Good afternoon and welcome once again to TD Cowen's 44th Annual Healthcare Conference. I'm Phil Nadeau, one of Cowen's biotech analysts, and it's my pleasure to moderate a fireside chat with Editas. We have with us today Gilmore O'Neill, CEO, and Erick Lucera, CFO. I'll hand it over to you guys, maybe initially, to give a brief state-of-the-company overview. What are the biggest strengths, biggest challenges? What does Editas need to do over the next 12 to 24 months to create value?
Great, Well. Thanks very much, Phil, and great to be here. From the point of view of the state of the company, I think things actually are moving very well. Just a little over a year ago, we outlined a new strategy with three pillars: advancing our lead asset, reni-cel, and that has been going very well on the execution side with some regulatory alignment, etc.
As we drive towards BLA and commercialization, the second pillar is around building and focusing our pipeline efforts on in vivo, and we are happy to be on track for a preclinical in vivo proof of concept this year. And then finally, the third pillar has been to really double down on BD efforts with a particular focus on outlicensing our IP as a source of non-dilutive capital formation.
We announced a number of deals last year, but the most recent was in December with Vertex, where we sublicensed a non-exclusive license for use of Cas9 for BCL11A editing to enable the Casgevy launch. From a point of view of the strengths of the company, we have very strong science. I would focus particularly on areas around computational biology, genetics, which are absolutely core elements of editing capabilities.
We also have very strong chemistry around guide RNA and obviously a robust CMC organization with a particular focus currently on bringing reni-cel and getting it ready for commercialization. The challenges really are around helping the world recognize the true transformative value of gene editing. I think it's a shared challenge for us all.
There is no doubt, in my mind and that of many others, that durable treatments delivered by editing in general and more specifically in vivo as we move forward are really going to be truly transformative because it's going to eliminate the burden on patients, take away large numbers of challenges with compliance, etc., and ultimately, I think, enable the use of really high-potency therapeutics across a much larger population than can be done currently.
And then I think what we have to do over the next two years or so really to get that overvaluation, which is going to be around execution. Executing on reni-cel, we've made a lot of progress, done a lot of key foundational work. I think we have line of sight to BLA and commercialization. We have to keep driving on that.
And I'm happy to say, and I should have said it in the strengths, that we have a very strong leadership team now with some very seasoned veterans who know how to develop, get across regulatory approval, and commercialize medicines, including our Chief Commercial Officer, Caren Deardorf. And then, as I say, execute on the in vivo, continue execute on in vivo, continue to execute on BD and IP licensing. So that is it in a nutshell.
Maybe drilling down on reni-cel a bit. For those less familiar, can you give an overview of its mechanism and how it can be differentiated from the other genomic therapies for sickle cell and beta thalassemia?
Yeah. So in general, the key therapeutic or biological hypothesis is that the upregulation of fetal hemoglobin as a homologue of adult hemoglobin is a therapeutic approach. That's because when you actually raise the fetal hemoglobin levels above about 30%, you will actually see a reduction or elimination of vasoocclusive events.
So that's kind of the underlying hypothesis. What differentiates our approach from that of others is that we have used our AsCas12a CRISPR enzyme, which is a high-fidelity, high-efficiency enzyme when compared to Cas9, and we use it to target the gamma globin promoter. Frankly, creating an edit within a region that is associated with the natural occurrence of hereditary persistence of fetal hemoglobin, we will upregulate fetal hemoglobin. We're actually seeing that very robustly.
I would finally say that with a head-to-head of our gamma globin target versus a BCL11A target, we see we expected to see, and in the non-clinical or preclinical side, we saw that not only do we get very robust fetal hemoglobin expression and it was durable, but we actually saw better red cell output, better red cell longevity. That interested us because we actually wanted to treat more than just one element of sickle cell disease, not just the sickling proclivity, but actually also manage and correct anemia. Indeed, our clinical data to date are seeing that consistently.
I think you're referring to the promising data you showed at ASH. Maybe taking a step back, what was the design of the ASH study, and what were the key endpoints that were disclosed in December?
Yeah. So the study is an open-label study. The key recruiting or inclusion criteria is that patients have to have severe sickle cell disease with at least 2 serious vasoocclusive events per year. In fact, our patient population has had an average of 4 vasoocclusive events per year. And those are serious events requiring hospitalization, etc. So you can imagine just how ill they are.
The primary outcome measures have been looking at vasoocclusive events as well as hematologic parameters. And we've been particularly focusing on fetal hemoglobin expression over time, time to and durability of fetal hemoglobin expression, and time to and durability of total hemoglobin increases.
What were the levels of hemoglobin that were achieved in the trial, and what level is thought to be necessary to prevent sickling?
So from a fetal hemoglobin point of view, the hereditary persistence of fetal hemoglobin expression variant when coinherited in patients who have these sickle cell mutations has suggested that levels in excess of 30% will almost eliminate vasoocclusive events. Levels above 20% massively reduce them. What we're actually seeing is we're achieving in excess of 40% and maintaining that durably for fetal hemoglobin.
And then for total hemoglobin, we have actually seen in all patients who have been followed for more than 4 months and this is what we presented at ASH those sickle cell patients have actually returned their hemoglobins into the normal physiological range. So where they were anemic before, they are no longer anemic.
And then briefly on the safety profile, anything notable? In particular, I think you noted one case of G2 polycythemia. Any update on that patient?
Yeah. So that patient is actually doing very well. With this grade 2 erythrocytosis or polycythemia, we do not believe, and the investigator doesn't believe, that it was related to therapy. It was unrelated to therapy. It was, in fact, we believe, related to the patient receiving iron therapy.
That iron therapy when stopped, and that was stopped at the time the patient had this asymptomatic detection of a grade 2 erythrocytosis during just a routine follow-up. And when the iron was stopped, that patient has actually now remained in the normal range for in excess of six months. This patient is doing very well. We did actually do, however, very comprehensive.
So notwithstanding seeing that contemporaneous relationship between the event and the iron, we actually also did a very thorough evaluation of the patient from the point of view looking at clonality, genetic screening for any significant changes that could drive a myelodysplasia or something like that, and found none of those. So with all that data together, the fact that the patient is actually doing very well, the reversibility of this observation with the discontinuation of iron and the persistence of the normal range, we and the investigators have agreed that this is not related.
You've got two updates from RUBY, both mid-year this year towards the end of the year. Can you provide an update on where the trial is today? So how many patients have been dosed since December? How many patients do you think you'll have in those future updates?
Yeah. So as we announced our earnings just last week, we have dosed 18 patients. We had dosed 11 in December. We announced 11 in December, so 18 just last week. We have increased enrollment from 27 at the end of last year to 40. So in fact, notwithstanding sort of that holiday, the end of the year, we really have executed very well with regard to dosing and recruitment.
With regard to the mid-year and the end of year, particularly the mid-year, I think we have multiple patients scheduled for dosing over the next few months. So we will include those patients in the mid-year review. I think it's also worth saying that we will certainly have at least 3-month follow-up for the 18 patients.
That range would be between 3 from FCQ point of view of 3 and in excess of 18 months of follow-up. So now we're not just building the numbers of patients, but we're actually building the duration of follow-up, which actually, again, will continue to reinforce our confidence in the durability of the therapy.
In the past, you've suggested that reni-cel could be differentiated, and you're going to begin to look at end-organ function to build a case for differentiation versus the other genomic therapies. Can you talk about how you will build that case? So first, what gives you confidence that there could be differentiation? Second, what endpoints will you look at for evidence of differentiation?
Yeah. So our confidence stems around a few things, obviously opinion from key experts, many of whom say, yes, anemia matters. Correction of anemia matters in general. It matters more specifically in the context of sickle cell disease, which when I was a medical student was called sickle cell anemia. I think more importantly, from an evidentiary point of view, the literature would suggest that degrees of anemia are associated with greater or lower levels of risk when it comes to end-organ or progressive end-organ damage.
From the point of view of what we're actually doing to monitor, in our study, we are collecting both clinical physiological parameters as well as patient-reported outcomes. We're looking at physiologic parameters for renal organ function, cardiopulmonary function, and other organ systems.
And then on the patient-reported outcome, we have a number of instruments which are capturing different domains, including fatigue, which is an additional and highly dominant complaint for patients with sickle cell disease.
With regard to the timing or when you can actually demonstrate that clinical differentiation beyond that, as per my opinion, one of the challenges we have and it's a good challenge and one I have had before in other disease areas is that when you actually introduce a high-potency medicine into a disease indication where endpoints have been developed or evaluated, you almost have to revalidate and understand what is the rate of change that you might see. So this is something that we're learning because we haven't had previous experience with high-potency therapies.
So their impact on the outcomes and the timing of when that outcome will move and declare itself and the numbers required to be confident about that declaration is something that we're evaluating in real time.
Last week, you gave an update on the discussions with the FDA over the clinical trials and the pivotal program. For those less familiar, can you provide that update today and also discuss what still needs to be nailed down with the FDA?
Yeah. Happy to. So we actually had we were very happy with the conversation with the FDA. And let me preface it by saying that that's against the background of receiving RMAT last October, which enables us to have more frequent meetings with shorter timelines between true request and meeting and to meet actually with senior officials within the agency.
So with regard to that specific conversation that we had more recently, we got a number of agreements. One is that the RUBY phase 1/2 is now a phase 1/2/3 study. It's a single study leading to ultimate approval, we hope. And that was very important. I think the second and it allows us to use all the data collected to date in addition to future data as part of the filing.
And then the second agreement we had was on the primary outcome measure around how we define and the collection of the vasoocclusive event outcome. I think the final piece that we are really pleased to have, frankly, still open because it allows us to evolve and develop it, is that against a backdrop of a benchmark set around the Vertex filing, where they originally filed with 20 patients in our efficacy cohort with additional safety patients and then supplemented that as it became clear just recently when the FDA published their documents with an additional 10 or so patients, we have that benchmark. But very importantly, we have RMAT enabling high-frequency interaction with the agency. But we also have an open-label study.
Remember I said the design of the study is open-label, which means that we can actually look at the data as they evolve and strengthen and use those data in the conversations that we continue to have with the FDA as we refine what that first BLA filing or clinical data package would be for the BLA, but again, against that benchmark of what we saw last year for Vertex's filing and approval.
So what needs to be defined is it the duration of follow-up and the patients? Do you have an agreement on specific patient numbers, or is that?
I think these are the kind of things that we will actually refine. We have overall agreement on where we will for the total study size. It's really what will be in that first BLA package.
Based on the precedent that Vertex has said, it seems to us like you should at least be able to file in 2025, if not perhaps sooner. Is there any flaw in that reasoning?
I think it's a plausible hypothesis. I have to tell you that one of the things philosophically that myself and the leadership team are very conscious of is that we would prefer to live in a world of under-promising and over-delivering. We're very conscious that that's been a key part of us in how we have been transforming the organization as it moves from a development platform to a commercial therapeutics company. But I think your hypothesis is plausible.
You've recently started an adolescent cohort. Can you talk about the specifics of that cohort? How many patients? What's the inclusion criteria? When could we see initial data?
So we haven't actually guided specifically to the total number of adolescents. But obviously, you can, again, use the benchmark from the Vertex's filing experience. More specifically, with regard to inclusion criteria, these patients really have to have, again, severe sickle cell disease with the same number of severe vasoocclusive events and they're aged between 12 and 18.
Actually, I should say we're very happy with the enthusiasm. We have patients lining up. In fact, activations are going very well for sites. I think it shows a lot of enthusiasm on the part of investigators, patients, and frankly, the institutions where the research is going on.
How does Editas size the sickle cell disease market, and what contribution do the adolescents have to that sizing?
Yeah. So we actually see more or less what we're seeing and obviously, we continue to evaluate that. But we agree kind of sort of with that consensus view is somewhere between 25,000-30,000 patients with severe sickle cell disease. That's out of a total prevalent population, identified prevalent population about 100,000 in the United States.
And that's really where we think about from an adult point of view. Now, because we're dealing with the prevalent population, it's kind of dominated by the adults. Just from a prevalence point of view, you would expect the adults to dominate. Obviously, as adults are treated, we will see that number or that ratio drop. But the adolescents would represent a fraction of that adult population.
We've seen somewhat different pricing strategies between Casgevy and LYFGENIA. Would you care to say which pricing strategy you think is better? Any initial thoughts?
Well, I suppose the first thing I should say is that announced prices and actual prices are always an interesting mystery box. It's a bit like how Boeing and Airbus price their planes. You never know what people are actually paying. And obviously, that'll be something that we will obviously learn over time as we evaluate. I mean, we're in a great position.
We're a fast follower with a potentially differentiated product that potentially would be best in class with that sort of, to date, universal correction of anemia. So that puts us in a very good position to actually also learn, benefit from the significant infrastructure build that Vertex and Bluebird will be carrying out, as well as actually learning as the payer landscape evolves and develops, and obviously, as we have our own interactions.
What do you think will be the key determinants of market share? Do you think it will be clinical differentiation? Is that going to be paramount? Will it be contracting? How do you think the market ultimately will determine which drug gets used and which therapy?
I could speculate on that answer. I would say, of course, guess where I'm coming from, that actually having that differentiation is important. I think differentiation on the clinical and the biological will be very important. I actually think differentiating the commercial journey and experience for patients will be important. I think to be more specific would be foolhardy at this point.
I think we have an opportunity over the next year or so or next year or so to actually see how it evolves and really adapt. But again, we're in a very good position to adapt and, frankly, to use and benefit from both the infrastructure that's being built as well as the experiences that the others have.
We've talked a lot about sickle cell disease. reni-cel is also being developed in beta thalassemia. Can you give a brief update on the status of the beta thal program?
Sure. So I think the first thing is that we have dosed 7 patients. We have enrolled 9 patients. We are progressing the program nicely and actually very happy with the data we've seen to date. We shared some late last year at ASH. Importantly, again, we're targeting a patient population that is transfusion dependent, not all thalassemia, but basically transfusion-dependent thalassemia patients. And again, the hypothesis is that by upregulating fetal hemoglobin essentially as a homologue, we can actually correct or come close to correcting the anemia, the profound anemia that these patients actually suffer from.
When should we expect the next updates from Editas?
We anticipate that we would be sharing. In fact, we have said that we would be sharing updates in the middle of this year and the end of this year as well.
In terms of differentiation, is there any reason to think there's something more or less differentiated in beta thalassemia versus sickle cell?
Well, I think our hypothesis, again, around the erythroid output still stands. I think as we are in clinical data, we have less clinical data to date. So as that evolves and collects, I would anticipate that we're actually going to have more confidence, certainly at the robustness of both the Fetal hemoglobin but actually the overall the total Fetal hemoglobin expression.
Turning to manufacturing, one element of cell therapies that tripped up a lot of companies, where are you in your manufacturing both in terms of the commercial process as well as scale-up?
So we're actually in a very good place right now. Just in the summer, we announced a deal or a partnership with Azenta. And by partnership, I mean that we're leasing their clean rooms in a new facility in Devens. And that is actually to build our commercial capacity. I think also I want to be careful about how we use the word you didn't use the word scale-up, did you? I heard that.
I don't think so.
Good. So.
I think it's in manufacturing scale.
Yeah. Yes. Okay. So I want to say it's manufacturing capacity because the real difference is that scale-up really doesn't apply. Forgive me for misrepresenting you, Phil. But we should talk about capacity because each patient provides their own starting material. So you don't have. There's no scaling here. The scale is the number of facilities you have to actually handle patients.
So we've essentially done this deal to enable or to make sure that we have that commercial capacity, that we can actually go through the various validations, et cetera, so that facility would be ready for launch. The beauty of our approach is that it is capital-efficient. We're not digging a hole and building a new plant. We're actually also controlling the risks that could be associated with tech transfer by using essentially leased clean space with our own people and our own processes in place.
We actually feel very good about the progress that we're making in getting ready for BLA and commercial launch.
Dating back to the early days of the clinical trials of reni-cel, there was a discussion with the FDA over the assays. You've clearly been in-depth conversations with the FDA about what manufacturing assays specs are necessary. Is that process finished? Do you have a final understanding of what the FDA needs to see in CMC ever going forward?
Yeah. We believe we have a very good understanding, a very good understanding of what we need. Yeah.
Perfect. Maybe in the last several minutes, turning to pipeline, IP, things like that. First, in the early-stage pipeline, recently, almost about a year ago, reprioritized the early-stage pipeline. Can you give us an update on the status of the early-stage pipeline and any programs that you've looked at?
Yes. So we are very happy to be on track for a preclinical proof of concept for in vivo editing this year. That's based on a lot of foundational work done last year where we basically have essentially strengthened and made some important investments in areas of our discovery group and reprioritizing resources in those discovery group to actually drive that focus on in vivo and developing and finding those enabling technologies that can actually advance and accelerate that.
Very importantly, we hired a new Chief Scientific Officer just six months ago, Linda Burkly, who has a significant experience in developing and bringing new medicines to the clinic and beyond. And so I think we're very happy with the progress we've made there. We've certainly talked very specifically about the gamma globin target and the targeting of HSCs for in vivo. And then we're interested in other tissues.
And that could include liver. I think finally, we have really developed, and I think Eric can confirm, a sort of a very rigorous set of selection criteria for targets. We want to be sure that the targets we select and choose to advance will be truly differentiated from standard care based on what CRISPR editing can do. We don't want to sort of pile into very competitive spaces with a lot of other players. But we actually also want to ensure that we maximize the probability of technical, clinical, and regulatory success as we build a pipeline that is going to be both meaningful for patients and commercially viable.
Turning to intellectual property, you did announce a licensing agreement with Vertex and CRISPR following the approval of Casgevy. In your mind, does this set a precedent for what's going to happen after the approvals of other Cas9-based therapies?
Eric.
Yeah. Thanks for the question, Phil. We've done a number of deals prior to the Vertex deal that go back to Bristol Myers Squibb on one end of the spectrum but also Vor Bio on the other. So we want to do sort of bespoke deals. From 30,000-foot, there's a high double-digit number of projects that are in development and a high single-digit number of companies that are working on half of those products. So there's a good number of companies that have a lot of products in the pipeline.
And we believe the Cas9, Cas12 IP that we license from Harvard and MIT is foundational. It is Kabili-like in the sense that everyone's going to have to, for lack of a better term, sort of have a discussion with us about accessing those rights. We're open to having discussions to construct bespoke deals that are win-wins for both us and potential licensors.
You mentioned bespoke deals. Does that mean we shouldn't look at the terms that you have for Vertex and CRISPR as a pattern to follow? Over what range?
Yeah. So I'll give you the range. So on the Vor Bio, on one hand, that was a smaller privately held company very early in development. So that's a more traditional bio bucks on the come. When you look at Vertex as a large publicly traded company which has already gotten essentially to approval, they never had paid us the upfront milestone. They never had given us the first in humans milestone. They never gave us the NDA filing milestone.
To some extent, the money that we had on signing of that and the construct of the deal was based on all of the past. But I would say as you look at sort of those historical Kabili-like payments, that's sort of the construct that I think is sort of out there. And how we kind of create that payment stream is really based upon negotiation.
In terms of additional business development deals, when you discuss bespoke for pipeline programs, would that be target by target? Are there therapeutic areas you're not interested in that you don't analyze as the whole therapeutic area?
Well, let me start by saying if you actually look at the way some of the deals we have done so last year when we refocused the pipeline, there were areas that we were actually actively pursuing in oncology that we actually gave or brought to Shoreline. And obviously, in addition, in the oncology space, we have deals with BMS, Immatics.
And indeed, those are disclosed on BMS's website for those who want to actually see that. And so in many ways, you could actually see that's an example of where we have built deals around oncology where we're not actively pursuing because, as I say, our technology is very powerful. Our IP is very strong. And know-how is very strong.
We want to be sure that notwithstanding our size and our desire to focus our resources in a way that's appropriate to our size and impact, we allow those technologies to be used across multiple therapeutic areas. I think that's kind of a nice example as sort of a high-level approach to think about development or business development.
Would you consider in-licensing or acquiring complementary technologies or assets?
Yes. I mean, we've actually been clear about that over the last year that we would essentially look to in-license complementary or complementary technologies to accelerate or advance us. And obviously, we have a number of approaches. We can actually, I think Eric has said it quite a few times as well, is that obviously, there are a number of ways to do it. But we have an additional lever in that we have that IP as well as one additional lever.
Maybe Bill Austin, just on the balance sheet, can you discuss your funding today? How much cash did you have as of year-end? And how long will that last you?
Yeah. Thanks, Phil. We think we're in a really strong financial position not only with the $427 million we ended the year at which gets us into 2026 but also the ability to monetize that IP portfolio as a source of non-dilutive capital in multiple ways. And from my standpoint as a CFO, that is a key reason why I came to the company was to have that extra ability to raise money that nobody else really has.
Great. With that, I think we are just about out of time. So thanks for an interesting discussion.
Thank you.
Thank you.
Thanks very much.