Editas Medicine, Inc.

Good day and thank you for standing by. Welcome to the Q1 2021 Adidas Medicine Earnings Conference Call. At this time, all participants are in listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0. I would now like to hand the conference over to your first speaker today, Ron Moldover, Investor Relations. Please go ahead.

Thank you, Julianne. Good morning, everyone, and welcome to our first quarter 2021 conference call. Earlier this morning, we issued a press release providing our financial results and corporate updates for the first quarter of 2021. A replay of today's call will be available on the investor's 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, Jim Mullen.

Good morning, everyone, and thank you for joining us today. In addition to Ron, I'm joined by Lisa Michaels, our Chief Medical Officer, and Michelle Robertson, our Chief Financial Officer. I'll start by providing some highlights from the first quarter and reviewing our broader corporate strategy. Then I'll hand it over to Lisa to discuss our clinical and preclinical progress, and then Michelle will provide an update on our financial results and cash position. We've had a strong start to the year. The brilliance trial for Edit 101 is progressing very well, and we expect to share clinical data by year-end. The first clinical site in the RUIDI trial for EDIT301 has been activated and has begun to screen and recruit patients. The pre-IND work for EDIT301 in beta thalassemia is advancing, and we expect it to be filed before year end. We've also made excellent headway in the manufacturing side as we prepare to involve patients in the RUIDI trial. We continue to progress our oncology platform with our longstanding partner, Bristol Myers Squibb, opting into another program this past quarter. And finally, our capital raise from January gives us a comfortable financial position to advance our clinical trials and preclinical pipeline. From an organizational leadership perspective, I'm pleased to announce that Dr. Mark Shearman will be joining us next month 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. There are two reasons why we believe Mark will be successful as Aditas' new CSO. First, his areas of expertise in ophthalmology, immunology, and neurology have considerable overlap with Aditas' current platform medications. Mark will advance our existing programs in these indications while utilizing our world-class gene editing technology to expand our preclinical pipeline into potentially other therapeutic areas. Second, and more importantly, Mark is a successful and respected leader of large global research teams. As Editas continues to grow, Mark's experience at companies like Merck and most recently at Applied Genetic Technologies will help facilitate the right structure to support our progress and allow us to attract the right talent. Mark's addition significantly strengthens our leadership team, and I look forward to having him join us on our next earnings call. In addition to recruiting Mark, I have spent time during the first months as CEO by meeting with every Editas employee, albeit mostly through a virtual format. These conversations help me appreciate what people draw to Editas and what we can do as an organization to attract and retain world-class talent. Speaking with every editor has only strengthened my confidence in our people and the technology and platforms that we are developing. By having these conversations across all levels of the organization, I had a chance to better understand the intricacies of our gene editing technology and our platforms and how we can synergistically leverage these existing assets towards further development. Both on top of our gene editing technology, we have three principal platforms. First, we have in vivo gene editing focused initially on ocular diseases. Next, we have the ex vivo platform focusing on sickle cell and beta thalassemia. And finally, we have our cellular therapeutic platform focusing on oncology. These three platforms have their own intrinsic values and they also provide us with building blocks for continued sustained growth. The programs within each of these vehicles serve within each of these platforms serve as vehicles for proof of concepts. Once we demonstrate that we can reduce our genetic technology to practical applications. Then we'll have actual products that could impact patients' lives in a way never seen before. These are not just three different areas of therapeutic indications. These are three different ways to use gene editing to solve different problems. And finally, being a leader in genomic medicine requires immense expertise and resources. As we continue to advance our programs, partnerships will be critical for development and commercialization. We will pursue opportunities to extend our leadership and accelerate, enable, and expand our pipeline. We believe we've been successful to date, as exemplified by our collaboration with Crystal Myers Squibb, a global leader in oncology. As mentioned, that partnership is progressing along, with BMS opting into an additional program this quarter. In addition to a declared development candidate at the end of last year, this marks another important milestone in the span of six months under this collaboration. further validating our technological expertise in the space. Overall, I'm extremely happy with our year-to-date progress. There are still challenges that we need to overcome, and I'm confident that we'll have the right people in place to accomplish our short-term milestones and our long-term objectives. With that, let me turn the call over to Lisa.

Good morning, Jim. Thank you. Let me start with a brief update on the brilliance trial for Edit 101. As you know, we initiated dosing in the second cohort earlier this year. And with our regained momentum, we continue to screen and enroll patients in the study. As part of our progress, a protocol-mandated meeting with the Independent Data Monitoring Committee is actually planned for this summer. And in this meeting, we will review the existing data and decide the necessary steps required to begin dosing the next two pediatric cohorts. It's an exciting milestone since LCA10 is an early-onset retinal degenerative disease resulting in significant vision loss and blindness. and LCA10 is the most common cause of inherited childhood blindness, affecting three out of every 100,000 children around the world. So I'm hopeful that we'll be able to report promising results in the future. We continue to follow all the treated patients for the primary endpoint of safety every three months for the first year, and concurrently we're collecting data to confirm the expected beneficial effects of editing. As Jim mentioned, we plan to share our initial clinical data from the BRILLIANCE trial before the end of this year, And our intent is to include data that represents patients from the first two cohorts of the trial. The progress and the learnings from the EDIT 101 trial are also being applied to advance other in vivo ocular programs. This year we have presented preclinical data for Usher syndrome 2A and retinitis pigmentosa IV at the most recent annual meetings for the Association of Research in Vision and Ophthalmology. and we've developed a human iPSC-derived retinal organoid platform, which provides a practical ex vivo model to study the effects of editing on the human retina. For OSH2A, the selected deletion of the exon 13 mutation restored OSH2 protein complex expression, and it rescued deficits in photoreceptor morphology. Now, these results provide evidence of the potential to restore functional AGE2 protein function and rescue loss of visual function in the human retina. As for RP4, we've demonstrated clinically relevant editing levels using a dual AAV editing system, which adds further validation to our therapeutic strategy. And we expect to declare a development candidate for our RP4 program by year end. Now, transitioning to our ex vivo programs, specifically EDIT301 for sickle cell disease and also beta thalassemia. We have actually completed our investor training meeting, which included investigators and their clinical trial staff on the protocol and the procedures needed through the complex steps that lead from patient enrollment to cell harvest and subsequent dosing. And I'm also very pleased to announce that our first clinical site for the RUPE trial for sickle cell disease has been activated. and that site has now started to approach patients for consent and screening. We anticipate dosing the first patient before the end of the year. Additionally, we are completing preclinical work required to support our application for the IND in beta thalassemia, and we are currently still on track targeting filing of the IND by year end. We continue to believe that EDIT301 can differentiate from other approaches through use of our proprietary engineered Cas12A enzyme. which specifically allows for editing at the beta-globin locus as opposed to other targets such as BCL11A. In doing so, we mimic a naturally occurring mutation associated with hereditary persistence of fetal hemoglobin. By demonstrating robust and sustained fetal hemoglobin expression and safety, we aim to have a best-in-class medicine to treat sickle cell disease and beta thalassemia. And finally, I want to mention our IPSC-derived MK cell programs. We recently presented two separate posters at the most recent American Association for Cancer Research. The data showed that NK cells that have been edited to knock out CISH and TGF-beta with our proprietary CRISPR-Cas12 enzyme demonstrated superior tumor-killing ability when compared to unedited NK cells. We've also showed that NK cells demonstrated improved cytotoxicity and enhanced metabolic function in certain tumor microenvironment. These findings support our belief that edited NK cells will play an important role in the future treatment of solid tumor cancers. And we're concurrently exploring additional edits containing knock-ins and knock-outs to further enhance the activity of NK cells. And so I will look forward to updating you more on that program before the end of the year. And with that, I'd like now to turn things over to Michelle to briefly run through the financial results.

Thank you, Lisa, and good morning, everyone. Editas continues to be in a strong financial position as our portfolio and operations advance forward. Our cash position as of March 31st, 2021 was $723 million compared to $512 million at the end of 2020. The proceeds we raised from our January equity offering have strengthened our balance sheet. We expect our current cash balance will fund our operating plan well into 2023. Our strong capital position leaves us poised to continue executing across our clinical and preclinical pipeline, funding our ongoing Brilliance and Ruby trial, while also enabling the advancement of additional candidates into the clinic and enhancing our manufacturing capabilities. Now turning to revenue and expenses, which we have also summarized in our financial results for the first quarter of 2021 in the press release that we issued earlier today. Revenue was $7 million compared to $6 million for the same period last year. The majority of the revenue recognized this quarter was attributable to our strategic alliance with Bristol Myers Squibb. Our operating expenses increased year over year by approximately $11 million. Research and development expenses increased by $7 million to $42 million, compared to $35 million for the same period last year. This increase was driven by non-recurring charges related to collaborations and success payments to our licensors, as well as higher spending across clinical operations and manufacturing for our two clinical programs. General and administrative expenses increased by $4 million to $21 million compared to approximately $18 million in the first quarter of last year. This is mainly a result of increased employee-related expenses. Overall, Editas remains very well capitalized. As mentioned, we have sufficient capital to sustain our operations well into 2023. We continue to be confident in the fundamentals of our technology and expect our strong cash position will help advance our business through a series of potentially important value reflection points. With that, I'll hand it back to Jim.

Thank you, Michelle. It's been a very busy past few months at the company. As I mentioned on our last call, it's truly an exciting time for us with the work we've been doing to advance our programs and explore new possibilities for gene editing. This incredible once-in-a-generation technology at the foundation of our science allows us to conceivably treat nearly every genetic mutation in the human genome. Our existing indications represent only a small fraction of diseases potentially addressable by our technological capabilities. Our continued progress solidifies our place among the pioneers and leaders of gene editing. Editas was originally formed in order to discover and develop a novel class of genome medicines, and on a daily basis, we continue to overcome the numerous technical challenges of transforming gene editing technology into clinically practical therapeutics. We'll continue our efforts to expand the reach of gene editing across our platforms and look forward to updating you on additional future developments. As always, we thank all of you for your interest and support. And with that, we'll open it up to questions and answers. Operator?

Thank you so much. We will now begin the question and answer session. As a reminder, if you wish to ask a question, please press star one on your telephone. If you wish to cancel your request, please press the hash key. Again, it's star one to ask a question. We'll pause for just a moment to compile the Q&A roster. First question from the line of June Lee from Trust Securities. Your line is open.

Hi, thanks for taking our questions. So looking at the ARVA poster for RP4, you set the threshold for therapeutic efficacy at 25% editing, which is higher than the 10% set for LCA10. How do you get there? And given, you know, this RP4 is a dominant negative condition and require knockout knocking strategy, you know, can you just walk us through the editing efficiency in VEDO that you expect? And I have a follow-up.

I'll jump in, but I'm going to give you the clinicians rather than the scientific answer more than anything else. For the LC10 program, the main modeling data more or less suggested that at least 10% of normal retinal function would be required in order to be able to restore or at least have some level of best visual acuity. It's only a threshold result. And in fact, 10% was identified at the lowest threshold at which we would expect to be able to start to restore vision. Our non-clinical data more or less suggests that we're actually able to achieve editing deficiencies that are much higher than that. And in fact, the current dose that we're using in the clinical study in the mid-cohort is actually predicted to provide 30% or better levels of editing. So part of the dose finding of the study is to actually determine what the appropriate level of editing is really required to get optimal response. As for the RP4 program, you're absolutely right. This is actually one of the real nice benefits of doing gene editing. Like LCA10, a CEP290 gene, the RP4 gene is actually way too large to be able to replace through a normal gene therapy type approach. And as a consequence of being able to edit, we're able to make the corrections. In the particular case of RP4, because it is an autosomal dominant effect, the editing efficiency needs to take into account both the ability to knock out the dominant gene, which is causing the mutation, as well as to actually knock in a gene that's able to replace the vision. So what we have projected here at the moment is 25% is the expected threshold to be able to get that response, but our ability to actually treat in the clinical setting may be higher.

Okay, looking forward to this clinical data. And for the LCA-10 that you're advancing, so for the second cohort and following, have you changed any inclusion criteria to sort of accommodate the enrollment? And how has the enrollment been since the vaccinations have rolled out? And can you remind us how many patients you've dosed so far?

So far to date, we have dosed four patients. The way the protocol is currently written is that the first two patients were selected largely on the basis of being only light perception and were dosed at the lowest dose expected to provide some level of protective editing. The primary purpose of the study really is more dose finding related to potential safety concerns. Because we saw no safety concerns in those first two patients, we actually made modifications to the protocol in order to allow enrollment of patients who actually have some measurable visual acuity and not be quite so strict in restricting the total patient population enrolled. And that protocol change was actually made just before the beginning of the year. Probably the most important thing is that small change in the protocol by itself has actually allowed for much easier identification of patients. And we actually are very well tracking moving forward to be able to continue enrolling and completing this mid-dose cohort as well as being able to at least start, if not complete, the third-dose cohort by the end of the year. As for COVID and vaccines, I mean, honestly, it's really the real benefit for us has been somewhat of the loosening of travel restrictions and also loosening of restrictions within the hospitals themselves that have allowed patients to travel to the treatment sites and to get their therapy. And so at the moment, I'm not sure that COVID vaccination has changed anything, but it has made things easier for being able to get the patients to the treatment centers.

Got it. Just remind us, how many sites are capable of doing this, that are trained properly?

Well, at the end of the day is we really have, we're really going to sites and centers where we have people that are comfortable with retinal injections. And really at the moment we're continuing to expand our sites with looking at-we already have clinical sites that have been set up as part of our non-interventional study, our natural history study. In fact, those patients are beginning now to roll into the treatment center study. So it's very nice that we have nice baseline observations on these patients as they begin to move into the study. but we are somewhat trying to limit it to a number of different sites and centers where we know that the retinal surgeons are very comfortable and able to give us reproducible and consistent injections in the back of the eye.

Got it. Thank you.

Thank you so much. Your next question from Kari Casimo from J.P. Morgan. Your line is open.

Hey, good morning, guys. Thanks for taking my questions, two of them for you. First one is, what's the gating factor to dosing patients in the Ruby trial since sites are active and investigators are trained? What more needs to happen there? And then with regards to your LCA10 program prior to the IDMC meeting this summer, do you have to dose any additional adult patients to have a sufficient safety package prior to dosing pediatric patients? If so, how many more do you think you'll need? Thank you.

Okay, Corey, thanks for the question. So the first question is, what does it take, I guess, to dose a patient in the Ruby trial? We actually, in terms of site selection, identified two sites and centers that had already told us they had patients asking for the transplant and had pre-identified patients who would be willing to undergo the treatment. So those centers, at least one of those two centers, is now up and running, and we're expecting the second one relatively shortly. So at that point, it gives the site the opportunity to directly approach the patient to go through the details of the protocol and have consent signed. At this point, we actually start a fairly laborious process that's consistent across the entire space, and that is the ability to freeze patients with sickle cell disease is actually a relatively complicated and stepwise process. So once the patient is identified and they've undergone all the screening procedures, they either need to start a transfusion regimen or already be on a chronic transfusion regimen, which allows these patients to basically dilute down the hemoglobin S because the process of mobilizing cells and putting them through the phoresis procedure actually can precipitate sickle cell crises, and they can be quite severe. So it takes a bit of time to be able to get the patient to the screening, then start the transfusion regimen, and then schedule them to come in to have the phoresis procedure. And since multiple different, it's not, you walk in the door one time and walk back out the door and have it done. Patients actually do have to come back on consecutive days in order to collect enough cells that can be used for the editing process. At that point, the cells come back to Editas where we will do the editing procedures. And then once we've been able to complete that, we will return back to the sites and centers to schedule the patient coming in for the, for the, for the process in order to give them treatment. Once we've calculated all of those procedures in days and months, you're actually probably looking at about four to five months from the time that the consent is signed until the patient is treated. And that's why we're communicating the plan to actually start to be able to dose the first patient by the end of the year. But we're actually pretty confident that we have a number of patients who've already demonstrated interest in advance. To the second question, Based upon the protocol, the IDMC decision is made based upon the observations from the first cohort and two patients in the second adult cohort. The decision on whether or not safety has been adequate in those adults is really the decision tree in order to know whether or not we can open up the enrollment to pediatrics. It's primarily a safety decision, but as part of this and also our deep dive into the data, we will be looking for signals of efficacy and signs of editing that we would at least show that there is a potential benefit for the patients moving forward. And so that meeting is scheduled for June, and we're hoping that that will determine for us whether or not we can go directly in children at that point in time, or whether or not the DMC would like to have a few additional adults treated before we do that.

Okay. Thank you, Lisa. I appreciate all the color.

Thank you so much. Next question for Sayal Nadeau from Cohen & Company. Your line is open.

Good morning. Thanks for taking my questions. First one is just to follow up to Corey's. In terms of efficacy measures that you're going to look at at the IDMC meeting, can you give us some sense what you would consider promising and meaningful signals of efficacy? And then more broadly, what do you hope to achieve in the adult patients and what do you hope to achieve in the pediatric patients in terms of visual acuity and Is stabilization good enough, or do you really hope to see improvements?

Okay, so in this patient population in general, what we've observed is there's not a lot of decline of vision in the late follow-up of these patients. So the majority of the vision loss actually takes place during childhood. So, of course, one of our real goals is to try to get into the kids sooner than later when we hope that between neuroplasticity as well as some level of experience in vision, will actually benefit the patients and potentially give them a better benefit. But at the end of the day, in LC18, what's unique about this particular disease is that the retina is more or less intact. There's not a significant amount of degeneration of the outer layer. So once we're able to restore normal ciliary function in the photoreceptor, we're actually hoping that we'll have normal function of the photoreceptor. It really comes down to the brain's ability to interpret those results. So in terms of the clinical outcomes that we're looking, I'm really looking at twofold. One of them is just functional evidence of having an effect of the edit itself. And that can be measured solely in terms of following the anatomy of the back of the eye to see if there's been any changes related to the procedure itself, whether or not we're actually seeing changes in responses to light that could be measured in terms of pupillary responses, since these patients tend to have very slow pupillary responses, as well as responses to different types of colors of light, all of which will give me a signal of whether or not the editing has actually resulted in a physiologic change that I can measure in an objective manner. But, of course, the ultimate goal is having something that's meaningful for patients, and that will be part of the measurements that we're doing both for visual acuity as well as also our continued validation and observations of the patients going through a maze a little bit differently but similar to what was done by LuxTurnoff.

That's very helpful. Then second question on the 301 program, as I'm sure you're aware, there's a fair amount of controversy about preconditioning and just generally gene editing, gene therapy treatments in sickle cell following the cases of MDS and AML from a different program. Do you have any thoughts on the difficulty of treating sickle cell patients with genomic therapies in light of the cell-found conditioning or the type of vectors that are currently being used?

Well, I'm kind of philosophical about it, quite frankly, because I'm still not quite sure that we know what happened in the other study. And I think it's interesting that one of the patients who was originally said to have myelodysplasia now is being said to have a transfusion-dependent anemia, which still suggests something could be happening to those cells. The good news is it's not malignancy, and I think that's an important finding. Whether or not we feel confident attributing this to the busulfan, I'm almost an old-timer in this space. I was doing bone marrow transplants in patients with sickle cell disease as much as 30 years ago, and the toxicities associated with that, as well as much more intensive chemotherapy, plus the concerns related to graft-versus-host disease and rejection, the risk-benefit really does seem to be in favor at the moment in terms of both gene therapy and gene editing methods. At the end of the day, I think one of the biggest limitations to acceptance of the therapy, not just in this patient population, but in others who are also getting ex vivo products, is really the intensity of the chemotherapy. The next big step in this space is to have lower toxicity. So it's one of the things that we are looking at. At the end of the day, we're really looking right now for proof of concept of our modality, showing the efficiency of our edits and the advantages of targeting the beta locus as opposed to BCL11A. But the next steps will, of course, be looking at other conditioning regimens that can lower the toxicity and maybe even improve the acceptance of the therapy.

Perfect. That's very helpful. Thanks for taking my questions.

Thank you so much. Next question from Gina Wong from Barclays. Your line is open.

Thank you for taking my questions. I have two. One is regarding the Ruby trial in sickle cell disease. I'm just wondering if you can give us a little bit update regarding the partial clinical hold, and for the product consistency that FDA is looking for, do you need to clear that in order to also file R&D for beta thalassemia? Second question is more like the technology platform question regarding your eye disease indications. I think all of these indications are using AAV as a delivery vehicle. Just wondering, what is the longest and in what data you show the safety, given that the CRISPR-Cas9 packing AAV could be long-lasting?

I'm going to skip the second question because I'm not fully prepared to be able to answer you on the non-clinical data that has supported the program, but I will focus on the first one that you asked, which is the clinical hold. So the first thing I want to say is the clinical hold for the sickle cell program is actually kind of a distinctly different creature than the beta thalassemia program. basically what the agency is looking for is clear evidence in a consistent manner of our ability to reduce sickling in those cells. And for beta thalassemia, that's not really the relevant outcome. In fact, in beta thalassemia, hemoglobin F is probably our ability to demonstrate conversion to hemoglobin F is really going to be probably the more important thing. So the good news is that as of at least of today, we don't have any concerns regarding the potency for beta thalassemia or the assays that we have in place. For sickle cell disease, it's not holding us back in any way or form. We are at the moment completing a number of non-clinical studies to support our plans on how to move forward with the potency assay, and we are going to engage with the agency this summer. This has always been something we were going to do in parallel. It doesn't actually interfere with our plans moving forward. We hope to have the clinical hold lifted in time for us to start the main part after the run of the study.

Okay, thank you.

Thank you. Next question from Diago Sot from Credit Suisse. Your line is open.

Hi. Thanks for taking our question. This is Roger on for Diago. So you shared some preclinical data, Arvo, on your in vivo ocular programs. Could you just briefly highlight the key differences in construct among these programs and whether or not they're modular? Thanks.

What do you mean by modular?

in the sense that it could be potentially applied to, you know, other indications within ocular diseases or any other areas that you're exploring in the future?

So I think one of the things that's really interesting about the targets we're hitting in the ocular programs is that between RP4, OSH2A, and LCA10, these are programs that probably cannot be treated by traditional gene therapy type methods. And the reason why is because two of them are genes, in the case actually for all of them, two of them, the genes are definitely way too large in order to be able to be treated through a traditional gene therapy approach. Therefore, there's a clear advantage to editing the gene in order to correct the mutations that result in the disease. And also the same thing with RP4. Rhodopsin is also an extremely big gene. But the problem with those diseases is that they're not recessive inherited, they're autosomal dominant inherited, which means that the gene being produced actually is partly what creates the loss of vision and blindness. So again, we have a very clear ability here to be able to knock out the portion of the gene that's not functional and to knock in a corrected gene to allow for normal function in the eye. So they're very different. So the approach to these genes really shows some of the advantages of why editing is the right approach, whereas gene therapy and then putting in a gene construct would not be able to correct these diseases. In terms of modular, I guess you're talking sort of the cut and paste, whether or not we can just insert these. This is actually very high precision medicine, and it's very directed. So each one of these is really targeted to the specifics of the disease. However, we are building upon similar platforms moving forward because our growing experience with subretin injection, our experience with being able to demonstrate the efficacy to translate the findings from one program in the eye to the other, as well as to help us build additional models. It really is a stepwise progression, leading to higher levels of not only proof of concepts, but also higher levels of editing efficiency.

All right, thank you.

Thank you. Next question from Jay Olson from Oppenheimer. Your line is open. Jay Olson, your line is open. You can now ask your question. Okay, let's proceed to the next question. It's from Yanan Zhu from Wells Fargo Securities. Your line is open.

Hi, thanks for taking our questions. So first on the Usher 2A syndrome program, have you started IND-enabling studies, or if not, what is the timeline for starting that IND-enabling study? Thank you.

So we're still in the process of identifying the first clinical candidate and the timeline. I'm hoping we'll be able to communicate more later this year.

Thanks. And for the RP4 program, you mentioned you're pursuing a knock-in, you know, knock-out, knock-in strategy. I was curious because there are many mutations that underlie this condition. When you are knocking in, obviously the gene is very big. You couldn't knock in the whole gene. Could you give us some idea how many of the disease-causing mutations would you be able to address with your knock-in approach?

Yes, so you're right in the part that, to a certain extent, the knockout is going to be part of the value of this from the perspective of being able to reduce the autosomal dominant expression. I'm not really quite prepared to give you a sense of the total range of what we're actually knocking in, but I'd be happy to follow up with you.

Got it. And in terms of your NK cell strategy, Could you give some updated thoughts in terms of the broad applications that you might be pursuing with the IPSC and KCL strategy, such as antibody-mediated or CAR-NK type strategy? Thanks.

Yeah, so no details yet quite at this point, but I think it's very helpful to just simply say that the data that we have at the moment supporting the CISH TGF beta knockout is actually quite impressive from the perspective of being able to show evidence of the ability to overcome the microtumor environment and also TGF beta suppression of immune responses. So I think the key thing that's really helpful here is that we really are committed to going into solid tumors, and an easy entry place from that perspective would be targeting those tumors that have high production of TGF-beta. As for the additional knock-ins and double knock-outs that we're talking about, we'll be able to provide more information on that later.

Got it. Thank you for the call.

Thank you so much. Next question from Steve Seedhouse from Raymond James. Your line is open.

Hey, good morning. Thanks for taking the question. I was hoping you could just comment on the safety of the mid-dose patient. I know you mentioned no safety signals in the first two patients. So I was wondering if you could comment on that. And relatedly, it sounds like you are currently cleared or maybe even, as we speak, dosing the fifth and or sixth patients in the study. I just wanted to verify if that's the case.

So in terms of safety, there have not been any safety signals that have required us to do any additional observations. We're actually feeling pretty optimistic, at least for the ability to progress to the next doses in the study, and the next patients are being lined up, scheduled as we speak.

Okay, perfect. Thanks for that. And then I might be misremembering this, so please correct me if I'm wrong, but I guess I thought the adult high-dose cohort would be completed as well before advancing to pediatrics. or maybe contemporaneous with that cohort. It sounds like you're obviously looking to open the pediatric dose cohort after the middle dose. I just wanted to clarify if you still intend to enroll and treat the higher third dose cohort in adults, or if you're seeing anything in the data that suggests you don't either need to or want to test that third dose.

The only thing that would keep me from going up to the next higher dose would be any safety concerns because I really need to explore the entire dose response and translation to efficacy. If you remember with Luxternal, which didn't appear to have a dose response curve, they ultimately made the decision to go with the highest dose because it was safe and there was no way to discern whether or not it's an advantage to a lower dose. In this particular case, we do think that the nonclinical data actually supports that we do have a dose response. and that we can achieve even higher levels of editing. So as long as there's no safety concerns, I will be going ahead to the adult high-dose cohort anyway. The protocol that I inherited, and the one that's working quite well at the moment, basically allows for a DMC evaluation after the dosing of the first adult patients to allow dosing of the pediatric patients at the same dose level. So we wouldn't start the pediatric patients at a higher dose level until after we evaluated safety in adults.

That's right. Okay, I appreciate the clarification. Thanks for the questions.

Thank you. Our next question from Madhu Kumar from Goldman Sachs. Your line is open.

Yeah, thanks for taking our questions. So kind of following up on June's question at the beginning, so the 10% threshold that was described before, so that wasn't LCA-specific, and the 25% threshold described at ARVO was kind of specific to rhodopsin, but it seems like it could be generalizable. So practically today, what do you think is the fraction of corrected photoreceptors that are going to be needed for clinical benefit in LCA10 based on all the data you have right now?

Well, for LCA10, based upon the data we have, what I'll certainly say is that the non-clinical data certainly supports that at our mid-dose level, we would predict to be able to achieve editing efficiencies of at least 30% or higher. And moving on to the higher dose, we're actually looking at 50% or higher. So with the ability to be able to translate actual edits to vision, part of the study is going to help us define what the actual number of edits required or at least would be predicted in order to result in meaningful vision. And that will be one of the secondary outcomes of the study.

Okay, cool. So then kind of following from that, so this 30% for the mid-dose kind of average productive editing rate. So, I mean, as I said, that's an average diet. So, the distribution. So, if, say, 25% is the threshold, like, what fraction of patients would you expect to be below that 25% threshold if the average productive editing rate is 30%, practically?

Well, the average editing is actually a little bit higher. I'm only talking 30% as the threshold. That's what we're expecting to see at that dose.

Okay. Cool. And then, Okay, so thinking about the INK cell program, so we saw the data in AACR was pretty interesting, and we looked at the tumor cell killing data. As I recall, the ratio of INK cells to tumor cells in those experiments was 5 to 1. So if you use a lower ratio, maybe it's arguably more physiologically relevant to how you will therapeutically intervene, what kind of killing rate can you achieve with your effector INK cells?

Okay, so for that level of detail, I would probably refer you to the clinical scientist, to the research scientist who ran those studies.

Okay, cool. Thanks very much, everyone.

Thank you. Your next question from Luca E.C. from RBC. Your line is open.

Well, fantastic. Thanks so much for taking my questions, and congrats on all the progress and bringing Mark on board. Maybe circling back on Phil's questions earlier in the conversation, the recent setback for Bloober Bio, I guess what's your appetite for exploring a collaboration with some of the novel companies that are developing busulfan-sparing preconditioning regimens? So any call there would be great. And the second question, maybe for the ocular pipeline, this is my understanding that you were transferring the manufacturing from AbbVie to a CDML. Wondering if you have any update there and whether you think that the FDA may potentially ask you at some point to run a bridging study there. So, again, any caller will be great. Thanks so much.

So, Lisa, did you want me to try to take that one?

Yeah, I'm also thinking about the first one at the moment, but I just lost track of what my thought was. I apologize. Okay.

So the simple short answer to the manufacturing question is, at least for the trials that we have planned and the cohorts we have planned, we don't need to make additional material. You're correct in that there will ultimately be some product comparability questions that we will have to answer. Of course, we are going to try to do that mostly through analytical techniques and maybe some in vivo non-human studies. That would be the attempt. We have not had a conversation with the FDA about whether they would require anything in addition to that. A lot of this always turns on how well you can characterize the product you have. I think we have pretty good characterization assays, et cetera. And then it also is always a little bit dependent on just what the FDA's recent experience with similar things are, and that's always a bit hard to predict.

Super helpful. And maybe the first question was around novel preconditioning regimen that spare busulfan. Any appetite there for collaboration or any big picture thoughts? Thanks.

So I guess I'll fall back on a similar answer that I had earlier, and that was basically that at the moment I'm really focused on getting proof of concept of our editing platform and our ability to show meaningful edits in the patients. As we move forward in the clinical programs, I do think that having new conditioning regimens is going to be important because And I think that in order to have overall acceptance, the opportunity to test those will also become important. Because even if we're able to reduce the toxicity, we don't know that the efficacy of the treatment will be changed or reduced as a consequence. But the appetite is there.

Thanks so much.

Thank you so much. Next question from Matthew. Harrison from Morgan Stanley, your line is open.

Hi, thanks for taking our question. This is Costason for Matthew. One quick question from us on the 102 program. From what we understand, the safety is somewhat the risk, given that it's using the CRISPR-Cas9 platform, but we were wondering how much work do you need to do on this front, on the safety, prior to IND to de-risk the program at this stage? Thank you.

So what's the question about safety related to? Because we do normal safety and toxicology testing as part of all of our IND-enabled programs, so I'm not sure that I see something that's different.

In the ARVO, I'm referring to the ARVO data because there was no safety data there. That's why what you are planning to do...

So I don't think we're anticipating any unusual or different safety package and tox package than was required for 101. Okay.

Thank you.

Thank you so much. Next question from Jay Olson from Oppenheimer. Your line is open.

Oh, hey. Thanks for taking the question. Can you walk us through the timeline to file an IND for the NK cell program? And then for the manufacturing of your NK cell program, is that something that you would do in-house?

So do you want me to take that one? Um, Lisa, I can, I'll take both sides of it. Um, so timeline for the IND, um, we have a number of constructs that we have developed. We've been, um, consulting with opinion leaders to make a decision about what first construct to move forward with. Um, you have seen data on the, on the fish TGF beta, but that by no means is the only sort of construct that we've been working on, although I don't believe we've disclosed the other constructs. With respect to the manufacturing, we would anticipate doing the initial clinical manufacturing either largely in-house or partially in-house, along with a strategic partner on that, which would be CatalanT, on the manufacturing side. Um, so I think that's, you know, yet to be finalized, um, and whether we'll do the entire process in house or do part of the process in house and part of the process at cattle. And, and there's a, there's actually a place in this process, in the processes that we're developing where there's, uh, a natural sort of handoff point, if you will, in the process, if you desire. Some of that just comes down to, you know, how many batches, you know, we think we're going to need to make.

Great. Thanks for taking the questions.

Thank you so much. We don't have any further questions at this time. Jim, you may proceed.

Okay, thanks. Thanks so much for all the questions. We've got a few questions that we need to tidy up and get back to you with some answers on. It'll be great to have Mark Sherman on the next call because I think some of those were probably more in his wheelhouse. than maybe in Lisa's, but I want to thank everybody for participating in today's calls, for the great questions, and for your support as we try to bring this transformational new technology and turn it into real medicines to help patients. Thanks so much, and we'll talk to you next quarter.

That does conclude our conference for today. Thank you for participating in the All Disconnect.