Thanks, everybody. Luca Issi, senior biotech analyst here at RBC Capital Markets. Today is a great privilege to have Editas for us, with us for the fireside chat. Representing the company, we have Gilmore O’Neill, Chief Executive Officer. Gilmore, thanks so much for joining us. How are you doing today?
Good, thank you. Good to be here. Thanks very much, Luca.
That's great. That's great. I got a long, long list of questions here, but it would be great if you could give us a little bit of an intro on Editas, maybe what kind of progress has the organization made?
Sure
over the last few months, and importantly, what's ahead here for Editas?
Yeah. So, we've made substantial progress over the last few months. I think the key elements, I would say, are that our, our reni-cel asset is now a late stage in pivotal, with the agreement by the FDA that we can transition our sickle cell RUBY study from a Phase 1/2 to a Phase 1/2/3. We have just last week announced we had completed enrollment of our adult cohort. We had announced a few months ago that we had started or opened our adolescent cohort. That has actually already recruited a number of patients and is actually enrolling and screening actually faster than we had expected.
So that's going very well, and we're on track to present a data set of at least 18 patients with 2 months-21 months of follow-up from the RUBY study, and also an additional 8 or so patients from our EdiTHAL study at EHA, our European Hematology Association, just next month. And the abstracts were published just yesterday from a data cut from February. Obviously, there'll be another data cut closer to EHA. And I should say, in the meantime, since our last disclosure, we've also continued to dose or had additional patients dosed in our study. So that's on reni-cel. On the in vivo side, very excitingly, we have made progress. We're actively evaluating delivery technologies. We're obviously focusing largely on nanoparticle delivery for in vivo.
But very importantly, we were very clear when we articulated this new vision and new direction for Editas just the beginning of 2023, that we are focusing on functional upregulation. We're not. We don't want to target knockdown. We believe that that's already a very crowded space, both with our peers in editing, but actually also with small interfering RNA, antisense, et cetera. And so we've had made progress. We haven't shared those targets, but we're very happy with the progress there and sort of that internal validation of this approach, and look forward to sharing more in the future around that.
And then finally, on the BD side, you know, in the last few months, I think an important moment was the deal that we executed with Vertex in December to enable their launch of Casgevy with a global non-exclusive license to Cas9 IP for BCL11A to enable Casgevy. And that was very important because, among other things, it extended our cash into 2026, but also, very importantly, allowed for a very public acknowledgment of the validity and value of our IP. And I think even more importantly, shows and validates a lever that we can pull. We're actually very fortunate to have that lever where we can actually finance non-dilutively, you know, our activities going forward. Then in the coming months, I've already told you about EHA.
We will actually be sharing more reni-cel data later in the year. And actually, what we actually have set in sort of our publicly stated goals are to achieve a preclinical proof of concept for in vivo editing. We will give updates later this year on when, where, and how we would share that. As I say, continue to progress reni-cel— Excuse me. Sorry. So sorry.
Yeah. No, it's all right.
And obviously continue to actively on the BD front, both from the point of view of bringing in enabling capabilities to accelerate our in vivo. And obviously, to you know, continue to sort of non-dilutive financing.
Great. Great, great. Great overview. Maybe in terms of data, can you just recap what you have seen so far for reni-cel-
Yeah
... and maybe some of the key differentiating features? On both conceptually, what are some of the key differences-
Yes
in terms of your molecular biology and what you are seeing so far clinically.
Yeah
-versus Vertex and bluebird bio?
Yeah, happy to do so. Let me start with the clinic, and then I'll sort of back engineer that to the preclinical and the biology. So what we're actually seeing is, first of all, and it's actually in the abstract for—let's just focus on RUBY and sickle cell from yesterday. The abstract shows that we have robust, well in excess of 40%, so on average, about 45% upregulation of fetal hemoglobin in our sickle cell patients. It is—we have seen no, that is, we have not seen severe vaso-occlusive events, notwithstanding this in a population with a mean severe vaso-occlusive event rate of about 4 per year for each year for the 2 years prior to enrollment.
So 4 per year for 2 years before enrollment, no severe VOEs after, with, as you'd expect, with that level of fetal hemoglobin regulation. But, and this is where we actually think there's a key element of differentiation, we are seeing all our patients have corrected their anemias to well within the physiologic range or normal range. And so all the women are well within the normal range, all the men well within the normal range by 4 months, certainly. And we say 4 months because that's usually sufficient time to distinguish or make sure that all transfusions received during their transplant are washed out, so this is real. But more importantly, it is sustained and has been sustained past that. And what does that mean in terms of a population mean?
We're seeing a population mean for our abstract of 14.4 g/dL for our population, which is right what you'd expect it to be, with 50% women with a range of 12-14.5, and for men, between 13.5-17. So we're smack bang in the middle with 50/50 split. So I think that's an important differentiator, both from a population mean when you compare it to the others. But very importantly, also understanding that we're seeing all the patients to date have corrected their anemia, and anemia is important. When I was in medical school, it was called sickle cell anemia, and these patients have to tolerate significant amounts of fatigue, and that's a significant complaint from a clinical point of view, in addition to the VOEs or vaso-occlusive events.
So we're really looking forward to seeing what the impact of is that clinical point of view going forward.
Sure, sure. That's great. Maybe on safety, if I can ask, if I recall it correctly, at ASH, there was one case of grade-
Mm-hmm
... two polycythemia. It was potentially related to reni-cel-
Yeah.
If I recall it correctly, that poster also said that the investigations in terms of understanding the etiology-
Yeah
... of that event was ongoing.
Yeah.
Any-
Yes
... update of that one?
Yeah, happy to. So I, I think we gave the most recent update at, you know, just a couple of months ago. What we determined this was unrelated. The investigator determined it was unrelated. We agreed with that assessment. More importantly, and very specifically, this was a transient event. It was associated temporally with the administration of supplementary iron therapy. It actually has not repeated or recurred, since the cessation of iron therapy, which was made about 2 months after its initiation and at the time of the recognition of the asymptomatic, polycythemia. And when we say polycythemia, it was erythrocytosis. It wasn't a polycythemia vera.
In addition to that temporal assessment, a detailed evaluation of looking for clonality, or looking for any mutations or edits that would be associated with a risk of a myelodysplastic syndrome was negative. And so both from an affirmative and from a, the affirmative and non-affirmative elements of the assessment showed this was not related, and the patient has remained very well. It was asymptomatic throughout the whole time, has remained well and has remained well within normal range since that initiation. That's now 12 months, more plus.
Okay. Okay. Okay, that's very helpful. Can we talk about the timing of the BLA? Obviously, you recently aligned with the FDA, and obviously-
Yes
... CRISPR bluebird bio sets-
Yes
... a precedent in terms of-
Yes
... like, how many patients-
Yeah
... of what kind of follow-up. I believe they filed on, you know, roughly 20 patients with 12-18 months of follow-up.
Mm-hmm.
So that puts you in the second half of next year. One, is that a reasonable assumption to have? And two, how should we think about your initial BLA filing, whether that filing will include or not-
Yeah
... adolescent patients? Is that gonna be filing concurrently, adult and adolescents, or is it gonna be sequential? Like, any thoughts there?
Yeah. So, we haven't actually shared the specifics of our final BLA strategy, simply because we are obviously talking to the FDA. We are very fortunate in that we have RMAT, which allows us to talk to the agency at a higher frequency than that is the normal norm. So that certainly is an opportunity that we are using and exploiting. With regard to your statement about the precedent, yes, the benchmark was set by Vertex with the 20-patient efficacy dataset with 16-18 months of follow-up. It is important to note that notwithstanding maintaining the PDUFA after that original completion of submission date, they did, according to the correspondence published at the end of January of this year, have to they did submit an additional 10 patients in their dataset.
So we basically have a range. And, you know, so we're very excited about the fact that we are going to be talking about 18 patients with at least 2 months-21 months of follow-up at our at the EHA presentation. We've obviously continued to dose, you know, in the meantime. And so we can sort of get a sense, but obviously, we're not going to commit to what that final date would be until we really are much closer to and agreeing with the FDA what's agreed. But I will tell you, in my experience in the rare space, and, you know, our CMO also has. You know, I was a CMO in the past.
Our current CMO, we've both worked in the rare space, and we've had experience about where precedent is set, and so that kind of benchmarking is reasonable, but it's not set in stone. You know, our experience tends to be is it, it either is the same or maybe a little lower, but that would be determined. We'll be able to talk about more of that at appropriate time.
With regard to the breadth of the label, I think the key thing I would say is that we are very excited by the fact that we're able to announce at our Q1 earnings just last week that we had completed enrollment of our adult cohort and have actually already enrolled a number of adolescent patients, and are actually screening at a rate and enrolling at a rate maybe that exceeds, not maybe, that does exceed what we had anticipated. So I think overall, that puts us in a very good place from the point of view of preparing and agreeing with the agency what would be what we would file with and the timing.
Got it. Got it. Super helpful. Maybe as you start thinking about the commercial opportunity in the U.S., I find it fascinating that, you know, Vertex and bluebird bio presumably talked to the same payers for an extensive period of time, and then they still priced this very differently.
Hmm.
What justifies that dichotomy? That's question one. And two, how are you thinking about pricing for your program?
... So I'm afraid I'm going to give you an unsatisfactory answer to the first part of your question, which is I can't possibly comment on what other people were thinking in that dichotomy. You know, obviously, I think the pricing has, you know, does reflect some of the issues around cost of goods, et cetera. We are not anywhere close to our pricing. We don't need to have that discussion right now. We're obviously doing a lot of work to understand that, and we will talk about it, you know, much closer, you know, to a launch.
Okay.
Sorry about that non-answer, but-
No, no, that was, that was very helpful. Maybe just a quick question-
Sorry, there's one thing I want to say, though.
Yeah, please.
Forgive me, but it is worth pointing out that a very conservative advisory organization, ICER, kind of said, put their anticipated price smack bang in the middle of that. So, you know, that is unusual, you know, I would say, and I, I think it reflects something that I think it's easy to forget. I have been very lucky in my career. I've had six drugs that I've directly had my hands on that were approved. I have never seen efficacy like we see here, and I'm not just talking about our product. I'm talking about gene-edited, CRISPR gene-edited products, where you have essentially a response rate of 100%, biological response rate of 100%, and almost 100% clinically. It's, it's something we've never seen. You've never seen it before. I've never seen it before. Our ancestors have never seen it before.
So I think sometimes it's easy to forget, and we should just pause and reflect just how phenomenally powerful this technology is, from the effect size it has and the robustness of things. We're not actually kind of looking at it. It's not kind of a, what is it? You know, progression-free survival, where you're kind of squinting and you're trying to look at a p-value. This is just... You don't need to submit it to a statistical test to see it-
Sure
... or be convinced. Sorry, I just had to pause there, but it is just phenomenal data. So I think that's probably what helped ICER, and also in the context of the cost of supporting a patient with sickle cell disease. In the lifetime, these patients may spend millions, up to $10 ,000,000, in supporting them in what is already a compromised and truncated life. As I said, our patients in our trials have had a mean severe VOE rate per year of four episodes. One patient, one of those patients, very characteristic or illustrative, an average of 100 days inpatient in the United States, and you know how sick you have to be to be inpatient in the United States. So I think it's just worth pausing and thinking about-
Sure
... how you're going from 100 days per year to zero days, and, and it's just phenomenal. Sorry, I just get-
No, no, very, very helpful, and I think the, the commentary on efficacy is-
Yeah
... obviously very clear. I mean, I'm going back to the bluebird bio, but bluebird bio's day, the first time it actually showed that data at ASH was like it was really, really, revolutionary. However, I do believe we have to balance the excitement on the efficacy with some of the limitations that we have around this procedure. This is not like-
Yes
... an off-the-shelf therapy.
Yes.
This is not like a small molecule.
Yeah.
This is, it's complication. It's-
Yes
... you know, you need busulfan-
Yeah
... and chemotherapy and all that. And maybe related, but I think you had a plan to develop the next generation-
Yeah
... preconditioning-
Yeah
... that could potentially spare busulfan, which could-
Yeah
... obviously go a long way. However, you recently announced that you're no longer putting a lot of resources behind that.
Yeah.
Can you just walk us through the rationale why you think-
Sure
... that's the right strategic decision for Editas?
Sure. You know, let me just open up by acknowledging the truth of what you say is that, that this current procedure, you know, an autologous ex vivo therapy, does create a burden, very much on the patient, as well as on the infrastructure demands it creates, which is one of the reasons, in fact, it is a key reason, why we have really pushed and in the pivoting of the strategy to really focus on our in vivo pipeline work, with upregulation of the focus, remembering that our reni-cel ex vivo is an example of indel-driven upregulation of a functional homologue or protein. So, I've just planted the in vivo piece. We'll come back to that, but let me address the question directly about the milder. Our view of the milder conditioning was the following: The regulatory and development path is complex.
It is not simply. And in fact, the way it progress now is it's driven largely by going into oncology before you go to, dare I say, I use the word advisedly, more benign hemoglobinopathies. Although if you suffer from sickle cell disease or thalassemia, you won't regard this as benign diseases, but you know what I mean. And that has created challenges. It's been a challenging development landscape, and frankly, it also would mean that we would take—it would defocus us from where we are actually trying to focus. And one of the key things I did when I came to Editas is says we have to focus. So that was one piece.
The other piece is that those therapeutics are being developed by good companies, and we are remaining in touch with them, and we remain in touch with the academic experts as well to monitor that. Our view is, as these molecules come to market and are approved, they will be adopted by transplant agencies and then, or transplant centers, and then be used universally across their protocols. So we felt from a deployment of capital, what's the best way for us to focus? And we felt that the best way to focus is to sort of watch and monitor that space, which is adequately enabled, we believe, and then really, really more focus our resources on going to the next generation, which is the in vivo.
We've said with regard to in vivo that we are focusing on hematopoietic stem cells as one tissue, as well as other tissues, including the liver. In all cases, our internal focus would be on functional upregulation.
... Got it. Yeah, sounds like you have mentioned in vivo three times over the last answer. So I'm supposed to ask you questions on in vivo, but I won't. Or at least not yet.
You answered them already.
At least, at least not yet. Just a quick question, maybe on sickle cell disease. How are you thinking about the opportunity ex US? Again, to me, it was striking how Vertex was super excited-
Yeah
-about the opportunity in Middle East-
Mm-hmm
and outside the United States. They actually even said that the opportunity in the Middle East can be just as big as the United States-
Mm
if not bigger. How are you thinking about tapping that market?
So, since my arrival, we have talked about the upside of partnering outside the United States. We really felt that as a small company with our resources, we should focus on the US, both from a logistic point of view, from a development point of view, et cetera. But we've been very open to that point about looking outside. We have talked about looking for a partner with a large footprint who can touch all these markets, but we're particularly attuned to the opportunity in the Middle East, and are very aware of that opportunity around the hemoglobinopathies, largely driven by, you know, a high prevalence of the diseases, and frankly, a very well-developed transplant infrastructure. So, you know, we would share Vertex's-
Yeah
view of that, of the Middle East. And there are some other jurisdictions on the planet which might be of particular interest. So we talk about ex US, but I think what really has been becoming clear now is there's a little sort of zeroing in on where is the real unmet need, and where is the infrastructure that creates the opportunity to develop, or how to say, impact substantially that unmet need?
Got it. Got it. I suspect I'll ask a question on in vivo, so now I will ask a question on in vivo. You mentioned it already a few times, this focused on upregulation versus-
Yeah
Other companies being focused on downregulation, which obviously I appreciated. But how are you thinking about indication and indications?
Yeah
-prioritizations? How are you thinking about targets? Like, how are you thinking about tissues? Is it fair for us to assume-
Yeah
that you're gonna first focus liver targets, or -
Mm-hmm.
Like, walk me through all that.
Yeah. So we have, Okay, so delivery is one issue for selection. I think the opportunity and the unmet need is another, where there's going to be clear differentiation from the current standard of care. And frankly, there are other elements where how much information exists in the, in our genetic databases to further de-risk those targets. So let me take them one at a time. From a delivery point of view, you know, obviously, with our human validation of our Cas12a enzyme, and the targeting of the gamma-globin promoter, for reni-cel, and I left out the biology. I never asked you a biology question earlier on.
Sure.
But the reason we thought that was important and maintain its importance is because it doesn't just upregulate gamma-globin, but it actually is very good and actually is a much more robust, how should I say, supporter of red cell output, which we saw preclinically, and we're now seeing clinically. Sorry. But anyway, we maintain that interest. So that's an area of interest, and we are actively evaluating that, really from a targeting point of view. We have talked about other tissues, but the liver is one. I think, some people have said, "Liver, really?" A lot of people there. But that's why I think we felt it was important to acknowledge, you know, highlight where we're driving to, which is functional upregulation rather than knockdown. So that's important. So that's kind of from a delivery point of view. Then you think about the disease indications.
As I say, we want to go for diseases amenable to upregulation, where it will make a differentiated clinical benefit over the standard of care. And then finally, I touched on how you further de-risk. So I'll just give an example. One way that we have substantially, and others, I mean, it wasn't just we, but you know, in fact, it was de-risked, was the idea of upregulating fetal hemoglobin, was de-risked by a natural experiment, where there are natural variants that cause hereditary persistence of fetal hemoglobin, where that natural variant is co-inherited with sickle cell disease or was found because it wasn't spotted clinically. It was seen when people froze hemoglobin and saw the coexistence of sickle hemoglobin and fetal hemoglobin, but said that these people look great. So that was sort of a natural experiment.
How you can actually use similar, and there are other examples of that, in the genetic, in well-curated genetic databases or biobanks to help de-risk. Those are other ways that we would actually select to maximize the probability of technical success, you know, focusing on rare, severe diseases where we can maximize the size of the signal and to maximize the probability of, regulatory success, and ultimately, by truly differentiating, maximize the probability of commercial success.
Got it. Got it. Super helpful. Maybe last question on IP. You already touched upon it earlier. Obviously, your deal with Vertex sets a comp for any other type of negotiations, I would imagine. And I think that also sets a comp in term of the timing of a deal. Obviously, that deal happened when the drug got approved.
Mm-hmm
-or really close to get approved. So should we... How should we think about potential new deals going forward? Should we assume that those deals will happen when the product is getting closer to commercial-
Mm
or can those deals happen actually earlier? Like-
Yeah
Walk me through your IP strategy here.
So the deals can happen at any time in the life cycle of a medicine. The Vertex comp sets a guardrail and a valuation close to launch, but we have other deals. For example, we did a, we announced a deal last year with Vor. And what we actually. So those are two very differently structured deals. One, for, as appropriate for a company that is sort of in cash burn mode, is, you know, early in development and actually wants to get sort of the best, you know, the optimal value. Every deal is kind of a biobucks, a biobucks-heavy deal, whereas the deal that we did with Vertex very late, obviously had more substantially larger set of upfronts, and milestones because many of those had effectively been deferred until the deal was done.
And obviously, you know, while we're very flexible, in this case, it actually used kind of fixed annual payments, which might be more acceptable and meaningful to a company that actually has significant earnings, and it's kind of an EPS type model. So essentially, what we've got is guardrails, both around timing, early or late, as well as the structure about is it sort of royalty-heavy or annual fees. And obviously, we're very flexible and want to work, and I think we've demonstrated flexibility and ability and a willingness to work with and balance our needs and our valuation with the needs of a partner or licensee.
All right. Super helpful. Lots more questions, but no more time. Gilmore, thanks so much for joining us here, and best of luck for the rest of your conference.
Thank you.
Thanks, everyone, for joining us.
Thank you very much.
Thanks again. Appreciate it.