Editas Medicine Inc (EDIT) 2021 Q1 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Q1 2021 Editas Medicine Earnings Conference Call. (Operator Instructions) I would now like to hand the conference over to your first speaker today, Ron Moldaver, Investor Relations. Please go ahead.

Thank you, Juliann. 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 Investors section of our website approximately 2 hours after its completion. After our prepared remarks, we will open the call for Q&A.

As a reminder, various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change.

Now I will turn the call over to our Chief Executive Officer, Jim Mullen.

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 RUBY trial for EDIT-301 has been activated and has begun to screen and recruit patients. The pre-IND work for EDIT-301 in beta-thalassemia is advancing, and we expect it to be filed before year end.

We've also made excellent headway on the manufacturing side as we compare to enroll patients in the RUBY trial. We continue to progress our oncology platform with our long-standing 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 2 reasons why we believe Mark will be successful as Editas' new CSO. First, his areas of expertise in ophthalmology, immunology and neurology have considerable overlap with Editas' current platform indications. 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 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 month as CEO by meeting with every Editas employee, albeit mostly through a virtual format. These conversations help me appreciate what people are drawn 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 the 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.

Built on top of our gene editing technology, we have 3 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 3 platforms have their own intrinsic values, and they also provide us with the 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 gene editing 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 3 different areas of therapeutic indications. These are 3 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, best exemplified by our collaboration with Bristol-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 a span of 6 months under this collaboration, further validating our technological expertise in this space.

Overall, I'm extremely happy with our year-to-date progress. There are still challenges that we need to overcome, and I have confidence 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 2 pediatric cohorts. It's an exciting milestone since LCA10 is an early onset retinal degenerative disease, resulting in significant vision loss and blindness. LCA10 is the most common cause of inherited childhood blindness, affecting 3 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 and every 3 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 2 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 4 at the most recent annual meetings for the Association for Research in Vision and Ophthalmology. And we've developed a human iPSC-derived retinal organoid -- excuse me, I'm choking for a moment -- retinal organoid platform, which provides a practical ex vivo model to study the effects of editing on the human retina.

For USH2A, 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 USH2 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 EDIT-301 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 RUBY 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 the IND by year end.

We continue to believe that EDIT-301 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 NK cell program. We recently presented 2 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 microenvironments. 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 knockins and knockouts 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 31, 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 trials, 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 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 collaboration and success payments to our licensers as well as higher spending across clinical operations and manufacturing for our 2 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 inflection 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 placement 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're continuing 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?

(Operator Instructions) First question from the line of Joon Lee from Truist Securities.

So looking at the ARVO 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 this RP4 is a dominant negative condition and required knockin/knockout -- knockout/knockin strategy, can you just walk us through the editing efficiency in vivo that you expect? And I have a follow-up.

All right. I'll jump in, but I'm going to give you the clinician's rather than the scientific answer more than anything else. For the LCA10 program, the main modeling data more or less suggested that at least 10% of normal retinal function would be required in order to have -- 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 limit the lowest dose that would -- the lowest threshold at which we would expect to be able to start to restore vision. Our nonclinical data more or less suggests that we're actually able to achieve editing efficiencies that are much higher than that. And in fact, at 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. And this is actually one of the real nice benefits of doing gene editing. Like LCA10, the 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 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 LCA10 that you're advancing, so for the second cohort and following, are you -- 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 how many -- can you remind us how many patients you've dosed so far?

So far to date, we have dosed 4 patients. The way the protocol is currently written is that the first 2 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 productive editing. The primary purpose of the study really is more dose finding related to the potential safety concerns. Because we saw no safety concerns in those first 2 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 more -- 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, 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. And 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 injection. 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. And 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 are able to give us reproducible and consistent injections in the back of the eye.

Your next question from Cory Kasimov from JPMorgan.

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?

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 2 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 1 of those 2 centers is now up and running, and we're expecting the second one relatively shortly. So at that point, it gives the center, 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 [pherese] patients with sickle cell disease is actually a relatively complicated and step-wise 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, because the process of mobilizing cells and putting them through the pheresis 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 pheresis 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 process in order to give them treatment.

Once we've calculated all those procedures in days and months, you're actually probably looking about 4 to 5 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 the second -- 2 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 of our deep dive into the data, we will be looking for signals of efficacy and signs of editing that 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.

Next question from Phil Nadeau from Cowen and Company.

First one is just a follow-up to Cory's. In terms of the 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 you achieve in the pediatric patients in terms of visual acuity? 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 [LCA], 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 effective 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 long as -- 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 LUXTURNA.

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 busulfan conditioning or the type of vectors that are currently being used?

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 to be happened to those cells. The good news is it's not malignancy, and I think that's an important find. Whether or not we feel confident attributing this to busulfan, I'm almost an old timer in this space. I was doing bone marrow transplants and 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 stop -- 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 could lower the toxicity and maybe even improve the acceptance of the therapy.

Next question from Gena Wang from Barclays.

I have 2. 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 IND for beta-thalassemia? Second question is more like the technology platform question regarding your eye disease indications. I think all of these indications you're using AAV as the delivery vehicle. Just wondering, what is the longest animal data you show the safety, given 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 nonclinical day that supported the program, but I will focus on the first one that you asked, which is the hold. So the first thing I want to say is the clinical hold on the sickle cell program is actually kind of a distinctly different creature than the beta-thalassemia program. Essentially 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, 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 nonclinical 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. And we hope to have the clinical hold lifted in time for us to start the main part after the run of the study.

Next question from Tiago Fauth from Credit Suisse.

This is Roger on for Tiago. So you shared some preclinical data at 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?

What do you mean by modular?

In the sense that it could be potentially applied to 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 2 of them are gene -- in the case actually for all of them, 2 of 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 of whether or not we can just insert genes. 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 subretinal injection, our experience with being able to demonstrate the efficacy to translate the findings for one program in the eye to the other, as well as to help us build additional models, it really is a step-wise progression, leading to higher levels of not only proof of concepts, but also higher levels of editing efficiency.

Next question from Jay Olson from Oppenheimer. Jay Olson, your line is open. You can now ask your question.

Let's proceed to the next question is from Yanan Zhu from Wells Fargo Securities.

So first, on the Usher 2a Syndrome program. Have you started IND-enabling studies? Or are you -- if not, what is the time line for starting that IND-enabling study?

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

And for the RP4 program, you mentioned you're pursuing a knockin and a knockout/knockin 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 knockin 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 on -- in terms of the broad applications that you might be pursuing with the iPSC and NK cell strategy, such as antibody-mediated or a Car NK type strategy?

Yes. 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 micro tumor 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 knockins and double knockouts that we're talking about, we'll be able to provide more information on that later.

Next question from Steve Seedhouse from Raymond James.

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 2 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 5th and/or 6 patients in the study. I just wanted to verify if that's the case.

We're -- 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 dosage in the study, and the next patients are being lined up, scheduled as we speak.

Okay. Perfect. 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 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 LUXTURNA, 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 was 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 is 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.

Your next question from Madhu Kumar from Goldman Sachs.

So kind of following up on Joon'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 nonclinical 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 on that. So this 30% for the mid-dose kind of average productive editing rates. So I mean it's like an average guide. So the distribution. If, say, 25% is the threshold, 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. Okay. And then thinking about the iNK cell program, we saw the data at AACR was pretty interesting. And we looked at the kind of the tumor-killing -- tumor cell killing data. As I recall, the ratio of iNK cells to tumor cells in those experiments was 5:1. So if you use a lower ratio, ratios maybe are even 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 scientists -- to the research scientists who ran those studies.

Your next question from Luca Issi from RBC.

Congrats on all the progress and bringing Mark on board. Maybe circling back on sales questions earlier in the conversation, the recent setback for bluebird 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 color there would be great. And the second question, maybe for the ocular pipeline, it's my understanding you were transferring the manufacturing from AbbVie to a CDMO. 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 color will be great.

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

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

Okay. So the question is -- 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, but not -- 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, and we 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?

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. And I think that in order to have overall acceptance at 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 won't be changed or reduced as a consequence. But the appetite is there.

Next question from Matthew Harrison from Morgan Stanley.

This is Kostas on for Matthew. One quick question from us on the 102 program. From what we understand, the safety is somewhat it is 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 derisk the program at this stage?

So what's the question about safety related to? Because we do normal safety and toxicology testing as part of our -- all of our IND-enabling 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 trying to do...

That's the work that will follow. So, yes.

Okay.

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

Next question from Jay Olson from Oppenheimer.

Can you walk us through the time line 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, Lisa?

Yes. Thank you.

I'll take both sides of it. So the time line for the IND, we have a number of constructs that we have developed. We've been consulting with opinion leaders to make a decision about what first construct to move forward with. You have seen data on the CISH and TGF-beta, but that by no means is the only sort of construct that we've been working on. Although we haven't -- 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 and along with our strategic partner on that, which would be Catalent on the manufacturing side. So I think that's yet to be finalized on whether we'll do the entire process in-house or do part of the process in-house and part of the process at Catalent. And there's actually a place in the processes that we're developing where there's a natural sort of handoff point, if you will, in the process, if you desire. Some of that just comes down to how many batches we think we're going to need to make.

We don't have any further question 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 will be great to have Mark Shearman on the next call because I think some of those were probably more in his wheelhouse than maybe Lisa's. But I want to thank everybody for participating in today's call, 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. You may all disconnect.