Editas Medicine Inc (EDIT) 2022 Q1 法說會逐字稿

Good morning and welcome to the Editas Medicine First Quarter 2022 Conference Call. (Operator Instructions) Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Ron Moldaver, Investor Relations at Editas Medicine.

Thank you, Operator. Good morning everyone, and welcome to our First Quarter 2022 Conference Call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates. A replay of today's call will be available on the Investor section of our website, approximately 2 hours after its completion. After our prepared marks, 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 and updated by our subsequent filing. 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 statement, even if our views change.

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

Thanks, Ron. And Good morning, everyone. I'm joined today by several members of the Editas Executive team, including Mark Sherman, our Chief Scientific Officer; Michelle Robertson, our Chief Financial Officer; and Charlene Stern, our General Counsel.

We made excellent progress this quarter and look forward in more meaningful milestones this year. In the BRILLIANCE trial for LCA10, we dosed the first pediatric patient with EDIT-101. This marks the first time ever a child was dosed using in vivo CRISPR gene editing, an incredible accomplishment. Given that LCA10 is one of the leading causes of inherited childhood blindness, pursuing the dosing of younger patients is potentially a critical step forward to treating this disease. And yesterday, at the ARVO conference, we presented data further supporting the favorable safety and immunogenicity profile, EDIT-101. We expect to complete dosing of our pediatric mid-dose cohort in the first half of 2022 and initiate our pediatric high-dose cohort later this year. We're also planning on providing clinical update for EDIT-101 in the second half of the year.

Later today at the ARVO conference, we'll present non-human primate data with EDIT-103 for retinitis pigmentosa, demonstrating the unique design of our in-vivo knockout and replace [candidates to] preserve retinal function. That program is advancing towards IND-enabling studies, which we expect to start by the end of the year.

Our EDIT-301 program for sickle cell disease and beta-thalassemia continues to screen and enroll trial patients. For sickle cell we've successfully added several patients' cells ex vivo and are on track to begin dosing before the end of next month, and for beta-thalassemia later this year.

Our cellular therapy programs are advancing. We showed impressive iNK preclinical data. We'll have new data on EDIT-202 later this month at ASGCT. And we're pleased to have our longstanding partner, BMS, opt into a seventh alpha beta T-cell program.

The US Patent and Trademark Office recently issued a favorable patent interference decision to the Broad Institute, affirming our foundational CRISPR Cas9 intellectual property position. Charlene's joining us today and she'll discuss the implications of that decision in more detail in a few minutes.

And finally, we're excited to announce a new leader for our organization Gilmore O'Neill, and I'll comment on that in a few moments. But first I'd like to briefly review our clinical programs. As mentioned, we dosed our first pediatric patients in BRILLIANCE study for EDIT-101 for LCA10. It's the first time that in vivo CRISPR gene editing medicine has been administered to a child. This is a significant milestone for many young individuals living with disease, their families, as well as for the medical and scientific field.

The interest and support we've received from the entire patient community has been overwhelming, and it gives us enormous sense of enthusiasm as we continue to apply our gene editing capabilities to other genetic diseases. This is the first of 4 planned pediatric patients in the mid-dose cohort, which we expect to complete before the second half of the year. Then, following Independent Data Monitoring Committee assessment of the safety data, we will begin dosing the pediatric high-dose cohort, which we expect to initiate later this year. To date, EDIT-101 has been safe and well tolerated in treated patients. The viral shedding data presented yesterday at the ongoing ARVO conference supported the program's favorable safety profile. The clinical data demonstrated the EDIT-101 viral shedding was transient, indicating no systemic viral persistence following the administration. There's also no correlation between EDIT-101 dose levels and the levels of viral shedding, as we expected based on other ocular gene therapies, including those using AAV5.

A more comprehensive clinical update in the BRILLIANCE trial will be provided in the second half of the year. This update will include safety and efficacy assessments on all patients who have had at least 6 months of follow-up evaluations, including at least 12 months of data on the adult, mid-dose cohort, and at least 6 months of data on the adult high-dose cohort. We anticipate these data will lay the foundation for the registrational trial of EDIT-101. And as we've said in the past, we're exploring the most relevant and sensitive endpoints to support the registrational trial development, continuing to evaluate how we can most effectively interpret trial information, while always considering what is most meaningful to the patients.

In addition to the trial data, we're also looking at our natural history study data to identify the most reproducible measures. We'll present some data on that study at the upcoming TIDES conference, with additional findings later in the year.

Moving to EDIT-301 and our [XPO] platform, the Phase 1/2 RUBY trial for sickle cell disease is enrolling study patients, and we are in track to begin dosing the first half of 2022 with initial top-line clinical results expected by year end. We have completed apheresis cycles in multiple patients to collect enough cells to edit and restore a healthy level of fetal hemoglobin. These patients have already had their cells extracted, their extracted cells edited, and we're in the process of scheduling their actual dosing, where we re-infuse their edited cells. This requires an extended hospital stay so that each patient can undergo the required preconditioning regimen necessary to have their edited (CD)34 cells successfully administered back to them.

We're also preparing to initiate the Phase 1/2 trial of EDIT-301 for the treatment of transfusion-dependent beta-thalassemia or TDT. EDIT-301 recently received a rare pediatric disease designation for beta-thalassemia, which it has for sickle cell disease as well, and we remain on track to dose the first TDT patient this year. We're very excited as we approach the first patient dosing EDIT-301. We believe this program can be a onetime treatment for both sickle cell disease and TDT. Our unique approach recreates the same protective mutations that result in hereditary persistence of fetal hemoglobin. Patients with these protective mutations are essentially asymptomatic. We're also utilizing our Editas engineered AsCas12a enzyme, one of the most specific enzymes in the gene editing field to make these precise, complex edits. Because of the natural validation underlying the approach grounded in human genetics, we believe EDIT-301 will be a safe and durable approach to treating both of these indications.

Finally, I want to mention the upcoming management change we announced a few weeks ago. Starting June 1st Gilmore O'Neill will take over as CEO and I will assume the role of Executive Chairman. Gilmore brings an incredible breadth of experience to Editas, including 20 years in genetic medicine and clinical development, both as a physician and a scientist. He is overseeing the development of numerous successful products, many addressing rare disease indications, as they made their way from early discovery to launch and now accessible to patients worldwide.

As Executive Chairman, I'll be working closely with Gilmore and the rest of the Executive team to drive long-term value. When the announcement was made, one frequently asked question we received was why now. The simple answer is that Gilmore is the right person for the job and this is the right time. His creative experience of drug development, including preclinical and medical, is exactly what Editas needs today, not in a year or 2, but now. We're an excellent position with 2 early stage clinical programs making good progress, with several preclinical and we'll continue to enhance our technology and capabilities to address other clinically significant indications. This is exactly the right moment in time to bring in Gilmore where we can leverage his expertise to address later stage clinical trial design, prepare the next several clinical programs and select the next clinically relevant targets to pursue. His experience and passion for creating genetic medicine will add depth and vision to our team for years to come.

Now I'd like to turn the call over to Charlene to update everyone on the recent patent decision regarding the foundational IP surrounding Cas9. For some background, Charlene was one of the first people to join Editas that launched the company in 2013, and she was, and continues to be instrumental in developing the company's IP strategy. I'm thrilled to have her join us this morning. Charlene?

Thank you, Jim. And Good morning, everyone. Since the founding of Editas, we have placed substantial importance in securing robust intellectual property protections covering our scientific discoveries. We were pleased with the recently issued, favorable patent interference decision from the US Patent and Trademark Office reinforcing Editas' foundational intellectual property position. This was the second favorable ruling determining that Broad Institute was the first to invent the use of CRISPR Cas9 editing in new eukaryotic cells. Those patents are owned by Broad and exclusively licensed to Editas Medicine for the development of medicines for people living with serious diseases. This decision means that Editas is uniquely positioned to make licenses available to those companies interested in using Cas9 for developing human therapeutics. Given the size of the US patient market and the number of companies vying to develop CRISPR Cas9 medicines, the decision supports Editas to engage in broader licensing discussions regarding future CRISPR-based medicines.

As anticipated, the University of California group, known as CVC, filed its appeal of the US PTO's decision to the Federal Circuit. That appeal will focus on whether the USPTO decision was factually supported and whether it correctly applied the law to those facts. Those facts were thoroughly reviewed by the USPTO, and we believe it correctly applied the law. Thus we believe that the Federal Circuit will affirm the Patent Office's decision. We remain confident that the validity of Broad's patents will continue to be maintained, further strengthening at Editas' IP position.

Regardless of the appeal outcome or potential settlement between Broad and CVC, our exclusivity agreement means that we are the party responsible for any licensing discussions as CRISPR/Cas9 products enter the market. Looking at the next several years, Editas will continue to play this important role as the CRISPR gene editing market matures.

Although the interference focused on Broad's CAas9 portfolio, importantly, Editas is the exclusive licensee of both the Cas9 and the Cas12a patent estates for making human medicines. As such, we are able to issue exclusive and non-exclusive sub-licenses for Cas9, Cas12a as well as Editas' owned patents in the field of human therapeutics. This includes in vivo and ex vivo therapeutic uses.

Again, our intellectual property is one of the most important facets of the company. We've always believed that our cutting edge science is one of the ways we attract world-class scientists. Their research subsequently builds on top of our existing platforms and capabilities for which we seek new patent protection. That is why at every step of the way, we try to protect the intellectual properties surrounding our gene editing advancements while bringing novel medicines to patients in need of them.

With that, let me turn the call over to Mark to review our preclinical programs.

Thank you, Charlene. We're making strong progress with our preclinical pipeline and we've just announced compelling data for several of our programs. First EDIT-103 for Rhodopsin-Associated Autosomal Dominant Retinitis Pigmentosa. RHO-adRP is a disease of the retina leading to blindness typically later in life, although a significant number of patients experience onset of symptoms in their early years. There are currently no approved treatments. EDIT-103 uses 2 adeno-associated virus vectors or AAVs to knockout the disease causing mutant rhodopsin gene while simultaneously replacing that aberrant gene with a functional one. The knockout of the gene in the retinal photoreceptor cell can only occur if the components for the replacement gene are also delivered to that same cell. This approach can potentially address more than 150 gene mutations that cause RHO-adRP.

As Jim mentioned, we'll be presenting preclinical data on EDIT-103 at ARVO later today. That data reports that EDIT-103 achieved nearly 100% productive editing in non-human primates, generating over 30% functional rhodopsin gene replacement, resulting in corrected protein levels which, in this study, proved to be at therapeutically effective level.

The program is moving rapidly toward the clinic, and we expect to initiate IND-enabling studies before the end of 2022. We're especially excited for this program because it serves as a proof of concept for the treatment of other autosomal dominant disease indications where a gain of negative function needs to be corrected.

We're also very pleased with the progress we're making with our iPSC-derived NK cell medicine program for solid tumors. Using our proprietary engineered AsCas12a nuclease (inaudible) technology, we've developed engineered NK cells that we believe have potent antitumor activity and substantially increased persistence, an important limitation with many existing NK cell approaches.

At the American Association for Cancer Research Conference in April, we reported in vitro and in vivo preclinical data on the enhanced tumor-killing capacity of a double knock-in iNK cell. A [cleavable] CD16 and membrane-bound IL-15 were knocked into cells, increasing antibody dependent cellular cytotoxicity, or ADCC while prolonging iNK cell persistence in vivo. These 2 knock-in edits have thus far produced tremendous preclinical results. And as many of you are aware, our EDIT-202 construct incorporates these edits with the knockout of cytokine inducible [USH2] containing protein or fish, and TGFßR2. These 2 knockouts are designed to enhance the function of the iNK cells with the 2 knock-ins supporting our belief that EDIT-202 will be a differentiated allergenic cell therapy.

To our knowledge, this is the only program that incorporates these 4 edits in a single engineered NK cell. New preclinical data on EDIT-202 will be presented at the upcoming American Society for Gene and Cell Therapy, or ASGCT, conference. We'll show in vitro and in vivo data, demonstrating significantly augmented AGCC against multiple solid tumor cell lines, and prolonged in vitro persistence in the absence of exogenous cytokines. EDIT-202, combined with trastuzumab, resulted in greater reduction in tumor burden and prolonged survival in an ovarian cancer mouse model when compared against the antibody plus wild type iNK cells.

An important element of our iNK products is the actual cell editing and clone selection process, which allows editor scientists to identify single clones, having the precise combination of edits desired while eliminating those having unwanted editing results. It's an exquisite approach to limit the risk associated with a complex gene editing process, because we can characterize a single clone extensively and know that we have exactly what we want, with no off-target edits or chromosomal abnormalities, for example.

We believe our cell therapy platform has the potential to create highly active, off-the-shelf NK cell therapy medicines that could be used for the treatment of multiple types of solid tumors. In addition to our in-house oncology programs, our productive partnership with Bristol Myers Squibb around alpha beta T-cells continues to advance, with BMS opting into a seventh program.

We believe that these programs could result in novel, potent T-cell therapy approaches for cancer. The BMS programs leveraged several of our unique platform technologies, including the proprietary Cas9 AsCas12a nucleases and our guide RNA design to create autologous and allogeneic approaches in immuno-oncology. The most advanced program from this collaboration is in IND-enabling studies and we look forward to continuing our collaboration with BMS to develop important new medicines for cancer.

Finally, I'd like to say a few words on the recently issued FDA guidance for industry on human gene therapy products, incorporating human gene editing. The safe development of gene editing therapies is, as you would expect, of foremost importance to Editas. We were very pleased to see that the FDA guidance is highly consistent with the steps that we've already taken to ensure the safety of our products. We rigorously characterize on and off target editing as part of our preclinical development activities and we see ourselves as being at the vanguard of gene editing computational biology and bioinformatics software development. We also pay particular attention to the stringency and quality required to design, manufacture, and test genome editing components being considered for our product development. We've always placed the highest priority on ensuring patient safety, and closely review and follow the FDA's recommendations and guidance in our development plans.

With that, I'll turn the call over to Michelle to review our financial updates.

Thank you, Mark, and 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 first quarter of 2022. I'll take this opportunity to briefly review a few items. Our cash, cash equivalents and marketable securities as of March 31st were $566 million compared to $620 million as of December 31st, 2021. We continue to be disciplined with our expense management and our cash runway extends into early 2024. Revenue and operating expenses were relatively flat year-over-year. Revenue for the first quarter was $6.8 million compared to $6.5 million for the same period last year. And that slight increase was mostly driven by our collaborations with BMS.

G&A expenses for the quarter were $20 million compared with $21 million for the first quarter of 2021, and R&D expenses were $38 million this quarter compared with $42 million for the same period last year. This decrease was driven by success payments triggered during the first quarter of 2021, which there was no similar activity in the first quarter this year, slightly offset by increased manufacturing in clinical investments. Overall Editas remains in a strong financial position as we advance our programs.

With that, I will hand it back to Jim.

Thank you, Michelle. We're looking forward to an exciting set of milestones for our programs and company in 2022. We expect to complete dosing in pediatric mid-dose cohort for EDIT-101 in the first half of the year and the second half of the year, we'll initiate dosing for the pediatric high-dose cohort and provide a clinical update on the program.

With EDIT-301 for sickle cell disease, we anticipate dosing the first patient in the first half of 2022 and provide top line data by year end. And we also expect to have the first TDT patient dose as well.

We're advancing EDIT-202 iNK cell therapy program towards IND-enabling studies and we expect to release additional preclinical data as we move towards that goal. We'll continue supporting BMS as they advance their alpha beta T-cell programs toward the clinic. We'll further advance our innovative platform technologies such as our innovative SLEEK platform that enables our cell therapy programs. And on the top of our internal objectives, we anticipate business development efforts for future development and commercialization opportunities.

We have a robust pipeline and technology platform secured by a broad foundation of intellectual property that was recently affirmed by the USPTO ruling. We're excited by the advances across our pipeline, and we aim to bring these programs to patients so they can benefit from the tremendous potential of gene editing.

And finally, I'll, once again, welcome Gilmore to the company. I still plan engaging with many of our stakeholders, including our investors, and look forward to maintaining a productive dialogue. We thank all of you for your interest and support. And with that, we'll open it up to questions and answers.

(Operator Instructions) Our first question comes from Joon Lee with Truist.

We're getting a lot of questions from investors on sickle cell disease recently. So as you discussed your trial with the FDA and what sort of trial – the study size and the duration, [a follow-up] the FDA is asking for – to get a 301 approved. Can you share any information around that? And I have a follow-up.

Well, I mean, we haven't – probably our next engagement with the FDA will be after we have completed dosing of the first few patients in the trial. At this point, we don't have any reason to believe that our pathway to – through clinical trials is any different than what we've seen from the competitors. So I still anticipate that we're probably looking for 40 to 60 patients, plus or minus, and the same efficacy outcomes that they're looking – and durability outcome that they're looking for, whether it's Bluebird or CRISPR or anybody else.

Great. And so the second, most inbound question is around your [BDM] licensing strategy, given your favorable IP position in the U.S. So what types of BDM licensing [yield] do you have in mind in the foreseeable future?

So we envision doing a wide range of licensing deals. We're going to continue to do both exclusive and nonexclusive licensing. This would be true for both Cas9 as well as Cas12a. I would expect that some of these arrangements may be strategic licenses, partnerships and collaborations, where others I would expect would be straight licenses.

Okay. And a quick one, if I can. Since you dosed the first pediatric patient in April for EDIT-101 and requirement of 6 month follow-up prior to data disclosure, can we expect something around October? Or is your data disclosure strategy such that you're going to wait until all 4 pediatric patients have been dosed by the end of the first half, which will put data disclosure towards the end of the year?

Yes. So the data disclosure we've talked about, we've talked about the adult mid dose, the adult high dose, and then previously we said we would have – we would expect that we would update on, sort of, the safety outcomes from the first pediatric patients at that readout, which October – that's probably October, November, probably a reasonable timeframe to be thinking about. But unlikely that we'll have – we'll try to actually have complete cohorts of data going forward before we try to report out on the efficacy part. But the safety obviously is a little bit more of a rolling information.

Our next question comes from Joel Beatty with Baird.

For potential BD, do you see that happening for some of your lead agents that are in the clinic or entering the clinic within the next year? And if so, are there certain time points or catalysts that you'd like to have before that could make more sense?

Yes, Joel, good question. And I've, in the past, tried to address this a bit, so let's start with 301, the sickle cell disease beta-thalassemia. It's always been my view that over the longer term, we would want a commercial partner for that product, particularly for outside the US, but potentially to share some of that inside the US. And [inevitably], that comes with – probably they become a bit of a development partner in the late stage. I have – we thought about that probably a couple of years ago and concluded that the better time to engage on those conversations was once we start to get some clinical data because in my view, that's what the bigger partners are always going to look to, and that's where we can create, sort of, the maximum value for ourselves.

So that's one. I would say a second area that we look to is with the iNK platform, the IO spaces, particularly, as you know, it's complex, it's expensive. And there, we would look to – for partnerships, to enhance both our depth of expertise, as well as just the ability to finance and run clinical trials over a longer period of time. And ultimately commercialize. That's not an area where I think we're likely to play any time, that I can see.

In the ocular space, we like those programs, there's a suite of those programs, and some programs that we have not yet disclosed. We'll start to talk about those later in the year. But those are small enough clinical trials and targeted enough in what I'll call high unmet need, but not hypercompetitive space. We'll – our current thinking is we continue to just own those.

And then maybe lastly, to expand a little bit on what Charlene said, there's certainly some areas that we have thought about and done some work in. But it's a question of, could we accelerate and create more value for everybody by partnering those up sooner rather than later. And I'm, in particular, thinking about potentially in vivo targets.

Our next question comes from Dae Gon Ha with Stifel.

Two question is from me, 1 on 101 and 1 on 301. So looking at 101, your recent competitor, not in the gene editing space but using ASO, read out, sort of, their comprehensive analysis following their Phase 2/3 disappointment, and couldn't really find anything in terms of trial misconduct. And so just wanted to get your take on what your thought process is when it comes to de-risking of your trial. And when you commented on, Jim, in your prepared remarks, on looking at additional endpoints through the natural history study, I think so far, we've only seen the BCVA, FST and navigation. So any additional endpoints that you've collected that hasn't been presented that you're, kind of, leaning towards based on the natural history analysis? That's question.

One on 301, just curious, since you seem to be following the rubric of a competitor that's about to file by the end of the year, recognizing there are some point of differentiation here, but can you set some expectations for the year-end data? And specifically, is it HBF content that's going to be the point of differentiation or VOC, since we've already seen some pretty compelling data from your competitor?

Yes. Okay, so let's see, ProQR – so the first question was really 101 and endpoints and what, if anything, do we make from the ProQR? So yes, we had – as you know, we've talked about visual acuity, we've talked about retinal sensitivity with FST and we've talked about mobility. There are other measurements that we have used in that trial such as (inaudible) and OCT and other things. What we haven't spent time talking about is also patient-reported outcomes. So that would probably be the other element that we're interested in making sure we match up what the patients and physicians are reporting, to connect to the more objective data, which would be maze visual acuity, retinal performance, sensitivity, etc.. So those would be the kinds of things that we're thinking of looking at, and probably the ones that we've not spoken about much are the patient-reported outcomes.

What are we doing is we're trying to learn as we go, plus to use the information from the natural history, to ensure that after we get past the sentinel patients – so remember, the sentinel patient for each one of our dose groups is always light perception only, so very, very poor incoming vision. And to make sure that we select patients after that, that are most likely lead to be to be able to show a response with those endpoints that we're using. And particularly, it's visual acuity, retinal sensitivity, ability – mobility measurements.

So that's actually the logic for extending the cohorts that we've talked about before. So we'll add at least another 4 patients probably in the high-dose adult cohort.

So did I answer – Mark, did I get all the questions on that one? I'm looking over at Mark to make sure (inaudible) questions.

I think the other thing, the ProQR data is a valuable dataset for us to track, right? So it was very unfortunate for the patients, and then, that they got the surprise they did with the Phase 2/3. So we know that we have to focus on response rate and true performance against the endpoints before we make the decision on the registrational trial. So I think that's going to be helpful.

Yes. And I'd say, unfortunately, I think if ProQR got pushed into this – I'm guessing, I'm speculating, probably got pushed into this sham procedure as the control. I don't think that's something that we could do in any event. But I also don't think it's – based on everything we've seen through the natural history study, that it's actually warranted or you'd even get a test (inaudible) IRB. So that's just an editorial comment.

301, if I remember Dae, your question is, well, what's our expectations for data by year end? And what will we have that will start to point to differentiation? So expectations for data by year end is really going to be for the patients that we will have dosed by then, engraftment, and we'll start to see the fetal hemoglobin levels. There will not be sufficient dataset to make any conclusions on VOCs or anything until sometime next year. So from that perspective, then you'll have to look at how people want to extrapolate, if you will, preclinical data and actual data in the clinic to decide whether to think about differentiation on either efficacy or durability.

Mark, do you have any else that we should add to that?

Only that we're making very good progress on generating the dataset to respond to the FDA on the questions that they had on the study. So that's going really well.

So if I may add just one quick follow-up to the 101 question, on the press release, and you said this previously, your goal here as of next steps would be to expand one or more dose levels in the adult cohort. So would it make sense to expedite that process by at least starting on the mid dose since you've already dosed low and mid, and we might be seeing some kind of a dose response in the mid-level? And then depending on the high, decide on whether to pursue that second dose expansion, whether low or high? I hope that makes sense.

So, now that you gave me a really difficult question, Dae, I'm looking over to Mark.

It's a good question. So we are looking at the data – we're going to look at the data as it rolls out. As you heard, we've dosed the first pediatric patient in the mid-dose cohort 2. So I think we really want to make sure that we have, taking a close look at the data, both the safety data as well as any emerging information that comes from the efficacy assessments. And use that to drive final decision on whether we expand in 1 or both of the available cohorts for the adults.

Yes, the preclinical data would say the high dose is most likely to have the best effect, but as Mark said, we just have to react to the data, as we see it roll in.

I mean, we will have 6 months' data on the mid dose and 12 months' data on the low dose that we'll report next. And then as you recall, we finished dosing of the initial 4 adult patients in December of last year. So that data will come through in the third quarter as well.

Our next question comes from Debjit Chattopadhyay with Guggenheim.

This is Ry Forseth on for Debjit. For EDIT-301, could you walk us through the timing between subject dosing and how you account for the necessary engraftment time and safety evaluations?

Sure. So once a patient has their cells, we infuse – we expect approximately 40-day period over which we are going to monitor neutrophil engraftment. That's the first step, followed by patient engraftment with general safety evaluations and clinical chemistry. So at that point, when we have proof of engraftment, that'll be the trigger for the second patient to be dosed, and then they will go through a similar evaluation.

Our next question comes from Steven Seedhouse with Raymond James.

I had one on sickle cell and one first on LCA10. Just looking at the viral shedding data from ARVO, the – as you looked across the patients, there's like 6 or 7 orders of magnitude difference in virus [copies] and it doesn't look like it's related to dose. And then on the X-axis, most patients have below-the-limit-of-detection viral shedding, but there's 1 that is detected out to week 6. So I just wanted to ask, what are the drivers, I guess, of just the heterogeneity here and what are the implications? Does it tell you anything about pharmacodynamic expectations or safety expectations?

And then the question on sickle cell is just, appreciating that your hypothesis, sort of, lends to an expected difference in safety long term, but I'm curious if, around the time of transplant, whether it's engraftment time or early safety events, if your preclinical data suggests you'd expect to see differentiation versus the BCL11A approach.

So I'll take the first one on viral shedding. So you are correct. The data is somewhat variable, I would say. Based on my prior experience, this is exactly what you expect with the sub-retinal administration of AV viral vectors. There are variability in the way that the virus is administered, meaning sometimes the volume of the blood maybe slightly different, occasionally you'll get reflux and (inaudible). So just generally, this is a, kind of, a messy procedure to get type data on viral shedding. I think the overall message is it's in line with what we would expect from an AAV-based therapy. There's no clear dose response or relationship to the administration, and it's just a general, pretty benign response.

The expectation is given sub-retinal administration, that the vector really doesn't get much beyond the eye in any appreciable amounts. And I think that's essentially what we're finding, albeit, on occasion, you'll get to medicalize but in general, that's what we would expect.

And so your question on 301 was about engraftment and anything about our product that is likely to point to early differentiation. That's a question of watching the data, which is what we're going to do, and seeing how it, in fact, mimics what we've seen in the preclinical. So if it indeed mimics what we've seen in the preclinical, we'd expect to have quite high – we'd expect the engraftment to be what we've seen with other programs similar to this, and that we have very high editing levels, etc. So I don't – and hopefully that will also correspond to clinically relevant production of HBF. And we'll see how high that is. I don't know that once you get beyond a certain threshold, anybody actually knows how much higher is better.

Mark, I don't know if you have anything to add to that?

No, I think you're correct. We think the high editing efficiency of the AsCas12a nuclease is really important here. We know from the preclinical data that we are getting very good editing of the progenitor cells, which could be a determinant of the durability of HBF or general response. And that we know with the mechanism that we are pursuing, we don't get any lineage skewing following editing. So I think that could be an important factor that plays out over the longer term.

Our next question comes from Jay Olsen with Oppenheimer & Co.

This is [Chow] on the line for Jay. I guess for adding EDIT-101, you mentioned you are looking for more sensitive endpoints and also maybe patients that are more responsive to the treatment. Just wondering if the same applies to the pediatric patients and also if you're collecting patient-reported outcome from those pediatric patients.

So yes, the same logic would apply to the pediatric patients going forward. And I just want to be careful about how we describe how we're selecting patients. So it's less about, do we think the product works or doesn't work, and it's probably more about, over what range are these endpoint sensitive enough to actually pick up a difference, right? so that's really more, what we're trying to target here, is to ensure that the incoming – the baseline site for the patients is in a range where these endpoints will work – and as you can appreciate BCVA and even the [Berkeley], if they have very, very low vision coming in, it's not a very useful – there's not too much information you're going to get from that. And by the same token, if they have very good eyesight coming in, their ability to maneuver through the maze is already at, sort of, the top of the scale. Right? So I just use those as, kind of, examples of how we think about adjusting the incoming – the inclusion criteria, if you will.

Do we have more questions?

Our next question comes from Rick Bienkowski with SVB Securities.

But first, I was hoping you could clarify exactly where in development EDIT-202 program is. I know a lot of your recent scientific presentations have highlighted this program, but I don't believe we have any guidance for an IND filing. Could you maybe discuss some of the work that's ongoing for EDIT-202 and what steps need to be completed before an IND filing?

And then I have a second question. The press release guided for cash (inaudible) into early 2024. Could you also just dive into some of the major assumptions around this number, including maybe how many clinical programs you expect to advance in parallel and whether or not this is dependent on any incoming milestones?

Maybe I'll – this is Mark, I'll take the 202 questions. So you are correct. We haven't yet given specific guidance on the date of the IND filing but as you can imagine, all of our efforts are directed towards completing the data package that will be necessary to file an IND, which includes all of the pharmacology and toxicology work preparations for an IND-enabling GLP toxicology study, which includes both the pharmacology side, but also the preparation of the cells. We – clinical clone selection and then expansion and differentiation of that to produce sufficient cells to conduct all of these studies.

So that's where we're going right now. And as the plans solidify, we'll, maybe later in the year, give more guidance on narrowing a date as to when we think the IND could be available.

And I'll take the second question, Rick, so our cash runway is based on – includes our current plan. So our current clinical programs, as well as our pre-clinical programs that we've spoken about. And it does not assume any incoming cash from milestones or [DD].

So essentially everything that we just then talked about in our clinical or preclinical pipeline moves forward at pace.

Great. I just wanted to follow up on the EDIT-202 program. So the press release mentioned advancing internal and external manufacturing capabilities in tandem. Is that perceived to be a bottleneck for the IND filing as well? Or is that just work that's ongoing in parallel with the other preclinical work?

It's the latter, it's just the approach we're taking to develop a methodology for the expansion and differentiation, and then the transfer of that methodology to an external CDMO.

But we don't view that as –

(inaudible)

Yes, normal business. And we don't view that as (inaudible) to moving this program to the [client].

Our next question comes from Madhu Kumar with Goldman Sachs.

This is Rob on for Madhu. I was just wondering, does the high-dose cohort of BRILLIANCE include any homozygous IVS26 patients?

I don't believe so at this point in time.

Yes, we haven't release the specifics of the patients included in that cohort, but, as you know, homozygous patients constitute probably about 10% of the population. And so we're focusing on the entire population, not just those.

Our next question comes from Luca Issi with RBC Capital.

Just a few ones here. So (inaudible), maybe circling back on a few prior questions, maybe ask a little bit more directly, and I understand lots of moving part as the data still evolving, but what will be the end point that you will pitch the FDA today as the primary endpoint for LTA10?

And then the second, on the IP, can you just talk about how we should think about a long-term implications, given you now have the upper hand in the US, but my understanding is the CVC in a stronger position in the EU. Would it be fair to assume that this will all come down to cross-licensing agreement between the parties where the economics depends on the geography?

And then lastly, can you just give us any update on the Chief Medical Officer search and maybe remind us who is the ideal candidate, given the breadth of the pipeline, which obviously spans ophthalmology, hematology, and oncology?

Luca, you're assuming that we can remember a compound question. Do you want to start with (inaudible)?

Yes. With 101. Yes, we haven't made that decision yet. As we've indicated, there's a lot of data coming in and the decision will be data driven, based on what that looks like in both of the adults, hopefully in the pediatric patients. And that will guide our final choice, but right now, still under evaluation.

Charlene, do you want to take that?

Sure. So we see tremendous value in our IP, and we think that we have a significant longer term opportunity to think about how we license the technology. The USPTO decision is very favorable to Editas and Broad. And we believe that that decision will be upheld on appeal. We also believe that the majority of drug development and commercial sales will play out here in the US. And so that really underscores the importance and value of the IP that we have.

Yes. I mean, I've looked at all of the models that everybody's put together for Cas9 programs that might get commercialized. And it always looks like it always did, which is 2/3 or more of the revenue's going to come out of the US market. And then there's also an underlying presumption in what some of the companies are saying, is that we actually need anything for FTO in Europe. And that's by no means clear at all. So, and particularly for our sickle cell program, remember, we're using Cas12. And so that's – the Cas9 question is completely irrelevant for our sickle cell program. And it's not clear that we need anything else at this point in time for FTO for any of our other programs outside the US.

And the (inaudible)

Yes.

Yes, no, go ahead.

Mark was just adding, the 202 program uses the AsCas12 as well. So anyway, so you had another – I'm sorry, go ahead.

Got it. Super helpful. Last one on the Chief Medical Officer search.

Oh, Chief Medical Officer. See, I told you if you asked me a compound question, I wouldn't get it. So we're in the process of interviewing people. What's the perfect candidate? It needs to be somebody that is a clinician scientist, and why that's important here is, obviously, they need to know how to develop a program and they have had to see – they have to have been part of and overseen successful clinical development from, sort of, the beginning to the end. Because, as I've said before, real clinical development starts in Phase 4, right, after you get your initial approval.

And then the reason they need to be, the scientist part is this is a highly technical area that's moving fairly quickly. They need to be able to put partner very closely with Mark's team, as they think about what are the next targets, right? So that we make sure we match up not only targets that are technically doable, but that are clinically relevant. And that we can foresee a pathway develop. So that's a second.

And lastly it has to be somebody that, sort of, knows and has overseen the building and the expansion of a high-functioning medical organization and has had to have that experience. So I think those are the profiles we're looking for and for sure, from the people that we're interviewing, we're getting those. So I'm very optimistic we're going to get a very high quality candidate here that is going to be a real addition here to what's now a nicely building team.

So remember, Mark has done a great job in not even 12 months – right, Mark, not 12 months yet – of really getting the research focused and getting all of these programs moving, the pre-clinical and the technology development. The clinical part of it is moving much better than it was. And I think we had a CMO added into Gilmore's experience, [now] we've really got the team necessarily to drive this business for years to come.

Our next question comes from Gena Wang with Barclays.

This is Tom for Gina. We have 2 questions, one for 301 for the sickle cell disease and one for 101. So for sickle cell disease, given the dosing interval for the safety and engraftment evaluation, how many patient can we expect for the year end update? And for 101, I know it's earlier and everything should be data driven, but just want to get your assumption, would you need additional pediatric cohort expansion to further guide the dose selection or trial design for the pivotal trial?

The number of patients by year end was the first question on 301.

Yes. Our expectation will be that by year end, we will have dosed 2 patients. As I indicated earlier, the start of the trial is very carefully monitored. So the first patient has to get at least out to week 6 before we will be able to confirm that the edited product has been grafted and that patient's immune system is being reconstituted. So that takes us –we've indicated that the first patient will get dosed by the first half of the year. So that takes us into, sort of, the third quarter. And then we hope to get at least 1 more patient dose before the end of the year.

And we may have more than that, but what Mark's referring to is what we will have for data that we've discussed is really, I think, people can expect 2 patients. And then your question of 101 and…

Yes, so I think it was the cadence of the additional dosing. So I think we're sticking with the guidance we've given that we expect the pediatric mid-dose cohort to complete dosing by mid-year, and that we will initiate the dosing of the high-dose pediatric patient cohort by year end. And similarly with the adult expansion cohort, 1 of those to be initiated and hopefully completed by year end.

Our next question comes from Liisa Bayko with Evercore ISI.

I think most of my questions have been answered. I guess, just one outstanding. For EDIT-103, as we're thinking about endpoints and it's obviously very complex in these ocular diseases, what kind of endpoints make sense to, kind of, track this disease? I know vision loss tends to occur later in life. Is this something that's, you think, more easily measured in by some of the endpoints that are commonly used, or might require some kind of metrics? Just curious how you're thinking about the regulatory approach here.

Yes. So it will be our intention to use most of the same exploratory endpoints for the Rhodopsin indication as we do for 101. As you probably know, this is a rod photoreceptor disease so the initial decline occurs in peripheral vision. So (inaudible) will be an ideal way of looking that. And so right now, we will do all of the things that we've been doing for 101, which includes monitoring retinal sensitivity, the, sort of, anatomical evaluation by OCT and so on, patient-reported outcomes. All of those types of typical measures we will take a look at because this is not an indication for which there is a therapy already. So in this patient population, we'll have to see which of the endpoints is the most responsive to the treatment.

And some of these endpoints will be a little easier to conduct on these patients because they are coming in with good eyesight, at least central vision. And you don't have the [stigmas] and things that make some of the data hard to collect with certain groups of the patients in 101.

Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.