Editas Medicine, Inc. Aktie

Okay. Hi, everyone. Good morning. Thank you for joining us. I'm Jasmine Fels. I'm one of the biotech analysts here at Barclays, and we're very happy to have Editas Medicine here with us today. So we have Gilmore O'Neill, who is the President and CEO; and Amy Parison, who is the CFO. So thank you, both, for joining us.

Thank you.

Great to be with you.

Great. Okay. All right. Let's start with the basics. So can you give an overview of your platform and your approach to gene editing and how that's differentiated from others in the broader space?

Yes, we're happy to. So Editas is an in vivo CRISPR therapeutics company. And what we mean by that, and we're fully focused on that is that we deliver our CRISPR editing machinery intravenously, a simple IV infusion using lipid nanoparticles.

And we really differentiate ourselves from others in a number of ways. The key way is that we use CRISPR only to do things that other modalities cannot do. And specifically, we are making edits in noncoding DNA to increase the levels of expression or upregulate disease mitigating or rescue proteins. And an example of that is our LDL receptor upregulation program, EDIT-401, which can reduce LDL cholesterol levels across multiple animal species, including nonhuman primates, by 90%. I mean, which obviously has potential to be transformative in the management of cardiovascular disease.

I think the other element that's important is that we are -- from a platform point of view is that we actually have a delivery technologies in collaboration with Genevant for delivering to the liver and our own proprietary targeting LNP for going to other tissues outside the liver. I think the final thing I just want to say is that -- and I think we pride ourselves on this is that we have an organization that is really focused on execution on that in vivo space and is doing it in a very cost-efficient and capital-efficient manner. I think that we can see that reflected in our most recent earnings.

Yes. Okay. Awesome. That's a great overview. I want to touch on safety briefly first because there's been a lot of debate recently about gene therapy or safety. So can you go over, I guess, just the inherent safety profile of, say, AAV-based gene therapies versus gene editing and how those are different? And with your approach, kind of what you would expect to see on a safety basis?

Sure. Well, I think there are a number of fundamental differences between an AAV delivery vector and the use of lipid nanoparticles with a gene editing payload. The gene editing payload basically is highly targeted. So we can actually use machine learning and computational biology to very precisely select the target that we want to edit. And that actually helps us deal with one of the hypothetical risks, which is of off-target editing. And for example, in our 401 program, we have actually developed a very robust package looking at off-target editing and essentially have a very good profile there.

I think the key other element to think about when you think about AAV is that AAVs have -- are very liver-tropic. And no matter what tissue you want to deliver to, they can actually be associated with hepatotoxicity. Now they're a very effective therapeutic delivery.

I think the other thing that really separates us beyond the safety when you talk about CRISPR editing versus AAV is the AAV doesn't integrate the copy of the gene that it delivers to the cell. That copy sits adjacent to the DNA inside the nucleus. But when a cell divides, that gene or transgene does not replicate. In the case of CRISPR editing, because we've made the edit in the genome, the human genome, every daughter cell of a cell that divides will carry the edit, which means that from a durability point of view, we should actually have a very robust durability. So from a benefit risk point of view, I'd say that CRISPR has a very favorable profile for a therapeutic.

Yes, absolutely. Okay. Awesome. Let's get into the lead program, 401 for LDL-C lowering. So I guess, first, can you just give an overview of the target and the biology underlying the asset?

Yes, absolutely. So I think a couple of things. One is that 401 on its own has the potential to be a really great therapeutic with a 90% mean reduction in LDL cholesterol. And I say that with a degree of confidence based on the observation that the nonhuman primate has been very effective at predicting not only the success and the effect size of a therapeutic or biological effect in moving from the monkey to the human for CRISPR editing of the liver, particularly in vivo CRISPR editing liver, but it's also been highly predictive of the effect size and the biological effect size for cholesterol lowering meds across a number of modalities. So we're very excited about that.

Now how are we actually achieving something like that when the others have really achieved like with PCSK9, 50% to 60% reductions in the statins, something lower than that? And we believe that the key reason is that we are essentially increasing the direct synthesis of the LDL receptor protein. And we're doing that through, again, leveraging the power of human genetics. More specifically, at the core of our upregulation or differentiation strategy is to interrogate large human databases of genetic -- or genomic data to identify natural variants that have gain of function. And as part of that exercise, we've identified a number, but the LDLR was one that jumped off the page, and it had been published by other authors a couple of years ago. And essentially, an Icelandic kindred with 7 members has a gain of function deletion of the 3 prime untranslated region, which is a regulatory domain of the LDLR gene.

But there are a couple of important distinctions. One, it's noncoding. It's untranslated. It's in the title. And the second is that it specifically increases the levels of LDL receptor by stabilizing the messenger RNA, increasing its half-life, which means that more copies of the protein can be translated or copied off that messenger RNA. It is very well tolerated in the individuals who have this gain of function mutation who have maintained excellent health. And very importantly, they have LDL cholesterol levels which are substantially lower than their peers in Iceland. And indeed, they have LDL cholesterol levels in the range of 15 to 35 milligrams per deciliter. And that's a very important level because that's a level that is associated with maximal risk reduction related to LDL cholesterol and even more precisely has been associated with levels that if achieved in people who have existing atheroma, would shrink that atheroma.

So it's a very powerful target. And we've actually leveraged it in optimizing our strategy by looking at that region in the 3 prime UTR and walking across it to identify the optimal guide RNAs that we've used. And that's what we have selected and achieved this very high reduction in LDL cholesterol.

Yes. Let's get into the data, I guess, that you're seeing preclinically. So you mentioned 90% reduction in LDL-C. Are there any other data points that you want to highlight?

Yes. I think the key thing is the consistency of that LDL cholesterol reduction. We're seeing it not only in healthy nonhuman primates, but we've actually also demonstrated it in wild-type mice on a high-fat diet and also in mice that are carrying a single copy, they're heterozygous for a loss of function of the LDLR gene itself. They're effectively genotypic models. I'm very loathe to call them any other kind of model, but they're a genotypic model of one of the commonest forms of a heterozygous familial hypercholesterolemia.

And in all of those -- across all those animals -- and by the way, those heterozygous animals were on high-fat and normal diets. And in all cases, we achieved a similar magnitude of reduction. And what that really means is very importantly, it doesn't matter where the starting baseline of the LDL cholesterol is, we're still achieving 90%. So that's really important.

I think the other data point I want to highlight from a safety point of view is that the doses at which we actually saw this effect were very well tolerated by the nonhuman primates and mice. And all we saw were mild -- some mild elevations for a couple of days in the first week for the transaminases, which rapidly resolved. And that's very important because that was not associated with any indications of risk or safety. In other words, there was no complement activation, no cytokine activation, no coagulation changes. And as I say, these animals did very well.

I think the final thing, just to put that in perspective, is that's the kind of profile that we really now understand about lipid nanoparticles that you want to see in the nonclinical species to predict a good translation of safety to humans. So we're very excited about that sort of balance of high efficacy and high tolerability and safety.

Yes, that's really good to hear. What have you seen in your work so far on durability? Because I think one of the key advantages of gene editing is that it's theoretically one of the most durable.

So what we've actually shown publicly at our scientific meetings is we've actually shown murine or mouse data out to 3 months, and we've actually maintained that durable effect. Obviously, we have ongoing durability studies and look forward to sharing more about that, but we're very pleased. I think overall, what I would say is that when it comes to execution over the last 2 quarters since we actually shared -- first shared our LDLR data, we have just grown more confident in our nonclinical data package as it grows.

Yes. Okay. What about off targets? I think that's a key question for gene editing is like, what kind of specificity do you get?

Yes. So I'll just restate what I was saying earlier because obviously, that's something that comes up. We are very confident about that. In fact, we have developed a very robust package. And my confidence in our -- the robustness of our package really stems from a couple of things. One is that we've actually presented similar packages to agencies, the FDA particularly, over the last couple of years. And those were very well -- they were very good, well accepted and frankly, even more robust than the safety package that was used for the approval of CASGEVY, which will be sort of the lead and the first approved CRISPR product. So we feel very good about that.

I think the other point is that many of the technologies that we use to generate that, we made publicly available as a company. And for example, our CALITAS technology, which is part of our computational biology package for moving -- looking across the genome, human genome and multiple human genomes with all the variants that can occur globally, is used by most sponsors that we're aware of as part of their packages. So we actually feel very good about that. And again, we'll be sharing more of that information at a future date.

Okay. Great. So I know we expect human proof-of-concept data this year. So I guess for that, what are you -- what will we get first? And what are you looking to see in terms of efficacy?

So we're looking to -- and we're tracking well to having achieving early proof of human proof-of-concept by the end of this year. It will be a Phase I study. That's Phase I study. We'll have a number of escalating dose cohorts, and we're looking at 3 to 6 patients per cohort. We're really targeting having at least our first cohort dosed by the end of the year.

The nice thing about the LDL cholesterol is the response is very rapid. We've seen that consistently across our preclinical species. LDL cholesterol is very easy to measure. So we anticipate having LDL cholesterol levels and obviously, safety parameters and labs. So we're really, as I say, tracking to that and really looking forward and very excited about seeing that.

Is there a specific threshold that you're looking for, for LDL-C lowering?

So we basically ultimately are checking or tracking to and desire to see a superior efficacy over the current standard of care. We will -- probably with the first dose cohort, I'm not sure that we necessarily get to that full threshold, but we do anticipate or look to see biological effects. It's important as we move beyond that early human proof-of-concept that we will actually have a number of dose cohorts that we will dose into the following year.

Okay. And then in terms of safety, what makes you comfortable? I guess, I think preclinically, there's some level of transaminase elevation, but it's transient. What could you see that would make you confident going forward in humans?

I think continuing to see that translation to humans is what's going to give us confidence. And I will say that our confidence is driven not just by the preclinical observations, that empiric data that we've seen, but actually also by the fact that our partnership with Genevant for the liver delivering LNP is a very good partnership. They're really wonderful partners.

But very importantly, the components that are in our LNP that they used, they have actually had in other LNPs that have been in humans. So all but one of those components has been in humans, which again is significant derisking. So we have sort of a multiplicity of experience, prior experience as well as our own empiric preclinical data that give us confidence about that safety and tolerability in humans.

Yes, absolutely. What is the -- can you talk about the initial patient population that you see as the target first?

Yes. So the patient population we select for sort of preliminary for the Phase I is obviously a patient population where you want to have a benefit risk that is appropriate for an investigational drug at this point. And one patient population that sort of sits in the sort of very high-risk of cardiovascular disease are heterozygous familial hypercholesterolemia patients. So that's a patient population that we are looking at for our Phase I.

It is worth highlighting that when you look beyond Phase I, that there are other segments of the hyperlipidemia patient population that sit in that very high-risk category. And that includes patients who had a prior arterial vascular event, [ HAPS ], heart attack, myocardial infarction or stroke, but who also are refractory to current therapies. And it is important to note that both in HgFH, these patient populations and in fact, the broader hyperlipidemia patient population, the majority of patients are not achieving target even now with current therapies, even with combinations that they take chronically. So I think there is an enormous opportunity there.

But as I say, our first -- our initial population is HgFH refractory patients. And then obviously, we can look to other high-risk patients. But within the context of the United States, that represents around 10 million patients when you combine the 2 groups.

Yes, there's absolutely an unmet need as well. So for HgFH first, can you talk a little bit about the landscape and where you see 401 fitting in?

Yes. So with regard to where we would see it fitting in for usability in the clinic, we actually see that, that refractory HgFH population represents several hundred thousand patients. They are currently using combinations of therapy. And as I say, a substantial proportion, if not a majority of these patients are not getting actually to target. And those target levels are moving, and they're moving lower. They're not moving higher, as is always the case with preventative medicine. So many of these patients can't achieve levels of 40 milligrams per deciliter or 50 milligrams per deciliter or even 70 milligrams per deciliter.

So we're trying to actually -- and what we anticipate with a 90% reduction is an ability to really get those patients to target and frankly, simplify the life that they lead with those patients. The medicines, instead of using a combination of chronic therapies, it's possible that a single dose of a single medicine will actually help them get to target.

Yes, absolutely. And you mentioned a little bit about the different populations and up to 10 million patients potentially. Like is that 10 million what you think ultimately the size of the population that is addressable with this therapy?

Well, I think what that represents is at least 2 niches of a broad hyperlipidemia patient population. And I think that's where we can see ourselves going preliminarily. And the reason for that, obviously, it's a new medicine. It's a new modality. I think people will need to get comfortable. And obviously, some of that involves balancing the benefits, which are potentially very high, with the sort of yet to be determined risks, which really become clear with use in large populations. And so -- but these are patients, that 10 million patient population represent people who have already got a significant risk, a very high risk and are unable to achieve the target levels of cholesterol reduction that they need to achieve to actually get their risk down.

Yes. Okay. I want to touch on that a little bit, I guess, because we hear a lot about gene therapy and gene editing for rare disease. But in these more common diseases, like what do you think is the appetite for a modality like gene editing? And how do you open up those larger, more common opportunities for a new modality?

So we actually think that by actually focusing on where the unmet need is -- and that actually is hugely beneficial. So I think we have to look at a number of ways. We have to look at it through the lens of a patient. Patients with HgFH, patients who have had a significant arterial cardiovascular event, they know what happens if they don't manage that risk. So this is not a sort of a silent risk to them. This is a known risk for them. Either they've seen a relative, or they've had an event themselves. And so -- and they also find themselves where they are trying to get to a target. And frankly, the advice they will be getting from the physicians and what the physicians are saying to us is that these patients have run out of options. But the risk is still very elevated.

And so we actually think that adoption there in that particular patient population is something that is actually very feasible because it's a known quantity that the patient is trying to deal with. They're out of options. And when we talk to KOLs, they actually see that patient population as certainly an obvious patient population to actually initiate this kind of therapy to start with.

Yes. I think that's a good point with silent disease, there's like a real tangible risk. Absolutely. Yes, that's very interesting. We're excited to see the data later this year. What about after 401, what's next for you?

Well, one of the important things we did over the last couple of years because we had 3 years ago, announced that we were pivoting to be a fully in vivo company. We accelerated and completed that pivot last year, and as part of that work, have actually generated within our discovery, a number of programs. Indeed, last year, we had 2 programs moving very well. We selected the 401 program to move forward.

And we have, as I say, a number of assets both for the hepatic platform -- so the beauty of CRISPR editing is that once you've actually built a platform that can deliver to a given tissue or cell type, if you change the target, you can actually -- all you need to do is change 20 nucleotides on the guide RNA. So it's a much simpler prospect. It also means you can leverage the investment on the CMC, the pharmacology, the tox. And obviously, your regulatory and there's a regulatory mechanism now here in the States and actually also evolving in other jurisdictions where you can simplify the package, the time and the cost to get to the clinic. And we have a number of additional programs, all focused on non-coding edits that upregulate rescue proteins. So we will share those at an appropriate time for the liver.

And then obviously, we have our targeting LNP. And where we -- one of the things that we have talked about before is our ongoing optimization of our in vivo HSC, that is hematopoietic stem cell targeting program and specifically with an already validated payload for the treatment of sickle cell and thalassemia. So these are things that are sitting in discovery that at the appropriate time and -- that appropriate time will obviously where the markets change and we can actually expand our investment.

So we're very excited about that pipeline. But at the same time -- and it goes back to some of my initial remarks -- we're absolutely laser-focused on getting 401 to human POC. A lot of attention, effort, resources dedicated to that and driving that forward. But obviously excited by the potential follow-up that can build on that future success.

Yes, very exciting. And building off of that, I think the in vivo component is something that it helps as well. So can you talk a little bit about what's proprietary to your technology and how you've been able to open this up where others have struggled?

Well, I think there are a couple of things. First of all, with regard to proprietary information, we obviously have significant exclusive rights to foundational IP around this. But beyond that, we've built significant know-how around identification of targets for -- noncoding targets for upregulation. We've built a lot of the machine learning, and computational biology tools to help us optimize and do that. And so I think that's very well, dare I say, protected for us.

I think the other point is that we have, certainly in the extrahepatic space, our targeting LNP technology which is proprietary to us, and obviously, a very strong relationship with Genevant for our liver delivery. So we believe that our differentiation is well protected around an IP point of view, just from a technical know-how, expertise and capabilities. And then from a delivery point of view, as I said, we have that proprietary tLNP technology and I say a very strong relationship with Genevant.

Yes, interesting. Okay. A question for you, Amy. What does your cash runway look like?

Yes, sure. So we have cash into Q3 of 2027. We ended the year 2025 with $146 million of cash. And as Gilmore said, we feel very confident that we'll be able to deliver on all of the upcoming milestones with that cash runway.

Okay. Awesome. Yes. And I think we're almost out of time. So just to finish up, can you highlight, over the next maybe 12 to 18 months, like what are the key catalysts, there's data? What else will we see from the company?

Well, I think the key catalysts we're looking to, obviously, a major catalyst we see as that early human proof-of-concept at the end of the year. Between now and then, we will obviously have a substantial bolus of nonclinical and CMC data, essentially the package for our CTA IND. Obviously, clearing a CTA IND would be another catalyst, and then that early proof-of-concept. Then going into beyond that 18 months, selecting the dose or going to our pivotal.

Yes. Great. Well, an exciting time. Thank you so much, Gilmore and Amy, for being here. And thank you, everyone, for joining us.

Thank you.

Thanks very much. Thank you.

Good morning, everyone, and thank you for joining Editas Medicine webinar to unveil our lead development candidate, EDIT-401. This webinar is being recorded and can be accessed in the future through the same link or through the Investors section of the company's website. After our prepared remarks, we will open the call to Q&A. [Operator Instructions]

As a reminder, various remarks that we make during this presentation about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC as updated by our subsequent filings. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements even if our views change. I'd now like to turn the call over to our CEO, Gilmore O'Neill.

Thank you, Dana. And good morning to you all. With me today are Linda Burkly, our Chief Scientific Officer; and Amy Parison, our Chief Financial Officer, who will join us for Q&A.

Today, we are taking a critical step forward in our vision to be a leader in, in vivo gene editing by developing CRISPR-based medicines that are best-in-class or first-in-class therapeutics. To date, we have made steady progress in advancing our liver and HSC programs, including presenting preclinical advances that we're incredibly proud of. With these advancements, we have been laser focused on selecting a lead in vivo candidate that shows exceptional potential to be a transformative medicine that it can advance towards human proof-of-concept data as quickly as possible within our current cash run rate.

Today, we are delighted to introduce our lead program, EDIT-401. EDIT-401 is a potential best-in-class onetime in vivo CRISPR gene editing medicine designed to significantly reduce LDL cholesterol or LDL levels, demonstrating an unprecedented mean reduction of 90% in our preclinical studies and has the potential to transform the hyperlipidemia treatment paradigm by dramatically reducing the lifetime risk of cardiovascular events.

With such exciting results, we have selected EDIT-401 as our leach development candidate to lay the foundation for our future in vivo gene editing portfolio. We have selected EDIT-401 as our lead development program because our EDIT-401 preclinical studies in nonhuman primates and all other tested models have consistently demonstrated a 90% mean reduction of LDL where the current standard of care, statins and PCSK9 inhibitors have been shown to achieve only 40% to 60% mean reductions.

EDIT-401 has the potential to be a onetime treatment providing a lifetime reduction of LDL and durable lifetime cardiovascular risk reduction. EDIT-401 has a sizable market potential with favorable health care system economics, EDIT-401also provides a very attractive business model that we expect to be aligned with typical biopharma margins, and EDIT-401's compelling preclinical data support rapid progression to human proof-of-concept studies.

Accordingly, we are moving EDIT-401 towards the clinic with expected human proof-of-concept data by the end of 2026. Atherosclerotic cardiovascular disease, or ASCVD, is the leading cause of death worldwide and imposes a significant burden on the U.S. health care system with national expenditures projected to reach over $300 billion in 2035. Elevated LDL so-called bad cholesterol is a major cause of factor in cardiovascular disease because it progressively and silently accumulates arterial roles, leading to blockages and major cardiovascular events, which include heart attack and stroke.

It has been well documented that a 40-milligram per deciliter reduction of LDL has been associated with a 20% reduced risk of cardiovascular events over 5 years. Indeed, very low levels of LDL maintained over lifetime contribute to even greater risk reduction. But the current standard of care fails to achieve desired reductions of LDL in up to 75% of patients with established cardiovascular disease and frequently requires multiple therapies and lifelong adherence.

Elevated LDL, also known as hyperlipidemia is a highly prevalent disease affecting over 70 million patients in the U.S. alone. Given EDIT-401 in passive reduction of LDL to date, we are confident in the potential of EDIT-401 to deliver meaningful benefits beyond the current standard of care across multiple segments of the hyperlipidemia population, which are highlighted in this slide. The current standard of care for hyperlipidemia has demonstrated mean reductions of LDL of 40% to 60%. As you can see in this figure, the 90% mean LDL reduction we have seen in our preclinical nonhuman primate studies of EDIT-401 supports our belief that EDIT-401 may provide reductions that go well beyond the reductions demonstrated by existing therapies, intensively reducing LDL for as long as possible provides maximum benefit to at-risk patients.

Key opinion leaders and experts to whom we have spoken confirm the LDL reduction potential of EDIT-401 will be transformative to the management of hyperlipidemia.

I'd now like to pass the call over to Linda, who will walk you through our EDIT-401 program in more detail, including our differentiated approach with functional upregulation and a very exciting data emerging. Linda?

Thank you, Gilmore. Before I share more detail on EDIT-401, I want to take a moment to review our Indigo strategy to develop a pipeline of gene editing medicines for patients with serious diseases. Our in vivo strategy is based on our Indel technology. to edit noncoding elements to achieve functional upregulation of gene expression to address loss of function or deleterious mutations.

To be clear, our strategy is not the knockout strategy that others in gene editing are pursuing. Why is the difference between our functional upregulation strategy and the knockdown strategy used by other companies matter? First, with an upregulation strategy, we can go after targets that others cannot address with knockdown approaches. And second, our approach allows us to optimize gene upregulation and devise editing strategies with the potential to be differentiated, best-in-class medicines, even where other approaches such as knockdown may apply.

The results of our EDIT-401 strategy have yielded impressive efficacy data in nonhuman primates supporting our belief that EDIT-401 may result in greater reductions in LDL than current treatment options as well as other products in development. We believe our novel in vivo editing approach with EDIT-401 is derisked by a naturally occurring variant in the LDLR prime untranslated region or UTR that leads to significant LDLR upregulation and consequently, robust reduction of LDL and offers a validated model for therapeutic gene editing.

This natural variant was discovered in 7 individuals within a single Icelandic family. It was associated with significantly lower LDL levels as low as 13 mg per deciliter when compared to Icelandic non-carriers shown in this slide on the panel on the left. And notably, there were no observed adverse health consequences among those individuals. Derisked by this naturally occurring proof of therapeutic strategy EDIT-401 creates an optimized and proprietary deletion within the 3 prime UTR of the LDLR gene.

EDIT-401 increases the liver's production of the LDLR protein, a protein that removes LDL cholesterol from the bloodstream. EDIT-401 deletion of regulatory elements in the LDLR 3 prime UTR increases the stability of the LDLR mRNA, thereby resulting in increased production of the LDLR protein.

Our preclinical data has demonstrated at least a sixfold mean increase in LDLR protein following treatment with EDIT-401. The same level of increase has not been observed with targeting of PCSK9. Thus, EDIT-401's ability to increase LDLR protein levels in hepatocyte supports its ability to dramatically reduce LDL levels by facilitating increased clearance of LDL.

The EDIT-401 program utilizes the proprietary CRISPR Cas9 enzyme, and dual guide RNAs to target the LDLR 3-time UTR to upregulate LDLR protein expression. The LNP delivery strategy involves encapsulation of CRISPR/Cas9 mRNA and dual guide RNAs in a single GalNAc-targeted LNP for transient expression of gene editing cargo using validated LNP components accessed through a strategic partnership with Genevant.

We have demonstrated impressive proof-of-concept data with a single dose of EDIT-401 in preclinical studies using healthy nonhuman primates. As shown on this slide, all 4 dose levels from 1.5 mg per kg to 4 mg per kg, demonstrated a 90% mean reduction from baseline in LDL levels. The marked reduction was observed as early as 48 hours after dosing and was sustained for the 1-month study duration. Importantly, there were no adverse effects observed. Transient increases in liver enzymes resolved within 1 week. It is worth noting that NHP data provides strong translational insight into LDL responses in clinical studies based on interventional studies in this therapeutic space.

We believe the biomarker response and projected clinical efficacy physician EDIT-401 to be a best-in-class medicine for reduction of LDLs. But what is the relevance of EDIT-401 in the presence of elevated baseline LDL In this study? A single dose of EDIT-401 nearing surrogate was administered to wild-type mice on both a regular and high-fat diet. LDL baseline was threefold higher in wild-type mice on a high-fat diet compared to wild-type mice on regular diet.

In this graph, we show that dosing with the EDIT-401 murine surrogate achieved 90% mean reduction of LDL in the wild-type mice on high-fat diet as compared to vehicle-treated wild type mice on high-fat diet. And what is the relevance of EDIT-401 in the presence of reduced LDLR function. In addition to studies in wild-type mice, we have demonstrated proof of concept with the EDIT-401 murine surrogate in the LDLR heterozygous mass model, which harbors a loss of function mutation in one of their LDLR alleles, mimicking a genotype of HgFH as expected, these lines have higher LDL levels than wild-type mice. As shown on this slide, the EDIT-401 murine surrogate achieved proof of concept with 90% mean reduction of LDL in the heterozygous LDLR mice.

In summary, EDIT-401 has demonstrated a robust and consistently 90% mean reduction of LDL in non-human primates, mice with elevated baseline LDL and mice heterozygous for LDL receptor loss of function. EDIT-401 has the potential to deliver meaningful benefits across multiple segments of the hyperlipidemia population.

I'd now like to pass the call back to Gilmore.

Thank you, Linda. EDIT-401, as Linda says, is uniquely positioned to be a potentially best-in-class treatment medicine for hyperlipidemia because our EDIT-401 preclinical studies in nonhuman primates and all other tested models have consistently demonstrated a 90% mean reduction of LDL, EDIT-401 has the potential to be a onetime treatment, providing lifetime reduction in LDL and durable life type cardiovascular risk reduction and EDIT-401 has a sizable market potential and EDIT-401's expected typical biopharma margins provide a very attractive business model.

With these attributes, we envision that EDIT-401 will be a transformative medicine that will allow a patient to receive a onetime infusion as an outpatient clinic that delivers a lifelong reduction in LDL far exceeding that provided by existing therapies. There will be no concerns for noncompliance and no need for mobilization or conditioning. EDIT-401 has the potential to not only benefit the patient by meaningfully reducing the risk potential cardiovascular events but also significantly reduce the overall cost for the health care system payers and the patients throughout their lifetime.

And because EDIT-401's compelling preclinical data support rapid progression of human proof-of-concept studies, we are moving EDIT-401 towards the clinic with expected human POC data by the end of 2026. In closing, even as we have selected EDIT-401 as our lead clinical priority. We remain very excited by the very real preclinical progress that we've made across our portfolio, including with our hematopoietic stem cell program, as well as the meaningful success we have previously achieved in the clinical or acquire programs.

We are confident our pipeline will follow that trajectory and remain committed to accelerating our other programs when additional resources become available. [indiscernible] while our disciplined approach to capital allocation will keep the focus of our resources on the advancement of our LEAD-401 program in the clinic, we continue to work on optimizing candidates for our HSC program and exploring other tissue and cell types. We look forward to sharing more with you in the coming months. Thank you very much for your interest in Editas, and we are happy to answer questions.

[Operator Instructions] We'll take our first question from Jack Allen with Baird.

Congratulations on the progress, lots of interesting data as it relates to EDIT-401. I guess the first question I had on 401 and then I do have 1 quick follow-up was on where you plan to start testing 401 like what patient populations could you look at I know hypercholesteremia is a huge indication as you apply lay out, but there are some familiar components to the disease as well. Do you plan to go after general [indiscernible]? Or could it be the heterozygous familiar hyperclustering that you receive first.

So thanks very much, Jack, for your question. we actually laid out a number of segments in the patient population. And obviously, the AFH and other refractory segments would be an obvious place to go. But HgFH is certainly a consideration. The sort of the final selection will obviously depend on discussions with regulators, et cetera. But I think you're absolutely right in highlighting that sort of more refractory segments of the patient population.

Got it. And then just very briefly, I wanted to ask about the ex liver side of the business as well. Your last slide seemed to outline having proof of concept from an ex liver tissue type in 2027, but you're keeping a broad and potentially not necessarily committing to the hemopoietic stem cell program, at least that's how I read it. Is it not clear that the hemolytic stem cell program is second in line now? Or are you still deciding on your follow up?

Thanks, Jack, for that clarifying question. Our commitment to the preclinical advancement and optimization of our HSC program and other extra [indiscernible] remains strong. The highlighting of the third tissue is actually related to sort of an additional commitment, our objective that we laid out at the beginning of this year.

But our commitments across the preclinical [indiscernible] remains strong. As I say, we are using opportunity with our disciplined allotment or allocation of capital to 401 to allow us to do further optimization with our HSC program and look beyond.

Next question comes from Samantha Lynn Semenkow with Citi.

Congratulations on the progress and the disclosure for EDIT-401. A couple of questions for me. Just first, is there evidence that reaching 90% LDL reduction would result in lower cardiovascular risk versus what we see currently with the current standard of care in the 48% to 60% range? And then I have a follow-up.

Yes. Thanks, Sam. Thank you very much for the question. I think we can draw from the clinical interventional trials that have gathered data on this. We know that every 40 mg per deciliter lowering of LDL-C there's a roughly 20% risk reduction for cardiovascular risk over 5 years. But we also know from the interventional trials that the patients that achieved even lower levels of LDL experienced even greater risk reduction and notably no safety risks associated with them.

In fact, the safety outcomes were similar across all the LDL-C ranges. So I think the greater risk reductions with even lower LDL levels supports the principal, the longer, the better. And also lifelong lowering of LDL-C is associated with being greater risk reduction, cardiovascular disease, and that's supported by genetic evidence with individuals who carry mutations that have lots of functions that get very low LDLs.

So I think we feel very confident in our strategy, but thank you very much for that question. I hope that answers your question.

Yes, that's very helpful. And then I guess just maybe a theoretical one, how do you anticipate the LDL reduction you've seen thus far in the mice will translate to humans. Is the 90% reduction with a dose that is translatable to humans first off? And then is there a risk that you might see lower LDL reduction? Or is the expectation based on the data we've seen across the gene editing landscape that what you see in mice is reasonably translatable to humans.

Yes, Sam, thanks again for the question. So we're seeing the 90% reduction in both the NHPs and in the mine. In the HP space. This has been very translatable the LDL reductions from the NHPs to the humans and the dose levels that we're seeing, we have actually seen 90% reduction at all the dose levels that we tested. We haven't actually established our minimally efficacious dose. But we're projecting that a human dose will be below 1 mg per kg. So we're very viewing very favorably the translatability to humans because of the translatability of LDL lowering in this space and the observations in the NHPs.

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

Congrats on the progress here. Two questions. First, curious if you looked at modulating the upstream 5 prime region as well in your preclinical work. I just wonder if the increasing promoter activity might lead to higher LDLR levels versus just stabilization of the transcript. And thinking about a competitive landscape, in LDL-C potentially shifting from injectables to orals over the next couple of years.

I guess how do you see a gene editing product like 401 fitting in? Would this be positioned for the most severe patients or is maybe the onetime and 90% lowering differentiating enough in your view?

Thanks, Alex. I'll have Linda answer the first question on different targeting strategies, and then I'll deal with your second question.

Yes. Thanks for the first question. We really wanted to derisk our strategy by -- with human genetics, and we focused on trying to find natural human variants that would inform and derisk our strategy. So the information from the Icelandic variant and individuals carrying that was very important to us to use that information to derisk both the efficacy and safety. So we really focused on the 3 [indiscernible]

Thank you very much, Linda. And with regard to your competitive landscape question and positioning of this, there are a number of points to make. First, EDIT-401 does have a really significant separation in the effect size that it gives to LDL reduction compared to existing therapies. And that in itself is very important. As you quite rightly pointed out, there are important segments of the patient population that we've identified, that experts identified and even our discussions with payers have identified, where they have recognized segments that would certainly benefit from such therapy.

It's worth highlighting when you look beyond that, that 75% estimate 75% of patients treated with established liver disease or alert cardiovascular disease or hyperlipidemia, do not achieve their targets for a number of reasons. So if you combine Linda's point that lower, longer, better and you combine that with the compliance. You can actually see the span of segments across we can actually deliver this therapy.

Next question comes from Joon Lee with Truist.

This is Mahdi on for Joon. First question is, and I have a follow-up. How factually, you mimic the mutation in the Icelandic population. Is that the 2.50 Kb deletion or is just your removing the microRNA sites in that region?

Thanks very much for the question, Joon. We are not sharing our exact proprietary optimized strategy for upregulating the 3 prime deletion in the LDLR 3 prime UTR. It is not exactly the [ 2.5 kb Indel ] because it is a proprietary dilution. But we are obviously removing regulatory elements.

Interesting. Thank you. It appears that unregulated upregulation of LDLR might induce some cellular toxicity. And even might increase the risk of atherosclerosis in patients with APOE4 variant. So could you please elaborate on your long-term safety for your approach in contrast to other LDL-C lowering methods like PCSK9 inhibitors and ANGPTL3?

So let me just -- you're asking a question about the potential for high levels of LDL upregulation causing some cell toxicities and actually what are the long-term risks. So what I would actually say is before I pass over to Linda sort of at a very high level, we've actually been thinking about this carefully. And I think there are a couple of things. First of all, we do have derisking on the genetic side, the Icelandic cohort and pedigree while small, is still really important in actually assuring us about the long-term safety of this approach.

In addition, we also have some pharmacologic partial derisking in that the way that PCSK9 knockdown or inhibition actually drives LDL reduction is by reducing the recycle or destruction of LDLR. So you have some partial validation there.

Linda, I don't know if you want to add to that.

Well, I think that part of the -- we can draw on the other current treatments that do increase LDLR expression albeit through their own mechanisms and at lower levels, obviously, which is why they're not reducing LDL to the greater extent. But in the interventional trials where there were patient cohorts who did achieve very low levels of LDL on the order of 10 to 20 mg per deciliter we can expect that in those cases, LDLR was increased to a greater extent. So I think we can infer that without safety outcomes there that there were -- that somewhat derisked the question that you're posing Joon.

Our next question comes from Phil Nadeau with TD Cowen.

So in terms of the reduction that you need to achieve in people, what do you think is the minimal effective level. 90% obviously would be a big improvement over standard of care. But what's the minimum reduction you think you need to achieve in order to have a viable product?

And then second, basically preclinical experiments, do you have a sense of what percent editing of the liver cells as necessary to achieve that level of reduction.

Thanks, Phil. I think I'll let Linda take the second question. With regard to the levels required to reduce, I think there are a couple of points. Obviously, we have seen long-term follow-up data over the years that demonstrate that mean reductions of 60% certainly confer benefit. But I think it's very important to say that we're very confident about the transformational levels of reduction that we're seeing in our hands for a number of reasons.

First of all, it is biologically plausible, driven by both the genetic validation in that Icelandic Kindred. The fact that we're seeing significant upregulation of LDLR or increase of LDLR levels. And then finally, that experience that Linda called out that interventional studies of cholesterol lowering or LDL specifically lowering in nonhuman primates has demonstrated a high positive predictive value for translation from the preclinical state to the human.

I think the final piece I'd just remind everyone is that in long-term follow-up studies if you go from percentage to absolute reductions for every 40-milligram per deciliter or because it's most -- much of that has been published using SI units, 1 millimole reduction in LDL-C, you actually reduce the risk, the cumulative cardiovascular risk over 5 years by 20%. And actually, that lifetime risk is even further reduced. So you can anticipate that with a higher percentage reduction, you're going to get a higher milligram per deciliter and therefore and this is why we feel that you can see in the future a significant reduction in cardiovascular risk with this approach.

Thank you Gilmore. So I can take the other part of your question about which is as to what percent editing we need in order to achieve the effect -- so because we have this very nice dose response, we did various doses in NHP. And all of them, as you saw, a very remarkably lowered LDL by 90%. However, we were able to analyze in those animals, the percent editing and the percent of and the level of LDLR protein upregulation, and we have analyzed all of that data. So we do have an evaluation of the level of editing that we need to achieve in order to get the 90% reduction. And we do look forward to sharing all on that data. We're not disclosing that data. in today's webinar, but we will be sharing that data at a future scientific venue.

Our next question comes from Bill Mohan with [ Clear Street].

So my question is, how do you expect the prescribing and patient community to think about the trade-off here between a lifelong reduction in LDL-C versus other potential options that for any reason, if a patient does want to withdraw drug, they retain that option just for any theoretical concerns in that -- on that.

Yes. Thanks very much, Bill. So the way we are thinking about this is that One thing that is very clear is that a substantial proportion, 75% of patients have great difficulty achieving target and even to achieve target requires multiple interventions or at the very minimum, a lifetime commitment to remember to take a medicine that is actually managing a risk factor that is signed accumulating but can actually create catastrophic consequences.

Now the way we see it to start with is that you can actually see that within that patient population of hyperlipidemia, there are certain segments that are even more likely to be refractory and in higher risk so we could actually see that early embrace there. But more importantly, we don't just speculate on that, we have actually topped 2 KOLs. We've talked to treating physicians -- and they -- and by the way, it's also worth saying that payers have identified populations or segments with our patient population or segments within the hyperlipidemia population for whom this kind of high efficacy, single infusion lifelong reduction would be beneficial.

And as a follow-up, looking forward to the human proof-of-concept data, Obviously, we'll want to see LDL-C reduction and a clean safety profile, but are there any other observations or measures that you would expect to want to call out that you're looking forward to from that readout.

I think there are a number of things we might look at, but I think you called out the main ones, which will obviously be the LDL-C reduction that the dosing -- the dose level at which we see that and the safety profile. I think those are the key elements.

Our next question comes from Jonathan Miller with Evercore ISI.

Congrats on taking your candidate here. I was going to ask as a follow-up to some of the comments you've made about particular market segments. Obviously, different patient populations have different baseline levels of LDLR. Do you expect that you'd see differential efficacy in patients that already have robust LDLR expression and maybe their hypercholesteremia or hyperlipidemia is coming from some other issue. Would you expect that you would put some sort of gate on inclusion criteria around baseline LDLR when you're thinking about the patient segments that you start with.

Thanks very much. Before I pass it on, I just wanted to highlight 1 point. I think when we look at the consideration of baseline levels of LDL-C. I think the important thing to highlight is, one, that LDLR upregulation in theory, in genetically defined human kindreds, the Icelandic population. And indeed, in our nonhuman primate experiment has shown significant reductions.

In addition, because this -- you asked your question about baseline, we have seen these reductions at low baselines and high baseline levels of LDL-C. Hence, the experiments that Linda shared, including the LDLR heterozygous mouse model and then the mice with a high-fat diet that had a high significant elevated baseline levels.

Yes. So thank you, Gilmore’. I can add a little bit to that. So first of all, I can break it up into 2 parts, like delivery because we're using a GalNAc targeted LNP, which is LDLR independent, we should have the ability to target segments regardless of their level of LDLR on the surface, we shouldn't have a difference between the patients who have more or less LDLR and then once you're in those different patients, because we're increasing -- we're going after the root cause of the disease by increasing the production of LDLR.

So we should be able to address different segments of patients that have low or high LDLR by elevating their amount of LDLR. This is very different, obviously, than PCSK9 inhibitor that backs to rescue, if you will, existing pool of LDLR and that is very much dependent on how much LDLR is existing in the different patients depending on their level -- so I think the answer to your question is our strategy should be agnostic, if you will, to the patient.

And then, Jonathan, you asked a question, would you anticipate restrictions inclusion criteria or label. Those are questions, obviously, that will be identified as we go forward. We don't anticipate necessarily a need for that as the development evolves. But as I say, our data and very importantly, discuss regulators will inform that later in the program.

Our next question comes from Soumit Roy with Jones.

Congrats on new target and the new asset. Not sure if I missed it, have you shown us the LDR expression levels compared to pretreatment -- and if not, what is your internal benchmark that you're going to use for the LDR expression itself their PCSK9 or statins or cholesterol absorption inhibitors.

So let me just -- if I may -- Soumit, let me just sort of resummarize the question the way I think I understand you're asking, which is -- do we have an understanding of the allelic effects or possibly another way which did the level of editing that we're seeing at the liver. And then how are we measuring LDLR upregulation. And is that correct?

Yes.

So I think from the point of view of the degree of allelic editing in the liver, we haven't actually shared that and that was Linda pointed that out, go ahead.

Yes. I think I pointed out that we've evaluated that. We're going to be sharing that in the future, scientific venue.

And then the other one is about the LDLR upregulation is that we have actually been able to measure that in our nonclinical experiments. And in fact, I think it's summarized in some of the data -- in fact, all the data slides for both the nonhuman primates as well as the low fat diet mice and the LDLR heterozygous mice.

But you're looking, obviously, an expression in the liver.

Right. So they were looking at expression in the liver, we're looking at total liver lysate we're maturing total LDLR protein. And we -- as we stated, we're seeing at least a sixfold mean increase in the LDLR protein levels was able to give us this 90% reduction in the NHPs. I hope that answers your question.

And then, Soumit, you asked about benchmarking as well. And I think we had -- we do cite some references there, but the experience, looking at PCSK9 and its effect, which show -- has demonstrated significantly lower levels of LDL up regulation simply because instead of increasing the amount of protein produced it essentially decreases the amount of protein that is being recycled or pulled down from the cell surface and destroyed in the -- in sort of the lysosome or cleanup system of the cell. And of course, if you're doing that, you basically have a limit to the capacity that you can because there's only a set amount of protein being made by our strategy increases the amount of protein being made.

And so that benchmarking, as I say, and that literature would support has demonstrated is see substantially lower increases levels of LDLR. Does that help?

Certainly helps. As I understand the cholesterol metabolism is a complex process with multiple proteins and pathways. Do you know if there are any genetic data available? Or will you be looking into long-term changes to the regulation of the LDR or gene itself, patients who are already on statins or other drugs, essentially trying to understand if 3 Prime UTR is the only regulatory unit for the expression level of the gene or there are other compensatory mechanism can kick in.

Soumit, if I can -- I'll address that. And Linda, do you want to add to that? You're quite right, [indiscernible] is highly complex. However, I think it's good to know that we have been looking at the biochemistry of this system for well over 60 years. The regulatory elements that regulate LDLR expression and other cholesterol metabolizing enzymes, both on the synthetic side, the biosynthesis side and the catabolism or breakdown side have been very well characterized and to date, we have been very pleased both in our preclinical experiments to see that the animals are tolerating as well.

We follow up very importantly that we have also a genetic validation. And obviously, LDLR, I should say, manipulation even though at a more modest level, with PCSK9 has not demonstrated adverse events and this is also important to notify or acknowledge not just in PCSK9 inhibition pharmacologically but even PCSK9, I should I say, loss of function gene or genetic variants in humans.

So overall, we actually feel that we are in a very good state here.

Right. And obviously, we'll also be conducting a long-term durability study to demonstrate the durability of our editing approach.

Next question comes from Eric Schmidt with Cantor.

My congrats as well, fascinating data, fascinating biology as well. I wanted to ask Linda about this Icelandic family. It looks like the family members have maybe about twofold increase in LDL receptor expression, but you're getting more like a sixfold increase. So what explains that? Is there some heterozygosity in the family numbers genetic makeup?

Yes. The family members are carriers of the 2.50 kb Indel. So they're not homozygous for it, their carriers. And they -- even though they have the roughly 2 to threefold roughly increase, they have LDL levels that are as low as 13 mg per deciliter.

So they have a range and the low end is 13. I think it ranges from 13 to roughly 70 mg per deciliter. So we empirically have determined with our optimized strategy that we can achieve the 90% reduction with very tight error bars instead of this range that's seen in the Icelandic family with our proprietary deletion and that we need roughly to achieve this threshold of sixfold protein increase. So we're trying to get a very consistent effect.

Okay. So if anything, you'd expect more LDL receptor upregulation and even greater level than the family genetics?

Yes. And like exactly.

And then on to the safety, I think the slides that you presented suggested that the LNP was accessed through the Genevant partnership and consists of clinically validated components. Can you -- can you talk about whether the LNP itself with the specific composition of makeup that's been used in patients before.

The components have been the various components have us in clinic, the actual LNP itself has not been used in the clinic, but all of the different components have been used in the clinic. So we've now progressed them into our LNPs into our NHP study. They were very well tolerated up to 4 mg per kg. There were no clinical adverse observations in our study. So we are very pleased with the tolerability profile.

So will this be essentially in Editas for proprietary LNP formulation that you access through the partnership?

I think that the strategic partnership, as you say, is with Genevant and we haven't gone in or disclosed how -- who owns [indiscernible], but essentially, the key thing is that this is a great strategic partnership. We're very happy with how it's going. And I would say it's a really good collaboration if you want to talk about [indiscernible] we're not sharing.

Our next question comes from Yanan Zhu with Wells Fargo.

Congrats on the progress. This is an [indiscernible] for Yanan.

Sorry, forgive me.

Can you talk about the safety profile of EDIT-401 have you seen any off-target editing and any observations on deeper enzyme elevations or thrombocytopenia in NHP.

Thanks very much, [ Juan, ] for that question. Linda?

Yes, I can speak to -- we are designing our -- we design our cargo, our nuclease, our test nucleus and our guide RNAs to be highly specific through our bid design. We do this design and testing through a specificity generation of the specificity package. And we do this through basically a very comprehensive assessment using many orthogonal assays. These involved in silico assays, biochemical assays and cell-based assays.

So this is the process that we've taken on our guide RNAs through, and we're very pleased with where we are in terms of our specificity package. So -- that's what I can share with you at the moment. Also with respect to your other question of the LFTs, we saw it very transient in the NHPs that resolved were back to normal within 1 week.

And we didn't see any thrombocytopenia.

Changes in any coagulation or any hematology parameters whatsoever. So on both counts, the specificity package and the liver function test, we're very pleased.

Yes, so durability, you mentioned that you need more studies to evaluate your...

Sorry, [ Juan, ] you're very -- sorry, an to interrupt. You're very muffled. I'm having -- I can't make you out at all.

I'm sorry. Is it better now?

That's better. Yes, that is better. Yes. All right.

So on durability, you mentioned that you need more studies to evaluate durability -- can you talk about whether redosing is possible if needed?

Yes. So, so far, we've shown, as you could see on 1 of the slides, that we have durability out to 12 weeks. You saw that on one of the slides where we studied [indiscernible] that had been better high fat diet and we maintained our 90% reduction in LDL. So we're very pleased with that study. Typically, 1 would do as part of their development package. A longer durability study of at least 1 year. So we are embarking on that study as part of our package. And your other question, redosing -- so yes, we -- based on our analysis from our NHPs, we do believe we would have, if needed, we would have room for redosing. We don't want that we would need that. But if so, we have room for that.

Our next question comes from Gena Wang with Barclays.

Can you discuss any expectations on time lines, downstream or pivotal development like how many patients or follow-up would be needed for safety database requirements and anything else in the package like in silico assays, et cetera.

Thanks very much, Tony, for that question. I think it's obviously it's very early days to be looking downstream. We actually believe that this medicine has a potential to treat multiple segments of patients population. I think different segments may have different requirements, which obviously determined by regulators, but that's something that we will look forward to the near future. I will tell you, however, that with regard to our human POC studies, we anticipate with the very large effect size that we're seeing and the positive predictive value of nonhuman primates in translating cholesterol lowering medicines or LDL lowering medicines into humans that with that effect size, we would really require a small population in which to detect that biological effect size.

Got it. And then I guess on the next update on that note, will you all be announcing like for clinical trial initiation, like which segment that will be going into initially? And then other details around that at the next update.

[indiscernible] it's hard to say, but we will at the next update. But the population that we will select or population segments that we will select for that human first in human. We'll obviously be agreed with regulators and IRBs. And I think that is the appropriate time to finalize it. But as I said, I think, in a previous answer, we are aware of a number of segments. It's likely that we would start with more refractory patients, so an HgFH or high-risk arterials cardiovascular patients with -- who are not coming close to achieving target will be 2 obvious segments that we could start in. But obviously, that will be a matter for discussion and agreement with regulators and institutional review board committee.

Our last question comes from Mitchell Kapoor with H.C Wainwright.

This is Katie on for Mitchell. Very exciting data. I was curious if you have considered looking at plaque formation or other markers beyond just the LDL-C reduction?

Katy, thanks very much for that question. That is something obviously that has been looked at in other studies. It usually takes larger patient populations and occurs later in development of the program. Based on -- so what we would in our early first-in-human studies, we'll be looking at LDL reduction and various safety parameters. Obviously, the evolution or maturation or reduction of Platt are elements that could be looked at later in the development program.

Thank you very much.

This concludes the Q&A portion of today's webinar. Thank you for joining. You may now disconnect.