Please. We're very happy to have Editas Medicine here with us today. We have Gilmore O'Neill, who is the President and CEO, and Amy Parison, who is the CFO. Thank you both for joining us.
Thank you.
It's 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?
Yeah, we're happy to. 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 non-coding DNA to increase the levels of expression or upregulate disease mitigating or risk 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 non-human primates, by 90% mean, which obviously has potentially transformative in the management of cardiovascular disease.
I think the other element that's important is that from a platform point of view, 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.
Mm-hmm.
I think the final thing I just wanted to say is that we pride ourselves on this, that we have an organization that is really focused on execution on that in vivo space and is doing it, you know, in a very cost-efficient and capital-efficient manner. I think that we can see that reflected in our most recent earnings.
Yeah. 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 safety. 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 off-target editing. For example, in our EDIT-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 you know element to think about when you think about AAV is that AAVs are very liver tropic.
No matter what tissue you want it delivered to, they can actually be associated with hepatotoxicity. Now, they're 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.
From a benefit-risk point of view, I would say that, you know, CRISPR has a very favorable profile in.
Mm-hmm.
for a therapeutic.
Yeah, absolutely. Okay. Awesome. Let's get into the lead program, 401, for LDL-C lowering. I guess first, can you just give an overview of the target and the biology underlying the asset?
Yeah, absolutely. I think a couple of things. One is that EDIT-401 on its own has the potential to be a really great therapeutic with a 90% mean reduction in LDL cholesterol. I say that with a degree of confidence based on the observation that the non-human 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. It's also been highly predictive of the effect size and the biological effect size for cholesterol-lowering meds across a number of modalities. 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%-60% reductions in the statins, something lower than that? We believe that the key reason is that we are essentially increasing the direct synthesis of the LDL receptor protein. 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. As part of that exercise, we've identified a number, but the LDLR was one that jumped off the page, and indeed had been published by other authors a couple of years ago.
Essentially an Icelandic kindred with seven members has a gain-of-function deletion of the three prime untranslated region, which is a regulatory domain of the LDLR gene. There are a couple of important distinctions. One, it's non-coding. It's untranslated, it's in the title. 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. Very importantly, they have LDL cholesterol levels which are substantially lower than their peers in Iceland. Indeed, they have LDL cholesterol levels in the range of 15 mg/dL-35 mg/dL .
That's a very important level, because that's a level that is associated with maximal risk reduction in relation 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. It's a very powerful target, and we've actually leveraged it in optimizing our strategy by looking at that region in the three prime UTR and walking across it to identify the optimal guide RNAs that we've used. That's what we have selected and achieved this very high reduction in LDL cholesterol.
Yeah. Let's get into the data, I guess, that you've seen pre-clinically. You mentioned 90% reduction in LDL-C. Are there any other data points that you want to highlight?
Yeah. I think the key thing is the consistency of that LDL cholesterol reduction. We're seeing it not only in healthy non-human 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 loath to call them any other kind of model, but they're a genotypic model of one of the commonest forms of heterozygous familial hypercholesterolemia. 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.
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%. 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 non-human primates and mice. All we saw were some mild elevations for a couple of days in the first week for the transaminases, which rapidly resolved. That's very important because that was not associated with any indications of risk or safety. In other words, there was no complement activation, cytokine activation, no coagulation changes. 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 nanoparticle that you want to see in the non-clinical species to predict a good translation of safety to humans.
Mm-hmm. Okay.
We're very excited by that sort of balance of high efficacy and high tolerability and safety.
Yeah, 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.
What we've actually shown publicly at our scientific meetings is we've actually shown murine or mouse data out to three 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 two quarters, since we first shared our LDLR data, we have just grown more confident in our non-clinical data package as it grows.
Yeah. Okay. What about, you know, off-targets? I think that's a key question for gene editing is like what kind of specificity do you get?
Yeah. 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 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. Those were very good, well, accepted, and frankly, even more robust than the safety package that was used for the approval of Casgevy, which would be sort of the lead and the first approved CRISPR product. 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. For example, our CALITAS technology, which is part of our computational biology package for 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. Again, we'll be sharing more of that information at a future date.
Okay, great. I know we expect human proof-of-concept data.
Yeah.
this year. I guess for that, you know, what will we get first, and then what are you looking to see in terms of efficacy?
We're looking to, and we're tracking well to achieving early human proof of concept by the end of this year. It will be a phase I study. That phase 1 study will have a number of escalating dose cohorts, and we're looking at three to six 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. We're really, you know, 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?
We basically ultimately are checking or are 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 those cohorts that we will dose into the following year.
In terms of safety, you know, what makes you comfortable? I guess, you know, I think preclinically, there's some level of transaminase elevation.
Yes.
It's transient.
Yeah.
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, you know, confidence. I would say that our confidence is driven not just by the preclinical observations, that empirical data that we've seen, but actually also by the fact that, you know, our partnership with Genevant for the delivering LNP is a very good partnership. They're really wonderful partners. Very importantly, the components that are in our LNP that they've used, they have actually had in other LNPs that have been in humans. All but one of those components has been in humans, which again is significant de-risking. We have sort of a multiplicity of experience, prior experience, as well as our own empirical preclinical data to give us confidence about that safety and tolerability in humans.
Yeah, absolutely. Can you talk about the initial patient population that you see as the target first?
Yes. The patient population we select for sort of preliminary for the phase one is obviously a patient population where you want to have a benefit risk that is appropriate for an investigational drug at this point. You know, one patient population that sort of sits in these sort of very high-risk category for cardiovascular disease are heterozygous familial hypercholesterolemia patients. That's a patient population that we are looking at for our phase one. It is worth highlighting that when you look beyond phase one, that there are other segments of the hyperlipidemia patient population that sit in that very high-risk category.
That includes patients who've had a prior cardiovascular event, as you know, heart attack, myocardial infarction, or stroke, but who also are refractory to current therapies. It is important to note that both in HeFH, 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. I think there is an enormous opportunity there. As I say, our first, our initial population is HeFH refractory patients, and then obviously we can look to other high-risk patients. Within the context of the United States, that represents, you know, around 10 million patients.
Mm-hmm. Yeah.
When you combine the two groups.
Yeah. There's absolutely an unmet need as well.
Yes.
For HeFH first, can you talk a little bit about the landscape and where you see EDIT-401 fitting in?
Yes. With regard to where we would see it fitting in, you know, for usability in the clinic, we actually see that refractory HEFH population represents, you know, several hundred thousand patients. They are currently using combinations of therapy. 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, you know, and they're moving lower. They're not moving higher, as is always the case with preventative medicines. Many of these patients can't achieve levels of 40 mg/dL or 50 mg/dL or even 70 milligrams per deciliter.
We're trying to actually, and what we anticipate with a 90% reduction, is an ability to really, you know, get those patients to target and frankly, simplify the life that they lead for 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.
Mm-hmm. Yeah. Absolutely. You mentioned a little bit about the different populations and up to 10 million patients potentially.
Yes.
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 two niches of a broad hyperlipidemia patient population. I think that's where we can see ourselves going preliminarily. 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. 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 the risk down.
Yeah. 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.
Mm-hmm.
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?
Yeah.
for a new modality?
We actually think that by actually focusing on where the unmet need is, and that actually is hugely beneficial. I think we have to look at a number of ways. We have to look through the lens of a patient. You know, patients with HeFH, patients who have had a significant cardiovascular event, they know what happens if they don't manage that risk. This is not a sort of a silent risk to them. This is a known risk for them. Either they've seen a relative, they've had an event themselves. They also find themselves where they are trying to get to a target. And frankly, the advice they'll be getting from their 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.
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. 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.
Yeah. Yeah, I think that's a good point. It's not a silent disease. There's, like, a real tangible risk.
Yeah. Yeah.
Absolutely.
Yeah.
Yeah. That's very interesting. We're excited to see the data later this year. What about after EDIT-401? What's next for you?
Well, one of the important things we did over the last couple of years, because we had three 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 two programs going very well. We selected the four zero one program to move forward, and we have, let's 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.
It's a much simpler prospect, and it also means you can leverage the investment on the CMC, the pharmacology, the tox, and obviously your regulatory. There's a regulatory mechanisms 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. We have a number of additional programs all focused on non-coding edits that upregulate rescue proteins. We will share those at an appropriate time for the liver. Obviously we have our targeting LNP, and 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 or thalassemia.
These are things that are sitting in discovery that at the appropriate time, and that appropriate time will obviously be where, you know, the markets change and we can actually expand our investment. 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 EDIT-401 to human POC, a lot of attention, effort, resources dedicated to that and driving that forward. Obviously excited by the potential follow-up that can build on that future success.
Yeah, very exciting. Building off of that, I think the in vivo component is something that Editas does well. So can you talk a little bit about, you know, what's proprietary to your technology and how you've been able to open this up where, you know, others have struggled?
Well, I think there are a couple of things. First of all, with regard to proprietary information or IP, we obviously have significant exclusive rights to foundational IP around this. Beyond that, we've built significant know-how around identification of non-coding targets for upregulation. We've built a lot of the machine learning and computational biology tools to help us optimize and do that. I think that's, you know, very well, I dare 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.
We believe that our differentiation is well protected, you know, around an IP point of view, just from a technical know-how, expertise, and capabilities. Then from a delivery point of view, as I said, we have that proprietary TLNP technology and as I say, a very strong relationship with Genevant.
Yeah. Interesting. Okay, question for you, Amy. What does your cash runway look like?
Yeah, sure. We have cash into Q3 of 2027. We ended the year, 2025 with $146 million of cash. As Gilmore said, you know, we feel very confident that we'll be able to deliver on all the upcoming milestones with that cash runway.
Okay, awesome. Yeah, I think we're almost out of time. Just to finish up, can you highlight over the next, you know, maybe 12-18 months, like, what are the key catalysts? I mean, there's data. What else will we see from the company?
Well, I think the key catalyst we're looking to, obviously, a major catalyst we see as that, you know, early human proof of concept at the end of the year. Between now and then, we will obviously have a substantial bolus of non-clinical 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, you know, beyond that 18 months, you know, selecting the dose are going to our pivotal.
Yeah. 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.