Good morning. Thank you for joining the Guggenheim Securities Healthcare team at our sixth annual conference. I'm Debjit, and joining us from Editas Medicine is its President and CEO, Gilmore O'Neill. Thank you so much for your time, Gilmore, and, if we could start off with a very quick overview of Editas.
Sure. Good morning, and thanks very much, Debjit. Great, great to be here. Editas is a clinical stage company specializing in programmable CRISPR mediated gene editing. Our lead program is reni-cel, a cell-based edited therapy for the treatment of hemoglobinopathies encompassing sickle cell disease and beta thalassemia. And I think the real key interesting thing about Editas is that we are actually actively moving through a transition from what was a technology platform company to a commercial therapeutics company with three key strategic pillars. The first being to drive our reni-cel asset to BLA and commercialization, and I'm sure we'll talk a little bit more about that later.
Basically, to refocus, and move the company to a concentration on the development of in vivo therapeutics, which have the potential to truly unlock the real promise of genome editing. And then finally, to really ramp up, as we have over the past year, our business development activity, both through bringing in or partnering on enabling technologies to realize our in vivo editing vision, as well as, and very importantly, to exploit the IP that we have, essentially to generate additional non-dilutive source of capital, to enable us to realize our vision.
Got it. So you took over June 2022. The RUBY trial was clearly languishing before you came on board. You've seen some real momentum with the RUBY study.
Yeah.
Where are you currently with enrollment, and where is the next big sort of data set?
Yeah. So actually, RUBY is actually going very well, and RUBY is the sickle cell trial for reni-cel, which was formerly known as EDIT-301. And we've been very happy with the progress. We just last quarter announced that we had enrolled beyond 25 patients. We have continued to enroll, and we're on track to complete enrolling that—fully enrolling that study this year. In addition, we are initiating adolescent recruitment into the study, and our major data set presentation will be in the middle of this year when we intend to present a very meaningful and substantive clinical data set, which will be able to describe both vaso-occlusive events and, very importantly, hematological data.
And the reason that the hematological data are also important is because we believe that we are a fast follower, with the potential for best in class, because not only do we upregulate fetal hemoglobin to manage sickle cell disease complications, but very importantly, we have seen to date a very robust correction of anemia in all the patients who have achieved or reached 4-5 months of follow-up. And so we will actually be in a very good position to continue to confirm that observation in the middle of the year.
Got it. And have you seen or noticed any momentum following exa-cel's approval or?
Actually, you know, we're very pleased with the momentum. In fact, some people have sort of said: Well, will enrollment be a challenge? Will dosing be a challenge with the approval of other medicines? And we've actually not seen that at all. I think we've seen a couple of things going on. The first is at the sites, continued major enthusiasm with both clinical trial site investigators, KOLs, and indeed, patients. Actually, over the year, we've seen an uptick in inquiries and screenings, so we've been very happy with enrollment. Enrollment has really continued very robustly over the end of last year and into this year.
I think the other thing that's important from a very concrete point of view, a regulatory point, is that even two months before the approval of exa-cel, we were granted RMAT. One of the requirements for the RMAT regulation is that the agency, the FDA, sees continued unmet need. And so I think that was a very clear statement from them of a perception of remaining unmet need. It is also worth pointing out that beyond the regulation, they actually had the opportunity to see clinical data that we submitted as part of that application. We actually feel very good about that, and all the metrics that we have are pointing us towards a maintenance, if not growth in momentum.
So while reni-cel and exa-cel both increase fetal hemoglobin, you work very differently.
Yes.
Do you think that's gonna manifest in the clinical readouts?
Well, we believe that it already is at a hematologic level. So we, our mechanism, is different because in addition to using a different enzyme, Cas12a, as opposed to Cas9, we are actually targeting the HBG1 promoter to drive upregulation of fetal hemoglobin. And that actually replicates a naturally occurring set of variants in humans that drive upregulation of fetal hemoglobin. Very importantly, in a head-to-head comparison of our HBG1 promoter targeting, as opposed to BCL11A, which is used by exa-cel, in the non-clinical studies, we showed not only robust upregulation of fetal hemoglobin, but what we thought very importantly was a very robust increase or higher output of red cells, as well as red blood cell longevity and health.
And what that translated into humans, and what we've seen to date, is that by about 4 or 5 months of follow-up, all of those patients correct their anemia to physiologic ranges of hemoglobin. And why does that matter? Because in addition to significant complaints about vaso-occlusive events, and we don't need to go into detail there, patients also complain bitterly about fatigue. And, fatigue is obviously a key manifestation of anemia, and also anemia is a known risk factor for ongoing or continue end organ damage. So in addition to collecting the hematologic parameters, which I've described, we are collecting physiological parameters around renal cardiopulmonary health and other organ systems, as well as quality of life and patient-reported outcomes, which include domains in the instruments we're using that capture fatigue.
Got it. The current perception or current reality is it takes between 3-6 months from the time patient consents to—or the vein to vein time. Are there avenues to shorten that time?
Yeah, this is an area of real interest to us. It is one that we are where we are actually really leveraging all the learnings in the clinical trial space. So what are the factors that influence vein-to-vein time? First of all, these patients are actually very sick. To enter our study, to be eligible for the study, you have to have at least two vaso-occlusive events per year for the two years prior. And as you well know, a vaso-occlusive event, certainly a severe one, which is a requirement, you have to have severe ones, will actually cause a hospital admission. The average number of vaso-occlusive events that our patients have had, you know, in the two years prior to enrolling in the study is actually four events.
So if you imagine that every quarter, on average, a patient is having an event, that will disrupt some of the timing. But the other factors that we can actually manage are helping patients with scheduling, working around their, their lives. And then obviously, we have continuous work on our editing process, because in the vein to vein time, the patient has to have apheresis, they have to have their cells collected, then those cells have to go to a manufacturing facility and be edited, and then they have to go to quality checks. These are all areas where we can actually continue to tweak and learn from real-world experiences in the clinics to help inform the commercial journey that we have built for patients.
Talking about the commercial journey, is there something that Editas can do proactively to, obviously, there are a bunch of hurdles for these patients, right? The infertility issue comes up a lot. What can you do proactively to address that concern?
Yeah. So, that's a very good. The fertility is a very good example of what we have done, where we actually take best practices from around the centers and actually share those practices across the centers. We have to enable a more rapid and more satisfactory fertility preservation exercise for these patients. It is worth pointing out that fertility is already an issue for these patients because like any other end organ, the reproductive organs are actually also damaged by the sickle cell process. But what we do is we preserve eggs or sperm for these patients, and as I say, by applying best practices and generalizing and sharing them across the centers, that's one way that we can actually very proactively help shorten the time, the vein to vein time.
So that leads to the second question on the busulfan-based conditioning.
Yes.
What is Editas doing to circumvent that, say, with your next-gen pro- products?
Yeah. So we've actually done a lot of work there, analyzing and really building very strong relationships and contacts across the academic and sort of non-academic space with other companies and sponsors. Our current view at the moment now is that we really feel that we should deploy our concentration and focus on moving reni-cel and looking beyond reni-cel to our in vivo. We believe that when other non-busulfan or non-traditional conditioning becomes available, when centers embrace that, they will actually apply that across multiple products.
Got it. So let's talk about Editas 2.0 from a pipeline perspective. Across the genome editing landscape, the common criticism that we hear is pipelines are not differentiated, and you're going after diseases which are relatively well-served.
Yeah.
How are you thinking about the Editas 2.0 ?
So I think that's a very just observation for our industry, and we strongly believe that we should be selecting and going after targets where there's a differentiation advantage to editing, genome editing. We do not want to go into spaces where the patients are well-served. We actually talk about going after high conviction targets for our in vivo pipeline. I should have said, first of all, that our pipeline is focused on in vivo development.
So we want to go after high conviction targets we characterize as, first and foremost, ones where there will be clear differentiation from the standard of care, where there's. And that means there's a high unmet need, treatment is unsatisfactory, and, you know, frankly, the space is open, and not cluttered with others. And then, obviously, on top of that, we want to ensure that we're going after targets that are technically, have a high likelihood or probability of technical, as well as translatable, you know, clinical and ultimately regulatory success. That's how we're thinking about that.
Got it. As you think about In vivo targets, the obvious question then becomes delivery, right?
So how is Editas thinking about delivery and target organs beyond liver? Yeah. So we have been thinking about that, really quite robustly since, you know, before I even arrived, but we really doubled down on that. You'll be aware that we sort of stepped away from AAV delivery when we shut down our AAV inherited retinal disorder programs, and really have focused on, you know, nanoparticles, be they lipid nanoparticles or other nanoparticles. The beauty of the lipid nanoparticle is that we have some expertise inside the company, but again, going back to that third pillar around business development, we really have embraced, as our shift, the philosophy that just because somebody else made it, doesn't mean that it's not something we should look at.
So from a BD point of view, we are very interested in partnering those delivery technologies that actually enable us to accelerate or speed, because we believe speed is of the essence, both for the patients as well as actually for us and for our technology. Just waiting for that. The background noise. Oh, sorry. Sorry, got it, but—Welcome to New York. Yeah. So, along those lines, do you think CNS is an area that Editas is actually actively evaluating? So thank you for that. You know, it's not unreasonable question to ask a CEO who was a neurologist, about his potential biases. We are essentially, when we look beyond the liver, what we did actually say is that we're interested in hematopoietic stem cells, for obvious reasons.
We have a very good product in reni-cel. We've also solved two of the three problems. You know, we have solved the issue of a humanly validated CRISPR enzyme with our AsCas12a. We have solved and validated, humanly, the target, the HBG1-2. The delivery is the issue, and that's an area of particular interest that we're focused on. We've talked about that for the last year. You asked me about the CNS. I will never say never. I think the CNS is a very interesting space, but I will tell you that notwithstanding my past experience as a neurologist, I don't have a bias for CNS. We are being coldly dispassionate about the areas we go after.
We want to actually say, have high conviction targets where the probability of technical success and translatable success is high. And one of the challenges of CNS, obviously, is delivery. The other challenge is being able to measure biological outcomes in a robust manner. I think that space is evolving. We're continuously evaluating it. I have all the scar tissue from that area to you know to help guide us. But we are a little more agnostic. So I would say liver and HSC, we've talked about, and we are looking beyond that. Got it. The licensing agreement, the non-exclusive licensing agreement with Vertex, is that sort of the template when you think about your, you know, Cas9? Yeah. No, I think that was a very exciting development, I think, for us and for the field.
Just to be very clear, I've talked about AsCas12a, which is kind of the enzyme that we are actually leveraging. It's our own, engineered, high efficacy or high efficiency, high fidelity enzyme. But we also have non-exclusive, or sorry, we exclusively licensed the IP. Let me say that again. We have licensed exclusively the IP from Harvard, Broad, MIT, for Cas9. And we have... And this is another area in our strategy to really open up for business. So yes, the Vertex deal really was a very important moment because a large company, one of the largest companies in editing, essentially very publicly validated and valued that IP, and we see that as a potential template.
We have done other deals, and so we have essentially a set of terms or guardrails around the terms that we can actually share with companies at different stages of their development. But we're very excited by that potential. As I said earlier, we actually see that IP now having effectively its potential unlocked by that deal just at the end of last year. Got it. And beyond the AsCas12a, are there other CRISPR enzymes that you're actively evaluating or internally harvesting, either through machine learning or, you know? Yeah. No, it's a great question, Debjit. There are, as you're aware, multiple CRISPR enzymes. What I would say is our key driver is. Our key focus right now is AsCas12a.
We do actually maintain, again, a view, a vision, watching the horizon for other enzymes. But having a humanly validated enzyme that behaves really well in our hands is what I would say at the core of our current focus for driving. I will say that we are interested in continuing to build a toolbox, but I'd say the key focus now for translation and development is AsCas12a. Got it. And the second half of this year, I believe the plan is to unveil the second program from Editas? Yes. Well, what we're actually going to do is, and we've chosen our words very carefully, and I'll explain why. We are actually going to, we are targeting a non-human primate proof of concept for in vivo editing.
One of the things we just have to be careful about is, you know, the disclosure of the actual target, and I just want to be very candid with you about this. We are building our capability for delivery, and that will include not just the formulation, but ultimately the scaling and its the scaling up so that we can move into the clinic. There are others who have actually done a lot of that work, and if we share a target very openly, one of the beauties of CRISPR editing is plug and play.
You alter 20 nucleotides and a guide RNA, and you have a brand-new target, you know, within the formulation that hits a particular tissue. So that is something that really excites us about growing our pipeline. That second program, it will be our first in vivo, and that's going to unlock a lot of other targets for us. But it also enables us—you know, others can actually also, if they know what our target is, plug and play. So we have to. The reason I'm saying this very openly now is I want to sort of set expectations about what and how we will share that, announcement, you know, about our POC.
Awesome.
I hope that makes sense.
Totally.
Yeah.
To close out then, the data update from reni-cel, could you just reframe the scope?
Yeah
And the follow-up of those patients?
Yeah, happy to. So what we anticipate, and, you know, I actually just said it just last month, is that we will be sharing at least 18-20 patients of data with at least 3-4 months of follow-up. Some of those patients will have actually exceeded, will be approaching 2 years of follow-up or more than a year of follow-up. So that's essentially what you see on sort of what I call the hematological and efficacy data set. There will actually be more patients because we anticipate and will have dosed more patients and have other safety elements. But I would say at the core, this meaningful data set we're talking about is about 18-20, with at least 3-4 months of follow-up and hematological parameters.
We believe that that will actually be very significant for a couple of reasons. First, it actually will, again, we anticipate, reaffirm or confirm what we've seen to date, which is not just robust fetal hemoglobin expression, but correction of anemia in the treated patients. And I think in addition, we will have more safety data, but also, and I think this is important, it really starts to approach the numbers of patients that you would need to have for a BLA filing, you know, a year plus down the line, based on the parameters or, how should I say, guardrails or precedents set by the recent exa-cel filing and approval.
Do you think you'll be in a position to file a BLA in 2025, back end of 2025?
I've got to be very careful about that because, you know, this is contingent on a couple of things. The first, obviously, is coming to an agreement with the FDA, and that's always a very important series of discussions. I think we also have to be cognizant of some of the details of the original Exa-cel filing in that they did actually also file additional data, as it became clear when the review documents were published, that additional patients were submitted as part of that approval process. So we'll have to... You know, we're actually looking at that, and we'll be continuing our dialogue with the FDA.
The great thing about our position with the FDA is, as I said earlier, we have an RMAT, and that RMAT designation essentially grants us a far greater set of opportunities to access senior leaders at the FDA, and actually have detailed discussions with them over the coming, you know, years. And finally, it actually also gives the option for a priority review, amongst other things. So I think we feel very good about where we are, and how we can actually talk to the FDA, and we'll have even more clarity as the months go on about what it will take for filing.
A 45-patient data set in sickle cell is not going to be enough?
No, I'm not saying that at all. What I'm saying is that it really comes down to... I want to be very careful what we promise. That's one of the things I have said since I got and took this role, that I want to be absolutely clear, that there's no confusion what I'm saying. What I want to say is that I'm very happy with the progress we've made. I think that the data set that we will have in the middle of June really is a substantive and meaningful data set
and that meaningful number centers around what we saw in the original submission for exa-cel with the FDA, which sets a kind of a very good benchmark. And I think we're actually approaching that benchmark. What I want to be clear about is that we want to make sure that we have clear, agreements with the FDA, before I actually make any more promises beyond what we can infer from the benchmark data that we saw with exa-cel's original filing and approval.
Got it. To close out, from a transplant center capacity perspective, as you think towards the launch, do you think there are some reservations as between, you know, prioritizing oncology patients or other transplant indications versus sickle cell?
So we have not actually... In our ongoing research, we have not actually seen that as an issue. Obviously, capacity is going to be one of the issues that arises over the next year or so. And that's obviously something that has been a big focus for Bluebird and Vertex as they launch their products. What we see is that the medical centers will have to embrace and consider at all levels, at the C-suite levels, elsewhere, about enlarging their capacity. What I would say is this gives us a certain advantage. You know, sometimes actually being a fast follower is actually a good place to be, and being a fast follower with potential for best in class is a very good place to be because it enables us to, frankly, do two things.
It enables us, you know, downstream to benefit from the substantial work that the centers will be doing with Vertex, both Bluebird and the payers. And it actually also allows us to also adjust our the commercial journey we create for patients, and as well as, our engagement with payers, around access and reimbursement. So overall, from a capacity point of view, from a planning for our launch, we feel very good about actually being that fast follower with the potential for best in class.
Awesome. That's all the time we have. Gilmore, thank you-
Thank you.
So much for your time. Appreciate it.
Thank you very much. Lovely to see you.
Thank you. Thank you.