BioAge Labs Aktie

Good afternoon, everyone. Thank you for joining us. Really pleased to have with us the BioAge team. We have BJ Sullivan, Chief Strategy Officer; and Dov Goldstein, CFO.

To start here, the company is developing its NLRP3 inhibitor, BGE-102 in cardiovascular risk and ophthalmology and also advancing a pipeline of APJ agonist. Can you walk us through the portfolio strategy, where the assets stand today and the data expected over the next 12 months?

Yes. One, thank you for having us. Great to be here. So we are a clinical stage biotech company, and we are applying human aging biology as a lens for target discovery and development of therapies for cardiometabolic disease. As you mentioned, our lead program is BGE-102. It's a potential best-in-class NLRP3 inhibitor. So we recently released our full Phase I data, which included 2 cohorts of obese subjects with elevated inflammation at baseline. And there, we showed CRP reductions of 86% in both cohorts, which was really exciting for us because that essentially is on par with the CRP reductions that have been shown with the injectable modalities, you know, IL-6 in particular, that's currently in development for ASCVD. And so we have an oral modality where there's really no trade-off now in anti-inflammatory sort of horsepower.

So I'm sure we can go into those results in more detail, but we're developing this -- our anchor therapeutic area is cardiovascular disease. We're doing a cardiovascular risk proof-of-concept dose-ranging Phase II study that will read out by the end of this year. And our second therapeutic area, which we introduced earlier this year is ophthalmology, and we're doing a DME proof-of-concept study to really demonstrate target engagement in the eye, and we're going to initiate that study in the middle of this year and have results in the middle of next year.

So again, BGE-102 is our lead program. We're also developing both an oral and a parenteral APJ agonist. This is the target for the exerkine apelin and that's one of the strongest signals in our platform. It's associated not only with longevity, but also preservation of physical function. This is an exerkine that is secreted by muscles during exercise. And what we've shown preclinically is that you can essentially double weight loss and fully restore body composition back to that of lean control animals when you add it to an incretin.

So when thinking about the obesity market as it's evolving, the unmet needs on the oral side, probably still more the quantity of weight loss and getting that quantum on par with what we're seeing in the injectables, the injectables, now we're seeing bariatric surgery like weight loss, perhaps the sort of predominant value proposition there is body composition, but we're developing both an oral and a subcutaneous agonist to complement both sort of ongoing segments of that market.

Great. And you have collaborations right now with Novartis and [ Eli Lilly ] specifically, elaborate maybe on the therapeutic focus here and how partners leverage your platform in the financial terms?

Right. So we had a target discovery partnership with Novartis. And so this is looking for targets that sit at the intersection of healthy aging and exercise. And so what we built as a company is one of the world's largest collections of human aging data, which really look at healthy middle-aged people and then track them essentially to death with very detailed phenotyping and health records and so we can look and actually do apply [ modern omics ] now to biobank samples and ask the question, what is the biology that predicts not only longevity, but sort of very granular health outcomes and phenotypes. And so that's the data set that we contribute to the collaboration and Novartis has exercise interventional data sets that they're contributing. And so we're really looking for targets that sit at the intersection of those 2 things.

We also have a collaboration with Lilly, and that's really focused on molecule discovery. And so we're building drugs against targets that we've identified in our platform.

So starting with 102 here, can you explain the role of NLRP3 inflammasome pathway in neuroinflammation and cardiovascular disease? And you've talked about a novel binding site versus other drugs in this class. So how does this translate to differences in efficacy and safety?

Yes. So NLRP3 is one of the inflammasomes in the body. And essentially, it is a sensor and a transducer of signals that contribute to sterile inflammation. So if you think about in the ASCVD context, this is cholesterol crystals, oxidized LDL, metabolic stress, hyperglycemia, all of those are essentially sensed by NLRP3 and then converted into sort of a cytokine cascade, right? So NLRP3 regulates the production of IL-1 beta of IL-18. It also controls pyroptotic cell death and atherosclerotic disease progression. In DME, hyperglycemia is the key trigger, right? And that's then converted into sort of a cytokine cascade that drives the disease forward.

But yes, so again, this is one of several inflammasomes in the body, but it is the primary contributor to sterile inflammation. People have been trying to drug this for 20 years now. Originally, the MCC950 was the original tool compound. It's found in the ATPAs pocket and groups have been creating derivatives of that, that compound, novel chemotypes that target the same binding site. But what we did was we took a step back and actually did a DNA encoded library where we blocked that binding site to identify novel binding sites. So what we have is a -- not only totally novel chemistry, but a novel binding site that we characterized and detailed sort of structural biology of it. And as a result, we have issued IP that includes not just sort of the specific structures described, but broadly speaks to the ligands that interact with that binding site.

And what's interesting about it is that it can bind NLRP3 in any confirmation. So whether it's active or inactive, our pocket is accessible, which is unlike MCC950 and the derivatives thereof, which are only -- the pocket is only available when it's in the inactive form. And that may contribute to either onset of action as well as sort of the magnitude of the anti-inflammatory effect that we're observing. Essentially, all of the NLRP3 in the body is open to our [indiscernible].

With regard to your Phase I data that you've shown here, you reported up to 86% reduction in CRP within 2 to 3 weeks in obese subjects with high baseline CRP. How does that compare with other inhibitors or inflammasome targeting therapies in development?

Yes. So I think we look at the sort of differentiation across 3 key dimensions. So one is efficacy in terms of biomarker reductions, safety and tolerability as well as dosing. And so to speak first to the -- to the [indiscernible] in both of the cohorts that we tested in our Phase I [indiscernible] we were able to normalize CRP below the 2 mg per liter threshold in 87% to 93% of those participants. And that's really important because we learned from the CANTOS trial, which Novartis ran with our IL-1 beta antibody, showing that essentially the headline number in the MACE trial was 15%, which is a good result. But it was concentrated in the patients who achieved this 2 mg per liter threshold where they had a 25% benefit and those that didn't had essentially [indiscernible]. So we think that that's a really meaningful outcome.

And regardless of baseline in the 2 cohorts, we were able to normalize them to these -- the vast majority of patients to this important [indiscernible]. So we're thrilled with the biomarker efficacy. The safety tolerability was, in our view, exceptional coming out of the Phase I trial, really no observations of any kind.

And then importantly, dosing, I think we have a clear low-dose QD profile, which is not only commercially very important when you think about the ASCVD opportunity, in particular, where it's dominated by orals. It's mostly PCPs prescribing. People are used to taking a statin every day. So it's commercially very important. And then also in terms of like ultimately, strategic interest, there's a lot of value potentially in fixed-dose combinations and the sort of life cycle management strategies and the ability to combine NLRP3 with an oral PCSK9, a statin and sort of, again, drive value for across the franchise, but also maximize sort of patient acceptance and convenience.

So given these Phase I data, what are expectations for Phase II proof-of-concept data that's coming by year-end?

So the proof of concept is really, first and foremost, can extend the Phase I data, right? So we were -- the primary outcome is CRP reductions. What we're looking to see here is we sustained decrease in CRP and other inflammatory biomarkers. We're hoping to extend the safety tolerability findings from the Phase I. And we're also adding additional assessments like MRI imaging of the liver, where Ventyx previously showed, for example, benefit as a monotherapy in liver inflammation. So there will be additional assessments there.

The key outcome beyond that is really dose selection. As we think about the profile coming out of Phase I, we feel like we're feeling really bullish about it. And we want to maintain an aggressive time line going forward to enable a Phase III start next year. And so part of that was expanding the Phase II POC to include exploration of multiple doses, have confidence in what we ultimately carry forward into Phase III.

You talked about the dose -- the dosing work that you've done and you're looking at the 90-milligram in Phase II versus the 120-milligram in Phase I. What gives you confidence in achieving similar biomarker outcomes with the lower dose in the Phase II?

Right. So we're -- the top dose in the dose-ranging study is 90 milligrams QD. And we are expecting on an exposure basis that that's really going to give us 98% target suppression. So the drug does have a relatively long half-life and reaches steady state of about a month. And so the difference between the 120-milligram and 90-milligram dose is really an adjustment for that PK profile, right? So in the Phase I with 120 milligrams, we saw a 98% suppression of IL-1 beta at a week. We'll achieve that level at a month in the Phase II trial, but this is really a chronic medicine. And so again, it's sort of a pharmacokinetic extrapolation. The endpoint for the study to be [indiscernible].

The key read-through this year, we're just talking about this, but is the Phase III CV outcomes data for Novo's IL-6 inhibitor in the ZEUS trial. What level of MACE reduction would bode well for your drug and for the class overall?

Right. I mean so we're really looking for any significant MACE benefit here. I think, typically, a clinicians view 15% MACE benefit is sort of the threshold at which there's excitement. So we're looking obviously for a meaningful MACE benefit here. I would say that the way we think about this is actually the biology is probably more derisked by the CANTOS trial that we were talking about earlier, which is targeting IL-1 beta, which is directly downstream of NLRP3 and where patients who had -- who achieved sort of target CRP levels had a 25% MACE benefit.

But of course, if IL-6 shows a significant benefit here, you're saying that no matter where you are in this inflammatory cascade that blocking that provides clinical benefit for patients. And so that is, of course, broadly [indiscernible]. The way we think about this program, in particular, and the value of success in ZEUS is really anticipating a launch of an IL-6 drug in this space. I think right now, physicians only have low-dose colchicine, which is approved for inflammatory cardiovascular risk, has a lot of tolerability and drug interactions that make it used in clinical practice virtually nil.

And so the prospect of having a selective anti-inflammatory launch in the space, have growing physician awareness of inflammation as a treatable risk factor and have CRP routinely tested as part of your sort of annual workup. We think all of those would be very powerful in sort of market development for subsequent launch of an oral that can provide similar benefits in a more convenient sort of format.

And if the ZEUS study is unfavorable with regard to that outcome here, what is the read-through for you?

Yes. I mean, again, I think we map the biology more closely to CANTOS trial, but we won't swim upstream if it's sort of a catastrophic negative result, but we're cautiously [indiscernible].

The primary focus of the CV risk market has been LDL lowering with PCSK9s and statins with increasing focus on Lp(a) as a target coming up. Where do therapies targeting residual inflammation fit? And what is the market opportunity in that context?

Yes. So this is -- there was actually a really compelling paper in the New England Journal of Medicine, I believe, last year by Paul Ridker showing that hs-CRP was actually the most predictive risk factor for MACE in the 30-year longitudinal women's health study. And so it's a strong risk factor. It's an independent risk factor. And it's one where there's actually about 60% of ASCVD patients today have residual inflammatory risk, which is to say they have not achieved that target CRP level of 2 mg per liter. So we think that this is -- we're hoping that this will become a routine part of care where those patients who do have elevated CRP despite whatever background therapy they're on, will be initiated on a drug that can address that risk because, again, it's highly predictive and it is independent of these other sort of lipid biomarkers.

And do you plan to start a Phase III by year-end '27? Do you plan to advance independently or seek a partner here?

Yes. So I mean, I think right now, our focus is on enablement, I would say, all of the long lead time activities that we need to feel confident with this aggressive timing. So that includes doing dose ranging. It includes initiating a CMC campaign to support the initiation of a trial of that size. And of course, aligning on the design and all of the preparation for an end of Phase II meeting.

But Dov, do you want to speak to the partnership aspect?

Yes, sure. My pleasure. So as far as partnership, we strongly believe the best way to form a partnership potentially is for the company to be in a strong position to go ourselves. And that means, as BJ mentioned, preparedness, but also financial preparedness. This is an asset that makes sense already in the late-stage clinical setting to be done by a larger group, but we are prepared as a company.

Anything else we need to touch on with regard to this program?

I think we've covered the bases in ASCVD.

Perfect. Let's switch over to ophthalmology here with 102. With regard to diabetic macular edema and geographic atrophy, maybe speak to the mechanistic rationale behind moving into these disease areas.

Right, right. So I think that there's one sort of driver of sort of our therapeutic area strategy here is just the differentiation of the molecule and the ability to access these privileged compartments and the distribution profile of the molecule. So in our Phase I data, we show that we get excellent CSF penetration. We've shown in a range of preclinical species that we get therapeutic exposure in the retina. And so we're leaning into the [indiscernible] of the molecule to sort of expand the scope of indications that we can address, and ophthalmology is sort of our second anchor therapeutic area.

So to speak to the biology of it, the NLRP3, again, is a sensor of sterile inflammatory triggers. In DME, it's really responding to hyperglycemia, and that's what activates NLRP3. Geographic atrophy is a little bit different. It's almost like a neurodegenerative condition of the retina where you get accumulation of the cellular debris like Drusen, which has these amyloid components. And so you get deposition of all of the cellular debris and it's sort of a canonical pro-inflammatory trigger. So NLRP3 actually sits at the core of both of those diseases, but with different upstream drivers.

And any read-through from Roche's data for their IL-6?

Yes. So the vamikibart program has been sort of informative for us in thinking about our next steps here. I think first and foremost, this is an IL-6 in an intravitreal injection, right? They've shown efficacy now as a monotherapy with overall line. They released that data at ARVO a few weeks ago. They had shown incremental efficacy on top of VEGF. So I think on a very fundamental level, it tells us that selective anti-inflammatory strategies can provide incremental benefit in this patient population. It also showed that essentially the maximum benefit was achieved by 2 months of treatment. And so for us, thinking about a tractable POC indication where we're trying to, first and foremost, demonstrate target engagement in the eye, this is a tractable indication for us versus geographic atrophy, which is an area of enormous unmet need, but it does progress more slowly.

I think in thinking about IL-6, though, it's one of the -- it's one aspect of NLRP3. It's not the totality of the picture. I think NLRP3 does induce IL-6. It also VEGF is induced by IL-1 beta. You've got this sort of pyroptotic cell death when NLRP3 is activated in the retinal [ microvasculature ]. And so there is potential to have efficacy beyond what was demonstrated with these IL-6 modalities. And of course, without the sort of the complications that come with that [indiscernible].

For the DME study, we were looking forward to results in mid-2027 here. What percentage change in intraocular IL-6 will be clinically meaningful? And maybe talk about both the monotherapy in combination with anti-VEGF therapy and the incremental BCVA in each of those cases.

Right. So our POC study is going to have 3 arms. We're looking at BGE-102 as a monotherapy. We're also looking at VEGF as a monotherapy in VEGF combined with BGE-102. So there are 3 arms. We're going to treat for 2 months. And the primary endpoint is the percent change in IL-6, intraocular IL-6. So we're going to be doing aqueous taps on these patients so we can measure biomarkers in the [indiscernible]. We're powering the study for about a 40% change in IL-6, but I think it's going to be important for us to look at the totality of the data. So it will be a biomarker primary, but we're going to be doing functional assessments like BCVA. We'll be making anatomical OCT measurements like CST. And so we're going to be looking to see that the totality of the data sort of tracks that biomarker change, right, thinking about that pharmacodynamic effect.

And where would this drug be positioned within the market?

So I think that there are multiple compelling segments here. So if you think about DME, I think the obvious segment is the watch and wait patients. So they're about 40% of DME patients who have edema, but they don't have sufficiently compromised vision that ophthalmologists have initiated intravitreal therapy. And so if you can treat these patients with an oral and delay the onset of initiation of that therapy, that could be incredibly meaningful.

I mean I think for context, VEGF does work well in a lot of patients, especially in trials. I think in the real world, that picture becomes more complicated because you're talking about monthly or quarterly dosing that's challenging for sort of working-age people follow. So that's sort of one highly addressable segment.

On the other side of the sort of -- you sort of got early patients and then I think also late patients where you've got -- they've been on a VEGF, they're refractory in terms of the amount of disease control even when they're compliant. So adding on this mechanism to regain disease control would be very meaningful. And I think there, it's really just the clinical benefit, first and foremost, the convenience of a secondary [indiscernible].

For geographic atrophy, I mean, this has been a much harder indication historically than DME, particularly with regard to BCVA. What is the expected profile for your drug in geographic atrophy? And can the drug deliver functional improvement, noting the absence of approved assets as we just mentioned, showing that?

I mean that's, of course, the truth. I mean -- but the -- but -- yes, so geographic atrophy, it's -- this is essentially the terminal stage of dry AMD. It causes central blindness in the vast majority of patients. And there are approved complement inhibitors, so Syfovre and Izervay. They -- these are blockbuster products, but they -- right now, they slow lesion size by about 15%, right? And they require monthly injections. They haven't shown visual acuity benefits yet. So there's a ton of unmet need here. I mean the clinical need is really enormous.

And so in thinking about the positioning of this molecule, yes, an oral, less convenient, especially with the sort of majority elderly population, but just getting disease control of any kind, however you measure it, I think is a major step forward for these patients.

You've also talked about going into CNS-related chronic inflammatory conditions. Speak to the rationale there and the indications that may be of most interest.

Yes. So as we demonstrated in the Phase I, we do get really, really nice CNS exposure with the drug. Right now, we're very focused on ophthalmology as our way to lean into the sort of differentiated distribution of the drug. But thinking long term and the applicability of this mechanism, really the range of neurodegenerative conditions, in particular, are exciting because those are ones where you get accumulation of debris like alpha-synuclein or amyloids and then those are, again, pro-inflammatory triggers. So it's a lot for a small biotech to block and tackle, but there's a lot of promise in this mechanism for this sort of broader range of [indiscernible].

And then finally, Apelin, where it all started. But you do have an agonist here under development, one in collaboration with JiKang. In terms of therapeutic areas and focus, speak to expected profile and key near-term milestones.

Yes. So we are developing 2 APJ agonists, one for an oral small molecule and then a subcutaneous agonist as well. As you mentioned, we have a collaboration with JiKang Therapeutics, developing an agonist nanobody. And the profile here, again, is we're looking to increase both the quantity and quality of weight loss. And so we think that even as the obesity market evolves, I think a lot of key unmet needs remain. And so thinking about the oral space for incremental efficacy to really make it a competitive alternative to an injectable, it would be commercially valuable with body composition as sort of a nice upside.

And I would say, too, with limited increase in GI tolerability. I think our experience with this target is that it shouldn't lead to any sort of on tolerability issues that would make combinations with incretins challenging. And I think that, that's in contrast to other sort of mechanisms focused on certainly anabolics.

So on the parenteral side, injectables have achieved remarkable amounts of weight loss, but I think body composition and especially addressing that in a well-tolerated way remains a major unmet need. And so this is, again, where we're -- the optimal profile for a subcu would be to complement the injectable incretins. I mean you could even think about dose-sparing, too, to sort of take advantage of some of the synergistic weight loss. But either of those, I think, would be highly valuable.

Great. And maybe just here as a final question. Walk us through your cash position and cash runway and maybe just in the context of all these programs that you're advancing.

Yes. My pleasure. So at the end of the first quarter, we had $385 million of cash. All the all the programs we've outlined are included in the guidance I'm just about to give you. The only thing we haven't talked about is we're actively working on a backup compound for NLRP3 to potentially one of these 2 indications will be another molecule to split the commercial opportunity. But with all the programs we've talked about, we have cash runway into [ 2026 ].

And why would you -- just maybe the rationale for the second follow-on NLRP3 and the need to split the commercial?

Yes. Just to think about if we partner the ASCVD asset with someone and want to price it at a certain level and want to keep ophthalmology for ourselves and price it different gives us that flex [indiscernible].

Perfect. Well, with that, thank you so much.

Thank you very much, Salveen.

Thank you so much.

Good afternoon, and thank you for joining us today for BioAge Labs R&D Day. I'm Chris Patil, VP of Media at BioAge.

Before we begin, I would like to remind everyone that during this call, we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on our current beliefs, plans, expectations and assumptions as of today, and are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those expressed or implied by such statements. These risks and other factors can be found in our most recent annual report on Form 10-K, quarterly reports on Form 10-Q and other filings we have made with the Securities and Exchange Commission. We encourage you to review these filings as well as the full forward-looking statements disclaimer on the next slide for a more complete understanding of the risks associated with our business.

We undertake no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. A copy of the presentation materials for today's call are available on the Investor Relations section of our website at ir.bioagelabs.com.

Welcome to BioAge Labs R&D Day. Today, we'll be presenting an update on our lead program, BGE-102, our oral brain-penetrant NLRP3 inhibitor including our Phase I clinical results and our development strategy across cardiovascular and retinal disease. We're joined today by members of the BioAge management team and by four leading external experts who will share independent perspectives on the science and clinical opportunity.

Joining from BioAge are Dr. Kristen Fortney, our Co-Founder and Chief Executive Officer; Dr. Paul Rubin, our Chief Medical Officer and EVP of Research; and Dr. Dov Goldstein, our Chief Financial Officer.

We're also joined by 4 distinct guest presenters, Professor Matthias Geyer, Director of the Institute of Structural Biology at the University of Bonn; Dr. Michael Davidson, Professor and Director of the Lipid Clinic at the University of Chicago, Pritzker School of Medicine and CEO of NewAmsterdam Pharma; Dr. Brian Hafler, Associate Professor of Ophthalmology and Visual Science at Yale School of Medicine; and Dr. David Boyer, Senior Partner at Retina Vitreous Associates Medical Group.

Here is how today's presentation will flow. Kristen will open with a brief introduction to BioAge and our Lead program. Professor Geyer will then share structural biology insights into BGE-102's unique mechanism. Paul will walk through our Phase I clinical results in detail, followed by our cardiovascular development strategy. Dr. Davidson will speak to the role of inflammation in atherosclerotic cardiovascular disease. Paul will then introduce our ophthalmology program, and Dr. Brian Hafler and Dr. David Boyer will provide their perspectives on NLRP3 in retinal disease and on the DME and GA treatment landscape. Kristen will close with our pipeline and near-term catalysts, after which we'll take questions from the analyst community.

With that, I'd like to turn the call over to Dr. Kristen Fortney, our Co-Founder and CEO. Kristen?

Thank you, Chris, and thanks, everybody, for joining today for our R&D Day where we'll do a deep dive on our lead NLRP3 program, our science and the indications we're pursuing.

At BioAge, next slide. At BioAge, we're harnessing the biology of human aging to develop new therapies for cardiometabolic diseases. We built BioAge in one of the world's largest longitudinal human agent data sets. That platform validated through ongoing partnerships with Novartis and Lilly has produced a pipeline led by BGE-102. BGE-102 is our oral brain penetrant and NLRP3 inhibitor and a potential pipeline in a pill, targeting efficacy in line with injectable anti-inflammatories across multiple indications. On the cardiovascular risk front, we've already demonstrated potential best-in-class profile for CRP reduction. We've seen basically an 86% reduction in CRP in obese subjects and 87% to 93% of subjects achieved normalized CRP below 2 milligrams per liter. This is the critical threshold that believe will correspond to cardiovascular benefits.

And then on the ophthalmology side, therapeutic retinal exposure of our drug enables oral treatment of diseases, including diabetic macular edema where intravitreal anti-IL-6 has shown benefit. We have a very catalyst-rich year, our cardiovascular risk trial is s starting soon and will read out by end of year, and we're also starting middle of this year, our DME trial. Beyond NLRP3, we're also working on APJ agonists. This is an exercise mimetic for obesity that has the potential to increase weight loss and help improve body composition, and we're on track for IND submission by end of this year.

Next slide. Chronic NLRP3 activity drives disease and predicts poor human longevity. NLRP3 is known as a master switch to innate immunity and when it's chronically activated by metabolic stress, it can drive sustained inflammation that's directly linked to cardiometabolic disease and shorten the lifespan. We see this strong signal in our human cohorts, as you can see here on the top right, where individuals with elevated NLRP3 are predicted to live shorter lives and there's a very nice human genetic signal where mendelian randomization analysis links NLRP3 expression to heart failure.

Next slide. Our lead program, BGE-102, is well positioned to address diseases driven by inflammation in both the CNS and the periphery. BGE-102 is a potent, structurally novel oral brain penetrant NLRP3 inhibitor, and our Phase I data shows it has the attributes needed to address inflammation-driven disease across multiple organ systems. So just to walk you through a few of the highlights here, we have potential best-in-class potency demonstrated by our 1-point nanomolar, IC90 and the human ex vivo whole blood stimulation assay. We've shown 24-hour IC90 coverage, the 60-milligram once a day dose. And as I already mentioned, we've seen really profound potential best-in-class CRP reductions with 87% to 93% of subjects showing normalized CRP reduction after 2 to 3 weeks of treatments in line with anti-injectable anti-IL-6 drugs. To date, we have a very attractive safety and tolerability profile from our safe Phase I study, all AEs to date mild to moderate, self-limited and no dose dependency. And we have large safety margins coming out of our 3-month GLP tox study. We also have potential best-in-class CNS penetration with a 0.7 Kp,uu CSF and a very strong IP position for our novel chemistry.

Next slide. One of the unique features of our molecules is our novel binding site. So as you can see on the left here, the binding site indicated in purple is where many of the other NLRP3 inhibitors bind including MCC950. And in contrast, BioAge has a novel binding site, which leads to potential advantages. We can bind both inactive as well as active NLRP3. On the bottom right of this slide are 3 papers that we put out over the past couple of years about our novel chemistry, novel biology and also novel binding site.

And I'm going to hand it over now to Dr. Matthias Geyer, our structural biology collaborator to take you into more depth on our novel binding site.

Thank you very much for the invitation and for having me here. What I would like to show you in the next couple of minutes is a new way to inhibit the NLRP3 inflammasome. And there are 3 ways that makes the BGE-102 compound different from any other compound that is in the clinic. As first here, this is human NLRP3. It consists of 3 domains. You see the regulatory NACHT domain. You see the sensory LRR domain here at the bottom and an ADP binding site. And what we discovered as biochemists [indiscernible] is the BGE-102 binding site, which you see here at the top, it's close to regulatory helix, which is required for membrane attachment. And that's where the compound is binding to.

You see here in the hinge between these 2 domains the MCC950 binding site which is already targeted by the Pfizer and Zofran [ neural analog ] that exists since 20 years. And we determined the structure, the cryo-EM structure of BGE binding to NLRP3, and that's shown here in green. You see nicely at the top how these compound glues the regulatory helix at the bottom in order to fix it and inhibit its rotation. And the MCC950 binding site is shown here in the hinge, the site is less accessible in between these 2 domains. And looking at these binding sites, the NLRP3 protein exists in at least 3 different confirmation.

So what you see here to the left is NLRP3 bound to ADP. That's the inactive state. And upon the priming step, which can, for instance, be a phosphorylation, the activation occurs. This requires a 90-degree rotation that you see in the middle. And then ADP is being bound by these AAA+ ATPase. So this is the active state but only then is the point of no return. So when this active state when 10 proteins come together and form this disc assembly, which is shown here to the right. So this is the NLRP3 ADP inflammasome, and that's the signaling competence state that leads to inflammation.

And interestingly and importantly, the BGE-102 binding site is accessible in all 3 states. So this means that not only the inactive state can be targeted or the active state, but even the signaling competent state, for instance, for providing degradation. And that's a unique pharmacology approach because it's able even to active -- to target hyperactive mutations of these proteins. And the third feature is that BGE is selective for NLRP3 specifically. And there's not just one, NOD-like receptor NLRP3, but 22 in humans. There are 14 NLRPs and another 8 NLR like NLRC. And within this family, already the closest to NLRP3, which is NLRP12, has in the 26 residues that makes the binding site for BGE-102, already 8 residues are different to NLRP3. You see this one, NLRP10, 6 and 1, but they have 13, 15, 16 residues different. And that's shown in this cartoon here to the right that these different amino acids lead to clashes with the compound, meaning that basically the compound is not able to target any of these other family like -- not like receptors. And this provides a lot of specificity for BGE-102 for specifically targeting NLRP3.

So to summarize this, there are 3 structural features that set BGE-102 apart from any other compound that is in the clinic against NLRP3. And that's the binding site here at the top that is unique from every other inhibitor. That the binding site is accessible both in the resting state as well as in the active display confirmation. And thirdly, that the BGE-102 binding site is selective for NLRP3 within the inflammasome family.

And with that, I'd like to thank you, and thank for the attention.

Dr. Paul Rubin will now walk us through BGE-102's Phase I clinical results.

Thank you. Our Phase I program was a comprehensive dose escalation study in healthy volunteers as well as in obese participants. It was designed to show pharmacokinetics, pharmacodynamics and to measure key inflammatory biomarkers, including hsCRP. The obese cohort was particularly interesting in that patients that do have obesity are representative of patients that might be in later studies in cardiovascular disease is that they have both risk factors and have increase in inflammation. The study consisted of 3 components: the single ascending dose study, which consists of 36 subjects as well as 9 obese subjects, and we looked at doses between 10 milligrams and 120 milligrams and the 60-milligram dose we looked at both fed and fasted.

The multiple-ascending dose cohort was healthy volunteers that included 18 subjects at 60 milligrams and 120 milligrams for 14 days and a multiple ascending dose cohort, which consisted of obese subjects with CRPs at baseline were greater than 3 and this was 41 subjects where we looked at 60 milligrams for 21 days and 120 milligrams for 14 days. As I mentioned, the obese MAD cohorts are particularly relevant in that they are representative of populations that we will study in the future, including cardiovascular subjects. And this particular group in our Phase I was designed to mirror our Phase II eligibility criteria in subsequent trials. Next slide.

Now fortunately, the study met all our key trial objectives. The drug was safe. It was well tolerated. The PK was dose proportional, which clearly supported once daily dosing, and we showed potent suppression of IL-1 beta which is kind of the main marker for the activity in an NLRP3 inhibitor. Also, we showed up to 86% CRP reductions in obese subjects, which was very robust. In general, the safety -- from a safety perspective, all adverse events that were recorded were mild-to-moderate, self-limited, and there was no dose-limiting toxicity seen. The pharmacokinetics were dose proportional and the half-life of this drug clearly supports a once a day dosing schedule. The pharmacodynamics revealed that we can achieve greater than 90% IL-1 beta suppression after a single dose for 24 hours at both the 60-milligram and 120-milligram doses. And interestingly, when we measured CSF levels via lumbar puncture, we showed that at these doses, we exceeded the IC90.

In obese subjects, 86% CRP reduction of both the 60 milligrams and 120 milligrams was seen and 87% of the subject to 60-milligram and 93% at 120 milligrams showed CRP reductions that were below 2, which is considered very clinically relevant.

Next slide. Across the full program, BGE-102 was very well tolerated with an adverse event profile was very similar to placebo. We only saw mild-to-moderate treatment emergent adverse events. They were all self-limited. They clearly were not dose dependent. There were no serious adverse events and no subjects were discontinued because of adverse events. The adverse event rates were comparable to placebo. And as you could see, it was 61% versus 59%, which is also typical of a Phase I study. And there were no clinically meaningful changes in vital signs, in laboratory analysis or electrocardiograms.

Next slide. Now before going through the actual biomarker data, I'd like to orient you as to the baseline characteristics of the obese cohort. These participants had BMIs in the mid-30s and meaningfully elevated CRPs, again, similar to the population we plan to enroll in subsequent trials in Phase II. There were 2 active cohorts plus placebo, 60 milligrams, where there were 19 subjects, 120 milligrams showed 14 subjects and placebo with 8 subjects. The median baseline CRP varied between 4.85 and 6.3, which is well above the 3 milligrams per liter high CD risk threshold. It was a clearly diverse population, and this included 31.6% African-American representation in the 60-milligram cohort.

Next slide. The obese MAD cohort safety and tolerability was also -- as represented here, was quite clean. We saw no signals that would cause any concern. There was a very low rate of related treatment-emergent events and all these were mild-to-moderate. There were no discontinuations due to drug. There were no serious adverse events or severe treatment-emergent adverse events. We did not see any neutropenias, thrombocytopenia or infections in this particular trial. Next slide.

I'd now like to walk you through the pharmacokinetic and pharmacodynamic data from our healthy volunteer cohorts, which established a foundational PK/PD profile for BGE-102. Next slide. In our single ascending dose cohorts, 102 showed dose-proportional PK across the 10-milligram to 120-milligram range. And this is very, very good for creating a foundation as to how we want to select our dose. There was also a dose proportional exposure between the 10-milligram to 120-milligram.

Next slide. With repeat dosing, both the 60-milligram and 120-milligram doses showed accumulation approaching steady-state trough concentrations above the IC90 for IL-1 beta, confirming full 24-hour target coverage with once-daily dosing. Both doses maintained trough above the human ex vivo IL-1 beta IC90 and that's in near steady state by day 14 and both cleared the IC90 threshold and could explain this comparable downstream biomarker effect.

Next slide. Now an important differentiator is the fact that BGE-102 crosses the blood-brain barrier and show CSF concentrations at the 120-milligram level well above the IC90 by day 14. The 60-milligram was also above the IC90 at this day 14 level. And in fact, the Kp,uu CSF of 0.7 is the best that we've seen reported. And the fact that this drug does get into the brain allows us to potentially explore CNS-related chronic inflammatory conditions. And the same molecule can also address retinal disease. So it establishes this possibility for us having this pipeline in a pill concept.

Now moving forward from kinetics to target engagement, we demonstrated 90% IL-1 beta suppression at the 60-milligram trough and 98% on at 120-milligram, which is essentially completely shutting down the target. We believe that this inhibition, which does relate to also IL-6 inhibition and that they are clearly sequential provides the pharmacodynamic basis for downstream decreases in both CRP and IL-6.

Next slide. We looked at IL-1 beta suppression over a 24-hour period after a single dose after a dose at day 8, and then again, after a single dose on day 14. And what you could see here on day 1 is that you do see corresponding to the Cmax, a relatively robust inhibition of IL-1 beta at 10 hours, but it reverses as the drug levels decrease. So it suggests that this effect is indeed reversible. By day 8 where you're getting kind of approaching steady-state levels. You're seeing very significant inhibition across the full 24 hours, and that's even more profound by day 14.

So we believe that we can achieve and this is measured complete inhibition of IL-1 beta throughout a full 24-hour period. Now interestingly, when you look at the PK at day 8 of the 120-milligram dose. We know that if we gave 90 milligrams, we modeled this, we will achieve the same levels at 90-milligram at steady state. So we could essentially achieve the same level of inhibition using a dose as low as 90 milligrams.

Next slide. Now I'd like to move on to the obese MAD cohorts. As we mentioned, we believe these are particularly relevant because they have both cardiac risk factors as well as a hyper-inflamed state, as indicated by increases in CRP.

Next slide. Now as mentioned, our Phase I included 2 obese MAD cohorts, and we looked at a 60-milligram dose and 120-milligram dose. And this was specifically designed to evaluate exploratory marker end points in the population we do intend to treat in Phase II. As you could see, the obese population had a baseline BMI between 32 and 42, baseline CRP greater than 3. They were not allowed to be on incretins. And we looked at the 60-milligram dose for 21 days, the 120-milligram dose for 14 days. We believe that data from these cohorts directly influence our ability to choose appropriate doses for our Phase IIa study.

Next slide. Now interestingly, both the 60-milligram and 120-milligram dose showed an 86% medium decrease in CRP relative to placebo. This, again, is the best that we've seen reported and provides us with a possibility of having a best-in-class performance. It's also comparable to injectable IL-6 antibodies. We believe that the comparability of 60 milligrams and 120 milligrams at or near the ceiling of the hsCRP dose response curve allows us to explore both potential doses or at least the exposure is related to both of these doses.

Next slide. When we look at absolute CRP levels over time, we see that both doses drive median CRP from elevated baselines down to approximately 1 by day 7. This is well below the 2 threshold that we believe cardiovascular benefit begins to kick in and as demonstrated by the CANTOS trial.

Now when you look at it, in both cases, independent of the dose, you're seeing by day 7 that the CRP levels are driven down to approximately 1. So they both performed the same way even despite the fact that the baselines were slightly different with the 60-milligram being higher than the 120-milligram. And then this is maintained throughout the full observation period.

Next slide. Now as mentioned, getting CRP below 2 has been shown to be clinically relevant in terms of decreasing outcomes significantly. So this is an important level. When we look at the numbers of subjects that reached that threshold, we're quite struck by the consistency of the drug. We could see that 80% -- 87% of those patients at 60 milligrams and 93% of those at 120 milligrams reached this level. And interestingly, we got 60% to 71%, who were actually below 1. And the belief is that where 2 is clinically relevant, the lower the better, where you can get continued benefit by driving this even lower.

So this links our data to the outcomes in the CANTOS trial. And remember, when -- in the CANTOS trial, those subjects that had a CRP below 2 showed a 25% reduction in MACE.

Next slide. Looking at IL-6, you can see that both the 60 milligrams and 120 milligrams had significant decreases in measured IL-6 levels ranging between 55% to 78% in the 60-milligram, and 58% to 69% in the 120 milligrams, and it was clearly different than placebo. And again, this confirms the fact that our drug is hitting its predicted targets that reducing IL-1 beta resulting in IL-6 decrease, ultimately reducing CRP.

Next slide. Now where we didn't have elevations in IL-6 as an entry criteria in the CSF for this particular trial, we did find that 2 subjects when we explored these did have elevations in IL-6. And in both cases, the drug drove IL-6 levels down by day 14.

Now we believe this is related to CSF production and reduction in that when you compare the CSF levels to the plasma IL-6 levels, you see the CSF levels were significantly higher, suggesting that this is not just a simple case of diffusing from the plasma into the brain, and this drug is actually having an effect on decrease in IL-6 in the CSF. So again, it's underscoring the fact that we can look at this drug as a potential therapy for chronic inflammatory conditions in the brain.

Next Slide. We also saw that both the 60-milligram and 120-milligram doses resulted in comparable decreases in the levels of fibrinogen, another important risk factor, ranging between 23% and 30%. So in fact, taken with the CRP and the IL-6 levels, BGE-102 suppresses a broad spectrum of the inflammatory cascade, which theoretically can address multiple risk factors with a single oral molecule.

Next slide. So with the Phase I data as the foundation, I'd like to turn to our clinical development strategy, essentially how we plan to advance 102 into proof-of-concept studies across multiple indications. We're going to focus on our cardiovascular plans as we've recently increased the size of our planned Phase IIa study as part of our prioritization of enabling a Phase III start by the end of next year.

Next slide. Now BGE-102 penetrates both the brain as well as the retina. And therefore, we believe we can address inflammation-driven diseases across multiple organ systems, including both the eye and the brain, as mentioned before. Cardiovascular and metabolic in the periphery is also possible, plus other diseases where you're seeing a chronic inflammatory component that is, in some ways, causative for these particular diseases. We can consider things like insulin resistance. We can consider MASH, all have been shown to have a link to upregulation of the NLRP3 inflammasome. Right now, as mentioned, our lead indication is cardiovascular risk, but we're also going to be exploring ophthalmological indications as the second therapeutic area.

Next slide. The cardiovascular opportunity for an oral anti-inflammatory is substantial. Inflammation is known to be an independent risk factor that's on par with cholesterol. The addressable population in the U.S. is approximately 15 million patients, and the channel dynamics strongly favor oral versus other modes of therapy. Elevated CRP increases cardiovascular risk across LDL strata. It's additive to LDL as a risk factor and not redundant with lipid-lowering, 60% of the 25 million ASCVD patients have elevated CRPs. Now we believe that we can pursue not only the secondary prevention, which has been looked at before, but potentially high-risk primary prevention, especially because oral administration allows us to do this like statins, which started at secondary prevention and expanded to the much primary extents of its larger primary prevention population. We believe we can achieve this with this mechanism.

We believe, again, that over 80% of statins are prescribed by PCPs and that's also because of the oral highly preferable way that this is administered. So again, we believe that this can emulate that particular lesson, which has been taught by these drugs. Also, we look at the fact that this is oral allows us to add these to statin regimens or combined in fixed dose oral combinations in the future. This, we believe, will open the full primary care channel, an opportunity that we don't believe is achievable with injectable compounds.

Next slide. Now we've designed our Phase IIa proof of concept to characterize the full dose response of CRP with arms specifically chosen to support optimal dose selection for later development. In this study, we'll have 4 arms, which includes placebo, 30 milligrams, 60 milligrams and 90 milligrams once a day, 40 per cohort with a 12-week treatment period.

Our eligibility for this study is very similar to our obese MAD cohort while we'll see BMIs of 32 to 42, CRPs greater than 3 and having 1 additional CV risk factor in addition to obesity. The primary endpoint of this study is percent change in CRP. But a key secondary endpoint will be normalization rates. That is the number of subjects that we can reduce CRP to below 2 mg per liter and below 1 mg per liter. Exploratory endpoints will include Lp(a) fibrinogen, IL-6, MRI, which will look at both liver and body composition and other metabolic parameters. We'll also get a chance to look at body weight as a function of time while on this drug.

Now we believe the 90-milligram high dose is rational because, as I mentioned before, 90 milligrams at steady state will provide exposures that are comparable to the 120-milligram dose at 1-week. And if you recall, that 1-week 120-milligram dose provided maximal or optimal inhibition of IL-1 beta. So we believe we can achieve that with the 90-milligram dose at steady state.

And then the other doses along with the 90-milligram will allow us to characterize the full dose response curve. And we anticipate data from this trial in the second half of 2026.

We'll now turn to Dr. Michael Davidson, Professor and Director of the Lipid Clinic at the University of Chicago, Pritzker School of Medicine and CEO of NewAmsterdam Pharma.

Thank you. I'm excited to talk to you today about a topic that I'm very passionate about that is the anti-inflammatory strategies for atherosclerotic cardiovascular disease. Let's start with the next slide.

So the debate about inflammation and heart disease actually goes back more than 150 years, and we had this concern whether inflammation was associated with heart disease or if inflammation was causal for heart disease. In fact, I always found myself on the other side of the debate with Paul Ridker, arguing, it was just an association and not causal. And of course, over time, based on data, especially the CANTOS trial, I had to change my opinion, and now I'm firmly in the camp that inflammation is causal for heart disease, and now we have exciting approaches to modify that risk.

Next slide. So when we discuss inflammation and heart disease, it's important to point out the concept of residual inflammatory risk. And when we consider a patient in the -- in your clinic or that you're evaluating for risk, you think about different types of residual risk. And it turns out that inflammatory risk is actually one of the most common residual risk factors that needs to be modified to further reduce risk and roughly half the patients that we see have some form of inflammatory risk that puts them at greater risk for cardiovascular disease in the future.

Next slide. So what's the magnitude of that risk when you think about it. And we you look at it in different ways, the CRP being the broader way to think about it, and then IL-6, which is a -- the actual cytokine that induces CRP production. Both of them predict major adverse cardiac events, CV death and total death across multiple trials. This is from the STABILITY trial, which had a very large data set to consider both CRP and IL-6 for predicting cardiovascular events over 3 years.

Next slide. So what is this residual risk as it compares to other residual risk factors like elevated LDL or elevated Lp(a)? Of course, both LDL and Lp(a) are very important targets of therapy. LDL has been our mainstay of preventing cardiovascular disease. Lp(a) is an exciting novel target that has important data reading out probably this year. When we think about the risk associated with each of these modifiable targets, you can see that actually high inflammatory risk as designated by elevated CRP, has by far the greatest relative risk reduction. So not only is residual inflammatory risk very common, but from an associated hazard ratio, is actually the most potent of all the residual risk factors.

Next slide. So when you think about a patient that is before you with high LDL, you put them on a statin and the LDLs come down and the LDL levels are improved, but still not low enough. So we still talk about low is better for LDL levels. And now the new guidelines have endorsed below 70 or even below 55 for high-risk patients. When it comes to relative residual inflammatory risk, the statin only brings those -- that CRP level down very modestly. So that CRP remains elevated as a marker of that residual inflammatory risk. So the question is, what can we do about that residual inflammatory risk. And now we have evidence of benefit for modifying their risk through the cytokine pathways.

Next slide. So here's an illustration of the targets for reducing inflammatory risk. And we look at the very upstream of NLRP3 inflammasome, that's what stimulates a different cytokine release. So we can target it IL-1 beta, upstream or IL-6 downstream. And when we think about how to improve that risk associated with cardiovascular disease, and it's multiple targets to consider. I'm going to focus right now on the IL-1 beta first and then talk about IL-6 next.

So let's go to the next slide. So this is the breakthrough for improving residual inflammatory risk, and that was the CANTOS trial. Up until this point, again, I was not in the camp that inflammation causes cardiovascular disease. It was just the risk marker. But the CANTOS study changed all that. We had 3 different doses of Canakinumab an IL-1 beta inhibitor and placebo. And that was compared in a high-risk population with cardiovascular disease.

The next slide shows the actual data. What we see is that the major adverse cardiac events were reduced by 15%. And if you look at the typical MACE 4 -- MACE 3, which is CHD death, non-fatal MI stroke, then we add in revascularization, there is a 0.83 hazard ratio with 17% reduction of cardiovascular events. Now the point though is that when you look at the responder analysis, which is very important for how we think about future anti-inflammatory therapies.

Next slide. We see that when you look at on-treatment CRP levels or on-treatment IL-6 levels. The magnitude of benefit is even greater in up to a 50% reduction in mortality, if the IL-6 levels or CRP levels are lower -- achieved lower levels during the trial on treatment levels.

Next slide shows it in a little bit different way. When we think about the magnitude of that benefit across the other known treatments that we use all the time for LDL-lowering, for example, we see that -- we see somewhere between a 14% to a 20% reduction with LDL-lowering therapies, GLP-1 is about 20% reduction. When we think about anti-inflammatory therapies from CANTOS, on treatment, achieving a CRP below 2 and IL-6 below the lowest tertile we see a 30% and 35% relative risk reduction. So if we're able to achieve these very prominent benefits on CRP, we can, therefore, see a very prominent benefit on reducing cardiovascular events.

Next slide. So now I want to move on to my own development of Ziltivekimab. And again, we started the development of Ziltivekimab before the CANTOS trial. When the CANTOS trial came out, we pivoted away from another indication to ASCVD and we deliberately chose a dose of an IL-6 inhibitor that we thought would be the sweet spot for reducing CRP effectively, but not having the adverse effects associated with IL-6 inhibition. So we see that a very prominent dose effect, even though a very low dose of Ziltivekimab, an IL-6 ligand inhibitor resulted in very prominent CRP reduction.

Next slide. So we look at on-treatment responder analysis. All 3 doses achieved a very prominent benefit on getting CRPs below 2, which was the threshold in which the CANTOS trial showed this tremendous morbidity mortality benefit.

Next slide. However, it's also important to point out that anticytokine therapy affecting the inflammasome, we see benefits across the board on multiple biomarkers that are associated with atherosclerotic cardiovascular disease. And I point out these 3 because these 3 are linked to the causal pathway for heart disease. Fibrinogen being a very important effect on thrombosis, SAA having a direct toxic effect on the vasculature as does haptoglobin. So we see these very prominent benefits of an IL-6 inhibitor across the board affecting what we think are causal factors for atherosclerotic cardiovascular disease.

Next slide. And now with Ziltivekimab, acquired by Novo Nordisk after the RESCUE Phase II trial, I'm very gratified to see that this approach has been taken by Novo Nordisk and then other companies as well are now evaluating this for many major adverse cardiac event reduction type trials. The most prominent of course, being the ZEUS trial, which focused on a population of those with chronic kidney disease and high CRP with atherosclerotic cardiovascular disease. And this ZEUS trial is important because it will be the first IL-6 inhibitor to be going into this population that the CANTOS trial showed a very prominent benefit.

In the subset of patients with -- in CANTOS that had ASCVD and CKD, there was a very, very, very profound absolute benefit. And what's important about that is because when you have CKD, chronic kidney disease, and inflammation, LDL-lowering therapies are not nearly as effective. And so this is a population where LDL lowering does not seem to be the main driver of reducing cardiovascular advances. So that's also being looked at across the board in acute coronary syndromes or in heart failure. And there are others that are now looking at the same approach, producing major adverse cardiac events in other CVOTs as well.

Next slide. Now moving on, I want to talk about NLRP3 inhibitors and how they are potential for being an oral IL-6 with comparable reductions in hsCRP, which is important because it's upstream. And now we have, as you'll see data coming. We have the ability to lower CRP as well as an IL-6 inhibitor, but also by being upstream may be affecting other cytokines that also play a role in atherosclerotic cardiovascular risk.

Next slide. So here is the potential that if we go upstream with NLRP3 inhibitors, oral inhibitors, we also block IL-18 as also -- as pyroptosis as well. And when you look at the effects of IL-18 as well from the CANTOS trial, that also is a contributor in that residual risk and lower the IL-18 level, also the lower cardiovascular. So the benefit here of having an upstream inhibitor does provide that additional cytokine protection that you don't get from IL-6 inhibition alone.

So I'm excited about where we are with both IL-6 inhibition and now the oral approaches within our NLRP3 and how we can utilize those therapies to further reduce risk in our patients. Thank you very much.

I'd now like to turn to BGE-102's second therapeutic area, that of ophthalmology. Now I'll walk you through the disease biology, our preclinical data and the design of our planned proof-of-concept study in diabetic macular edema.

Next slide. Now beyond cardiovascular risk, BGE-102's brain and retinal penetration opens a second therapeutic area in ophthalmology. And we believe an oral anti-inflammatory has the potential to be transformative for retinal disease.

Now this will be a new mechanism in the space previously dominated by single MLA therapies. Diabetic macular edema has been looked at being treated with both anti-VEGFs as well as -- and geographic atrophy has been shown to be treated with -- successfully treated with complement inhibitors. They're both heavily saturated around single mechanisms. Our drug would have a lower treatment burden where it's oral versus intra-ophthalmic injection, which can be up to monthly. And it drives real-world adherence. Current outcomes lag clinical trials due to noncompliance. So this oral -- the ability to give it oral can enhance compliance and possibly increase efficacy rates.

This also allows simultaneous treatment of bilateral disease. For example, you don't need to inject 2 eyes with an oral drug. So it also addresses systemic risk factors, in our case, including hyperglycemia and systemic inflammation. BGE-102 has demonstrated therapeutic retinal exposure across multiple preclinical species, including primates.

Next slide. Now NLRP3 sits at the nexus of disease biology in both diabetic macular edema as well as geographic atrophy. The upstream triggers are different, but both pathways converge on inflammasome activation and downstream pathology that BGE-102 is designed to suppress. In diabetic macular edema, hyperglycemia plus oxidative stress leads to NLRP3 stimulation causing release of IL-1 beta, IL-6 and VEGF, resulting in vascular leakage and vision loss. Pyroptosis in endothelial cells, another effect of the NLRP3 inflammasome contributes to the disease process. So blocking NLRP3 can also by decreasing pyroptosis add additional benefit.

In geographic atrophy, cellular debris, such as drusen and lipofuscin, then stimulates NLRP3 activation, leading to pyroptosis, RPE atrophy and photoreceptor loss. IL-6 inhibition has begun to validate the anti-inflammatory approach in DME, but IL-6 is only one downstream arm. NLRP3 inhibition addresses the full cascade, including [ IL-13 ] and pyroptosis that we mentioned previously. And monotherapeutic antibodies do not address these multiple downstream factors.

Next slide. Now we've done multiple preclinical models that kind of confirmed that this particular mechanism does have potential benefit. For example, a Streptozotocin mouse model as demonstrated here, this is of diabetic retinopathy, orally administered 102 monotherapy restored retinal vascular integrity in a dose-dependent fashion. So a clean preclinical readout, the BGE-102 reaches the retina therapeutic exposures and modifies diseases.

So this was, I think, a very interesting and relevant outcome. In this study, fluorescein angiography showed a reversal of retinal vascular leakage back toward health controls at both 20 milligrams and 50 milligrams per kilogram. Claudin-5 which is a measurement of vascular integrity show that tight junction integrity was preserved at the microvascular level. And this was shown with monotherapy. There was no anti-VEGF combination needed to demonstrate this vascular protection.

Now BGE-102 also addresses the systemic risk factors driving diabetic macular edema. In a diet-induced obesity model, oral BGE-102 improved insulin sensitivity at a level comparable to Semaglutide. And the effect recapitulates the NLRP3 knockout phenotype, which has been shown by other investigators. So we can improve not only directly effects on the retina, but also those factors that can contribute to onset and potentiation of the disease as well. In this study, we showed that [ HOMA IR ] was improved at day 26 with oral BGE-102 therapy. And the effect size was in line with what was seen with Semaglutide subcutaneously administered. It also recapitulates, as I mentioned, is NLRP3 knockout mouse phenotype, confirming on-target mechanism for the metabolic benefit. So in summary, the single oral therapeutic can not only affect ocular inflammation, but the underlying drivers of this particular disease.

Next slide. On the geographic atrophy side, oral delivery of BGE-102 an analog of BGE-102 prevented age-related lipofuscin accumulation in a natural occurring AMD mouse model. This directly addresses one of the canonical inflammasome triggers in geographic atrophy. We did this study in HET3 mice, which are mice that are more comparable to normal healthy animals as they age. And we compared this to age-matched controls. Now interestingly, these animals with age develop lipofuscin punctae, which are very similar to what's seen in geographic atrophy. And we're able to study the ability to reduce these -- the accumulation of these lipofuscin punctae versus age-matched controls. We showed a significant benefit. The translation implication here is that an oral inflammasome inhibitor reaching the retina can address an upstream driver of this particular disease.

Next slide. Now we've designed our DME proof-of-concept study to answer a key translational question. That is whether or not oral BGE-102, can reach the eye and suppress intraocular IL-6 levels, the same target that intravitreal anti-IL-6 antibodies have validated in diabetic macular edema. This particular study is a 3-arm trial with 30 patients per arm. We'll have an anti-VEGF plus oral placebo arm, an anti-VEGF plus BGE-102 arm and a sham plus BGE-102. So we'll look at this drug as a monotherapy as well as in combination with anti-VEGFs.

The primary endpoint in this case will be the percent change in intraocular IL-6. This is a PD study demonstrated -- designed to demonstrate target engagement in the eye and not necessarily visual acuity outcomes. However, we will look at these as exploratory endpoints, including additional intraocular biomarkers, plasma biomarkers, best corrected visual acuity, CST, both structural -- as we're seeing both structural and functional signals. The treatment will be through 8 weeks with follow-up after that 8-week period.

We'll now turn to Dr. Brian Hafler, Associate Professor of Ophthalmology and Visual Science at Yale School of Medicine.

Good afternoon, and thank you for giving me the opportunity to present today. Today I want to walk you through the scientific and clinical rationale for targeting NLRP3 inflammasomal retinal disease with the primary focus on diabetic macular edema, and then share how the same biology makes that into dry macular degeneration and geographic atrophy.

The core idea is that diabetic macular edema remains a high burden disease despite effective anti-VEGF therapy and human biomarker data suggests that a substantial component of the disease is inflammation rich, not purely VEGF-driven. And this creates an opportunity for an oral therapy that acts upstream of multiple inflammatory mediators.

In this context, oral inhibition of the NLRP3 inflammasome with the potential to reduce inflammatory cytokines, reduce vascular leakage and either complement existing anti-VEGF therapy or in selected patients potentially provide an alternative approach. In diabetic macular edema, the initiating stress is metabolic. Chronic hyperglycemia leads to oxidative stress which activates the innate immune pathways in the retina, including microglial activation, [indiscernible] cell dysfunction. That inflammatory environment can then activate the NLRP3 inflammasome. Once NLRP3 is activated, we see downstream production of inflammatory cytokines, including IL-1 beta, IL-6 and TNF alpha. These cytokines can contribute to blood-retinal barrier disruption, vascular leakage and ultimately, macular edema.

So in diabetic macular edema, NLRP3 acts as an upstream inflammatory amplifier that sits above several mediators relevant to leakage and retinal thickening. In geographic atrophy, the biology is different at the initiating step, but the inflammatory logic is similar. The initiating stress is driven in part by drusen accumulation. Drusen can activate innate immune pathways, including microglial activation. That again converges on NLRP3 inflammasome activation. In macular degeneration NLRP3 activation leads to inflammatory signaling including IL-1 beta and contributes to retinal injury and degeneration. And over time, that can cause geographic atrophy where we see loss of the RPE and photoreceptors. Diabetic macular edema is one of the major causes of vision loss in patients with diabetes. We have effective therapies, especially intravitreal anti-VEGF agents. But the real-world burden remains high. In pivotal and real-world studies, patients often require repeated intravitreal injections. I in the first year treatment, treatment intensity can be substantial.

In protocol T, a median of 9 intravitreal injections were given in year 1 across treatment arms. And this matters for several reasons. First, the treatment burden is high for patients. These are often working age individuals, many with systemic diabetes complications who need frequent visits, imaging, monitoring and injections. Second, not all patients respond completely. Even with anti-VEGF therapy, some patients have persistent edema, retinal thickening and incomplete visual recovery. So all anti-VEGF therapy has changed its standard of care. There remains room for differentiated mechanisms. And that's when oral therapy becomes especially interesting. An effective oral treatment for patients could reduce procedure burden, expand treatment options and address disease biology that is not fully captured by VEGF inhibition alone.

Now I want to move from the clinical burden to the human biology. Because the rationale for targeting NLRP3 is not simply that oral dosing is convenient. The rationale is that human diabetic macular edema has an inflammatory component, and this component is measurable. And one of the most important pieces of the rationale comes from human aqueous humor studies. In the 124-patient study, eyes with diabetic macular edema showed higher levels of multiple inflammatory and angiogenic mediators compared with diabetics eyes without macular edema. And these included IL-1 beta, IL-6, IL-8 and VEGF. And what's important is not simply that these markets were elevated. And the key point is that inflammatory markers correlated with anatomic measures of disease, including macular thickness, macular volume and disease severity. And that really tells us that diabetic macular edema is not just a VEGF disease. It's also an inflammation rich disease, and that's an important distinction.

Anti-VEGF therapy addresses a central downstream mediated vascular permeability. But it might not fully address the upstream inflammatory program that contributes to edema, vascular dysfunction and tissue stress. That's why aqueous IL-6 is a particularly useful pharmacodynamic marker. It sits in the inflammatory pathway. It's measurable. And from a clinical development standpoint, it's a clear translational bridge. If targeting NLRP3 is engaging the relevant biology, we would expect to see also targeting IL-6. And the important question will be whether the modulation of inflammasome-related biology shows a clinical signal in diabetic macular edema related to visual acuity. And in this randomized Phase II clinical trial patients receiving [ Ebemicabar ], which blocks IL-6 in combination with Ranibizumab every 4 weeks demonstrated a trend towards a consistently greater improvement in vision compared to Ranibizumab alone.

And taken together, these data suggest that blocking IL-6 in addition to standard anti-VEGF therapy may provide incremental visual benefit beyond blocking VEGF alone. Lamivudine is an oral nucleoside analog reverse transcriptase inhibitor, developed as an antiviral drug that suppresses inflammasome activation indirectly, including through NLRP3 like signaling. An exploratory clinical data for randomized trial at valuing Lamivudine at week 4, the Lamivudine group showed a 9.8 letter best-corrected visually acuity signal, compared with minus 1.8 letters in the control group. And this really suggests that modulating inflammasome link biology may have clinical relevance in diabetic macular edema. And the reason this matters is that we're not starting from a purely theoretical mechanism, but we have human inflammatory biomarker data and exploratory clinical evidence suggests that this pathway may be relevant to visual outcomes.

BGE-102 is an oral inhibitor of the NLRP3 inflammasome. It's important because NLRP3 [ consists of ] several inflammatory mediators relevant for retinal vascular disease, including IL-1 beta, IL-6 and TNF alpha. And in diabetic macular edema, the disease involves several overlapping processes, metabolic stress, vascular dysfunction, inflammatory activation, breakdown of the blood-retinal barrier and ultimately, fluid accumulation in the macula. And anti-VEGF therapy targets one of the most important downstream drivers of vascular leakage. But NLRP3 inhibition has the potential to act earlier in the cascade by reducing inflammatory signaling that could contribute to leakage and retinal injury. And because it's oral, it's differentiated from current injection-based therapies. And that oral profile was not a minor feature. In retinal disease, route of administration is central to the patient experience. And this is a cartoon showing the mechanism of NLRP3 activation in microglial cells leading to the cytokine release from a [ review ] recently published in [indiscernible] in immunopathology.

And these data from a paper I published in Nature Communications communication is showing that IL-1 beta, a downstream effector of NLRP3 drives VEGF-A expression and retinal vascular leakage. And IL-1 beta is one of the key downstream cytokines produced after NLRP3 inflammasome activation. The top row shows intraocular injection of PBS in the mouse eye with the photoreceptors on the bottom and the [indiscernible] on the top. And the control is relatively limited VEGF-A expression. The bottom row, the intraocular injection of IL-1 beta, we see increased VEGF-A signal in the retina as shown by yellow colocalization on the right. And this matters because it shows that VEGF may in part be downstream of inflammatory signaling. So mechanistically, if we inhibit NLRP3 upstream, we may reduce IL-1 beta signaling. And if we reduce IL-1 beta signaling, we may also reduce VEGF-A linked vascular leakage.

And I'll now shift to the second part of the presentation, the role of the NLRP3 inflammasome in dry macular degeneration because NLRP3 may have broader relevance beyond retinal diseases like diabetic macular edema to also geographic atrophy. And this review was recently published, showing on the left panel of healthy eye with the optic nerve in the macula in the center. In both juvenile macular degeneration and age-related macular degeneration in the center, there are yellowish drusen deposits in the macula. And the right panel shows an area of macular atrophy from RPE and photoreceptor loss. Drusen contain inflammatory signals in the outer retina that can activate the NLRP3 inflammasome. And this provides an important mechanistic bridge between AMD pathology and inflammasome activation.

And in dry macular degeneration geographic atrophy, inflammatory activations are thought to contribute to the progressive degeneration of the RPE and photoreceptors. And drusen components in yellow can activate NLRP3 which can contribute to cell death. So NLRP3 inhibition becomes a rational strategy to exploring geographic atrophy. This is a cartoon of a healthy retina on the left from a review recently published. And the right panel shows the retina with dry macular degeneration. Drusen contained both oxidized lipids and amyloid beta which is a pro-inflammatory component relevant to geographic atrophy. In the mouse model macular degeneration on the right, subretinal amyloid beta causes RPE degeneration, shown by of the lack of healthy RPE. And in the NLRP3 knockout mouse, the RPE is protected and the healthy RPE percentage returns to normal. As NLRP3 is not just associated with retinal degeneration in this model, it appears to be functionally involved. And these data support the idea that inflammasome inhibition may be relevant in geographic atrophy.

And then the next question is whether inflammasome inhibition has shown signal in human geographic atrophy. In early clinical data from an intravitreal inflammasome inhibitor implant, K8 in geographic atrophy. In the low-dose cohort, there is a 53% reduction in GA lesion growth at month 3 compared to untreated eyes. This is directionally interesting and consistent with the broader hypothesis that inflammasome biology may be therapeutically relevant in geographic atrophy. And for context, Pegcetacoplan, a C3 complement inhibitor showed a 17% reduction in lesion growth at 12 months in OAKS and DERBY Phase III trials. And these data are useful as a human signal because the inflammasome inhibition can be explored clinically in geographic atrophy. And fluoxetine, which is a weak inhibitor of the NLRP3 pathways is retrospective evidence of decreased macular degeneration incidence. And taken together, the macular degeneration data suggests a NLRP3 inhibition may be relevant beyond diabetic macular edema to also drive macular degeneration geographic atrophy. Thank you.

We now turn to Dr. David Boyer, Senior Partner at Retina Vitreous Associates Medical Group.

Hello. My name is David Boyer, and I have the privilege today of talking to you about diabetic macular edema and geographic atrophy, and the treatment landscape. Let's talk about diabetic macular edema first. Diabetic macular edema is the leading cause of vision loss in working-age adults. There are about 27 million patients globally, about 25% of all patients will develop diabetic macular edema within 10 years of diagnosis. And the average age is about 60. So some of these people are still working at the time of diagnosis.

What are the reasons? Well, elevated HbA1c is the largest risk factor for diabetic macular edema progression. That is a long-term test indicating 3 months of the average glucose, and it indicates the higher the number, the worse control they have. So this is characterized now by central vision loss with distortion. And you can see on the right what normal vision would be and further right, you can see the effects of having diabetic macular edema. The treatment standard of care today is still anti-VEGF therapy. However, anti-VEGF therapy does have some problems. So first of all, it's an intravitreal injection that has to be given frequently. And even with intravitreal injections, not all patients will do well. Diabetic macular edema progresses, secondary to hyperglycemia driven vascular fluid leakage that causes central vision loss. The cartoon on the left shows hyperglycemia breaking down the retinal blood barrier showing some edema, some thickening of the retina, fluid eventually accumulates in the macula, which is visible on the OCT, which is an area down below.

And eventually, with persistent fluid, the photoreceptors are damaged leading to permanent central vision loss, 45% of diagnosed patients are treated with anti-VEGF. That still leaves you about 55% that are observed probably because of the need for intravitreal injections. These are the patients that doesn't want to do it. It's time-consuming and it's not one injection and done, they have to be given on a continued basis. Certainly, 55% of the patients that are observed may have mild vision impairment. But again, over a long period of time, this can progress to structural damage on the OCT. Anti-VEGFs initiated become the center -- for center involving vision loss. First line, again, as I said, was anti-VEGF and the second line would be intraocular steroids, which carry with it the risk of cataract formation and intraocular hypertension.

Compliance is a very big challenge for all of us that treat these patients. We know from clinical studies that if we treat the patients on a constant basis every 8 weeks and continue that treatment, we can maintain their vision. But in the real world, this doesn't occur, the number of injections that are given in the real world are much less than are given in clinical trials. So we see a marked reduction in the number of injections that are given over the period of time, possibly because the patients get tired of coming in, possibly because the drugs don't work as well. But less injections are given. And this unfortunately correlates extremely well with poor vision than one would expect from clinical trials.

Here, you can see the real world with 4.2 gain of vision, where in the clinical trials, we had anywhere between 10.7 and 13.3 letters of improvement. Here in the real world, only 4.2 letters of improvement, indicating that we're not following the criteria mainly because they're not coming in, they get sick, they can't come in for the injections. So that causes them to lose vision on a chronic basis.

But even with strong compliance, even when the patients come in, 50% of the patients in the clinical trials continued to have a persistent fluid even when they used Aflibercept, Bevacizumab or Ranibizumab. And you can see here from the columns, the number of patients with persistent fluid at 4 weeks up to 24 weeks is still rather large in these trials. An effective oral agent could benefit not only the patient's current treatment, but it can allow for a treatment at a much earlier stage. Basically, you can see here the patients that are observed with no visual impairment, mild visual impairments still are being observed even though they may have some edema and the treated patients that are inadequately controlled about 25% or well controlled about 20%. If an oral agent was present, treatment can be administered in the observed phase and hopefully prevent any progression to patients developing significant macular edema.

What about geographic atrophy? Geographic atrophy is one of the leading causes of blindness in the elderly, characterized by irreversible central vision loss. We know dry macular degeneration is overall, the leading cause of blindness and geographic atrophy is a form of dry macular degeneration. It is the most severe form, estimated about 18 million patients by the year 2040 and rapidly growing as this occurs in patients as we get older. So the average age is 75. But as you get into the '80s and '90s, which many of the patients now are living to, the incidence of geographic atrophy increases. It is characterized by a loss of central vision, poor low light acuity, meaning that the patients need more light to be able to read, see menu and even drive at night. It causes blurred or distorted vision. And 5 years' time to legal blindness is seen. In 10 years it's virtually total legal blindness. There are several approved therapies, but no therapy up to this point has shown benefit to date in keeping or preserving vision or improving vision.

And geographic atrophy is really characterized by continuous neurodegenerative decline, drusen build up and initial RPE begins to dysfunction and the RPE cells lead to photoreceptor degeneration as the photoreceptors are the ones that convert light into visual signals. The patients lose the photoreceptors and they lose areas of vision, and they eventually get to atrophy at which time they have areas what we call, scotoma, in those areas that patients cannot actually see. The effect of geographic atrophy on quality of life is devastating and eventually can make it impossible for independent living. You can see that it impacts driving, reading, traveling as much. It also impacts work, whether they're volunteering, self-confidence, finances, mental health and even relationships with significant other, friends and family members. As they can't see well enough people will wave to them, and they're afraid that they don't want to wave back. They don't know who they are.

The approved complement inhibitors in the first year will reduce growth by 15% to 20%. But again, the visual acuity continues, unfortunately diminished. You can see here on the bottom part of the left slide, where the visual acuity diminishes, whether they're receiving monthly every other month or sham. The visual acuity continues to worsen.

The lesion growth, however, is impacted in a positive manner. We have 2 studies, the OAKS and DERBY trial here. And you can see that the progression or the size of the lesion, the size of the scotoma will increase in the sham group as compared to the actively treated group, but still no improvement of visual acuity in any of these treatments that we have available. The complement inhibitors are really only prescribed by 10% of patients, mainly because of the fact that the -- it does not affect the vision per se. It does reduce the scotoma, it does cause the patients to preserve more aspects of their vision, but the central vision is unfortunately impacted and there's a very high treatment burden.

The treatment is given every 4, 6 or 8 weeks. The office visits for the caregiver and the patient are burdensome. And the injection sites, given injections every 4, 6 or 8 weeks to the elderly patient is not easy. So an effective oral therapy could rebalance the efficacy and treatment burden, We can treat earlier, we can treat -- as patients get very small lesions, where we right now will observe them because we don't want to put them through the problem of giving injections on a frequent basis.

So this is an area that the oral agents can really make a big difference. It can be used in an earlier stage of dry macular generation. What happens is you have drusen dry macular degeneration with pigment alterations early and about approximately 20% of patients with dry will go on to developing geographic atrophy. We only treat the ones with geographic atrophy right now. There's no injectable treatment for dry macular degeneration, which is very, very common except for taking the AREDS supplements and asking patients to eat a Mediterranean diet.

There's a number of approvable end points. So one of the problems that we have when we treat patients with good vision is how do we know that we're really impacting the quality of life or we're really helping the patient. And one of them is the easy layer that's being evaluated in several trials. It's a photoreceptor rich band observed on the OCT. It's a crucial biomarker for assessing the RPE and photoreceptor health and it's correlated very well with vision loss. And the FDA has said that reduction and easy attenuation loss precedes the GA and is a strong predictor of visual function and recognized as an approvable endpoint. [ Stealth ], which is a subcutaneous injection has gotten FDA approval for the easy attenuation as an endpoint. And so rapidly, we're expanding new horizons for finding the benefits of these treatments early. And hopefully, we will be able to employ oral agents at a much earlier stage to preserve photoreceptors and reduce vision loss.

I want to thank you very much for your attention.

I'd now like to turn the call back to Kristen for our pipeline summary and to open the line for questions.

Thank you, Chris, and thanks to all our speakers today. I'll close with a brief overview of our pipeline and our near-term catalysts. BGE-102 is advancing in 2 therapeutic areas. Our APJ agonist is moving toward IND, and our platform partnerships continue to generate additional programs. As you can see on the slide, we have an important catalyst coming up this year for BGE-102. Our cardiovascular risk study is starting soon and will read out by the end of the year. Our DME study is starting mid of this year and will read out mid of next year. And we're on track to submit an IND for our APJ agonist by the end of the year. Our collaborations are progressing well, and we have a very strong cash position. Next slide.

And with that, we're happy to take your questions.

Our first question comes from Abi Novick from Citi. As we think about competitive positioning versus other NLRP3 inhibitors, the use of the absolute or placebo-adjusted reduction in hsCRP as the more important measure? Paul, do you want to take this one? I can't hear you, Paul.

Sorry, I was on mute. Yes, I mean, there have been established thresholds that are considered to be relevant. So we believe that it is the absolute amount that is more important to reach that established threshold. When we look at our data, we have very robust ability to get patients below that 2 level. So that's independent of where this placebo contribution is irrelevant. If you can get below 2 or even lower that's considered beneficial. So that's our -- generally we believe that it is the absolute level and not placebo corrected. That's most important clinically.

Yes, so instead of the raw percent reduction, we believe that getting people below the threshold is the critical difference and importantly with the placebo variation and CRP it is very rare to see people go below that threshold too.

Next, we have a question from Sam Semenkow from Citi. On the magnitude of CNS penetrants how translatable is surpassing the IC90 in CSF to penetrating brain tissue. Do we know what potency is being achieved across brain regions. Paul?

Yes. I mean we haven't looked at specific brain regions in general. We have done some experiments proving that this drug is centrally active, and you can get -- with systemic administration, you can get decreases in IL-1 beta within the brain. So we've proven that, that that's the case. We've spoken to a number of experts specifically in this regard. And what our understanding is the levels in the CSF correlate very highly with levels in the intracerebral ICF -- in the interstitial space within the brain. So we believe that, yes, the IC90 and the CSF should be very correlative to what's actually active in the brain.

Next up, Mike Ulz from Morgan Stanley. Seeing is there are multiple doses that show significant reductions in CRP and favorable safety. Can you talk about the strategic advantages 102 could offer with potential dosing flexibility as you think about development in different patient populations?

Yes. Right now, it's unknown how much inhibition is required for clinical efficacy. What we have with our drug is the ability to go from midrange to complete inhibition at safe doses. So I think that does provide an advantage that if it requires 90% plus, we can do that, at least we showed safety in our Phase I trials or if you need lower, that's easy just by reducing the dose. So I think it absolutely does offer a flexibility in the way that we select doses depending on what's required for each individual disease that we pursue.

And whether it gets into the brain or not as well, yes. Next up, Andy Hsieh from William Blair. Given the rapid onset of 102, did you gather patient-reported outcomes in these Phase I studies? And if so, what are some initial patient feedback on 102? That's an interesting question because these massive inflammation changes happen super-fast. But I don't think we're really looking at this. Yes, Paul?

We didn't. Yes, it's actually a great suggestion. In retrospect, maybe we wish we did because we did see these rapid, but we didn't have any specific patient-reported outcome instruments looking at quality of life or overall well-being. So we didn't have anything regarding that, yes.

Another question from Andy, is there a biological difference among ASCVD patients presenting with elevated CRP and those who don't. Michael, do you want to take that one?

Sure. I think that the key thing is that there's a subset of patients that have high CRP that are different from those that don't have high CRP and there tend to be those that have insulin resistance, cardiometabolic risk, central obesity, chronic kidney disease. It turns out they also have very high morbidity and mortality in general. So those are the key ones that we think about when we consider who has that residual inflammatory risk that we can address very well with 102.

So it's -- if you understand the type of patient that you can see in a clinic, they do stand out in those regards. But there are other factors, like, for example, they could have inflammatory diseases, RA, inflammatory bowel disease that also would put them in that high residual inflammatory risk. So it is a kind of a mixture of different types of patients, but the bottom line is they all have very high cardiovascular risk and they could benefit from a therapy like this.

Next is Amanda Vera, Oppenheimer. Top of mind for most of us is HS data from a downstream agent, shared this week. How do you think about exploring additional indications beyond CV and DME? When can we see pursuit of other indications materialize?

So broadly here, I mean, that was an interesting data set that came out additional validation that IL-1 beta is involved in that disease. As you know, there's many indications where NLRP3 is implicated and where there's initially some validating data from IL-1 beta or IL-6. So we're really evaluating many different potential indications, looking for derisking human data, and there is the potential for us to add those over time if they meet our bar, if they meet our hurdle.

Next up, a question from Yas Rahimi from Piper Sandler. How does ZEUS need to show -- what does ZEUS need to show to establish inflammation as a key cardiovascular marker and how do we connect the dots between IL-6 and NLRP3? Do you think ZEUS is the right population and has it run long enough to establish CRP as a key risk marker? Michael, that's for you.

Sure. Well, I think just to step back, I mean, ZEUS was designed based on CANTOS. And we picked within the CANTOS population, those that would most likely benefit from an anti-inflammatory therapy. So those that got their CRP below 2, which is almost 100% of patients on Ziltivekimab in the Phase IIb trial. Those that had chronic kidney disease and, of course, pre-existing cardiovascular disease.

So it should work robustly on absolute risk. And I mean, I can't speak exactly what the duration and patient numbers are. But we know what I've heard is that the events rates were very high as predicted and the powering of the study, you achieve a 20% relative risk reduction, is likely to be achieved if the CANTOS read-through with zilti does actually materialize. So I think how that relates here is that we likely will see it. So that will validate IL-6 inhibition directly as a benefit. However, I think one of the key findings, 2 things could happen that really would help, I think, provide a good avenue for 102 as an oral therapy, of course, set of an injectable, but also that if there's still high risk even on treatment, that implicates maybe IL-18 as an additional target that can further reduce that inflammatory risk, which would be a very positive finding. That may not happen right off the initial data readout.

The other, of course, any related IL-6 safety issues or injection site reactions or things like that, that could be -- push people to an oral. But I think the advantage of having an oral therapy that can achieve the same degree of CRP reduction, which is linked to IL-6 reduction. I think we have a very appealing therapy for clinicians once this ZEUS validates the benefits here in a prospective trial.

Next, another question from Sam. How do you think about triaging the list of indications that could be addressable by 102? Specifically, what is your appetite for evaluating 102 in HS? What capacity do you have on your cash runway to expand into additional indications beyond ASCVD and ophthalmology?

We commented a little bit on our sort of appetite to go beyond these indications. And we're really looking for, again, it's like a large menu of potential indications to pursue. So we have a pretty high bar in terms of where we think the opportunity is and also where we think our molecule has unique attributes. For example, are really excellent high penetration. So -- and I'll let Dov speak to our cash runway and how that -- what capacity that gives us.

Yes. We put out Q1 results this morning where we disclosed that we had at the end of the first quarter $385 million. So we're very well financed and we're -- have a cash position that would allow us to do an incremental Phase II proof-of-concept study with 102 with those resources.

The next question is from Fiona Jia from Jefferies. How do you think the CRP data from the Phase I 102 trial. Can it translate to larger and longer Phase II and beyond 12 weeks? Any reason to believe prolonged NLRP3 suppression will have any safety impact. Paul, do you want to take that one?

Sure. I mean, based upon other studies where inflammatory meters in this cascade have been modulated. It just makes us believe that this should continue on for as long as the drug is present at therapeutic concentration. So it is our belief that the CRP will continue. In terms of increasing the magnitude, we'll just have to wait and see with longer exposure, what happens. It's already quite good. So anything beyond that would just be upside.

From a safety perspective, keep in mind that certainly when you're inhibiting inflammatory mediators, there's a hypothetical risk. But the difference in our drug is, for example, versus an antibody is we're only inhibiting the IL-1 beta that's associated with the NLRP3 inflammasome. So there are other inflammasomes, there are other cell types that can certainly launch an innate immune response. So we're not completely inhibiting this, which we believe will translate to less potential risk, for example, related to immunosuppression.

Yes. Yes. Similarly, with IL-6, it's interesting that these drugs are achieving similar CRP reductions but only reducing IL-6 by about 50%. So it's like a milder reduction versus an antibody potentially, which could give you a theoretical advantage from a safety perspective. We'll see how that translates with human data.

Next, Tom Shrader from BTIG. The ability to reduce lipofuscin could be active very early in GA pathogenesis. Do you have thoughts on how do I identify patients earlier in the disease? Brian, that one's for you.

Thank you. I think it's exactly the right question. Retinal imaging will be key, especially for the autofluorescence, which can identify elevated lipofuscin RPE potentially paired with AI-based modeling to identify patients likely to progress before GA actively evolves.

Next, another question from Yas. Dr. Hafler, how does the IL-6 percent change correlate to functional endpoints? Do you view that mechanistically NLRP3 would work equally well in both indications that we're considering DME and GA and what other retinal diseases would NLRP3 show promise in?

Maybe, Paul, do you want to take that one, the percent change in IL-6?

Sure. I think it's coming up later. Obviously, we believe that if you can get approximately 50% inhibition on IL-6, it's reasonable to assume that you're going to get some effect on functional endpoints.

Do you want to add to the mechanistic part of that question, Brian?

I mean, I think -- mechanistically, I think we don't know whether NLRP3 will work better in DME or GA. I think it's where we need to do the clinical trials.

Next, another question from Sam. How do you think about the commercial opportunity of an oral NLRP3 inhibitor combined with an injectable anti-VEGF? Does the requirement of an injectable drug as part of the combo negate the compliance benefits of an oral? You want to take this one, Dov?

Yes, my pleasure. So the important way to think about this question is around segmentation of the market. So patients are treated differently depending on the stage of their needs. There is a group of patients who don't get injectables that have watchful waiting. So diagnosed with disease, they're wet, but don't yet have decreases in their ophthalmologic indications, that's an ideal group you could treat with an oral and extend that period.

There's a group which you try to do VEGF injectable sparing and oral could potentially allow you to increase those intervals. And then there's a group that has VEGF or not -- isn't -- nonreactive to VEGF or they're resistant to VEGF and those, of course, could be potentially treated with an oral. In addition, the study will have a monotherapy arm. So we'll be exploring BGE-102 as a monotherapy against VEGF monotherapy and VEGF in combination. So there's some potential to understand already in the initial study, the effects of the oral therapy alone.

One more question from Mike. On the Phase Ib/II study in DME. What is the threshold for IL-6 reduction that you would view as a win? Also remind us if we should expect to see changes on endpoints such as BCVA at 8 weeks? Or would we require a longer follow-up. Paul, do you want to take that one?

Yes. As we said before, if we got 50% inhibition, we consider that very significant from a clinical perspective. At 8 weeks, things like BCVA, it's unlikely you'd see the maximum effect. We are looking at this exploratorily and hopefully, we will see some trends. And actually, that's why we're doing this study. The other thing that we'll be doing is measuring inhibition of IL-1 beta in the aqueous. And if we could correlate the degree of inhibition with magnitude of effect that will help us to understand what we expect and what doses to select.

So we believe and we're hopeful that we will see trends at 8 weeks, certainly in the OCT related measurements, that's more likely to show benefit. But BCVA, we hope to see an improvement in BCVA but it's unlikely to be the maximum improvement that we'd see if we treat longer.

We'll squeeze in one last question from Sam. And this one's for Brian. How exciting is the data for drugs targeting IL-6 in ophthalmology indications? And how does this impact your enthusiasm for targeting NLRP3 with 102?

Thanks, Sam, for the question. I think the IL-6 data is definitely encouraging and validates that upstream inflammatory pathways can be clinically relevant in ophthalmology. And NLRP3 is upstream in inflammasome biology and could affect multiple downstream mediators, including IL-1 beta. So I think the positive IL-6 has increased my enthusiasm for targeting inflammation and NLRP3.

Great. Thanks, everybody.

Thanks. Good job. Thank you. That was good.

Greetings, and welcome to the BioAge Labs Update Call. [Operator Instructions] As a reminder, this conference is being recorded.

I would now like to turn the call over to your host, Chris Patil, Vice President, Media. Thank you. Please go ahead.

Thank you for joining today's call. I'm Chris Patil, VP, Media at BioAge Labs.

Before we begin, I would like to remind everyone that during this call, we will be making forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on our current beliefs, plans, expectations and assumptions as of today and are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those expressed or implied by such statements. These risks and other factors can be found in our most recent annual report on Form 10-K, quarterly reports on Form 10-Q and other filings we have made with the Securities and Exchange Commission.

We encourage you to review these filings as well as the full forward-looking statements disclaimer on Slide 2 for a more complete understanding of the risks associated with our business. We undertake no obligation to update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

A copy of the press release as well as the presentation materials for today's call are available on the Investor Relations section of our website at ir.bioagelabs.com.

With that, I'd like to turn the call over to Dr. Kristen Fortney, our Chief Executive Officer. Kristen?

Thank you, Chris. Good morning, everyone. I'm Kristen Fortney, CEO and Co-Founder of BioAge Labs. We're very excited to share our Phase I results for BGE-102 today. We believe these data showing profound hsCRP reductions with a well-tolerated once-daily oral dose position BGE-102 as a potential best-in-class NLRP3 inhibitor, and they've given us strong conviction to really accelerate the program. We'll walk you through the data and our plans to advance into Phase II and beyond.

Next slide. Next slide. At BioAge, we're harnessing the biology of human aging to develop new therapies for metabolic disease. We built BioAge in one of the world's largest longitudinal human aging data sets, and that platform validated through ongoing partnerships with Novartis and Lilly has produced a pipeline led by BGE-102, which will be the focus of today's presentation.

BGE-102 is the company's oral brain-penetrant NLRP3 inhibitor, a potential pipeline in a pill targeting efficacy in line with injectable anti-inflammatories. From a cardiovascular risk perspective, we've shown potential best-in-class profile for CRP reduction, including an 86% reduction in CRP in obese subjects. And critically, we've restored 87% to 93% of patients to CRP levels below 2 milligrams per liter. This is a critical threshold that should translate into improved cardiovascular benefits.

This drug has potential beyond cardiovascular risk as well, and we're also pursuing a Phase II trial in ophthalmology. We believe that therapeutic retinal exposure can enable oral treatment of multiple diseases, including DME, where IL-6 has shown potential benefits. We have a number of upcoming catalysts. Our cardiovascular risk trial will read out by the end of this year, and our DME POC trial will read out in mid-'27.

Briefly, we have other programs at the company, and we're also rapidly advancing our APJ agonist program. This is a potential -- an exercise mimetic that has the potential to increase weight loss and also restore body composition together with an incretin drug, and we're on track to submit an IND for this program by the end of '26.

Next slide. I'm going to start with a brief overview of BGE-102 and the science behind NLRP3 inhibition before handing over to our Chief Medical Officer, Dr. Paul Rubin, to walk you through our Phase I results and our clinical development strategy going forward.

Next slide. Chronic NLRP3 activity drives disease and predicts poor human longevity. NLRP3 is a master switch in innate immunity. And when it's chronically activated by metabolic stress, it drives sustained inflammation that's directly linked to cardiometabolic disease and shortened lifespan. It sits upstream of IL-1 beta and IL-6 mechanisms that have shown great potential in CRP reduction and potential cardiovascular benefits as well. And it's very validated by human data, both external and internal to BioAge. There's a very nice human genetic signal. Mendelian randomization links NLRP3 expression to heart failure. And additionally, BioAge platform independently identified NLRP3, those individuals with lower activity at mid-age have lived longer in longitudinal human data.

Next slide. This slide summarizes our lead program, BGE-102 which is well positioned to address diseases driven by inflammation in both the CNS and beyond in the periphery. BGE-102 is a potent, structurally novel, oral, and brain-penetrant NLRP3 inhibitor. And our Phase I data show it has the attributes needed to address inflammation-driven disease across multiple organ systems. We have potential best-in-class potency based on our Phase I trial results so far, 1.8 nanomolar IC90 in the human ex vivo whole blood stimulation assay, 24-hour IC90 coverage at the 60-milligram once-a-day dose, suppressing IL-1 beta at 90% or IL higher levels.

And furthermore, as I mentioned, 86% CRP reduction, so really profound CRP reduction as well as normalization in line with injectable IL-6 drugs. The drug is very CNS penetrant as well. Our Kp,uu CSF is 0.7. This is also potentially best-in-class, and this really enables ophthalmology as well as neuroinflammation indications beyond our cardiovascular focus.

From a safety perspective, as you'll hear, we have a very attractive profile to date, all AEs mild to moderate, self-limited and no dose dependency. Coming out of our tox studies with our 3-month and our 1-month tox, we have very high safety margins of 50 to 97 fold at the 60-milligram dose. We also have a strong IP position and composition that matter through 2045.

Next slide. Importantly, our NLRP3 inhibitors are unique in terms of their chemistry, but also their binding site. So BGE-102 was discovered independently of the original MCC950 scaffold. And in fact, we have a binding site different to that of other NLRP3 inhibitors. The typical binding site of other inhibitors is indicated in purple here on the left, that's where MCC950 and other compounds bind. And in contrast, BioAge compounds bind at the green site. We've shown this. We published the structure together with Matthias Geyer.

And there's a couple of very interesting features of our novel binding site. One of the critical ones is highlighted here on the top right. So the BioAge binding site is available when NLRP3 is both active and inactive in both forms. And in contrast, the purple binding site is only available in inactivated NLRP3. So there's a theoretical advantage to our binding site that could translate into greater efficacy.

On the bottom right of the slide here, we've listed 3 key publications that BioAge has put out in the past few years just describing our chemistry, our biology and also our structural biology.

Now I'm going to hand it over to Paul Rubin, our Chief Medical Officer, to walk you through our latest clinical data.

Next slide.

Thank you, Kristen. I'll start with the overall trial design and key objectives, and then I'll move into the detailed results.

Next slide. So our Phase I program is a comprehensive dose escalation study where we initiated in healthy volunteers, but then we expanded it into obese participants, which represent a class of individuals that are more consistent with the ultimate population that we'll be studying in future studies. We were looking within this trial to characterize the pharmacokinetics, the pharmacodynamics and perhaps more importantly, relevant inflammatory biomarkers, including hsCRP.

This study had 3 components. We started with a single ascending dose, and that involved 36 volunteers plus 9 obese subjects. We then moved to multiple dose ascending doses, and that was 18 per cohort or 18 total, sorry, 60 and 120 milligrams, and we saw -- we treated those subjects for 14 days.

Then we moved into the MAD obese subjects, which was a total of 41 subjects, looking at 60 milligrams for a 21-day period and 120 milligrams for 14 days. Our obese MAD cohorts, as I mentioned, are probably the most clinically relevant population in that with obesity comes an increase in inflammation and potential risk factors that certainly are correlative with what you would see in patients that ultimately develop heart disease. So therefore, the study in Phase I was designed to mirror what Phase II eligibility might be.

Next slide. Our data very fortunately met all of our key trial objectives. It was clear from this study that the drug was safe and well tolerated. We showed that the pharmacokinetics was dose proportional with ascending dose. And it's clear that PK supports a once-a-day daily dosing. We showed that we have very potent and consistent suppression of IL-1 beta, which is the key activity of the inflammasome. And even more importantly, we showed that we can get up to 86% reduction in CRP in these obese patients. And we'll talk a bit in the ensuing slides as to how relevant that is in terms of potential for therapeutic benefit.

From a safety perspective, all of our adverse events were mild to moderate. They were self-limited, and there was clearly no dose-limiting toxicities. The PK, as I mentioned, dose proportional. So with ascending dose, you saw a linear increase in exposure. As mentioned, the half-life is clearly amenable to a once-a-day daily dosing. And then in obese subjects, we got up to 86% reduction of CRP at both the 60 and 120-milligram dose. Also, 87% of subjects at 60 milligrams and 93% of 120 saw that their CRP was reduced to below 2, which is considered normal and decreases the risk of potential outcomes related to cardiovascular disease.

Next slide. As mentioned in this study, BGE-102 is very well tolerated across the subjects. We had an event profile that we believe -- adverse event profile that we believe was similar to what is known for placebo-treated subjects. We only saw mild to moderate treatment-emergent adverse events. They were all self-limited. There was no dose dependency, and there was no drug-related discontinuations as well as no serious adverse events. The rate of adverse event was comparable active to placebo, 61% versus 59%. We saw no clinically meaningful changes in the vital signs, in laboratory analyses or electrocardiograms.

Next slide. So moving to the obese MAD cohorts. This slide represents what our baseline characteristics were. You can see that they were pretty consistent across the various dose groups, including placebo. We had 2 active cohorts, the 60 milligram as well as the 120-milligram group. There were 19 subjects in the 60, 14 and 120 and 8 in the placebo.

The CRP by design was elevated at baseline and that range from 4.85 to 6.3 milligrams per liter, which is well above the 3 milligrams per liter high CV risk threshold. We also had a diverse population with ratio representation across the spectrum.

Next slide. In the obese cohorts, the safety and tolerability was consistent with what we saw in the healthy volunteers and that there was clearly no signal that would preclude what we believe would be aggressive development of this compound. There were no treatment-related discontinuations, no serious adverse events or severe treatment-emergent adverse events. Importantly, we did not see significant effects on neutrophils, so there was no neutropenia observed, no thrombocytopenia or no infections, which is a hypothetical concern with any immunosuppressant agent, including one that might block IL-1 beta or IL-6.

Next slide. We're now going to go through the PK and the pharmacodynamic data from our healthy volunteer cohorts, which then established the foundational PK/PD profile for BGE-102.

Next slide. As you can see here with ascending dose, we saw dose proportionality observed in the single ascending dose cohorts, very nicely linear in nature and it was dose proportional across the spectrum from 10 to 120 milligrams, which obviously makes it much simpler for dose selection, especially as we have a good PD marker to look at the PK analysis and to correlate.

Next slide. In the MAD cohort, because of its longer half-life, we did see accumulation, but it started to approach steady state by the 14- to 15-day time points. We saw trough concentrations that were well above the IC90 for inhibition of IL-1 beta, which obviously was gratifying. This confirms the fact that 24-hour target coverage translated as being able to inhibit IL-1 beta across a 24-hour period is clearly possible with once-daily dosing.

Both doses, both the 60 and the 120 milligram consistently showed levels above the IC90. And as I mentioned, we are at 14 days, we are near the steady-state level. This allows us because not only did we see this nice effect on pharmacodynamic effects, but these doses were safe. So this allows us to test complete or near complete inhibition. And if that is necessary for optimal efficacy, we believe we can achieve that.

Next slide. We also looked at the kinetics in the CSF as we did lumbar punctures and were able to measure or quantitate the amount of drugs seen in the cerebrospinal fluid. What we found was that the 120-milligram dose showed mean CSF levels that were well above the IC90. And the 60-milligram dose was also above the IC90. So even at 60 milligrams, if we're interested in having an effect on central or central nervous system inflammation or control of, we have the ability to show at least a 90% inhibition in IL-1 beta.

With this CNS access, obviously, it expands the potential of this drug and confirms this idea that this drug is a mechanism in search of a disease or another way to approach it is, it's a pipeline in a pill. We also showed that the drug can not only address neuroinflammation, but we've shown that there's therapeutic levels in the eye, which will allow us to pursue retinal disease as well.

Next slide. When we go from kinetics to pharmacodynamics, you can see that at both the 60 and 120-milligram doses, you have over 90% inhibition at trough levels of IL-1 beta. So it's a very potent inhibitor, and it's demonstrated by actually measuring IL-1 beta in these subjects. So you can see at 60 milligrams, we had an average trough of 90% inhibition. And at 120 milligrams, we got as high as 98% inhibition.

Next slide. At day, we looked across a 24-hour period at day as well as day 14 as well as day 1 for that matter. And what we saw is that with the first dose administered, the day 1 dose, we did get to a peak inhibition that approached the maximum of 90%, but you could see that it reversed with time. So this provides evidence that the effect on IL-1 beta is reversible.

However, by day 8, with the levels, obviously, the drug is accumulated and the levels are increased, you could see we have virtually complete inhibition across a full 24-hour period. So this is measured as opposed to hypothetical. So we've documented that with a single dose of drug on a daily basis, you can get complete inhibition of the main dynamic endpoint IL-1 beta across a full 24-hour period, which obviously was gratifying and I think will give us high flexibility as to how we develop this drug.

Next slide. Now we'll move on to the subjects with obesity. Go on to the next slide. Now obese subjects represent a more extrapolatable population when we think about the indications that we'll be pursuing in the future, especially cardiovascular disease. Obviously, subjects with obesity have a risk factor for cardiovascular disease. They're hyperinflamed, which is similar to what you'll see in patients with cardiovascular disease and have a risk of achieving -- of getting these particular diseases.

In the obese MAD cohorts, we had 2, the 60 and 120 milligrams that we studied. We documented in the -- well, in the design, we assured that these patients had BMIs between 32 to 42. Their baseline CRPs were greater than 3. They weren't allowed to have concomitant incretins during the course of this trial. They had to be off incretins for the duration of this study. So in fact, we believe this population will mirror and provide a very relevant example of what we might see in the Phase II cardiovascular study.

Next slide. This slide shows the actual reduction of CRP across both cohorts in our obese populations. And as you can see, we have very significant and profound decreases in CRP that get to pretty close to maximum by day 7 and are continued throughout the course of the drug exposure. We're getting approximately 85% inhibition across the full duration of the study, which as far as we can see, is the best-in-class to date. This is significant from a clinical perspective. Obviously, the lower the CRP, the better is in terms of cardiovascular risk. So we were impressed and very gratified and happy with these data. This with an oral medication, I think, puts us in a very good position to compete with the injectables as when you look at the magnitude of the effect, it's as good as it gets.

Next slide. In both MAD cohorts, you see that the trajectory of the decrease of the inhibition is similar that by day 7, you're at essentially maximum inhibition, and this is maintained throughout the full dosing schedule. So for up to 21 days, it maintains at this maximum inhibitory rate.

Now looking at the fact that you're down below 1 is very important, in that when you look at data from previous trials, if you can get the level of CRP below 2, you get a significant benefit in outcomes from [ MACE ] data. So the fact that we're showing on average a very favorable inhibition, and we're well below this 2 level, which should be very important clinically.

And despite the fact that the baseline levels in the 2 cohorts were slightly different and that the lower dose was a bit higher, they had the same landing point, showing, again, attesting to the potency and consistency of the response to this drug.

Next slide. Now previous trials, specifically the CANTOS trial has demonstrated that if you can reduce CRP to below 2 milligrams per liter, you'll get up to 25% benefit below 2, and that will be increased even more if you can get below 1. What we're showing in our study is that at the 60-milligram dose, 87% of subjects landed below this threshold of 2. And at 120 milligrams, we get 93% of subjects. So the overwhelming majority of subjects are below this threshold, at least in our trial, which should translate into very significant clinical benefit in patients that have the potential for developing cardiovascular disease in the future.

Next slide. Now in looking at IL-6, this is a known mechanism that by inhibiting the NLRP3 inflammasome, not only you inhibit IL-1 beta, but that will result in significant inhibition of IL-6. And this was verified in this particular trial, where you could see at both the 60 and 120-milligram dose, we had significant inhibition of IL-6 up to 70% or 78%. So you're getting very significant and the magnitude effect is clinically relevant. So it just suggests that you can get effects on IL-6, which is a known inducer of cardiovascular risk and you can get significant inhibition at a magnitude that should be very clinically relevant.

Next slide. Now although the study was not designed to look at inhibition of IL-6 in CSF because we didn't -- it's impractical, obviously, to screen all these subjects and then only enter those trials with elevated IL-6, we did have 2 subjects that had elevations in baseline. And in both cases, the IL-6 was brought down significantly. So this attests to the fact that this drug does get into the brain, especially when you look at their plasma IL-6 levels and the levels in the brain were higher than the plasma. So we believe that this supports the fact that our drug is brain penetrant and it can inhibit a significant biomarker in the brain independently of what's going on in the plasma. This obviously supports looking at this for the treatment of inflammatory brain disease, cognitive dysfunction among them. So we look forward to exploring that in the future as well.

Next slide. We also looked at fibrinogen, which is an independent predictor of cardiovascular risks. And as you can see, we get up to a 30% inhibition of fibrinogen as well. So you're getting an effect on another important marker of cardiovascular disease. So it just also shows that this drug is very potent. It's not a -- it doesn't have an effect on a single marker, but have multiple markers that are all relevant in terms of providing risk or causing risk as it pertains to cardiovascular disease. So this should also, I think, provide an increased chance of an important benefit especially due to the fact that we're not only looking at a single risk but multiple.

Next slide. So with the Phase I data validating what we think the effects of 102 on these dynamic markers, which we know are correlative with cardiovascular disease, we're now going to turn to how we're going to develop this particular compound. We are going to initially focus on cardiovascular, as we've mentioned, and we have increased the size of our planned Phase IIa study as part of our prioritization of enabling Phase III start by the end of next year.

Next slide. So as mentioned, we had -- the overwhelming majority of subjects had their CRP reduced below the threshold level of 2. And this mechanism is through IL-1 beta. And as suggesting here and as a result of the CANTOS trial, if you can drive it below 2, you can drive a 25% MACE benefit.

Now the CRP, we believe, and data cited in the women's health study, the Quintile data showed that this CRP reduction is more predictive than LDL or Lp(a). So the fact that we do have this effect is probably more beneficial and more predictive of ultimately, cardiovascular risk. As mentioned, this was documented in the CANTOS trial, which did produce a 25% MACE reduction in those patients that had less than 2 milligrams per liter. So this provides clinical proof of concept for an anti-inflammatory cardiovascular therapy here.

Now the 25% MACE reduction observed was observed in patients with -- that were -- had a high severity rate. These are patients with diagnose atherosclerotic heart disease plus chronic kidney disease. Other studies suggest that if you can treat people, and this is a compound that's both safe and potentially effective and practical and you can treat people at earlier stages of diseases, you can actually have a greater effect than the 25%. So we believe this compound might expand the population that are amenable to this type of therapy.

Interestingly, there was an American College of Cardiology Scientific Statement that suggested that inflammation -- regarding inflammation, atherosclerotic vascular disease is no longer exploratory, but it's compelling and clinically actionable, and we intend to exploit that.

Next slide. Present therapies with IL-6 are all injectable and NLRP3 inhibitors provide the potential for oral reduction in IL-6 with comparable benefits, including decreases in CRP. Now NLRP3 inhibitors like BGE-102 are at the apex of the inflammatory cascade. They're upstream of 1 beta, IL-6 and CRP. And we are now seeing that these oral NLRP3 inhibitors can achieve reductions comparable to injectable IL-6 antibodies. So with this particular mode of therapy, they can be as good or better than what's personally out there related to IL-6. When you look at comparable data with the IL-6 inhibitors that are out there, NLRP3 inhibitors can provide benefit far greater than what they're achieving.

Now the oral format is not just a convenience advantage, it's also what makes this broad population coverage possible. Injectables, we don't think will ever reach primary care at scale. Oral inflammatories can be prescribed alongside statins by the same PCPs who manage CV risk today and inflammation treatment can be as routine as cholesterol treatment by virtue of these orally well-tolerated compounds.

Next slide. Now the pharmacodynamic effects of NLRP3 inhibition reaches beyond IL-6 and IL-1 beta and that it can also reduce IL-18, which is a known risk factor and also a cell death or pyroptosis, which is another risk factor that contributes to plaque destabilization. So again, the pluripotency of this effect can have a broader potential benefit than simply modulating a single mediator such as IL-6.

Next slide. Now the cardiovascular opportunity on an oral anti-inflammatory is substantial. Existing data suggests inflammation is an independent risk factor that's equivalent or on par with cholesterol. In the U.S., the addressable population is 15 million patients. The channel dynamics strongly favor oral therapies. So in fact, these 15 million patients is 60% of the 25 million of ASCVD patients, and they have elevated CRPs.

BioAge is pursuing not only secondary prevention, but as mentioned, potentially high-risk primary prevention. And as mentioned, like statins, which started in secondary prevention and expanded to much larger primary prevention population, we believe we can do the same thing with these oral NLRP3 inhibitors.

Next slide. We are intending to initiate a CV risk proof-of-concept trial, and we've designed this trial to characterize the full dose response as it pertains to CRP with arms specifically chosen to support optimal dose selection for later development. This particular trial will be a 4-arm study where we have placebo, 30, 60 and 90 milligrams once a day. We have 160 patients total, approximately 40 per group, and the subjects will be exposed for a 12-week period.

Eligibility includes BMIs between 32 to 42, a baseline CRP greater than 3 and at least one cardiovascular risk factor beyond obesity. The primary endpoint, as mentioned, will be percent change in CRP with key secondary endpoints, including normalization rate that means getting CRP, number of subjects that go below 2 and go below 1.

In addition, on an exploratory basis, we'll be looking at Lp(a), fibrinogen, IL-6, MRI of both the liver as well as total body, various metabolic parameters looking at glucose and insulin and body weights. We have chosen placebo, 30, 60 and 90 milligrams and that we believe it provides a range based upon our pharmacodynamic exploration. The 90-milligram dose, we believe, will provide exposures that are comparable to 120-milligram doses, and we know that the 120-milligram dose exposures cause maximal inhibition of the important pharmacodynamic endpoints. So 90 should provide equivalent when it reaches steady state.

As you know, as shown, 60 milligrams has already shown maximal hsCRP reduction and including 90% IL-1 beta reduction and the 30-milligram dose, it does show some reduction, but it's not as robust as the other 2 doses. So we think this provides a reasonable spectrum.

Next slide. So BGE-102 being an anti-inflammatory compound has the potential to address a large range of indications. Characteristics of the drug, including good brain penetration and reasonable penetration into the eye allows us to look specifically at ophthalmology. So our intention is to initiate a trial looking at diabetic macular edema. That's planned for mid-2026 with results in mid-2027. This will be an oral therapy, and we will look at it in combination with injectable VEGFs. We believe that an oral therapy could provide clear benefits versus the present injectable burden. So we're optimistic about the acceptability of this particular compound and its potential utility.

Neurodegeneration is also possible as this drug gets into the brain, as we showed in some of the data. And we have not yet announced a program, but we are certainly exploring the possibility of advancing this in those indications.

Next slide. What I'd like to do now is walk through the DME study design briefly, and we'll go into more depth at our upcoming R&D Day. At that particular day, we'll feature presentations from leading retinal disease experts in addition to internal experts. We've designed our DME proof-of-concept study to answer the key translational question whether oral 102 can suppress intraocular IL-6, the same target that intravitreal IL-6 antibodies have already validated in diabetic macular edema.

The study will have 3 arms, 30 per arm. One will be anti-VEGFs plus oral placebo. another will be VEGF plus oral BGE-102. That's our combination arm. We'll also have a Sham plus BGE-102, which is a monotherapy arm, which will test whether or not oral NLRP3 inhibition alone can suppress ocular inflammation.

In this instance, our primary endpoint will be the ability to suppress intraocular IL-6. This is a pharmacodynamic study as opposed to a true efficacy trial, but we believe by proving that systemic administration can have a significant effect on an important inflammatory marker that we can expand this drug to multiple ophthalmology indications. We'll be looking at visual acuity outcomes as secondary endpoints and exploratory endpoints, that is not the primary endpoint in this particular study.

We will be looking at BCVA as well as CST. Both structural and functional signals will be obtained. This will be 8-week treatment, and then we'll follow up after the 8 weeks.

Next slide. Okay. Thank you. I'm now going to pass this on to Kristen for the conclusion.

Thank you, Paul. I'll close now with a summary of our pipeline and our near-term catalysts. As you've heard, BGE-102 is marching forward in 2 different therapeutic areas. Our APJ agonist is moving toward IND as well. And also, our platform partnerships are continuing to generate additional programs. To briefly go through the milestones here on the slide. So for BGE-102, our cardiovascular risk POC, those results will be here soon in the second half of '26.

For our DME study, we're initiating that study in the middle of this year. We'll have results in the middle of next year. With our APJ agonist program, which we didn't discuss today, we are advancing both oral once a day as well as injectable once-a-week formulations with on track for IND by the end of this year. And then our partnerships based on our platform with Novartis and with Lilly are also marching ahead and delivering earlier milestones. We have a great cash position to bring our programs forward.

Next slide. And with that, we're happy to open the floor to questions.

[Operator Instructions] Our first question comes from the line of Yasmeen Rahimi with Piper Sandler.

Congrats on the data. Two questions for you. The first one is help us understand what -- obviously, between 60 and 120, both look very, very good, the rationale for selecting 90 mg dose group in your POC cardiovascular study. And what do you hope to see?

Question number two is, do we have a good understanding what matters more? Is it the magnitude of CRP reduction? Or is it getting the percentage of patients to normal CRP?

And then sorry, maybe the last one is, I know the study wasn't designed to look at other comorbidities, but is there an opportunity to look at -- there were any improvements in liver manifestation, whether it's liver enzyme improvement or MRI-PDFF, any liver-related assessments would be also appreciated. And I'll jump back in the queue.

Yes. Thank you for those questions. As it pertains to the rationale for the 90-milligram dose, what we based on was the fact that, at 120 milligrams at the 7-day period, we essentially saw maximal inhibition. Now the exposures achieved at 7 days with 120 are equivalent to the exposures that will be received with 90 milligrams at steady state. So in terms of achieving concentrations that will get maximum inhibition, we think that we'll get that at a lower dose at steady state. So there's no need to go to the higher dose from that perspective. Does that make sense?

Yes, very much.

And just to briefly add too, right, as you've seen, basically, the 2 doses we tested were indistinguishable in terms of the CRP performance. So we'll try them, both of them for 60 and 90 for the full 3 months to see if there's further differentiation.

And what was the second question? As it pertains to percent change in CRP, and this is my understanding of it. You can kind of look at it sort of like cholesterol. In actuality, lower is better. So you're trying to achieve it as to get to your CRP level as low as possible. Now the 2 milligrams per liter threshold was determined from previous studies that suggested that until you get below, you don't see these decreases in risk. But that decrease in risk can get even greater if you can get it below -- even further below 2.

So it's kind of both is your question. Lower the better, but 2 has been documented to be a threshold beyond which you start to see additional risk benefit. Yes. We are doing -- in our study, our Phase II proof-of-concept trial, we will be doing liver MRIs. So we'll be able to look at inflammation and look at similar outcomes that have previously been looked at to determine whether or not this mechanism has an effect on the inflammation in the liver.

Yes, there could be nice benefits there from the other data that's been put out.

Our next question comes from the line of Roger Song with Jefferies.

This is Fiona on for Roger. Congrats on the data. My question is also somewhat related to the dose response between the 60 and 120. Is it possible that you're hitting an efficacy ceiling even at 60 because both response seems to be good. And I recall that you said the CRP response with the 30 milligram is not as robust. Is that from the SAD study or some other measurements that you have collected? And I have a follow-up.

Yes. To your point, we could be hitting an efficacy ceiling, but frankly, it's too early to tell, right? These are small end and they were not distinguishable. So they saw very profound normalization rates. And that's exactly why we're going to carry forward 2 doses into the dose ranging just to make sure that we're capturing the full effect and the durable effect as well over a longer period.

Yes. And the 30-milligram dose, we obviously didn't look at it in terms of multiple dosing. So we're really basing it on effects on the pharmacodynamic marker on IL-1 beta. So you're seeing significantly less of an IL-1 beta effect, which we think will translate to a lower effect on CRP. So that's how we've made the determination.

That makes a lot of sense. I have another one on -- how do you think about the hierarchy between these biomarkers like CRP, IL-6, fibrinogen. It seems like the response over time does not necessarily go in the same direction. Just curious how you think about where to place these.

So CRP, we'd expect that to be profound and durable as we've shown so far and has been shown with the mechanism so far as well. Some of the other biomarkers like IL-6 or fibrinogen, the effects are not as profound, right? You're seeing maybe like a 30% to 50% reduction versus the close to 85% to 90% reduction you see with the CRP. So there, you'd expect to see less error, less noise in a larger cohort.

Yes. I think those findings also suggest that the effect on CRP could be driven by multiple things, not just IL-6. So you're seeing kind of an additive effect of these effects on pyroptosis, on IL-18 and IL-1 beta. You're seeing effects on multiple potential risk factors related to inflammatory markers.

Yes. It's really interesting that this class of drug seems to reduce IL-6 levels by around 50%, and that's been shown with other mechanisms, and yet you're achieving similar profound CRP reductions to the antibodies, right, which is exciting.

Our next question comes from the line of Samantha Semenkow with Citi.

Congratulations on all the progress here. A couple of questions for me. First one, also on dosing. I'm wondering if you think you'll need to go even further lower than 30 milligrams. Is that a possibility that you would need to go lower to see a dose response? And then apologies if I missed this, the dose in the ophthalmology study, is that going to be in line with what you're planning to use for the cardiovascular risk study? Or could you need, I guess, higher doses for that indication? And I have a follow-up.

I think, yes, it's possible to go even lower, but there's just so much we do from a practical perspective. And again, we're basing that on the effects that we're seeing on IL-1 beta. So when you look at 30 milligrams and you look at the PK/PD relationship, it definitely has a suboptimal effect compared to the higher doses where 60 and 90 seem to be close to equivalent at a much higher level. So that's the best we can do. Yes, it's possible that we get great effects at 30 milligrams, but I think that's a good problem to have.

And the dose in the ophthalmology study, is that going to be in line with what you're planning for the cardiovascular risk study?

Yes. When we look at the relationship between eye levels and plasma levels, and we believe that -- we're not -- actually haven't said that...

We haven't disclosed that...

We haven't disclosed it yet. But we believe we're choosing a dose that will provide maximum inhibition in the eye.

Yes, it will be a similar range.

Okay. All right. Understood. And then I noticed that you're going to be looking at Lp(a) in the cardiovascular risk study. I just wanted to get your thoughts on that for this mechanism. What is really driving the Lp(a) reduction that we've seen in some of your competitor data sets? And how do you think about the magnitude that you could see with BGE-102?

Yes. Lp(a) is one that -- where Lp -- the presence of Lp(a) drives inflammation and then inflammation in turn drives elevations in Lp(a). So there is clearly a relationship, but it kind of goes in 2 directions. So it's hard to know what happens in a short period of time. What we're going to do is look at this for a longer period of time, and hopefully, we'll be able to reduce the variability by more patients for a longer period of time and be able to show what should be an effect. But again, we'll measure it to find out.

More moderate than [ CRP ] for sure.

Got it. And then last question, if I could just squeeze one more in. You put a bunch of indications up on a slide that NLRP3 inhibition could be addressable. And then I know you don't think it was exhaustive. Can you just talk a little bit about how you're thinking about prioritizing where to go next? And the capacity that you have with your cash runway to do so?

Yes. We're well financed to take the program forward. And really, it's more about having indications that we're sure about, right? Like we're very excited about the opportunity in ASCVD in cardiovascular, and we're also very excited about the ocular opportunity for a number of reasons.

One of them is that they're very much derisked by existing data with IL-6. There's a very clear value proposition for a molecule like ours. Like in cardiovascular, we have potential best-in-class CRP reductions. In the ocular indication, it's a very unique feature of our molecule that we have great penetration into the eye and very nice preclinical efficacy. And we'll have a similar bar for any additional indications that we consider.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

Could you speak to the anticipated readthrough from Novo's ziltivekimab data that's coming later this year as you think about cardiovascular outcomes in relation with CRP? And then there clearly are a lot of questions about the dose work here. Can you just maybe walk to the thoughts about exploring 120 milligrams in other indications or the likelihood even in the study for higher efficacy with that dose?

If the ZEUS trial is positive, obviously, that welcome this mechanism because there's overlap in terms of ultimately what effect -- what biological effect it has in the body, but in this case, it would be with an oral medication. So there's obviously advantages as we've outlined from that perspective.

So in a positive scenario, obviously, it's very favorable for what we're doing. If the ZEUS trial were the negative, well, there's already confirmatory data for blocking IL-1 beta in the CANTOS trial, which we know that our drug is very potent. So there is already evidence that this mechanism can be beneficial from the canakinumab studies looking at cardiovascular risk and outcome. So I think either way, there's a rationale to continue.

Yes, we're excited for that readout. And your other question was around the 120 dose? So again, in terms of the cardiovascular effects, we basically saw identical effects so far at 60 and 120. The one point of differentiation is that you get a lot more brain penetration with the 120-milligram dose as you saw in our CSF data, we're basically fourfold above the IC90. So there could be potential for...

Yes, and also in the eyes study, what we are doing -- part of the study will be looking at both drug concentrations and effect on inhibiting IL-6 in [ atherosclerosis doing cAMPs ]. So that will give us a PK/PD relationship that can guide us in terms of future dose selection.

Our next question comes from the line of Jay Olson with Oppenheimer & Company.

Congrats on these impressive results. For your Phase II study protocol, what sort of background therapies will be allowed such as statins or GLP-1s? And in that study, should we be looking at placebo-adjusted hsCRP reduction or just focusing on absolute hsCRP reduction?

And then finally, recognizing that it's early to talk about a registrational clinical plan, can you talk about the potential use of hsCRP as a surrogate biomarker for a Subpart H accelerated approval contingent upon outcomes?

I'll start with the last one first. And obviously, this is -- we don't know for fact what's going to happen from a regulatory perspective. But when you look at the use of cholesterol as a surrogate, for example, it required validation studies. So until those validation studies exist and they might come out of these very large long outcome studies, I mean that's when they allow us to use CRP as a surrogate. You have to look at what has to be done for lipid-lowering agents to get the same consideration.

Yes. If people are on cholesterol lowering agents or antihypertensives, those will be allowed as long as they are on a stable dose.

And GLP-1s?

GLPs are not -- yes, GLPs are not allowed.

And in terms of hsCRP reduction, should people be focusing on placebo-adjusted or just absolute reduction?

Yes.

I mean, yes, I mean likely to be absolute right, you wouldn't expect in a Phase II there to be much of a placebo response there.

Yes, in a short period of time. So we'll be looking at, yes, absolute effects. And then obviously, in the secondary endpoints, we're looking at essentially response rates, you'll obviously be comparing that to placebo response rates.

Yes, exactly. You don't really see placebo normalization below 2.

Our next question comes from the line of Joseph Stringer with Needham & Company.

Just curious, in general, how did the CRP reductions look based on baseline CRP levels? And I guess for the few subjects that did not hit the CRP threshold levels of less than 2 and less than 1 mg per liter, can you tell us anything about these subjects that could maybe explain why they didn't hit those levels? And are there any implications here for the planned Phase II trial?

Yes. There's nothing out of the ordinary in the ones that didn't respond, and some of them came very close. And it could just be the time of exposure, but there was nothing unique about the ones that didn't respond.

Yes. And to your question about how CRP changed depending on baseline, the percent was similar, right? So if you're starting at a higher baseline CRP, you're losing more absolute CRP, right, but the percent was fairly similar.

Our next question comes from the line of Mike Ulz with Morgan Stanley.

Congratulations on the data update as well. Maybe just a quick one around safety. It looks like both the 60 and 120 mg doses are very well tolerated. Just curious if you can characterize some of the mild to moderate adverse events you're seeing? And then more specifically, if you're noticing any differences between the 60 and 120-milligram doses so far?

Yes. I'd say that in general, the side effects we saw fairly typical of a Phase I study. We did see headaches as one of the relatively more commonly reported, but these seem to be directly due to the fact that these patients had 2 lumbar punctures during the course of the trial. So in fact, we had a cohort that didn't have lumbar punctures and the rate of headache was much less.

Again, no dose group differences.

Yes it was -- nothing dose [ dependent ]. In fact, there were some opposite effects with lower...

Our next question comes from the line of Andy Hsieh with William Blair.

I'm looking at the brain penetration study that you did, it suggests that probably 50% of the drug is actually going into the brain. And I'm just curious if you can extrapolate that data into some ocular indications that you're hoping to start shortly. I'm also curious from a previous question in terms of headache, you talked about 6 patients experiencing that, no dose response. But I'm curious across the treatment -- active treatment arms in the placebo, are they mostly balanced?

Yes, there's balance across it, but we had much fewer placebos in the study than we had in [ active ]. It wasn't a 50-50 split. But as I mentioned, the headaches themselves seem to be not -- the majority are not related to drug and are related to lumbar puncture.

Got it. Now then in terms of the ocular?

Yes. There are some similarities between blood-brain barrier and blood retinal barrier. But in this case, it would be dangerous to extrapolate one to the other. So we've done some studies in animals to determine what the levels are in the eye and the free drug in the eye, and that's what we're kind of extrapolating from animal data.

Yes.

I see. Okay. And then last one for me. Looking at the IL-6 reduction. If you look at across 2 doses, there's actually a diminishing reduction over time, 6, 14 -- sorry, 7, 14, 21 for the 60-milligram dose and then day 7, day 14 for the 100-milligram dose. There's a reduction in the diminishing reduction over time. I'm curious if that's kind of a small number, a function of small numbers or maybe there's a biological rationale that you can explain?

We think that's most likely to just be a small end. Like if you look at the placebo response, right, that also bounces up from day 7 to 14 and then down again a lot by day 21. So it's likely driven by the end as opposed to anything biological. But of course, we'll look at this in our larger study next.

Ladies and gentlemen, this concludes our question-and-answer session. I'll turn the floor back to Dr. Fortney for any final comments.

Thank you, everybody, for joining us today and for your thoughtful questions. We're excited to continue advancing BGE-102 and our other programs, and we look forward to sharing our next update with you soon.

Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.