Editas Medicine, Inc. Q2 FY2021 Earnings Call

Good morning, and welcome to Editas Medicine Second Quarter 2021 Conference Call. All participants are now in a listen-only mode. There will be a question-and-answer session at the end of this call. Please be advised that this call is being recorded at the company’s request. I would now like to turn the call over to Ron Moldaver, Investor Relations at Editas Medicine.

Thank you, Darryl. Good morning, everyone, and welcome to our second quarter 2021 conference call. Earlier this morning, we issued a press release providing our financial results and corporate updates for the second quarter of 2021. A replay of today's call will be available on the Investors section of our website approximately 2 hours after its completion. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call 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. 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. Now I will turn the call over to our Chief Executive Officer, Jim Mullen.

Thank you, Ron, and good morning, everyone. I’m joined today by several members of the Editas executive team, including Mark Shearman, our new Chief Scientific Officer; Lisa Michaels, our Chief Medical Officer; and Michelle Robertson, our Chief Financial Officer. I want to start off by providing some highlights from the second quarter and reviewing our upcoming milestones. Editas had a strong first half of the year with excellent momentum across our platforms and lead programs. The EDIT-101 BRILLIANCE trial for LCA10 is proceeding very well, with the Independent Data Monitoring Committee recently endorsing the enrollment of the first of two planned pediatric cohorts. We have also started enrolling patients in the adult high-dose cohort. We expect to share initial clinical data from the EDIT-101 trial this September, marking the company's first-ever clinical data readout. The RUBY study of EDIT-301 for sickle cell disease is screening patients, and we remain on track to begin dosing by the end of the year. The pre-IND work for EDIT-301 in beta thalassemia is progressing, and we remain on track to file the IND before year-end. Additional data supporting the unique properties of our proprietary Cas12a enzyme was recently published in Nature Communications, and we plan to present new data on our multi-transgene knock-in proficiency at the upcoming Cold Spring Harbor meeting. These accomplishments further support the incredible potential of our gene editing platform. Our manufacturing capabilities for lead programs have advanced nicely, and we're ready to manufacture all clinical supplies for the RUBY trial. We continue to progress our oncology programs, including our iPSC-derived NK cell program that we are advancing in preclinical studies. Finally, we continue to make headway on our remaining preclinical programs, including ocular diseases. Additional updates on those programs will be provided later this year. On the leadership side, we had several important announcements last quarter. Dr. Mark Shearman joined the company as our new Chief Scientific Officer. Mark is an experienced executive who has brought multiple programs from ideation into and through the clinic and has led numerous successful partnerships. He brings an extensive track record of achievements in drug discovery and clinical development across multiple therapeutic modalities. Mark is two months into his new position, and I'm pleased to have him on the call with us today. We're also delighted that Dr. Chi Li joined us as Chief Regulatory Officer. Chi brings an extensive resume guiding over 30 development programs through regulatory processes, including multiple U.S. and global submissions, and he will be a critical part of our leadership team as we advance our pipeline. Finally, we're pleased to announce the promotion of Bruce Eaton to our executive team as Chief Business Officer. Bruce has been involved with Editas in various capacities since 2015, starting as a consultant, then a research collaborator and as a full-time leader of our Boulder Site. He has a successful track record, including more than 30 years of scientific operations, business development, and corporate strategy experience in both public and private companies. He has a deep understanding of biochemistry and biophysics for the innovation and development of medicines. Bruce's expertise at the executive table will have a critical impact on how Editas continues to evolve. Overall, I'm extremely happy with the progress through the first half of the year. With our expanded executive team, I have the utmost confidence we have the right people in place to lead Editas to the next phases of the company's growth and towards long-term success. With that, let me turn the call over to Mark for his first earnings call at Editas as Chief Scientific Officer.

Thank you, Jim, and thank you to everyone dialing in. So I'm thrilled to have joined Editas and to have the opportunity to lead an extremely experienced and dedicated group of researchers and scientists. My short time at the company has only reinforced my excitement in working with Jim, the rest of the leadership team and the exceptional people throughout the organization. To give you a brief background about myself, I've almost 30 years of drug discovery and development experience. And I've been fortunate enough to be a part of advancing around 15 drugs into clinical development. I began my career in academia, and then moved to the corporate R&D side where I conducted research into Alzheimer's disease, other neurodegenerative disorders as well as autoimmune diseases. For the last six years, I was the CSO at Applied Genetic Technologies Corporation, developing AAV gene therapies, mostly for ocular diseases. The impressive technology platform and the potential breakthrough capability of gene editing technology in the regenerative medicine space is what brought me to Editas. Most of my scientific work has revolved around ophthalmology, immunology, and neurology, all key areas of development for this company. To be able to apply Editas's vast technological breadth towards my fields of expertise was truly a remarkable opportunity. I've always been intrigued by new aspects of sides of technology that can improve the likelihood of being successful in drug development, which opens new treatment avenues for patients who otherwise might not have other options. Editas's gene-editing platform has the potential for both of those. It allows us to address certain diseases, not easily addressed with other treatments, while also developing differentiated new medicines. This company has what I believe to be an unparalleled capability to edit the human genome and I'm excited to be part of its mission to transform medicine. So two examples illustrate this point. Firstly, the recent publication in Nature Communications that Jim mentioned earlier, detailing an engineered AsCas12a nuclease, which we believe to be a significantly advanced enzyme with editing efficiency approaching 100% across sites in multiple cell lines, and high on-target specificity. This engineered nuclease alleviates many of targeted editing concerns often observed with Cas9 enzymes, consequently leading to an improved safety profile and making it ideal for complex therapeutic gene-editing applications. It also greatly reduces the process chemistry challenges associated with the manufacturing of high-quality guide RNA. This proprietary tool could be an important step forward in the development of novel therapies for serious genetic diseases such as sickle cell disease as well as providing significant opportunity to create engineered cell therapies for cancer. Secondly, the development of SLEEK technology, which stands for Selection by Essential-gene Exon Knock-in. We're excited to announce that this new gene-editing strategy enables us to achieve nearly 100% knock-in of functional transgene cargos at specific locations in the genome. We believe that this has broad applications, not only for substantially improving current gene-editing cell medicines like CAR T and CAR NK cell therapies, but beyond those applications, it could have immense potential in protein replacement strategies, for example. Details of this exciting technology will be shared later this month in an oral presentation at the Cold Spring Harbor Laboratory's Conference. So having been with Editas for about two months now, I've outlined my high-level priorities as CSO, which are: firstly, to continue to advance our current in vivo, ex vivo and cell-based therapy platforms; to progress our in vivo gene-editing ophthalmology programs and further strengthen our existing clinical pipeline; expand our world-class gene-editing capabilities and the delivery technologies they rely upon; and finally, to continue to grow and develop the scientific base and team that is second to none. With this impressive technology and world-class talented Editas, I'm excited to discover and develop revolutionary new medicines to help people living with serious diseases. With that, I'd like to turn it over to Lisa.

Thank you, Mark, and I wanted to simply say I'm excited to have you join us as part of our team. Okay, as part I'd like to start with an update on the BRILLIANCE trial for EDIT-101 for the treatment of LCA10. Last quarter, we completed dosing of the adult mid-dose cohort. And as Jim mentioned, we met with the study's Independent Data Monitoring Committee to review the safety data from the adult low-dose and mid-dose cohorts. The IDMC agreed with Editas that we could begin rolling the first of the two planned pediatric cohorts. And this is an important step in the trials since LCA10 is an early-onset retinal degenerative disease, which results in vision loss and blindness at an early age. And we believe that younger participants in the study could provide the best opportunity to achieve the greatest magnitude of clinical benefit. As a reminder, LCA 10 is the most common cause of inherited childhood blindness, and it affects 3 out of every 100,000 children around the world. So new therapeutic options are urgently needed. And we continue to believe that a single administration would be preferred over a chronic dosing regimen by clinicians, parents, and the community. In addition to enrolling patients in the pediatric mid-dose cohort, we're also enrolling patients in the adult high-dose cohort. Both cohorts are planned to have four patients each, and we expect to complete dosing of the two dose groups in the first half of next year. We intend to present initial clinical data from EDIT-101 at the International Symposium on Retinal Degeneration in September. Now, this is an exciting milestone as it will be the first time that Editas will present clinical data at a meeting. The data will include safety and evaluation of the measures of biological activity from the 6 adult patients that have been treated in the first two dose cohorts. Now, the primary objective of the study is safety. Our goal is to develop a safe treatment that is not limited by dose-limiting inflammatory reactions, does not induce abnormal changes in retinal anatomy, and most importantly does not result in loss of vision that the patient may have. Our analysis of this early data set will consider all the observations across the multiple measurements that have been collected and are currently being collected, which will be shown at the symposium. Representative endpoints could provide evidence of productive editing and may include measurements of retinal responses to light as well as clinically relevant outcomes such as reproducible improvements in patient-reported visual acuity, or in the ability to maneuver around objects at different levels of illumination. Following the main study protocol, we will monitor patients for both safety and for secondary clinical endpoints every 3 months for a year, and continue follow-up for two additional years. Collectively, observing patient trends at each planned dose level over time, will validate EDIT-101 as a viable medicine for LCA10 and also help de-risk our subsequent molecular programs. I am very happy with how this trial has progressed during this year, and we aim to maintain the same pace for enrolling and dosing patients in the next two cohorts. Now, moving to our ex vivo programs, specifically EDIT-301. As we've said before, we believe that EDIT-301 has the potential to be a differentiated and important medicine for sickle cell disease and beta-thalassemia patients. Our Phase 1/2 RUBY study of EDIT-301 is active in screening patients, and we continue to add trial sites. Our CMC group is ready to support us with all clinical manufacturing required for the size of the study. We also have received an approved clinical trial application from Health Canada, which will expand the number of potential study sites, and we remain on track to begin patient dosing by the end of 2021. Additionally, we also remain on track to follow our investigational new drug application for EDIT-301 in beta-thalassemia by the year-end. Providing further preclinical support of the potential benefits of EDIT-301, we presented additional data at the European Hematology Association Congress in June. This data shows that editing at the beta-globin locus using our proprietary Cas12a enzyme results in a highly robust fetal hemoglobin induction and erythroid progenitor cells. Importantly, this occurred at a high level of specificity, and no detection of off-target editing. EDIT-301 mimics a naturally occurring mutation associated with hereditary persistence of fetal hemoglobin, as opposed to other approaches that target BCL11A. This approach and the presented data support our view that EDIT-301 differentiates itself from other programs through its highly efficient editing and specificity, which we anticipate will result in optimal safety and efficacy, and by demonstrating robust and sustained fetal hemoglobin expression with both short and long-term safety, we aim to have a best-in-class medicine to treat sickle cell disease and beta-thalassemia that will hopefully lead to longer lifespans for these patients. Our clinical operations teams for EDIT-101 and 301 have already been working very tirelessly to move these programs forward. And I truly believe that the sooner we can get our medicines to patients, the sooner we can deliver on our promise to transform people's lives. And with that, I'd like to turn things over to Michelle, to briefly run through the financial results.

Thanks, Lisa, and good morning, everyone. I'd like to refer you to our press release issued earlier today for a summary of our financial results in the second quarter, and I'll take this opportunity to briefly review a few highlights. Comparing the first half of this year to last year, total operating expenses increased by approximately $25 million. This was primarily related to an increase in stock-based compensation of $14 million as well as a $9 million success payment due under one of our institutional licenses that was expressed in full during the first quarter of this year. The remaining increase is driven by our expanding critical regulatory and manufacturing efforts to support both our BRILLIANCE and RUBY trials and the pre-IND work for EDIT-301 in beta-thalassemia. Quarter-over-quarter, total operating expenses were $56 million in the second quarter compared to $63 million for Q1. Excluding stock-based compensation of $12 million in Q1 and $14 million in Q2, and the $9 million success payment in Q1, operating expenses were essentially flat in the first two quarters of this year. Editas' balance sheet and cash position remains very strong. Our cash balance as of June 30 was $698 million compared to $723 million at the end of Q1. This capital will allow us to execute on our strategy to progress our clinical programs, further develop our pipeline and continue to build our internal manufacturing capabilities. We anticipate that this cash position will fund our operations well into 2023. With that, I'll hand it back to Jim.

Thank you, Michelle. The first half of this year has been very productive for Editas and the gene editing community. We continue to see important accomplishments in the field, including a successful demonstration of in vivo gene editing. This milestone reflects ongoing maturation of this novel therapeutic modality and immense potential for the technology. It supports the fundamental notion that a gene editing medicine administered directly to people can have a clinical benefit. And more importantly, this marks a monumental milestone for patients living with genetic diseases. Validating the potential power of CRISPR gene editing is a major stride forward for the genomic field and for the people who we are trying to help. As I've said in our previous call, it's truly a remarkable time to be involved in gene editing. I believe we have an obligation to utilize this once-in-a-generation technology to develop the best possible treatments for patients and promote progress within the scientific and medical communities. We thank all of you for your support and interest in the company. And with that, we'll open it up to questions-and-answers.

Thank you. We will now be conducting a question-and-answer session. Our first question comes from Gena Wang with Barclays. Please proceed with your question.

Thank you for taking my questions. I have two questions. The first one is regarding the LCA10 program. I think you mentioned the primary endpoint or like maybe a clinical measurement you will share. Just wondering like you mentioned visual acuity, wondering first of all, you also share mobility score. And then, how should we look at this in the context of a natural history when you share the data? And the second question is regarding the 301 for sickle cell disease. Just wondering has the FDA partial clinical hold already resolved? And when you are seeing the on track dosing of first patient, do you expect that will be resolved before year-end?

Lisa, are you there?

I apologize for being on mute. To answer your first question about the EDIT-101 program and the upcoming RD2021 meeting, I can summarize that the main focus of the study is safety and dose-limiting toxicity. We will present data and cumulative safety information from the patients in the first two cohorts at that meeting. It's important to note that this is an ongoing study, and we are gathering a significant amount of data with two main objectives. The first is to demonstrate that editing has occurred in the eyes, which will serve as proof-of-concept regarding any anatomical changes in the retina or responses to light. The second relates to efficacy measures like best-corrected visual acuity and mobility. However, I want to emphasize that it's still early in the trial; the longest patient in the mid-dose cohort was dosed only in January. We are actively collecting data and our intention is to analyze all measurements in each patient moving forward, with plans to share comprehensive data on both efficacy and clinical outcomes. As for your second question about the 301 study, it's important to clarify that we are facing a partial clinical hold, not a complete one, to validate the clinical assays we are using to correlate dosing with clinical efficacy. This hold does not hinder our progress; we can still dose patients according to our protocol. However, we will need some patient data to lift the hold with the agency in the future.

Thank you.

Thank you. Our next question comes from the line of Matthew Harrison with Morgan Stanley. Please proceed with your questions.

Good morning, everyone. This is Costa Sean for Matthew. One question from us on EDIT-101. Can you please remind us what the stopping criteria in the high-dose cohort? Thank you.

So the stopping criteria is very clear across all different dose cohorts. And that is basically the dose-limiting toxicity. This would include inflammatory responses that cannot be controlled with the use of steroids and would also include any potential loss in visual acuity in any patient who has something that is measured.

Thank you.

Thank you. Our next question comes from the line of Phil Nadeau with Cowen & Company. Please proceed with your questions.

Good morning. Congrats on the progress. A follow-up question for me on 101. In your corporate presentation, you mentioned secondary efficacy endpoints in 101's trial, including macula thickness, electroretinogram, and pupillometry. It sounds like you're going to use those to figure out if there's sufficient editing going on in the retina. As I'm not at all that familiar with those measures, can you give us some idea of what changes you'd need to see to have confidence that there's a sufficient amount of editing in vivo, that there could be ultimately improvements of visual acuity in a young enough patient population?

Okay. So basically, the way I've been dividing it up is and I think you summarized it actually quite well. The first one is a lot of electrophysiologic measurements as well as measuring physiologic responses to either different colors of light. Pupillary responses to light being shined in the eyes, because these patients do tend to have either reduced or very sluggish responses. If we were to see consistent changes moving forward in any of those measures that at least would be a signal to us that editing is taking place in the back of the eye. This is sort of my indirect way of measuring it without the ability to actually measure the protein that's being created in the eye moving forward. As to the clinically relevant endpoints, I would agree with those that say that basically, definitely those are things that impact a patient's ability to function, such as visual acuity or also the ability to maneuver around the maze would be the approval endpoints and the ones that would bring most value to the patient.

Perfect. Another follow-up question on 301. And the answer to the last question, it sounds like you'll need some clinical data to validate the assays necessary to remove the clinical hold. Do you have a definitive agreement with the FDA on the amount of clinical data that's necessary, the number of patients or duration?

At this time, we have proposed a framework to demonstrate consistency of the product provided to patients through various measures. Our intention is to present this to the agency once we have supporting data.

Perfect. Thanks for taking our questions.

Thank you. Our next question comes from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.

Thank you for answering my questions. Regarding the biomarkers, the various measures you will investigate to determine if there is editing, do we know if these measures change simply due to a subretinal injection, or do they vary in response to a placebo? Do we have any insight into the reliability of these biomarkers? Thank you.

I would like to invite Mark to contribute if he wishes. One of the key points for us is that the biological markers are essentially physiological responses. These markers are objective measures that allow us to observe physiological changes. The issue with placebo is that it lacks blinding; both the physician and the patient are aware of which eye has received treatment. This is the main reason we are emphasizing reproducibility. A single measurement indicating a significant improvement in vision is insufficient; we need evidence of sustainability across various measures over time.

Yes. And if I could add, thanks for the question, Yanan. As you know from covering the companies that are administering subretinal AAV, there is a possibility of slight changes in and around the surgical procedure as the retina reestablishes and reattaches. Those are usually tracked by comparing to the untreated. And as Lisa pointed out, over time, they generally settle down within a couple of weeks. And so, all that data gets collected and tracked and the intention is to show over time a real treatment effect that's separate from a surgical line or any other intervention-related page.

Got it. That's very helpful. And for, you mentioned, the longest follow-up in mid-dose cohort is since January. What about the shortest follow-up? Does that patient finished? Will that patient have finished their 3 months efficacy evaluation by the time of presentation?

I can tell you we're coming down to the wire on that one. So I need to be able to see what the timing of that visits going to be.

Great. Thank you.

Yes.

Thank you. Our next question comes from the line of Cory Kasimov with J.P. Morgan. Please proceed with your questions.

Hey, good morning, guys. Thanks for taking the question. My question is on 101 and 301 recovered. So wanted to ask about the iPSC NK program. And if you could just update us on the progress you're making there and upcoming milestones we should be on the lookout for. Thank you.

Mark, do you want to handle that one?

Yes. So, we've indicated in the corporate presentation some of the changes that are being made. And we continue to develop the necessary editing for the final construct, and also the differentiation profile and process for that. And so right now that's really what we're focused on, and we'll be providing updates again later in the year on the progress.

Thank you. Our next question comes from the line of Joon Lee with Truist Securities. Please proceed with your question.

Hi. Thanks for taking our questions. For cohort two, are the patients enrolled also light perception only, like cohort one or are they able to perceive hand motion or better in the cohort two? And I have a follow-up on 301.

For 101, the protocol has been modified based on the safety observed in the first cohort, allowing us to move beyond just light perception patients. Each dose level includes one sentinel patient whose main role is to assess safety and ensure there are no inflammatory reactions that could restrict treatment for additional patients. The first patient has light perception, but subsequent patients can exhibit improved visual acuity.

Okay. Following up on that, the data shows that their visual improvements, including best corrected visual acuity and mobility, were noticeable as early as the first and second month. Is there any reason to think that the effects of 101 would be slower than those from antisense mediated exon skipping? I'm interested in your thoughts on the genetics of the onset of clinical effects between genome editing and other methods.

So regarding the absolute timing, we know from non-clinical data that optimal editing occurs about six weeks after injection. As Mark mentioned, there also needs to be some healing in the back of the eye due to the procedure. Therefore, the first measurement where we expect to see some changes would be at three months. However, since we are really looking for consistent responses and potential improvements, we will be monitoring it for at least six months or longer. Comparing the two different modalities is challenging due to the very different approaches.

Got it. And just for clarification, the cohort two will be four patients worth of data?

So each cohort is planned to be four patients and then we'll evaluate.

Okay. Thank you.

Yes.

Thank you. Our next question comes from the line of Tiago Fauth with Credit Suisse. Please proceed with your questions.

Hi. This is Jonathan on for Tiago. Thanks for taking our question. For EDIT-101 in light of the upcoming readout for the low and mid-dose cohorts for the adults, how should we be thinking about how these results may translate to the respective doses in the pediatric cohorts? What are the key differences we should be thinking about that? Thanks.

I believe we still need to learn more about the observations. Generally, after about three years of age, the anatomy and size of the human eye remain relatively stable. Most changes in the eye are usually completed by around six to eight years of age. Therefore, I don't anticipate significant differences in clinical response or safety. We will have the opportunity to evaluate this as we progress.

Got it. Thank you very much.

Yes.

Thank you. Our next question comes from the line of Steve Seedhouse with Raymond James. Please proceed with your question.

Good morning. Thank you. I'm curious beyond editing efficiency what advantages you anticipate from using the AsCas12a in sickle cell, such as cell viability, doubling time, and manufacturing success rate, compared to older nucleases that could lead to better clinical outcomes? Also, regarding the ultra nuclease, it seems compact enough to fit into AAV5. Do you have any thoughts on advancing that nuclease into LCA10, or for future ocular disorders, is it just a nuclease that you plan to use? Thanks.

So, maybe I can take those questions. So as you saw in the Nature Communications paper, the engineered Cas12a or Cas12a Ultra has a lot of very favorable properties. You mentioned some of them, specificity, the on-target editing, efficiency, and potency. One other factor, which is important for us also is the guide RNA size tends to be quite a bit smaller than the Cas9 guides, and that's important when you're manufacturing these guide RNAs because the fidelity decreases with the longer the length of the guides. And so we feel that that is definitely an advantage for intrinsic on-target editing. And the second part of your question, of course, yes, we can fit a Cas12a into an AAV and so we're looking to deploy that in some of the in vivo gene editing programs that we have ongoing and potential future ones and actively working on optimizing the potential configurations that you could use with respect to the guides. So all of that is in progress.

Thank you. Our next question comes from the line of Joel Beatty with Citi. Please proceed with your questions.

Hi, thanks for taking the questions. For the LCA10 program in the pediatric mid-dose cohort, what ages and disease statuses do you expect in the children? Do you anticipate enrolling them, and how might that affect the interpretation of clinical results compared to the first cohort we will be reporting on in September?

We have to balance a few factors because the protocol allows us to treat patients as young as 3 years old. However, a key goal for us is not only safety but also the patient's ability to cooperate during various observations. Ultimately, we are looking for a clear indication of efficacy. Therefore, when selecting the first patients for the cohort, we are considering their ability to participate in these observations. While there isn't a strict cutoff, we think about whether a 5 or 6-year-old can manage a long day filled with observations as part of our decision-making process.

Okay. Appreciate that. Thanks.

Yes.

Thank you. Our next question comes from the line of Jay Olson with Oppenheimer. Please proceed with your question.

Oh, hey, congrats on the progress and thank you for taking our questions. On the EDIT-101 data coming in September, can you talk about whether or not we should expect to see the clinical measurements fluctuate over the follow-up period or remain relatively consistent? And then for any safety signals, are there ways to tell whether potential side effects are coming from the administration procedure, the AAV vehicle, or the gene editing? And then I had a follow-up on SCD, if I could.

Okay. So I guess the first one is the consistency of measures. I just want to remind everybody, it’s still relatively young days for that middle-dose cohort. Because like I said, the first patient was started in June, and the next 3 patients were enrolled over the following 5 months, so for some of these patients, we won't have that much reproducible data just yet. As for the safety observations, it is one of the more important observations of the trial, not just short-term toxicity related to inflammation or problems related to the administration of the product, but also any changes that might occur in the eye moving forward. So that data is being collected prospectively.

Great. Thank you. And then for 301 in the SCD study, can you just talk about your timeline for completing the target enrollment in that study? And then maybe comment on what the FDA might want to see in terms of a follow-up period in SCD given some potential safety concerns from other companies using gene therapy?

So the second half of the question is we are expecting, and in fact, it's sort of standard across the entire gene therapy and gene editing space that long-term follow-up for safety will be a requirement. So pharmacovigilance is going to be something that all of us have to be addressing moving forward. As to our timeline, it's still again early days. We actually are actively opening up sites. We have a number of patients who are undergoing screening, and I'm focusing mostly on getting my first patient dosed by the end of this year.

Great. Thanks for taking the question.

Yes.

Thank you. Our next questions come from the line of Madhu Kumar with Goldman Sachs. Please proceed with your questions.

Great. Thanks for taking our questions. So when we think about EDIT-101, the high dose versus a median low-dose, frame those doses relative to the preclinical dose range you described in your previous studies. And then kind of following from that, what are you confident that a higher dose of 101 could achieve better outcomes for LTA patients? Thanks.

Mark, do you want to try that one, or you want me to bite?

No. The doses chosen for the clinical study are guided by the preclinical pharmacology and toxicology work conducted in mice and non-human primates. In response to the question about whether a higher dose will lead to better editing, we have evidence, especially from human models, that supports this idea. There is some indication from non-human primates that this might also apply. However, the data is less clear for non-human primates as their performance was not as effective as that of humans. In principle, the expression of the nuclease components and the productive editing increases with dose. Therefore, moving from the mid to high-dose, which is a threefold increase, we would expect to see better results. Nonetheless, the clinical data will ultimately determine this.

Thank you. Our next questions come from the line of Liisa Bayko with Evercore. Please proceed with your question.

Hi. Thanks for taking the question. I'm wondering as you think about the kind of available visual field for these patients for EDIT-101, can you maybe describe kind of with the way you're administering, how much is kind of, I don't know, in a way surface area would be available for editing? And is there anything you can do to kind of expand that further?

I guess I will start with, go ahead, Mark. We can compete over this if you want.

Across different fields where companies have introduced a bleb up to, for example, 300 microliters covering about a 20-degree area, so completely covering the macula, which is the important component here for the ability to restore cone function. So I hope that answers your question. But that's the intent with the current dosing paradigm.

So what you're indicating is that you can cover the entire macula with that, and that should be adequate for covering the visual field effectively.

Well, that's covering the majority, if not all of the cone expression, which are obviously contained in the maximum region, plus the rods, which also expressed more sparsely but expressed in that area. So again, this is, I would say, the standard approach to covering central retina AAV treatments.

Okay. And I would say that LCA10 is somewhat of a central retina, basically what's happened in many of these patients is there is a preserved area of cells of normal cells where there hasn't been degeneration. And actually, that's in the central retina itself. So these are the cells that are most likely the ones that we're going to have the best effect from?

Yes. And maybe just to add a point, I mean, companies have attempted to put the bleb either outside the mid-periphery, or in some cases, multiple blebs for the former approach. The disease quite often is heterogeneous in the periphery. So it's not that straightforward to actually carefully cover the degenerative rod area if that's what you were attempting to do. And then the challenge with the multiple bleb approaches on the one hand, yes, you can cover a greater area, but then you're introducing multiple retinotomies and one of the things you absolutely want to avoid is reflux of the product because as you may be aware, intravitreal dosing, which essentially what's been happening leads to a greater likelihood of ocular inflammation. So those are the tradeoffs that you're considering.

Okay. Okay, that's helpful. Thank you. And then for EDIT-301, as you kind of look at the data, the clinical data coming out from companies like Vertex, CRISPR and where do you see the opportunity? I know theoretically the kind of advantages you're describing, and those make sense, but sort of in a practical form as you kind of look at the data that's evolving, where do you see the opportunity to make a difference with EDIT-301? Thank you.

Well, let me take that one, Lisa. I think you have to take a little bit longer view of what trials in sickle cell and beta-thalassemia are attempting to accomplish, which is ultimately long-term morbidity and mortalities — or organ damage and extension of life, which is a big issue for these patients. So I think, as you see things unfold, yes, the initial data coming out of the other companies is actually impressive, and that's great for the patients. But I think we have to see how this unfolds over a longer period of time. And so, I would expect that this field, there'll be long-term efficacy and safety studies used in this field. And that's how things will differentiate. And then ultimately, as efficacy is demonstrated, and the safety is demonstrated, companies are going to go to work and some already are. What are the conditioning strategies or basically how to make the treatment burden as light as possible for patients? And that may also relate to the drug, the simplicity of the drug, how much drug you have to deliver, how many cells you have to collect, etcetera, etcetera. So I think there's a number of other variables that will come into play as things unfold.

Thank you. Our next questions come from the line of Luca Issi with RBC. Please proceed with your questions.

Thank you for taking my question. Congratulations on all the progress. I have two quick questions, one for Lisa and Mark, and the other for Jim. So for Lisa and Mark, since you're using AAV to deliver your construct, I understand the FDA is holding an advisory committee meeting on September 2 and 3 to discuss the safety of AAV. Are you planning to participate in that meeting, and what are your expectations going into it? Jim, looking at the bigger picture, what is your current perspective on business development? Considering the three main parts of your pipeline—eye conditions, hemoglobinopathies, and oncology—which do you see as core to Editas's future, and which might you consider partnering on? Also, do you have any interest in enhancing your pipeline through in-licensing?

I can address the first question. Yes, we will be participating in the FDA meeting to discuss some emerging issues with AAV. In response to the second part, people are utilizing a vehicle in various approaches and at significantly different quantities. The ocular space is one of the reasons this was one of the initial areas where AAV was used as a delivery method; it has a well-defined anatomy, allowing for precise delivery of the product in relatively low amounts—typically 100 to 1,000 times less than the doses used in other systemic administrations. This meeting will be significant. Some aspects related to integration or immunogenicity may be more pertinent to those in the DMV and hemophilia communities, who are using higher levels and clearly experiencing immune-related responses. However, the outcome of the meeting will provide guidelines and further direction, which is important to consider, and if it becomes relevant for SSRS, we will fully engage and participate.

So, let me address the second part regarding our overall business development strategy. In addition to building our leadership team that I mentioned earlier, we are also enhancing the depth of our team. With Mark now here, I'm excited about his presence. Lisa is finding some bandwidth to start considering the broader strategy, and we've brought on Bruce Eaton, allowing us to think critically about our strategy. Regarding our business development approach, having been in the industry for a long time, I have a pragmatic view on what we can execute and where we might require assistance. We have a productive relationship with BMS on the T cell side of oncology, and we've made considerable progress with our iPSC-derived NK platform. However, as we enter clinical development and proceed toward commercial stages, it will be beneficial for us to engage a partner. Identifying the right timing for this is always challenging, but it's a top priority. Likewise, I feel confident about advancing the 301 program clinically, but we would ultimately need a commercial partner, especially outside the U.S. I recognize that a commercial partner will expect to be involved in late-stage development as well. In terms of in-licensing, we are actively discussing various opportunities, which can take many forms. One significant challenge in gene editing is ensuring that the editing machinery effectively reaches the correct organism or cell type with the right efficiency and safety. Our three programs represent different approaches to delivering editing as a therapeutic, and we are open to exploring additional options. While AAV has its advantages, it also has limitations, and we are looking at other successful methods for appropriate indications and alternative delivery systems. Additionally, we are interested in technologies or therapeutic areas that complement our current efforts, such as ocular programs where we have a considerable interest, and we are keen on enhancing our pipeline in that area. I hope this provides clarity.

Fantastic. Yes, thanks so much. Appreciate it.

Yes.

Thank you. There are no further questions at this time. I would like to turn the call back over to management for any closing remarks.

Well, thank you very much, everyone. A lot of great questions today. Really appreciate all the interest. We will have — I know a number of conversations here over the upcoming days, and I greatly look forward to talking with all of you in the future. Thanks again, and I think we will call it a day. Appreciate your time. Take care. Bye.

Thank you for your participation. This does conclude today's teleconference. You may disconnect your lines at this time. Have a great day.