Editas Medicine at Wells Fargo Conference: Gene Editing Milestone

On Wednesday, 03 September 2025, Editas Medicine (NASDAQ:EDIT) presented at the Wells Fargo 20th Annual Healthcare Conference 2025. The company announced a significant milestone with EDIT-four zero one, a CRISPR-based gene editing candidate aimed at reducing LDL cholesterol. While the potential of this innovative treatment is promising, the company faces challenges related to market competition and regulatory approval.

Key Takeaways

• Editas Medicine selected EDIT-four zero one as its lead candidate for in vivo gene editing.
• Preclinical studies showed a 90% reduction in LDL cholesterol, surpassing existing therapies.
• Human proof-of-concept studies are expected to start soon, with data anticipated by 2026.
• The company is focusing on expanding its pipeline and optimizing other programs.

Financial Results

• Editas Medicine plans to advance EDIT-four zero one within its current cash resources.
• The U.S. healthcare expenditures for cardiovascular disease are projected to exceed $300 billion by 2035.
• EDIT-four zero one is expected to align with typical biopharma margins, offering a promising business model.

Operational Updates

• EDIT-four zero one has been selected as the lead development program, with preclinical studies showing significant efficacy.
• The company employs INDEL technology for gene editing, focusing on non-coding elements.
• A strategic partnership with Genovant supports the delivery of gene editing cargo via LNPs.

Future Outlook

• Human proof-of-concept data for EDIT-four zero one is anticipated by 2026.
• Editas is committed to expanding its pipeline, including the hematopoietic stem cell (HSC) program.
• Final patient population selection and clinical trial details await regulatory discussions.

Q&A Highlights

• Analysts inquired about target patient populations, with the company considering refractory segments such as HFH.
• Editas continues to advance its HSC and other extrahepatic programs.
• The competitive landscape highlights EDIT-four zero one’s potential due to its significant LDL reduction.

For more details, refer to the full transcript below.

Full transcript - Wells Fargo 20th Annual Healthcare Conference 2025:

Dana: Our lead development candidate, Edit four zero one. This webinar is being recorded and can be accessed in the future through this same link or through the Investors section of the company’s website. After our prepared remarks, we will open the call to q and a. To ask a question, please click the raise hand feature in the webinar portal. 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 ks, 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.

Gilmore O’Neill, CEO, Editas: Thank you, Dana, and good morning to you all. With me today are Linda Berkley, our Chief Scientific Officer and Amy Patterson, our Chief Financial Officer, who will join us for Q and 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 can advance towards human proof of concept data as quickly as possible within our current cash runway.

Today, we are delighted to introduce our lead program EDIT-four zero one. EDIT-four zero one is a potential best in class, one time, 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-four zero one as our lead development candidate to lay the foundation for our future in vivo gene editing portfolio. We have selected EDIT-four zero one as our lead development program because our EDIT-four zero one preclinical studies in nonhuman primates and all other tested models have consistently demonstrated a 90% mean reduction of LDL, where at the current standard of care, statins and PCSK9 inhibitors have been shown to achieve only forty percent to 60% mean reductions. EDIT-four zero one has the potential to be a one time treatment, providing a lifetime reduction of LDL and durable lifetime cardiovascular risk reduction.

EDIT-four zero one has a sizable market potential with favorable health care system economics. EDIT-four zero one also provides a very attractive business model that we expect to be aligned with typical biopharma margins. And EDIT-four zero one’s compelling preclinical data support rapid progression to human proof of concept studies. Accordingly, we are moving EDIT-four zero one towards the clinic with expected human proof of concept data by the 2026. Atherosclerotic cardiovascular disease or ASCVD is the leading cause of death worldwide and imposes a significant burden on The US health care system with national expenditures projected to reach over $300,000,000,000 in 2035.

Elevated LDL, so called bad cholesterol, is a major causal factor in cardiovascular disease because it progressively and silently accumulates arterial walls, leading to blockages and major cardiovascular events, which include heart attack and stroke. It has been well documented that a forty milligram per deciliter reduction of LDL has been associated with a twenty percent reduced risk of cardiovascular events over five years. Indeed, very low levels of LDL maintained over a lifetime contribute to even greater risk reduction. But the current standard of care fails to achieve desired reductions of LDL in up to seventy five percent 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 seventy million patients in The US alone.

Given EDIT four zero one’s impressive reduction of LDL to date, we are confident in the potential of EDIT four zero one 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 four zero one supports our belief that EDIT-four zero one 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-four zero one will be transformative for the management of hyperlipidemia.

I’d now like to pass the call over to Linda, who’ll walk you through our EDIT four zero one program in more detail, including our differentiated approach with function of regulation and the very exciting data emerging. Linda?

Linda Berkley, Chief Scientific Officer, Editas: Thank you, Gilmore. Before I share more detail on EDIT four zero one, I want to take a moment to review our in vivo 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 non coding elements to achieve functional upregulation of gene expression to address loss of function or deleterious mutations. To be clear, our strategy is not the knockdown strategy that others in gene editing are pursuing. Why does 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-four zero one strategy have yielded impressive efficacy data in nonhuman primates, supporting our belief that EDIT-four zero one 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-four zero one is de risked by a naturally occurring variant in the LDLR reprime 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 seven individuals within a single Icelandic family.

It was associated with significantly lower LDL levels as low as 13 mgdL 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-four zero one creates an optimized and proprietary deletion within the three prime UTR of the LDLR gene. EDIT-four zero one increases the liver’s production of the LDLR protein, a protein that removes LDL cholesterol from the bloodstream. EDIT-four zero one deletion of regulatory elements in the LDLR three’ UTR increases the stability of the LDLR mRNA, thereby resulting in increased production of the LDLR protein.

Our preclinical data have demonstrated at least a six fold mean increase in LDLR protein levels following treatment with EDIT-four zero one. The same level of increase has not been observed with targeting of PCSK9. Thus, EDIT-four zero one’s ability to increase LDLR protein levels in hepatocytes supports its ability to dramatically reduce LDL levels by facilitating increased clearance of LDL. The EDIT-four zero one program utilizes a proprietary CRISPRCas9 enzyme and dual guide RNAs to target the LDLR three prime ETR to upregulate LDLR protein expression. The LNP delivery strategy involves encapsulation of CRISPRCas9 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 Genovant.

We have demonstrated impressive proof of concept data with a single dose of EDIT-four zero one in preclinical studies using healthy nonhuman primates. As shown on this slide, all four dose levels from one point five mg per kg to four mg per kg demonstrated a 90% mean reduction from baseline in LDL levels. A marked reduction was observed as early as forty eight hours after dosing and was sustained for the one month study duration. Importantly, there were no adverse effects observed. Transient increases in liver enzymes resolved within one 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 position EDIT-four zero one to be a best in class medicine for reduction of LDL. But what is the relevance of zero one in the presence of elevated baseline LDL? In this study, a single dose of EDIT-four zero one 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-four zero one 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-four zero one in the presence of reduced LDLR function? In addition to studies in wild type mice, we have demonstrated proof of concept with the EDIT-four zero one murine surrogate in the LDLR heterozygous mouse model, which harbors a loss of function mutation in one of their LDLR alleles, mimicking a genotype of HEFH. As expected, these mice have higher LDL levels than wild type mice. As shown on this slide, the EDIT-four zero one murine surrogate achieved proof of concept with 90% mean reduction of LDL in the heterozygous LDLR mice.

In summary, EDIT-four zero one has demonstrated a robust and consistently 90% mean reduction of LDL in nonhuman primates, mice with elevated baseline LDL, and mice heterozygotes for LDL receptor loss of function. EDIT-four zero one 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.

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

With these attributes, we envision that EDIT-four zero one will be a transformative medicine that will allow a patient to receive a onetime infusion at an outpatient clinic that delivers a lifelong reduction LDL far exceeding that provided by existing therapies. There would be no concerns for noncompliance and no need for mobilization or conditioning. EDIT four zero one has the potential to not only benefit the patient by meaningfully reducing their risk of potential cardiovascular events, but also significantly reduce the overall cost for the health care system, payers, and the patient throughout their lifetime. And because EDIT-four zero one’s compelling preclinical data support rapid progression of human proof of concept studies, we are moving EDIT-four zero one towards the clinic with expected human POC data by the 2026. In closing, even as we have selected EDIT-four zero one 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 clinic with our prior programs.

We are confident our pipeline will follow that trajectory and remain committed to accelerating our other programs when additional resources become available. In that spirit, while our disciplined approach to capital allocation will keep the focus of our resources on the advancement of our lead four zero one 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: We will now take questions. Please use the raise hand feature to join the queue. Please limit your questions to one question plus one follow-up. We’ll take our first question from Jack Allen with Baird. Please unmute your line and go ahead.

Jack Allen, Baird: Hi. Thank you so much for taking the questions, and congratulations on the progress. Lots of interesting data as it relates to EDIT-four zero one. I guess the first question I had on four zero one, then I do have one quick follow-up, was on where you plan to start testing four zero one? Like what patient populations could you look at?

I know hypercholesterolemia is a huge indication as you aptly lay out, but there are some familial components of the disease as well. Do you plan to go after general hypochlorostremia or could it be the heterozygous familial hypokalostremia that you received first?

Gilmore O’Neill, CEO, Editas: So thanks very much, Jack, for your question. We actually laid out a number of segments, in the patient population. And obviously, the HFH and other refractory segments would be an obvious place, to go. But, you know, HFH is certainly a a a similar consideration. So the final selection will obviously depend on discussions with regulation, etcetera.

But I think you’re you’re absolutely right in highlighting the sort of more refractory segments of the patient population.

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

Gilmore O’Neill, CEO, Editas: Yeah. Thank you. Thanks, Jack, for that clarifying question. You know, our commitment to the preclinical advancement and optimization of our HSC program and other extrahepatic remains strong. The 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 core field remain strong. As I say, we are using opportunity with our disciplined allotment or allocation of capital to four zero one to allow us to do further optimization with our HCC program and look beyond.

Jack Allen, Baird: Thank you so much for all the questions.

Operator: Our next question comes from Samantha Smenkow with Citi. Please go ahead.

Gilmore O’Neill, CEO, Editas: Samantha, we can’t hear you, I’m afraid.

Samantha Smenkow, Citi: Hi. Good morning. Can you hear me now?

Gilmore O’Neill, CEO, Editas: Yes. Yes. Good to

Tony: hear How

Gilmore O’Neill, CEO, Editas: are you doing?

Samantha Smenkow, Citi: Congratulations on the progress and, disclosure for EDIT four zero one. A couple questions from 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 forty percent to sixty percent range? And then I have a follow-up.

Linda Berkley, Chief Scientific Officer, Editas: 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 forty mg per deciliter lowering of LDL C, there’s a roughly twenty percent risk reduction for cardiovascular risk over five 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 principle of the lower, the longer, the better, and also, you know, lifelong lowering of LDL C is associated with even greater risk reduction of cardiovascular disease, and that’s supported by genetic evidence with individuals who carry mutations that have lots of functions that get very low LDL. So I think we feel very confident in our strategy, but thank you very much for that question. I hope that answers your question.

Samantha Smenkow, Citi: Yes. That 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 or is the expectation based on the data we’ve seen across the, you know, gene editing landscape that what you see in mice is reasonably translatable to humans?

Thanks very much.

Linda Berkley, Chief Scientific Officer, Editas: Yeah. Sam, thanks again for the question. So we’re seeing the 90% reduction in both the NHPs and in the mice in the NHP space. This has been very translatable, the LDL reductions from the NHPs to the humans. And the dose levels that we’re seeing, you know, 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 one 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.

Samantha Smenkow, Citi: That’s very helpful. Thanks very much.

Operator: Our next question comes from Alex Flanagan from Bank of America. Please unmute your line and go ahead.

Alex Flanagan, Bank of America: Hey, guys. Thanks for taking our questions, and congrats on the on the progress here. Two questions. First, curious if you looked, at modulating the upstream five prime region as well in your preclinical work. I just wonder if increasing promoter activity might lead to higher LDLR levels versus just stabilization of the transcript.

And thinking about, you know, 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 four zero one fitting in? Would this be positioned for the most severe patients? Or is maybe the onetime and 90% lowering, differentiating enough, in your view?

Gilmore O’Neill, CEO, Editas: Thanks, Alec. I’ll have, Linda answer the first question on, different targeting strategies, and then I’ll deal with your second question.

Linda Berkley, Chief Scientific Officer, Editas: Yeah. Thanks for the first question. You know, 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 three pronged ETR.

Gilmore O’Neill, CEO, Editas: Thank you very much, Linda. And with regard to your competitive landscape question, and positioning of this, you know, there are a number of points to make. You know, first, EDIT four zero one 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 expert identified, and even our discussions with payers have identified, where they have recognized segments, that would certainly benefit from such therapy.

It is worth highlighting when you look beyond that, That seventy five percent, an estimated seventy five percent of patients treated with established liver disease or or sorry, established 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.

Jonathan Miller, Everscore ISI: Okay, great. Thank you.

Operator: Our next question comes from Joon Lee with Truist. Please go ahead and ask your question.

Mehdi, Truist: Good morning and thanks for taking our question. This is Mehdi on for June. First question is, and I have a follow-up, how faithfully you mimic the mutation in the Icelandic population? Is that the two point five kilobytes deletion, or it’s just you are removing the microRNA sites in that region?

Linda Berkley, Chief Scientific Officer, Editas: Thanks very much for the question, June. We are not sharing our exact proprietary optimized strategy for upregulating the three prime, you know, deletion in the LDLR, three prime ATR. It is not exactly the 2.5 kilobytes del because it is a proprietary deletion, but we are obviously removing regulatory elements.

Mehdi, Truist: 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 APOE four 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? Thank you.

Gilmore O’Neill, CEO, Editas: So let me just you’re asking a question about the potential for high levels of LDLR upregulation causing some cell toxicities. And actually what are the long term risks. So what I would actually say is, 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 de risking 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, don’t know if you want to add to that.

Linda Berkley, Chief Scientific Officer, Editas: Well, I think that part of the we can draw upon 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 ten to twenty 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, June.

Mehdi, Truist: Thank you.

Gilmore O’Neill, CEO, Editas: Thank you.

Operator: Our next question comes from Phil Nadeau with TD Cowen. Please go ahead and ask your question.

Gilmore O’Neill, CEO, Editas0: Good morning. Thanks for taking our questions. Just just two from us. So in terms of the reduction that you need to achieve in people, what do you think is the minimal effective levels? 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, based on your preclinical experiments, do you have a sense of what percent editing of the liver cells is necessary to achieve achieve that level of reduction? Thanks.

Gilmore O’Neill, CEO, Editas: 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 could for 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 translating from the preclinical, state to the human. And I think the final piece I just just remind everyone is that, in long term follow-up studies, if you go from percentage to absolute reductions, for every forty milligram per deciliter or because it’s most much that much of that has been published using SI units, one millimole reduction LDL C, you actually reduce the risk, the cumulative cardiovascular risk over five years by twenty percent. 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.

Linda Berkley, Chief Scientific Officer, Editas: Thank you, Dilmur. So I can take the other part of your question as a 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 the NHP. And all of them, as you saw, very, remarkably, lowered LDL, by 90%. However, we were able to analyze in those animals the 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 to, achieve in order to get the 90% reduction. And we do look forward to sharing all of that data. We’re not disclosing that data in today’s, today’s webinar, but, we will be sharing that data at a future scientific venue.

Gilmore O’Neill, CEO, Editas0: Fair enough. Thank you. Congrats on the progress.

Gilmore O’Neill, CEO, Editas: Thanks very much, Phil.

Operator: Our next question comes from Bill Mohan with Clearstream. Please go ahead and ask your question.

Gilmore O’Neill, CEO, Editas1: Hi. Good morning, and and thank you. So my question is, how do you expect the prescribing and and patient community to 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 wanna withdraw drug, retain that option just for any theoretical concerns in that on that.

Gilmore O’Neill, CEO, Editas: 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, seventy five percent 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 silently 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 talked to 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 or patient population or segments within the hyperdipineur population for whom this kind of high efficacy, single infusion, lifelong reduction, would be beneficial.

Gilmore O’Neill, CEO, Editas1: Thanks. And as a as a follow-up, looking forward to the the human proof of concept data, obviously, we’ll wanna see LDL C reduction and a clean safety profile, but are there any other, observations or or measures that you, would expect to want to call out, that that you’re looking forward to from that readout?

Gilmore O’Neill, CEO, Editas: You know, I think there are a number of things we might look at, but I think you called out the main ones, which will obviously obviously be, the LDL C reduction, the the dosing at the dose level of which we see that and, the safety profile. I think those are the key elements.

Gilmore O’Neill, CEO, Editas1: Thank you.

Gilmore O’Neill, CEO, Editas: Thank you very much, Bill.

Operator: Our next question comes from Jonathan Miller with Everscore ISI. Please go ahead and ask your question.

Jonathan Miller, Everscore ISI: Thanks so much for taking my question, guys, and congrats on picking 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 hypercholesterolemia 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?

Gilmore O’Neill, CEO, Editas: Well, thanks very much. Before I pass it in, I just want to highlight one 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, that Icelandic population and indeed in our nonhuman primate experiments 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 high significant elevated baseline levels.

Linda Berkley, Chief Scientific Officer, Editas: Yeah. So thank you, Gilmore. I can add a little bit to that. So, you know, first of all, we can break it up into two 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, you know, 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. I this is very different, obviously, than PCSK9 inhibitor that acts 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 on their level. So I think the answer to your question is our strategy should be, agnostic, if you will, to the patient.

Gilmore O’Neill, CEO, Editas: And then Jonathan, you asked the question, would 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, discussions with regulators will inform that later in the program.

Jonathan Miller, Everscore ISI: Thanks, guys. Makes sense.

Gilmore O’Neill, CEO, Editas: Thanks very much. Our

Operator: next question comes from Sumit Roy with Jones. Please go ahead and ask your question.

Gilmore O’Neill, CEO, Editas2: Good morning, everyone, and, congrats on new target and the, new asset. The not sure if I’ve missed it. Have you shown us the LDL expression levels compared to pretreatment? And if not, what is your internal benchmark that you’re going to use, for the LDR expression itself there? PCSK nine or statins or cholesterol absorption inhibitors?

Gilmore O’Neill, CEO, Editas: So let me just if I may, Sumeet, let me just sort of resummarize the question. I the way I think I understand you’re asking, which is do we have understanding of the allelic effects or possibly other way, which is the the level of editing that we’re seeing at the liver, and then how are we measuring LDLR upregulation. And is that correct? Yep. Yep.

Am correct? Yep. So I think from the point of view of the elite the degree of allelic editing in the liver, we haven’t actually shared that today. We And that was, you know, Linda point go ahead, Linda.

Linda Berkley, Chief Scientific Officer, Editas: I think I pointed out that we’re we’ve evaluated that. We’re going to be sharing that in a future scientific venue.

Gilmore O’Neill, CEO, Editas: 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 high fat, low fat diet mice and the LDLR heterozygous mice. But you’re looking obviously at expression in the liver.

Linda Berkley, Chief Scientific Officer, Editas: Right. So they were looking at expression in the liver. We’re looking at, total liver lysate, and we’re measuring total, LDLR protein. And we, as we stated, we’re seeing at least a six fold mean increase in the LDLR protein levels, was able to give us this 90% reduction in the NHPs. Hope that answers your question.

Gilmore O’Neill, CEO, Editas: And then, Sumeet, you asked about benchmarking as well. And I think, you know, we have we do cite some references there, but the the experience looking at PCSK9 and its effect, which show has demonstrated significantly lower levels of LDLR upregulation 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 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, increase 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?

Gilmore O’Neill, CEO, Editas2: Certainly helps. Yeah. As I understand, the cholesterol, metabolism is 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 area or gene itself, patients who are already on statins or other drugs? Essentially, trying to understand if three prime UTR is the only regulatory unit for the expression level of the gene or there are other compensatory mechanism can kick in?

Gilmore O’Neill, CEO, Editas: So, Samit, if I can I’ll address that. And, Linda, if you want to add to that, you’re quite right. Cholesterol on top of it 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 sixty 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 this well with follow-up. Very importantly, that we have also 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, or should I say, of function gene or genetic variance in humans. So overall, you know, we actually feel, that, we are in very good state here.

Linda Berkley, Chief Scientific Officer, Editas: Right. And, obviously, we’ll also be conducting a long term durability study to demonstrate the durability of our editing approach.

Gilmore O’Neill, CEO, Editas2: Congrats again on the data, and looking forward to the next round.

Gilmore O’Neill, CEO, Editas: Thank you very much.

Operator: Next question comes from Eric Schmidt with Cantor. Please go ahead and ask your question.

Gilmore O’Neill, CEO, Editas3: And 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 six fold increase.

So what explains that? Is there some heterozygosity in the family members’ genetic makeup?

Linda Berkley, Chief Scientific Officer, Editas: Yeah. The family members are carriers of the two point five k KD indel. So they’re not homozygous for it. They’re carriers, and they even though they have the roughly two 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 Mb per deciliter. So we, you know, we empirically have determined with our our optimized strategy that we can achieve the 90% reduction with very tight error bars, you know, instead of this range that’s seen in the Icelandic family with with our proprietary deletion and that we need roughly to achieve this threshold of six fold protein increase. So we’re trying to get a very consistent effect.

Gilmore O’Neill, CEO, Editas3: Okay. So if anything, you’d expect more LDL receptor upregulation and and even greater lowering than the family genetics.

Linda Berkley, Chief Scientific Officer, Editas: Yeah. And, like exactly.

Gilmore O’Neill, CEO, Editas3: And then on on to the safety, I think the slides that you presented suggested that the LNP was accessed through the Genovab partnership and consists of clinically validated components. Can you you talk about whether the LNP itself with the specific composition of makeup has been used in in patients before?

Linda Berkley, Chief Scientific Officer, Editas: The components have been the various components have been used 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 NHP study. They were very well tolerated, up to four mg per kg. There were no clinical adverse observations, in our study, so we’re very pleased with the tolerability profile.

Gilmore O’Neill, CEO, Editas3: So will this be essentially an Editas proprietary LNP formulation that you access through the partnership?

Gilmore O’Neill, CEO, Editas: I think that the strategic partnership, as you say, is with Genavant. And I we haven’t gone in or disclosed how who owns what. 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 infer beyond what we’re not sharing.

Operator: Our next question comes from Yanan Ju with Wells Fargo.

Gilmore O’Neill, CEO, Editas: Yana, we can’t hear you.

Gilmore O’Neill, CEO, Editas4: Oh, can you hear me?

Gilmore O’Neill, CEO, Editas: We can hear you now, Yana, and we have you now. Thank you.

Gilmore O’Neill, CEO, Editas4: Congrats on the progress. This is Kwon on for Yana. Can you

Gilmore O’Neill, CEO, Editas: talk Forgive me. Yeah.

Gilmore O’Neill, CEO, Editas4: Can you talk about, the safety profile of anti-four zero one? Have you seen any off target editing and any observations on liver enzyme elevations or thrombocytopenia in NHP? Thank you.

Gilmore O’Neill, CEO, Editas: Thanks very much, Kwan, for that question. Linda?

Linda Berkley, Chief Scientific Officer, Editas: Yeah. I can speak to, you know, we are, designing our we design our cargo, our nuclease, our Cas9 nuclease, and our guide RNAs to be highly specific, you know, through our, guide design. We do this design and testing of our through a specificity, generation of a specificity package, and we do this through basically a very comprehensive assessment using many orthogonal assays. These involve in silico assays, biochemical assays, and cell based assays. So this is the process that we’ve taken 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 of the, LFTs, we saw very transient LFTs in the NHPs that resolved, were back to normal within one week.

Gilmore O’Neill, CEO, Editas: And we didn’t see any thrombocytopenia

Linda Berkley, Chief Scientific Officer, Editas: Oh, with some changes in any coagulation or any hematology parameters whatsoever. So on both counts, the specificity package and the, liver function tests, we’re very pleased.

Gilmore O’Neill, CEO, Editas: Got it. Thanks, Kwan.

Gilmore O’Neill, CEO, Editas4: Yeah. That’s super helpful. Oh, really quick follow-up. So, your VLT, you mentioned that you need more studies to evaluate your

Gilmore O’Neill, CEO, Editas: Sorry, Kwan. You’re very sorry, Kwan, to interrupt. You’re very muffled. I’m having I I can’t make you out at all.

Gilmore O’Neill, CEO, Editas4: I’m sorry. Is it better now?

Gilmore O’Neill, CEO, Editas: That’s better. Yes. That is better. Yes. Alright.

Gilmore O’Neill, CEO, Editas4: So on durability, you mentioned that you need more studies to evaluate your your durability. Can you talk about whether redosing is possible if needed? Thank you.

Linda Berkley, Chief Scientific Officer, Editas: Yeah. So so far, we’ve shown, as you could see on one of the slides, that we have durability out to twelve weeks. You saw that on one of the slides where we studied mice that had been fed a high fat diet, and we maintained our 90% reduction in LDL. So we’re very pleased with that study. Typically, one would do as part of their development package, a longer, durability study of at least one year.

So we are embarking on that study, as part of our package. And your other question? Redosing. Oh, yeah. Redosing.

Yes, we based on our analysis from our NHPs, we do believe we would have if needed, we would have room for redosing.

Gilmore O’Neill, CEO, Editas: Got

Linda Berkley, Chief Scientific Officer, Editas: it. We don’t know that we would need that. But if so, we have room for that.

Gilmore O’Neill, CEO, Editas: Thanks very much. Great. Thank you.

Operator: Our next question comes from Gina Wang with Barclays. Please go ahead and ask your question. Gina, please go ahead and ask your question.

Gilmore O’Neill, CEO, Editas: Hi, Tommy. We’re not hearing you.

Tony: So sorry. It’s Tony on first, Jenna.

Gilmore O’Neill, CEO, Editas: We can hear you.

Tony: 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, etcetera?

Gilmore O’Neill, CEO, Editas: 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 for in the 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 re really require a a small population in which to detect that biological effect size.

Tony: Got it. Thank you so much. And then, I guess, on the next update, on that note, will 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?

Gilmore O’Neill, CEO, Editas: At the next it’s hard to say, but we will go at the next update. But, you know, the the population that we will select or population segments that we will select, for that human POC, first in human, will obviously be agreed with regulators and IRBs, and I think that that that’ll be the appropriate time to finalize it. But as I said, I think in a 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 AGFH or, you know, high risk arteriosclerotic cardiovascular patients with who are not coming close to achieving target will be two obvious segments that we could start in.

But obviously, that will be a matter for discussion and agreement with regulators and institutional review boardEPIX committees.

Tony: Got it. Thank you.

Gilmore O’Neill, CEO, Editas: Thank you very much.

Operator: Our last question comes from Mitchell Kapoor with HC Wainwright. Please go ahead and ask your question.

Gilmore O’Neill, CEO, Editas5: Good morning. 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.

Gilmore O’Neill, CEO, Editas: Katie, 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, you know, based on so what we would in our early first in human studies will be looking at LDL reduction and various safety parameters. Obviously, the evolution or maturation or reduction of plaque are elements that could be looked at later in the development program.

Operator: This concludes the Q and A portion of today’s webinar. Thank you for joining. You may now disconnect.

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