Editas Medicine, Inc. (EDIT) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining the EDIT-101 Clinical Update Webinar. This webinar is being recorded and can be accessed in the future through the same link or through the Investors section of the company's website. [Operator Instructions] As a reminder, various remarks that we make during this presentation about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC as updated by our subsequent filings. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements even if our views change. This webinar will be presented by Editas Medicine's CEO, Gilmore O’Neill; and our Chief Medical Officer, Baisong Mei. I'd now like to turn the call over to Gilmore for opening comments.

Thank you, Ron, and good morning, everyone. We have shared before that one important objective of the EDIT-101 BRILLIANCE study is to identify a population of LCA10 patients who have a clinically meaningful response to EDIT-101 and can be identified by baseline characteristics so that we can preselect patients that have a high probability of clinical response in future studies. For this analysis, we defined a clinical responder as a person who had a consistent clinically meaningful improvement in BCVA and positive clinical responses in at least 2 of the following 3 additional endpoints, full-field sensitivity test or FST, visual navigation course or the visual function quality of life, VFQ, a patient-reported outcome. So before handing over to Baisong, here are the key takeaways. EDIT-101 was well tolerated with a favorable safety profile. We believe that the BRILLIANCE study has demonstrated proof-of-concept of clinically meaningful CEP290 editing by EDIT-101 because 3 out of 14 treated subjects met the responder threshold having experienced clinically meaningful improvements in visual acuity measured by BCVA and having demonstrated consistent improvements in 2 additional endpoints. So having demonstrated POC, can we preselect patients more likely to experience a clinical benefit from EDIT-101. Looking at the baseline characteristics of the treatment responder patients, 2 of the 3 responders were homozygous for IVS26 mutations. That is 2 out of 2 or 100% of the homozygous patients treated. Now this is a small number of subjects, as you might expect in a Phase I study of a rare disease. Nevertheless, we believe that we have identified homozygosity as a baseline parameter that will allow preselection of patients most likely to experience clinically meaningful response in a registration study. Looking beyond genotype and homozygosity, we were not able to identify any additional baseline characteristics in the 3 responders that could be used to preselect additional patients with a high probability of clinical response for future clinical studies. Baisong, our Chief Medical Officer, will now take you through the [ enlightened ] natural history study and BRILLIANCE studies and show the data that leads these conclusions. Baisong?

Thank you, Gilmore. LCA10 is a rare inherited retinal disease. Characterized by profound visual impairment starting with early childhood, currently is without treatment. LCA10 is caused by mutations in the CEP290 protein in photoreceptor cells, resulting in significant field and central vision loss. The most prevalent mutation in the IVS26 mutation, which affects about 1,500 patients in the United States. About 20% of IVS26 mutation patients are homozygous positive patients with an estimated 300 patients in the United States. EDIT-101 deletes the IVS26 mutation and restore expression of full and functional CEP290 [ protein ]. The 101 clinical program, including 2 studies in IVS26 LCA10 patients. The first was the enLIGHTen Natural History study and then the second is the Phase 1/2 BRILLIANCE study. The Natural History study was a 12-month prospective study designed to characterize the clinical course of LCA10 and to understand the behavior of multiple endpoints to determine a threshold statistically meaningful change. This data from the Natural History study are being used to contextualize data interpretation of the BRILLIANCE study. The BRILLIANCE study was designed to evaluate the safety and tolerability of EDIT-101 in participants with LCA10. And to evaluate the efficacy of EDIT-101 or end point of visual function and visual quality of life and to identify a segment of patient population based on baseline characteristics in clinical responders, which will allow us select the patients with high probability of responding to EDIT-101 treatment in the future Phase 3 registration study. The BRILLIANCE study includes about low, mid and high-dose cohorts and pediatric mid and high dose cohorts. The study inclusion criteria allowed the enrollment of LCA10 patients with the homozygous or compound homozygous or compound heterozygous IVS26 mutation. The [indiscernible] also allows the recruitment of patients ages 3 and older. Key endpoints including safety and tolerability and efficacy and quality of life related endpoints, which will cover -- which I will cover later. To date, we have enrolled a total of 14 patients, 12 adults between 18 to 63 years old and 2 pediatric participants at 8, age 9 and 14 years old. 2 of the 14 participants are homozygous and the remaining 12 participants are compound [ with ] heterozygous. As you can see, participants have a broad range of BCVA and FST without a clear correlation to patient age. Two participants are enrolled in that low dose cohort, 5-ish in adult mid and high dose cohort and [ 2 PH ] with participants in middle cohort. Among the 14 participants, 11 had [ at least ] 6 months follow-up period, 7 of them had at least 12 months of follow-up. 3 participants had a 3-months of follow-up. During the follow-up period, EDIT-101 demonstrated a favorable safety profile . EDIT-101 was generally well tolerated across all cohorts and no dose limiting toxicity or drug-related SAE or ocular SAE [ were observed across ] cohort. The majority of AE were mild or moderate, which accounts for 90% of all AEs. Half of all AE was related to surgical procedures and are recognized the complication of subretinal injection. 7 of the 4 [ key ] participants, 50% of them reported no ocular AE related to EDIT-101. One patient reported a [indiscernible] ocular Grade 3 AE at 6 months, a non-serious vision impairment, which is improving. These participants enrolled the Natural History study to which the same experience similar vision fluctuation. Now we turn to the key endpoint used in our analyze of BRILLIANCE study. For the BCVA, a decrease in measurement indicates clinical improvement and an improvement on baseline of 0.3 LogMAR is accepted as clinically meaningful. For FST, a decrease in the score indicates improvement and our Natural History study demonstrate that an improvement of 0.6 is outside the range of noise and is specifically meaningful based on test and retest data. Our visual function navigation of all VFM increase the score indicates improvement and our Natural History study demonstrated that an improvement of 3 is [ statistically ] meaningful. Finally, for the patient-reported outcome, visual function quality of life or VS or VSP endpoint, an increased score indicate improvement and an improvement of 4 points has been determined to be clinically meaningful. As a result, the previous study responders are defined as meeting the threshold of clinically meaningful change for BCVA and meaningful improvement in 2 other endpoints. Now I will discuss the summary of efficacy for BRILLIANCE study. Among the 14 participants in the study, several participants showed improvement in one or more of the 4 endpoints as highlighted in the [indiscernible]. Now as I mentioned earlier, we defined a positive response to EDIT's 101 treatment as clinically meaningful improvement in BCVA and consistent improvement in at least 2 of the 3 other endpoints, patient report outcome VFQ, VFN and FSP. Indeed, 3 participants, as highlighted by Orange box on the screen, met the definition of a clinical responder. Looking at the baseline characteristics of the treatment responders, 2 of the 3 responders were homozygous IVS26 mutation. These patients are identified on the left. That is 2 of the 2 or 100% of the homozygous participants treated with responders. Looking beyond genotype and specifically homozygosity, we were not able to identify additional baseline characteristics that could be used to preselect patients with a high profitability of [ clinical responding ] in future studies. Whereas homozygosity is the only baseline parameter that can predict a clinical response based on the current state. These slides show some details of the results from the 2 homozygous patients. Please note that solid line represents data from the treated eye and the dotted line represents data from the contralateral un-treated eye. During the 12 months follow-up period, the 54-year-old homozygous patients whose data are presented in 4 panels in the top row, shows that a clinically meaningful BCVA response of 1.3 LogMAR at month 3 and month 12 as well. A meaningful improvement in visual function navigation and visual function quality of life VFQ over the course of 12 months. The FST also showed [ trended ] improvement for 4 lines for life of all 3 colors. This tested has a new injury at month 12 visit, which the investigator field might have compounded performance in the visual function navigation cost. In summary, these subjects show consistent and [ directionally ] positive response in 3 of the 4 endpoints and need the definition of a responder. During the 3 months or last period, the 14-year-old pediatric homozygous participants whose data are presented in the 4 panel in the [ bottom as well ] showed that clinically meaningful improvement in BCVA of 0.6, of 0.7 LogMAR, a meaningful [ FX key ] improvement for lives of all 3 colors and a meaningful improvement in children, VFQ. And this VFN score also showed trended improvement. We just noticed that these participants had improvement in the BCVA and video function navigation endpoint in both the treated eye and nontreated contralateral eye. We and the investigator and the steering committee members discuss this data in detail. And it was struck nevertheless, at the overall consistency of improvement in the treated eyes for all 4 key visual endpoints thus giving us confidence in our conclusion that these patients meet the definition of her responder -- such challenges on results of a treated -- untreated contralateral-eye have been reported in other LCA trials before. It is also worth noting that regulators tend to favor using treated patients as control rather than untreated contralateral eyes owing to such challenges in pivotal [ trials ]. In summary, EDIT-101 was well tolerated with a favorable safety profile. We believe that BRILLIANCE study has demonstrated Proof-of-Concept, clinically meaningful CEP290 editing by EDIT-101 because 3 of the 14 treated subjects met the responder threshold have experienced clinically meaningful improvements in visual acuity measured by BCVA and having demonstrated consistent improvement into additional endpoints. 2 of 2 homozygous participants are among the 3 responders -- as I mentioned earlier, there's some current data, the homozygous patients are the only population that can be predicted as responders. I will now turn the call back to our CEO, Gilmore, for his concluding remarks.

Thank you, Baisong. As you can see, BRILLIANCE demonstrates compelling evidence of clinically meaningful EDIT-101 driven genome editing in the retina of LCA10 patients with an IVS26 mutation. Now we have previously stated that in order to move forward to a registration study, Editas needs to see both consistent effects on a number of clinical outcomes in treated patients and a meaningful treatment benefit for a commercially viable patient segment. The [ burn ] data show that the only patient segment that we can predict to have a clinically meaningful response is homozygous for the IVS26 mutation. This segment of the already small population of patients with LCA10 is estimated to comprise only 300 patients in the U.S. The size of the population does not make it viable for Editas to advance this program alone. However, because patients are at the very center of our mission, we will therefore seek a partner to continue the development of this program. In the meantime, we will pause further enrollment in the BRILLIANCE study. But of course, we will continue the follow-up of all patients who have been already dosed. Additional earnings from the BRILLIANCE study include the demonstration of a satisfactory safety profile for CRISPR nuclease delivery by AAV to the retina, variability of disease phenotype and severity not simply predicted by age and the translational challenges in determining the baseline characteristics most likely to predict a clinical benefit. In addition, looking forward, Baisong and I since our arrival in the middle of this year are implementing the use of new therapeutic target selection criteria that use translational, clinical and commercial factors to maximize the probabilities of technical, regulatory and commercial success for our pipeline. Clinical execution is a top priority for us. We look forward to sharing more details around the criteria and our strategic plans in the coming months. We want to thank all the patients, their families, PIs, clinical sites and employees who have worked on this project and look forward to updating you in the future should we identify a partner EDIT-101 forward.

Thank you, Gilmore. We will now proceed to the Q&A portion of the webinar.

[Operator Instructions] First question comes from Joon Lee at Truist Securities.

This is Mandy for Joon and sorry for my bad voice. So the question would be how you will make this treatment a viable for a compound heterozygous is it improvement of editing efficiency and cutting out the dilution or the delivery to the right cells.

Thank you very much. I believe your question, I think what you're trying to ask is, are there alterations to the program or the molecular design that would improve or provide potential benefit to compound heterozygous patients. I think the best answer to give you on this is that when we look at the current dataset, with the construct that we have, which essentially targets the editing out of the deep intronic IVS26 cryptic splicing site. The only patients that we can see that would have a baseline characteristic that would allow us to preselect a patient population for a registration or future study would be patients who are homozygous for the IVS26. We haven't looked at or considered a different strategy from a therapeutic point of view because of the nature of the construct that we have built it today. I hope that answers your question.

Next question comes from Matt Harrison at Morgan Stanley.

Great. I just wanted to ask about how you think about investments in some of the other genetic eye disease programs that you have in the pipeline, just given today's data and either thoughts on -- somewhat similar to the prior question, thoughts on the construct and things you might want to do differently in those other programs or just how you think about the investment in those programs given the commercial opportunity.

I think the key things, the takeaways are sort of the read-throughs we have is that we are seeing a very satisfactory safety profile for [ AAV ] delivered CRISPR nucleases to the retina, which is a first -- the second is that we are actually seeing -- we have seen POC for editing. With regard to -- so that actually reads through to the IRDs. It is worth pointing out that when you look at our other preclinical programs, for example, 103, we have demonstrated higher editing efficiency, which would actually build on what we've seen today. I think finally, from a commercial viability point of view, the way we look at commercial viability and Baisong myself and members of the leadership team bring a substantial experience, indeed, between -- Baisong and myself a track record for 10 approvals and drugs to go to market. We are -- look at a commercially viable population through multiple factors, which includes not just the size of the population, but the unmet need, the complexity of the therapy and how we would interact with the existing medical therapeutic landscape as well as ascertaining and that's just to name it a few. I think -- the answer to the construct we have today and what we have changed, I think I've answered that in the previous question. But I think the key point, I think when you look beyond 101 is that, for example, our 103 constructs use the dual vector approach that has, in addition, a different and more robust editing efficiency in our preclinical data. And that is...

Our next question comes from Gena Wang at Barclays.

Also kind of follow the first 2 questions. Also, more -- you also mentioned what is the [indiscernible] other programs? Maybe if you can talk a little bit more for other indications of how you will select or prioritize the remaining program with this now become [ deprioritized ]? And also another question is how much cost savings you have now with the reprioritized the development path?

So when I think about the read-through to other retinal programs, I think I've actually addressed that. One thing I did [ leave as we ] talked about 103, when I talk about the editing efficiency is the use of a different promoter and the fact that it uses a single die, which actually those 2 things together are probably what's driving the efficiency of the editing that we see relative to 101. So I think the good news is that we have a proof-of-concept determined by the -- a very rigorous set of selection criteria. With regard to prioritizing, I was just mentioning that Baisong and myself joining in the midyear with a view to really moving this organization into a commercial therapeutics company while building its technology, we have outlined and are applying a new set of target selection criteria informed by factors coming from biology, translational biology, clinical and commercial factors to maximize the [ probability ] of technical, regulatory and commercial success to -- and these we are applying with our executive team as we evaluate our strategy and pipeline going forward and look forward to sharing that with you in the coming months. I think with regard to savings, we will actually be sharing with that with you in the coming months in the context of our evaluation of our strategy and pipeline.

Our next question comes from Philip Nadeau at Cowen.

Just a couple from us. First, maybe to ask the other questions in a different way. Why do you think the compound heterozygous patients didn't respond when initially you're optimistic they would? Do you think the threshold for the number of alleles or cells that need to be edited is higher? Or was the efficiency in the eye somewhat less than would have been predicted by preclinical studies? That's the first question. And then the second, a clarifying question. You mentioned on the pediatric patient that the contralateral eye also seem to have some improvements. That didn't refer to the BCVA is that correct? It seemed like from the chart, BCVA was only measured in the treated eye and that was the only one that improved.

Yes. So why the compound heterozygous? I think the issue here is that we certainly saw one compound heterozygote patients actually met our rigorous definition of a clinical responder. I think there are a number of hypotheses that would actually drive this. I think you touched on one, which is around the efficiency of [ allele ] editing 1 versus 2 potential targets. And I think the second, the centers around observations that the IVS26 cryptic splice site may actually be read through and indeed work -- published work looking at expression in fibroblast for CEP290 homozygous patients do demonstrate higher levels around the order of 50% expression of a full length CEP290 protein. So that's the first question. And I think you asked about the contralateral proven pediatric. In fact, the -- you've seen one line. The dotted line represents the contralateral eye is sitting -- they're basically on top of one another. That's why you didn't see it. However, I do want to make a couple of comments about that. Contralateral moving on BCVA. -- is actually not a lot of precedent, it's actually seen -- has been seen in multiple clinical trials of recent therapeutics, both for required diseases as well as congenial disease. And indeed, as Baisong said, it was observed even with the early development of alternate program. And we called out that early on because that's where an eye was treated and the other not. And it is for, I think, those reasons and but also many possible complex physiological explanations by this observe. But this is the reason why FDA and other regulators tend to favor using as controls untreated patients as opposed to an untreated eye in the same patient as the treated eye. So this is an observation of maybe 4. I think the final point I'd like to make is that notwithstanding observation, if you look at the data, you can actually appreciate that because of our requirement to have 3 out of 4 consistent and directionally positive movements to call a responder, we feel confident that this patient is a responder. And I think the fact that we see not only that, but within that, the patient-reported outcome actually also being consistent is all very supportive of that observation. That conclusion.

Our next question comes from Liisa Bayko at Evercore.

Sorry about that. So can you explain just sort of mechanistically why you think you're getting this particular mutation seems to be, I think, having the majority of the benefit. If you could -- is there some rationale there biologically?

Well, yes, Lisa, thanks very much for your question. I apologize, we didn't make it clear in the presentation. A subset, a subgroup of LCA10 patients have an IVS26 mutation and about 1,500 patients carry of -- a subset of 1,500 patients estimated in the LCA10 population carry the IVS26 intronic mutation. This is deep intronic mutation, which creates a cryptic splice site. That is the target of the editing therapeutic EDIT-101. And so the intent of the therapeutic is to actually remove either delete or potentially invert the segment of the intron carrying that mutation. So that's why that mutation is important. And then I think I've already said that in the context of the patient population who all had to carry at least one IVS26 26 containing allele as well as in other mutation, be it IVS26, homozygous, therefore, or another disease associated allele. We found that in this study, which was designed to do a number of things, but one he objective was to identify a responder population that could be pre-selective based on baseline [ characteristic future ] studies, we found that the homozygous patients, the IVS26 mutation were responders and would be easily identified.

Our next question comes from Jay Olson at Oppenheimer.

Can you tell us about how you're learning from one [indiscernible].

Sorry, Jay, you're very muffled, but I believe that your question you asked was, can you see or are there learnings from this 101 experience that would inform the selection of patients in other inherited retinal disease trials. And so let me attempt to answer that question. I hope that's the right question.

Yes.

Yes, okay, great. Thanks, Jay, for confirming. I mean I think key thing is, one, the 2 key learnings and a very important learning, obviously, is that we actually has demonstrated that we can safely deliver CRISPR nuclease to the retina using AAV. That is actually a very important step. And in addition, we have found that we can with the EDIT-101 construct edit and do clinically meaningful editing in patients. In this case, it was approximately 20% of the patients, and we can pre-identify going forward, a patient population was likely to respond. I think it's important, as I say that the 103 from an efficiency point of view has a higher editing efficiency and there are other issues which I won't revisit just now. But then with regard to would you design studies differently? I think the key thing here is that the Phase I BRILLIANCE study did exactly what it was designed to do. It was designed not only to determine and look at a dose range for maximum tolerated dose determination, which it has done. It was determined or designed to identify proof-of-concept. We would also asked to identify the outcome measures and their behavior in this patient population. And finally, it was designed to see if there were objective characteristics at baseline that would allow you going forward to preselect a responder patient population. And so I think actually, those are kind of the lessons that we learned to carry forward. But I think it's important to understand that there are elements in rare diseases where one must actually do the important exploratory elements of design that we carried out for this program.

Great. That's very helpful. And then maybe if I could ask one follow-up. Have you discussed with the [indiscernible].

Sorry, Jay to interrupt, I am going to actually [ call ] the next question just for a second today, you're very muffled again. I think you said how do you discuss this with the FDA and what is their feedback?

Yes, correct.

Okay. We have not had a detailed discussion with the FDA. But obviously, throughout the [ content of the ] study, we're continuously updating with data.

Okay. Great. And maybe one final question. Can you just provide some color around the characteristics of the ideal partner you would be looking for to collaborate on the 101 program going forward?

Yes, congratulations. You're completely clear and definitely we could hear you very well. Yes, obviously, we are looking for a partner who has an interest and expertise in retinal diseases and a genetic gene therapy in rental disease and who has a particular interest and a business model that will work in the context of a really ultrarare population.

The next question comes from Joel Beatty at Baird. Joe, you may now and ask the question.

Great. I guess, first for the severe ocular adverse event, what's your assessment on whether or not it was related to drug?

This is Baisong. We have detailed discussions with the investigator and IDMC about this case. And so we did see the fluctuation of the visual function and this patient is recovering with all the detailed analysis data, including OCT imaging, baseline characteristics -- and as I mentioned, also, this patient was in Natural History study and the IDMC review the data. So the conclusion was we can continue the dose, if we can continue to [ indulge ] the patient as we planned. There was no concern of specific value [ chain ].

Got it. And then one follow-up question related to efficacy and the findings that the [ efficacy to be loaded ] to homozygous patients, how does this match up with the preclinical data and this [ agent ]?

The preclinical data, a matchup did not predict this and largely because the preclinical data we're looking at and basically the animal model used or used in the preclinical data, we're really designed to look at the slice or rather the editing efficiency. The actual animal model does not actually manifest the phenotype with this IVS26 mutation inserted into the murine gene. So this is not predicted by the preclinical data. I think the key thing was that the study was designed to recruit a diverse group of patients and actually represented with a very good representation of the genetic epidemiology disease.

Our next question comes from Madhu Kumar at Goldman Sachs.

This is [indiscernible] on for Madhu. So the first question is how does the homozygosity effect influence the decision-making framework for the ocular -- for future update indications? And then second, how does EDIT-101 decision [ affect ]cash runway?

So thanks very much for the 2 questions. I think the first question is how does the observation of homozygosity for the IVS26 mutation influence our view of other diseases. It really -- it informs that if you want to go into the specifics, when we look at the 103, we're looking at [ north some dominantly ] driven disease. So that should not actually impact that. And so I think that's one key -- that's kind of the key answer to you. I think that's the key point of your question. But the point of view of the cash runway, there is clearly a potential saving. We will be sharing more details in the coming months.

Our next question comes from Yanan Zhu at Wells Fargo.

So perhaps 2 questions. One is on the confidence level that the homozygous patients population is indeed a responding population, given that the pediatric patient only had a 3-month follow-up. So what's your confidence level that the efficacy you observed could persist in future time points. The other question is, obviously, I'm wondering about this because this response in this population at least demonstrates gene editing could be effective if efficiency -- editing efficiency is sufficient. The second question is on the endpoint. So I'm wondering your bar, the bar you said, BCVA plus at least 2 out of the 3, 2 out of 3 other endpoints. Is that a decision made with input from regulators -- and how come -- for example, could you choose the quality of life as the primary, which seems like they are more responding patients or BCVA with only one other endpoints. So how did you come to this conclusion and whether that applies to other ocular programs?

With regard to our confidence, we actually are confident that the homozygosity for IVS26 is a predictor and would be a good predictor for preselecting patients with a high probability of clinical response. We're not saying it's 100%, but we're actually saying that it is a -- allows preselection of a patient population with a high probability. Why? Well, we have 2 out of 2, 100% of homozygous patients treated versus 1 out of 12 with a compound heterozygous. And that actually represents 2/3 of the responders we saw. You're correct. We have 3 months of follow-up for the homozygous pediatric patients. I think the durability question, obviously, remain and we will continue to follow that patient [ the ] treated patient. However, because the target is one of editing. We see this as a permanent and durable, it's not like expressing a transgene. This is a permanent or we're looking for edit and that we see. So I think that really is why we are confident of what we're observing here. And with regard to the rigor of the definition of a responder, this is where, Baisong and myself bring our experience and track record of bringing medicines through approval and to market. And our desire to ensure that we move medicines forward that have not only a high probability of technical success, but also a high degree and level of probability of regulatory and commercial success. The high bar is -- we actually felt very reasonable considering the novelty of the therapy and our desire to be absolutely sure that we can preselect and predict benefits going forward. We did not discuss that specifically with regulators, but believe that the bar here should be high. And then from the point of view, the quality of life as a primary outcome. I'm pleased that you call that out because this we felt with certainly compelling data for supporting the observations that we've made across the other 3 end points I think it is important to say that today, the regulators for ophthalmology have not approved based on a quality of life or patient reported outcome as a primary -- I think it's a strong supportive and that will be a matter of certainly a debate and discussion or negotiation with regulators. But we believe that using this rigorous threshold for defining a responder leaves no doubt about the fact of the observation and our conclusion that we've seen proof-of-concept of clinical meaningful editing.

And the last bit of the question on whether other ocular programs will adopt a similar bar?

We would actually be applying a similar bar. But and what I would say is that it's important to consider that in the context of [indiscernible] our preclinical [ 102 ] program. It's a different mechanism of disease and the patient population is different. And also the efficacy or the efficiency of editing is higher.

Our next question comes from Mani Foroohar at SVB.

I guess, a broader one since a lot of the previous analysts are dug in the nuance of this program. You talked a little bit about how you think about market opportunity, how you think about a threshold for appropriately sized market. I guess I'll start with the 2-parter. The first part being, even if one -- even if the response has not been largely limited to the homozygous patients, what was your original rationale why this market was large enough to be viable in pursuing whole hawk, not even limited to homozygous. And then secondarily, just I want to understand your philosophy on market opportunity, how do you think about competitive positioning as focus shifts to sickle cell, beta-cell, et cetera, other applications of your technology, how do you think about market opportunity in a world where you guys are 6, 7, et cetera, to market? And then I have a quick follow-up.

Yes. So how do we think -- I think there were 2 parts to the question. One was how are we thinking or how did we come to determine that the LCA10 population will be commercially viable? I think there are a couple of points to make. First of all, the LCA10 population and specifically IVS26 allele subpopulation comprises approximately 1,500 patients with relatively good ascertainment. And I think the original rationale is that, that was actually a reasonable population of commercially viable patient population. Nevertheless, when we actually look at the data and find that, in fact, the IVS26 homozygous are the ones or the patient population or segment in whom we can with conference preselect, that patient population, [ does is ] obviously substantially reduced. And that obviously was something that while it has to be determined by the Phase I study, which was designed to do precisely that, which is to say, is this -- what is the [ say size ] and nature of the patient population that is most likely to respond to this therapy. With regard to overall view of market opportunity and most importantly, the competitive intensity of the space. I think the first thing I'll do is challenge the characterization that our sickle cell 301 program is [indiscernible] it is not, which is much higher up than that. We're obviously looking forward to sharing data about that next month. And I think it's also worth pointing out that what we would hope to share will be that we have a competitive product with the long-term potential for differentiation. And in addition, I think it's important to point out that the patient population is actually substantially larger than that in the LCA10 IVX26 homozygous patient population and the orders of tens of thousands. And we believe that when we come to market with our 301 product, the vast majority of the present patient population will not have been yet treated owing to the challenges of developing that market, payer negotiations, et cetera. And then more importantly, as you talk beyond the 301 product and our entire pipeline, I previously shared that determining what is a commercially viable or attractive patient population comprises an analysis of multiple factors. I outlined a few, including the size of the population, ascertains complexity of the therapy, the unmet need. And as you quite rightly say, obviously, competitive intensity is a factor going forward.

Great. And a broader follow-up. As you move forward, you obviously like all management teams, you have [indiscernible] responsibility to shareholders, et cetera, be open-minded about strategic positioning. What dataset will you need to see from sickle or beta cell to pursue a restructuring and wind down, pursue a reverse merger strategy? Or is your plan to run straightforward along that you have the capital to pursue it?

Well, what I will say is that I don't think I can give a specific answer to that question. I think what I can say is that since my arrival midyear, I've been working with the executive team to talk about and evaluate our portfolio and strategy. I do be very confident in our -- in fact, I see even more confident in our ability to bring this science to the clinic based on the data we presented today. I look forward to sharing more data again this quarter. So essentially, Editas now will be sharing clinical data from 2 different programs within its pipeline. And I also feel confident that our cash runway is in a very good position for us to move forward with our 301 program as well as our pipeline, and I'd forward to sharing more details with you in the coming months.

Our last question comes from Lisa Walter at RBC.

Can you hear me?

Yes, Lisa.

Perfect. 2 questions for you. Just wondering, since EDIT-101, you commented that it did have a favorable safety profile with no dose-limiting toxicities. I was wondering if increasing the dose further was a possibility to see if there would potentially be a better response among the heterozygous patients. And second, on the Usher program, given this program has a similar mechanism of action to LCA10 as an exon [ cycling ] approach. What -- how should we think about this program after the results today?

Yes. With regard to the potential increasing the dose, I think the interesting thing is that we did actually show across the range of low, mid- and high dose, a good safety tolerability profile. One of the limitations to increasing the dose is [ fits with both plateau ] observation. And obviously, one has to be careful about the total dose of AAV delivered to the retina. And so we don't actually -- right now, we are not considering an increase in dose. With regard to your Usher or USH2A, sorry, we actually have been looking at preclinically developing an enhanced or improved editing efficiency over that [ seen with 101 ].

This concludes the Q&A portion of the webinar. I'd now like to turn the call over back to Gilmore for closing remarks.

So thank you all for joining this morning's webinar. Before signing off, I would like to remind you that we will be sharing 301 data update next month and look forward to sharing that with you and spending time with you. And very importantly, I want to thank all the patients, clinical investigators at clinical sites and Editas employees and researchers for the work in the in-licensed and BRILLIANCE studies that have actually brought us to a clear proof-of-concept and forward planning. And with that, I'd like to thank you all, and good morning.