seeing any imbalance in those features specifically from 007?

I'll answer the last one first, simply, no. As you saw, it's a remarkably clean safety and tolerability profile. And so that obviously has us -- is an important feature. One, to your point around thinking about some of the evolving muscle sparing therapies. But importantly, as we think about other weight loss medicines and again, bodes well for a drug that focus on body composition, fat loss and muscle sparing.

I mean as we noted, we didn't really see any clinically meaningful changes in lipids or LFTs or glucose or any other clinical laboratory measure.

Okay. And just real quick, lastly, do you have data on any patients yet through 6 months in the 240 mg cohort or is that sort of batched and received altogether at some point in the first quarter?

Yes, it's batched and received together. But getting back to an earlier point we made of, how do we expect to see, and I think our forward-looking piece of trying to see variability. We have an extraordinary amount of confidence in what happens as we continue to run the study forward. That's driven on both the fact sustained durable knockdown of the Activin E expression and really the strong translation that we can continue to see in the preclinical models that is so long as you're suppressing Activin E, fat loss continues. So again, the data that we continue to expect as a function of the duration of time so as along with Activin E is suppressed, we do expect to see continued fat loss.

[Operator Instructions] Our next question comes from Samantha Semenkow at Citi.

This is Ben on for Sam. To start, can you talk about the slope of that loss and the increase in lean mass? Are you seeing any plateauing in the lean mass. And then from a genetic perspective, what is driving the increase in lean mass?

Yes. I mean I think we continue to see the slope of that loss. And lean mass, it's interesting in preclinical data it goes up and stabilizes. So if that continues to translate, we continue to expect to see, and that's been seen in other muscle medicine. So we expect to see sustained support in lean mass with continued suppression again and that's really the biology and the genetics along as Inhibin E and Activin E is expressed, you'll continue to see fat reductions. And we see that slope in kinetics in our preclinical experience compared to semaglutide, and we now see it in humans. And again, I think it's astounding when we go back to the comparator and mice and we go back to our comparator data looking across studies in humans, that impact on GLP-1s on muscle is profound, right? 4.5 pounds decline at the beginning versus our -- which is purely fat. And so again, we expect those characteristics to continue.

And to add to Paul's point there, that's the expectation based on our preclinical, but to be clear, from the clinical, we only have a DEXA from baseline 0 and then now at 3 months. So we only have these two. So it's not really kind of a trajectory at this, which is two time for us with the slope.

And then as a quick follow-up, maybe based on your preclinical models. Have you observed any kind of ceiling effects in either the fat loss or the muscle preservation just sort of thinking ahead through to the 400 and 600-milligram cohort?

Yes. Muscle stays stable, that's really a function of the fact that you're not shifting -- I think we're all used to a number [ increase ]. You're not shifting to a starvation phenotype where you break down muscle to provide energy and you break down fat. What's unique again about INHBE its purely a fat loss component. And actually, if you follow the mouse data out, which is pretty interesting is the total body weight kind of crosses the sem-arm, which means that it actually shows that actually as long as you have fat to deplete, you're able to continue to decrease your fat content.

And that's another reason why when we think about this study where we have particularly low BMI in comparison to the historical when all of you are looking at obesity studies, if you look at BELIEVE it was nearly 30 BMIs or nearly 37. So when we think about having larger fat subcutaneously in-visceral, the magnitude of effect should actually be potentially larger like it was in an animal model. So again, bodes well for future subsequent studies in an obese population with a higher BMI and comorbidities.

Our next question comes from Salim Syed at Mizuho Securities.

Paul, congrats on the data. I know you mentioned that the data here is pretty tight on the [indiscernible]. Could you give us just some quantification to how tight it was just given we don't have any sort of spider plot data here just on that -- maybe some of the measurements, the 9.2% and the 4% that you provided. How tight exactly is this data?

Yes. I mean we can share the data that we shared today, all the subsequent data would be at future presentations. But I think the key is that we're getting strong exposure, strong consistent knockdown of activity, and it's translating across statistically significant changes from baseline and fat and increasingly muscle. And so again, when we talked to a number of you going into this several months ago, I think our thought was we would be fortunate in a Phase I study without diet or exercise with all comers with low BMI, that will be really nice to start seeing trends on this. And so the fact that we're actually delivering statistically significant reductions in both fat and on lean mass, I think, speaks to the power of the data.

Okay. And then just a follow-up. The data that's coming into 1Q, could you maybe just review that for us? Like what are your expectations for the 6-month data and for the next cohort 3 months data?

Yes. I think what's clear, and we've said this a number of times that the goal is are we on that curve of fat loss. I think with today's data, we delivered -- we are on the curve of fat loss with GLP-1s with muscle preservation and we expect to continue based on our preclinical experience that's long again, as we have sustained Activin E suppression, that we would expect those findings to continue. So muscle preservation continuing and fat loss continuing.

And so I think it, again, quotes very, very well, for our Q1 data updates over a longer duration, so where we expect to see that impact continue. And we're also going to learn about dose impact. Did that accelerate the curve? Does that help us push the doing frequency? And so again, I think the power is going to be in both looking at both the dose as well as most importantly, duration. So we'll have multiple data sets as we move through not just first quarter, but beyond on really elucidating the power of Inhibin E.

Our next question comes from Ben Burnett at Wells Fargo.

Excellent. I just want to ask about -- so you mentioned that there's no diet or exercise modifications. How was that implemented in the study?

Sure. Yes. So this is a typical first-in-human study. So in that context, you don't generally limit diet and exercise in the way that you would for a Phase II weight loss study. So that was just part of a standard approach to first in-human studies when you're looking at safety and tolerability. We anticipate for our Phase II studies, we would, in fact, include similar criteria as others have as well.

Most interesting way to look at this is it's a real-world study. I mean, I think it's always been something that we've become enamored in looking at the genetics of Inhibin E, that this is a population that's walking around that has a protective loss of function that drives reductions in abdominal visceral fat that has better cardiovascular outcomes as Erik said, in better type 2 diabetes outcomes. And so -- and as part of living their normal lives. And so -- in a lot of ways, the Phase I portion of the study gives us kind of a real-world environment with which to assess that. Indeed, that's true.

I mean even in mice, what was fascinating on the prevention of rebound weight gain is when we stopped the GLP-1 and pre-dosed with Inhibin E despite an increase of hedonic eating with an increase in core consumption those mice did regain weight. And I think it's just really important as we reframe kind of thinking about obesity therapeutics and kind of a completely different paradigm shift is it's not about cohort restriction and essentially starvation. This is about resetting the metabolism to driving fat loss, which allows you to preserve muscle. So it's really exciting, I think, as we think about obesity therapeutics going forward.

Okay. That's great. And can I also ask, I mean, so the hypothesis is sort of playing out that we're -- you're seeing muscle sparing. I think a lot of us are kind of looking at the GLP-1s and what else is sort of coming down kind of the obesity pipeline as sort of comps for what to expect. I guess if you are indeed show that you could spare a muscle, like what -- would love to hear like what ultimate level of fat loss you want to see for this to be commercially competitive?

I think we want to continue to see where we are. I mean I think we're starting at this point, and we'll continue to follow a downward trend. And we're on par with GLP-1 as it states at this very, very early time point. So I think it bodes really well that we're competitive with GLP-1s on fat loss. We see that in our preclinical models as well. But not to underestimate the power of sparing muscle. I mean muscle is an endocrine organ as well in terms of insulin-sensitive outcomes. So -- And also drives energy consumption, which actually ultimately continues to drive better body composition.

So I think in profile, we're on that path already as it stands. But I think stepping back and thinking about, to your point, just the evolving landscape, I do think this idea of how do you put patients on medicines, right, that very early time point for majority to loose a massive amount of muscle at those early time points.

You retain it, you lose fat. And that's all kind of thinking about monotherapy settings. I think one of the very interesting applications is this maintenance concept. Ultimately, if we think longitudinally about how to keep the patients with a better body composition having a once to twice a year shot, where you continue to drive fat loss and preserve muscle, we think is a highly competitive profile.

Our next question comes from Yun Zhong at Wedbush Securities.

So the first question on the lipid profile, I believe that press release said there were no meaningful changes in lipid profile. But I thought heterozygous carriers, they do have a better lipid profile. So do you expect the treatment to maybe lead to any metabolic benefit as GLP-1 does to reduce the risk of other comorbidities?

Yes. Based on the human genetics, we would indeed expect that lipid levels, glucose and other metabolic parameters would improve. Now remember that this is -- these are otherwise healthy overweight and obese individuals. So you wouldn't really expect a lot of effect in this patient regiment. We -- that's also one of the reasons why we're very excited about the Phase II trials in higher BMI individuals with some of those like high triglycerides or prediabetics, where we definitely would expect this to be beneficial with decreasing levels.

I see. And then the second question, given the lean mass increase in both treatment cohort and the placebo cohort, I understand that there was no modification in diet, but are you collecting data on any potential impact on diet or calorie intake or maybe even exercise pattern?