Good morning, and welcome to Editas Medicine's second quarter 2021 conference call. I would now like to turn the call over to Ron Moldaver, Investor Relations at Editas Medicine.
Thank you, Daryl. 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 two 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, James Mullen.
Thanks, Ron. 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 has had a strong first half of the year with excellent momentum across our platforms and lead programs. The EDIT-101 BRILLIANCE trial for LCA 10 is proceeding very well, with the independent data monitoring committee recently endorsing enrollment of the first of two planned pediatric cohorts, and we've also started enrolling patients in the adult high-dose cohort. We are also expected to share initial clinical data from the EDIT-101 trial this September. This will mark the company's first-ever clinical data readout.
The RUBY study of EDIT-301 for sickle cell disease is screening patients. 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. 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. We plan to present new data on our multi-transgene knock-in proficiency at 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. 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 Li brings an extensive resume guiding over 30 development programs through regulatory processes, including multiple U.S. and global submissions. 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 brings 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 and with our expanded executive team, I have the utmost confidence that we have the right people in place to lead Editas through 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 as Editas Chief Scientific Officer. Mark.
Thank you, James, and thank you to everyone dialing in. 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 James, the rest of the leadership team, and the exceptional people throughout the organization. To give you a brief background about myself, I have almost 30 years of drug discovery and development experience
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 science or technology that can improve the likelihood of being successful in drug development, or which open new treatment avenues for patients who otherwise might not have other options. Editas' 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. Two examples illustrate this point.
Firstly, the recent publication in Nature Communications that James Mullen 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 off-target and 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 RNAs. 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 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. 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 pre-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 build upon a research and development team that is second to none.
With this impressive technology and world-class talent at 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. I want to just simply say I'm excited to have you join us as part of our team. Okay. 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 James Mullen 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 enrolling the first of the two planned pediatric cohorts. This is an important step in the trial since LCA10 is an early onset retinal degenerative disease, which results in vision loss and blindness at an early age. We believe that younger participants in the study could provide the best opportunity to achieve the greatest magnitude of clinical benefit.
As a reminder, LCA10 is the most common cause of inherited childhood blindness, and it affects three out of every 100,000 children around the world, so new therapeutic options are urgently needed. We continue to believe that a single administration would be preferred over a chronic dosing regimen by clinicians, parents, and the patient 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. 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 six adult patients that have been treated in the first two dose cohorts. The primary objective of the study is safety. Our goal is to develop a safe treatment that's 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 would provide evidence of productive editing, may include measurement of retinal responses to light, as well as clinically relevant outcomes such as reproducible improvement 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 three months for one 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 ocular programs. I'm very happy with how this trial's progressed during this year, and we aim to maintain the same pace for enrolling and dosing patients in the next two cohorts. 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 in beta thalassemia patients. Our phase I/II 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 this phase 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 file our Investigational New Drug application for EDIT-301 in beta thalassemia by the year-end. Providing further pre-clinical support of the potential benefits of EDIT-301, we presented additional data at the European Hematology Association Congress in June. This data showed that editing at the beta-globin locus using our proprietary Cas12a enzyme, results in a highly robust fetal hemoglobin induction in erythroid progeny 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. 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.
With that, I'd like to turn things over to Michelle to briefly run through the financial results. Michelle?
Thanks, Lisa. Good morning, everyone. I'd like to refer you to our press release issued earlier today for a summary of our financial results for the second quarter. 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 expensed in full during the first quarter of this year. The remaining increase is driven by our expanding clinical, regulatory, and manufacturing efforts to support both our BRILLIANCE and RUBY trials and the pre-IND work for EDIT-301 for 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's balance sheet and cash position remains very strong. Our cash balance as of June 30th 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 James.
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 the successful demonstration of in vivo gene editing. This milestone reflects the 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. 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 people who we are trying to help. As I've said on a 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. With that, we'll open it up to questions and answers. Operator?
Thank you. We will now be conducting a question- and- answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. Our first questions come from the line of Gena Wang with Barclays.
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 the clinical measurement you will share. Just wondering, you mentioned visual acuity. Wondering first, will you also share mobility course score? How should we look at this in the context of a natural history when you share the data? The second question is regarding the EDIT-301 for sickle cell disease. Just wondering, has the FDA partial clinical hold already resolved? When you say on track dosing the first patient, do you expect that will be resolved before year-end?
Lisa, are you there?
Pardon. Gena, I apologize. I was on mute. I was trying not to cough into my microphone. To your first question, Gena, regarding what's going to be reported for the EDIT-101 program moving into the RD2021 meeting. I've already summarized. The primary outcome of the study really remains safety and dose-limiting toxicity. The data and the cumulative safety data of the patients who've been dosed in the first two cohorts will definitely be presented at that meeting. What I want to remind people is that this is still an ongoing study moving forward over time, and that we collect a quite large number of observations with two primary goals.
The first one is for the purposes of being able to demonstrate that editing has actually occurred in the eyes, and that would be a very interesting proof of concept for us to share regarding any potential changes that have occurred either in the anatomy of the retina or also reflections of responses of the retina to light. The second one regarding the efficacy outcomes that you've alluded to, such as BCVA and also for being able to maneuver in the maze. I want to remind everybody it's still quite early in the trial. The longest patient in the mid-dose cohort was only dosed in January, so we're still collecting data prospectively.
It's certainly our intent to look across the entire range of measurements in each individual patient moving forward, and that we will be sharing at least data that will be comprehensively looking at both the possibility of being able to show both efficacy as well as clinical outcomes at the study. Beyond that, I'm not yet prepared to give you more detail. To the second question with 301, I just remind everybody, it's not a complete clinical hold. It is a partial hold, basically in order to be able to validate the clinical assays that we're using to correlate dosing to clinical efficacy. It does not interfere at all with our ability to move forward. We are able to dose the patients in the trial, in an ongoing fashion, as already outlined in the protocol. It's actually having no impact on our ability to move forward.
We will need to have some patient data to correlate in order to be able to lift the hold with the agency later on.
Thank you.
Yeah.
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 on for Matthew. One question from us on EDIT-101. Can you please remind us what the stopping criteria are in the high-dose cohort? Thank you.
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's measured.
Thank you.
Thank you. Our next question comes from the line of Phil Nadeau with Cowen and Company. Please proceed with your questions.
Good morning, and congrats on the progress. Follow-up question from me on 101. In your corporate presentation, you mentioned secondary efficacy endpoints in 101's trial, including macular 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. Guess I'm not 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 in visual acuity in a young enough patient population?
Basically the way I've been dividing it up is, 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. 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, those 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 approvable endpoints and the ones that would bring most value to the patient.
Perfect. Another follow-up question on 301. In 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 the moment, we have at least proposed a matrix in order to be able to show across multiple different measures to show consistency of the product being given to the patients. The plan is to actually be able to present that to the Agency once we have data to support it.
Perfect. Thanks for taking our questions.
Thank you. Our next questions come from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.
Thanks for taking my questions. On the biomarkers, for lack of better words, the several measures that you will investigate to understand whether there's editing. Do we know that those measures, do they change simply by subretinal injection, for example? Do they change based on a placebo-type response? Do we have some understanding of how reliable those biomarkers are? Thanks.
And I invite Mark to jump in if he feels like he wants to add color to it, but I think one of the most important things for us is, first of all, the biologic markers are basically physiologic responses. These are purely objective measures that we can actually measure physiologic changes that can take place. The concern about placebo is that it is unblinded. Both the treater and the patient both know which eye has been treated, and this is the primary reason why we're actually focusing on reproducibility. A one-time measurement that shows a significant change in vision is not going to be enough for us. It really needs to be able to be sustained across multiple different measures over time.
If I could add. Thanks for the question, Yanan. As you know from covering other companies that are administering subretinal AAV, there is a possibility of slight changes in and around the surgical procedure as the retina reattaches. Those are usually tracked by comparing the untreated eye, and as Lisa pointed out, over time, they generally settle down within a couple of weeks or so. All of that data gets collected and tracked, and the intention is to show over time a real treatment effect that's separate from any surgical or any other intervention-related change.
Got it. That's very helpful. You mentioned the longest follow-up in mid-dose cohort is since January. What about the shortest follow-up? Will that patient have finished the three-month efficacy evaluation by the time of presentation?
I can tell you we're coming down to the wire on that one, so I'd need to be able to see what the timing of that visit's going to be.
Okay. Great. Thank you.
Yeah.
Thank you. Our next questions come from the line of Cory Kasimov with JP Morgan. Please proceed with your questions.
Hey, good morning, guys. Thanks for taking the question. My questions on EDIT-101 and EDIT-301 were covered, so I 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? Yeah. 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. 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 questions come from the line of Joon Lee with Truist Securities. Please proceed with your questions.
Hi. Thanks for taking our questions. For the Cohort 2, are the patients enrolled also light perception only, like Cohort 1, or are they able to perceive hand motion, or better in the Cohort 2? I have a follow-up on EDIT-301.
Okay. For 101, the way the protocol is basically written is based upon the safety that was seen in the first cohort, we were able to modify the protocol so that we could proceed beyond just light perception patients. However, at each dose level, we do have one sentinel patient who's enrolled primarily for the purposes of evaluating safety and making sure there's no inflammatory reactions that would limit treatment of further patients. The first patient is light perception, but each additional patient enrolled can have better visual acuity.
Okay. I have to follow up on that. If you look at the sepofarsen data, there are visual improvements, including BCVA and mobility evident as early as month one and month two. Is there any reason to believe that the effects of EDIT-101 would be any slower than the antisense-mediated exon skipping? Curious if you have any thoughts on the kinetics of the onset of clinical effect between genome editing versus antisense oligomer.
I guess the way, if you're thinking in terms of the absolute timing, we do know that from our non-clinical data that the optimal editing has occurred by about six weeks after injection. As Mark has alluded to, there also, because of the procedure, needs to be some healing that needs to take place in the back of the eye. The first measurement that we would expect to see some change would be at three months. However, because we're really looking for consistent responses as well as potential improvement, following it out to at least six months or longer is going to be what we're going to be looking at. It's hard to compare the two different modalities since they're very different approaches.
Got it. Just for clarification, the Cohort 2 will be 4 patients worth of data?
Each Cohort is planned to be 4 patients, and then we'll evaluate.
Okay, thank you.
Yeah.
Thank you. Our next questions come 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 there? Thanks.
I think we still have yet to kind of learn that in terms of the observations. In general, the maturity of the human eye, after you get about three years of age, at least the anatomy and the size of the eye are relatively similar. Most of the changes that occur in the eye are more or less completed by about six-eight years of age. I don't know that we're going to see a difference in terms of clinical response or safety. We'll have a chance to evaluate that as we move forward.
Got you. Thank you very much.
Yeah.
Thank you. Our next questions come from the line of Steve Seedhouse with Raymond James. Please proceed with your questions.
Good morning to you. First on EDIT-301, I'm just curious, beyond editing efficiency, what advantages you might anticipate from using the AsCas12a in sickle cell, specifically like cell viability, doubling time, manufacturing success rate, things like this, compared to legacy nucleases that may obviously correspond to improved clinical outcome. Also on that ultra nuclease, it looks like it's small enough to package into AAV5. Any thought on advancing that nuclease into LCA10 or, in future ocular disorders, is this the nuclease you're planning on using? Thanks.
Maybe I can take those questions. As you saw in the "Nature Communications" paper, the Cas12 engineered Cas12a or AsCas12a Ultra has a lot of very favorable properties. You mentioned some of them, specificity, the on-target editing efficiency, potency, all of that. 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 the longer the length of the guide. We feel that that is definitely advantage for intrinsic on-target editing.
To the second part of your question, of course, yes, we can fit a Cas12a into an AAV. 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. All of that is in progress.
Thank you. Our next questions come from the line of Joel Beatty with Citi. Please proceed with your questions.
Hi, this is Joel from Baird. Thanks for taking the questions. For the LCA10 program in the pediatric mid-dose cohort, what ages and what status of disease course in the children do you anticipate enrolling in? What could that mean for the ability to interpret clinical results compared to the first cohorts that we'll be reading out in September?
We've got a little bit of a balancing act in all of this because the protocol does allow us to go as young as three years of age in the treatment of the patients. I think one of the key outcomes that we want out of this is not just safety, but it's also the ability of the patient to be able to cooperate with the various different observations, because what we're looking for at the end of the day is a clear signal of efficacy. The selection of the first patients who will be treated in the cohort are being considered about their ability to participate in the observations.
I think there's no solid drawn line in here, but if you think about your five or six-year-old, whether they can sit through a long day of observations and walking through mazes, I think is part of our consideration.
Great, appreciate that. Thanks.
Yeah.
Thank you. Our next questions come 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? 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? I had a follow-up on SCD, if I could.
Okay. 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 three patients were enrolled over the following five months. 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. That data is being collected prospectively.
Great. Thank you. 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?
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, and 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.
Yeah.
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 question. When we think about EDIT-101, the high dose versus the mid and low dose, frame those doses relative to the pre-clinical dose range you described in your previous studies. Following from that, what's helping keep confidence that a higher dose of 101 could achieve better outcomes for LCA10 patients? Thanks.
Mark, do you want to try that one or you want me to bite?
No. The doses, as I'm sure you've already asked a similar question before, the doses chosen for the clinical study were obviously guided by the preclinical pharmacology and toxicology work that was done in mice and non-human primate. To address the question about whether we think a higher dose will lead to better editing, we have evidence, particularly in the humanized mouse model, that would be the case. I think in non-human primates, there is some indication that that could also occur. The data was, I would say, less clear in terms of the fact that the NHP guides were not performing as effectively as the human ones.
In principle, yes, the expression of the nuclease components and the productive editing increased with dose, going from the mid to high dose, which is a factor of three, going into it, we would have an expectation that that could yield better results. Obviously, the clinical data will have to bear that out.
Thank you. Our next question comes 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, with the way you're administering, how much, 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?
Go ahead, Mark. We can fight each other for this one if you want.
No. All I was going to say is that across different fields where companies have introduced a bleb up to, for example, 300 microliters, you're covering about a 20-degree area, so completely covering the macula, which is the important component here for ability to restore cone function. I hope that answers your question, but that's the intent with the current dosing paradigm.
Okay. What you're saying is you can cover the entire macula with a bleb, and so that should be sufficient in terms of.
So that's-
like kind of covering the visual field in a way.
well, that's covering the majority, if not all of the cones' expression, which are obviously concentrated in the macular fovea region, plus the rods, which are also expressed more sparsely, but expressed in that area. Again, this is a, I would say, pretty standard approach to covering central retina AAV treatments.
Okay.
I would say that an LCA10 is somewhat of a central retina. Basically, what's happened in many of these patients is there is a preserved area of normal cells where there hasn't been degeneration, and actually that's in the central retina itself. These are the cells that are most likely the ones that we're going to have the best effect from.
Yeah. Maybe just to update, 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 are attempting to do. The challenge with the multiple bleb approach is, on the one hand, yes, you can cover a greater area, but then you're introducing multiple retinotomies. One of the things you absolutely want to avoid is reflux of the product, because, as you may be aware, intravitreal dosing, which is essentially what's then happening, leads to a greater likelihood of ocular inflammation. Those are the trade-offs that you're considering.
Okay. Okay, that's helpful. Thank you.
For EDIT-301, as you look at the data, the clinical data coming out from companies like Vertex, CRISPR, 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 look at the data that's evolving, where do you see the opportunity to make a difference with EDIT-301? Thank you.
Do you want me to take that one, Lisa?
Well, you always answer it so well.
You got it, though.
I'm happy to let you take this. You usually answer it really well.
Well, yeah. I'll take that 1, James. 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 mortality, so organ damage and extension of life, which is a big issue for these patients. I think we have to see how this unfolds over a longer period of time. I would expect that this field, there'll be long-term efficacy and safety studies used in this field. That's how things will differentiate.
Ultimately, as efficacy is demonstrated and the safety is demonstrated, the companies are going to go to work, and some already are, on what are the conditioning strategies or basically how to make the treatment burden as light as possible for patients. 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, et cetera. 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.
Oh, terrific. Thanks so much for taking my question. Congrats on all the progress. Two quick one for Lisa and Mark, and the other one for James. For Lisa and Mark, you're obviously using AAV to deliver your construct, and I think the FDA is having an advisory committee meeting September 2nd and 3rd to talk about the safety of AAV. Wondering, 1, if you're planning to participate in that AdCom, and 2, what are your expectations getting into that event? Maybe James, for you, bigger picture, what's the latest thinking of business development when you think about the three big dimension of your pipeline, which is obviously the eye, hemoglobinopathies, and oncology, which of them you think are going to be core to Editas story going forward versus which one maybe you're willing to partner?
Maybe on the in-licensing side, do you have any appetite to actually bolster your pipeline via BD? Thanks so much.
Maybe I can take the first question. Yes, we will be participating in the FDA meeting to discuss some emerging issues with AAV. What I would say to answer the second part of that is people are using AAV for multiple very different approaches and at significantly different amounts. I think the ocular space, one of the reasons why this was one of the first areas that people used AAV as a delivery vehicle is because there's a very defined anatomy. You can deliver the product very carefully to the right place, and it's at relatively low amounts, one hundredth to one thousandth of the dose that some of the other systemic administrations are using. I think that meeting will be important.
I think some aspects of it around viral integration or immunogenicity are probably more relevant for the DMD and the hemophilia folks, where they're using much higher levels, and you do clearly have immune-related response. The meeting will result in some guidelines and some further direction, and that's obviously important to be aware of. If it becomes relevant for Editas, we'll fully participate and be part of that.
Luca, let me take the second part of that, which is sort of BD strategy overall. In addition to building the leadership group that I talked about early in this call, we have also been building depth below that leadership group. For the first time, and now Mark's here, I'm thrilled to have Mark. Lisa's getting a little bit of bandwidth to start thinking about sort of the broader strategy, and we've appointed Bruce Eaton, that we've really got the team together now to really rigorously sort of think about strategy. Let me take you to the sort of how we're thinking about BD. I've been in the industry a long time, and so I'm fairly pragmatic about what do we think we can execute and what do we think we will ultimately need help with.
We've got a nice productive relationship with BMS on the T cell side of oncology. We've made, I think, pretty significant advancements on our iPSC-derived NK platform. There's an area where I think going into clinical development and certainly further into clinical development and commercial that we will be best served if we have a partner in that. That will be something that we will look to. It's always hard to judge exactly what the right moment in time is to do that, but that will be a high priority. Similarly, with the 301 program, I feel very comfortable that we can advance that one clinically, but ultimately we would want a commercial partner, particularly ex-U.S. Certainly, I also know that that means if you get a commercial partner, they're going to want to participate at some meaningful level in the late-stage development, right?
Those would be sort of two bigger pieces. With respect to thinking about in-licensing things, we are actively talking about that. I think that can come in different flavors and forms. We have, as you know, what I consider the sort of the biggest challenge in gene editing is we can edit, we know that. It's can you get the editing machinery to the right organ or the right cell type at the right efficiency with an appropriate safety profile? When you think about our three programs, they are in some ways three different ways of delivering editing as a therapeutic. We'll look at additional ones. AAV, as good as it is, has its own limitations. We've seen other people with LNPs for the right indications, LNPs and or other different delivery modalities are certainly something we'd look at.
Lastly, things that potentially complement either our technology or a therapeutic area where we have an interest, for example, ocular, where we have a number of programs, we would certainly look to think about augmenting the depth of our pipeline there. Hopefully that helps.
Fantastic. Yeah, thanks so much. Appreciate it.
Yep.
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.