Editas Medicine Inc (EDIT) 2022 Q3 法說會逐字稿

Good morning, and welcome to Editas Medicine's Third Quarter 2022 Conference Call. All participants are now in a listen-only mode. There will be a question-and-answer session at the end of this call. Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to Ron Modeler, Investor Relations at Editas Medicine. Please go ahead, sir.

Thank you, Maria. Good morning, everyone, and welcome to our third 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 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 as updated by our subsequent filings.

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 CEO, Gilmore O’Neill.

Thanks very much, Ron, and good morning, everyone. I'm joined today by several members of the Editas executive team, including Baisong Mei, our Chief Medical Officer; Mark Shearman, our Chief Scientific Officer; and Michelle Robertson, our Chief Financial Officer.

I am pleased with the progress our team has made this quarter. We have continued to build on our company's foundational technology as we transform from a platform company into a clinical stage therapeutics company and focus on execution. We continue to evaluate ways to leverage our gene editing expertise for developing new therapeutics, and we will provide an update on this evaluation in the coming months.

Operationally, with our focus on clinical advancement, execution is a top priority going forward. With that, I would like to provide some recent highlights on our clinical pipeline programs. First, EDIT-301 for sickle cell disease and transfusion-dependent beta thalassemia. EDIT-301 utilizes a unique mechanism of action that added the promoter of the gamma-globin gene to disrupt binding of the BCL11A suppressor. This is designed to provide high and durable levels of fetal hemoglobin in patients with severe sickle cell disease and TDT, thereby resulting in reduced red blood cell sickling and sickle cell sufferers and reduction in anemia in TDT patients.

I would also note that our EDIT-301 program uses our proprietary AsCas12a engineered nuclease, which our preclinical data suggest results in higher fidelity and higher efficiency editing than Cas9. As a reminder, the initial patient dosing with EDIT-301 represents the first time that an autologous ex vivo drug product was edited using our AaCas12a engineered nucleus.

In the RUBY Phase I/II trial evaluating EDIT-301 to treat sickle cell disease, we have dosed the second patient and remain on track to release initial data from the RUBY trial by year-end. These data would include efficacy data from the first treated sickle cell disease patients as well as safety data from the first 2 treated patients. In the EDITHAL Phase I/II study for transfusion-dependent beta-thalassemia, we have completed apheresis and CD34-positive cell editing on the first patient and are currently scheduling dosing.

Let us now turn to EDIT-101 for LCA10, which is a devastating inherited retinal dystrophy caused by autosomal recessive CEP290 mutations that cause early severe visual impairment for blindness and talk about the Phase I/II BRILLIANCE study. The BRILLIANCE study is designed to achieve several objectives. We determine the safety of delivering EDIT-101 to retinal photoreceptors to identify a subpopulation of LCA10 patients characterized by baseline molecular clinical or physiological parameters who are most likely to benefit from therapy and to identify a dose that optimizes the benefit-risk balance of EDIT-101 and to identify the optimal end points to consider for a registration study.

An update on the BRILLIANCE trial will be provided this month through a press release and company-sponsored revenue. That readout will include safety on all dose adult and pediatric patients and efficacy on the adult mid-and high-dose cohorts. Data from our 1-year natural history study of 26 LCA10 patients with mutations in the CEP290 gene will be used to contextualize the BRILLIANCE data. In order to move forward to a registrational study, we would need to see a meaningful treatment benefit for a commercially viable patient segment. Baisong will provide further details in his remarks.

Beyond the BRILLIANCE trial, on the safety side, the EDIT-101 program lays foundation for subsequent potential drug development programs that utilize our AV-based in vivo platform in inherited retinal diseases. Thus far, we have been able to demonstrate safety and tolerability from EDIT-101, reinforcing the use of AV delivered CRISPR-based retinal therapeutics. Mark will provide an update on our preclinical pipeline as well as a summary of data recently presented at scientific meetings.

Let me now turn to our IP portfolio, which includes patents exclusively licensed from the Broad Institute and Harvard University that cover Cas9 for use in human therapeutics in the U.S. With our exclusive license, the granting of a sublicense on either an exclusive or nonexclusive basis is at our discretion. As you know, earlier this year, the Broad Institute prevailed for the third time, twice with the PTAB once at Federal Circuit against parties collector known as CDC. As anticipated, the CDC appealed the most recent PTAB decision and the Federal Circuit will review the ruling to determine where [the vol] was properly applied. The court will not hear new evidence, and we expect the court will deliver its decision in mid to late 2023.

We remain confident that the Broad will once again prevail. And a pennant court decision in the Broad's favor would reaffirm Editas' position as the exclusive licensor of the Cas9 therapeutic patents in the U.S., thus, all companies that are developing a product utilizing Cas9 and that plan to commercialize that product in the U.S. will need a license from Editas.

It is important in addition to remember 2 things about EDIT-301 on the IP front. First, it uses our proprietary Ascas12a nuclease, which is not the subject of any IP disputes, and therefore, EDIT-301 will not need a Cas9 license for commercialization. We believe that our strong IP position relates to Cas9 human therapeutics in the U.S. has the potential to be a significant value driver for our company with numerous competitor products in development using Cas9, including several in late-stage clinical development. We look forward to providing additional updates.

I will now turn the call over to Baisong, our Chief Medical Officer, to review the details of our clinical programs.

Thank you, Gilmore. Let's start with EDIT-301. As Gilmore noted, we recently dosed a second sickle cell disease patients in the Phase I/II RUBY study. Beyond the first 2 patients dosed with EDIT-301, we also have completed [Apricus] and successfully added CD34 hematopoietic cells from several additional patients. The RUBY study's independent data monitoring committee, or IDMC, is expected to review the available data this month. Once the committee has endorsed further dosing per protocol, we can then move to parallel patient dosing.

We are taking multiple measures to accelerate patient recruitment, including expansion of our trial sites. We will be able to include efficacy data from all treated patients in the RUBY trial in the future registration package.

So what to expect from the RUBY data released by end of this year. We plan to provide an update on safety and tolerability from both those patients, neutrophil and platelet engraftment data from both patients and key hematological parameters from one dose patient that will include total hemoglobin, fetal hemoglobin as well as sell [indiscernible] site with measurable fetal hemoglobin known as indiscernible .

Taking a step back, EDIT-301 is targeting the gamma-globin promoter mimicking the nature mechanism of hereditary persistence of fetal hemoglobin or HPFH. In sickle cell patients with HPFH, when fetal hemoglobin level is 30%, the patients usually have no vessel occlusive complications or end-organ damages. Therefore, as a threshold, we're aiming to achieve fetal hemoglobin level at least 30% at 4 to 5 months after dosing. If we can achieve these objectives, this would meaningfully increase our confidence in EDIT-301 being a differentiated and competitive product.

By using our engineered AsCas12a with a high editing efficiency and specificity by targeting the promoters of gamma-globin gene 1 and 2, we expect this will deliver robust fetal hemoglobin expression, suppressed vessel occlusive crisis and provides long-term clinical benefit to those leading with sickle cell disease.

Moving to our development efforts in transfusion-dependent beta-thalassemia. In our Phase I/II EDITHAL trial of EDIT-301, the study is designed to assess the safety, tolerability and preliminary efficacy of EDIT-301. The first patient in the study has been enrolled and completed the freezes. We have completed editing of the CD34 CD34 hematopoietic cells to be infused back into the patient, and we are scheduling the dosing date for this patient.

Switching over to EDIT-101 for LCA10. The BRILLIANCE study IDMC recently met as part of the normally planned meetings. We are pleased that EDIT-101 has maintained a satisfactory safety profile, following its review of the available clinical data, the IDMC recommended a continued BRILLIANCE study and has endorsed continued enrollment in all active cohorts. As Gilmore mentioned, we are on track to provide an update on available clinical results from the BRILLIANCE study this month.

The update will include available safety data on 12 adult and 2 pediatric patients and efficacy data on adult patients. The adult efficacy update was including 1 year of data from adult mid-dose cohort and 6 months data from the adult high dose cohort. The BRILLIANCE study has multiple efficacy-related endpoints. The goal is to identify optimal outcome measures for demonstrating clinical meaningfulness in LCA10 patients who suffer from significant and disabling early onset visual impairment. These endpoints measured, busy psychophysical outcomes that including full field sensitivity, functional outcomes, including visual navigation costs, visual function outcome, including best corrected visual acuity, or BCVA, and measures of visual quality of life that including National Eye Institute [VSQ 25] instruments.

I'm happy with the progress that we are making in improving the execution of our clinical program, and I want to thank our patients, investigators and staff members at the state size for their contribution and support in helping us advance these new therapeutics.

With that, I will now turn the call over to our Chief Scientific Officer, Mark, to discuss our preclinical programs.

Thank you, Baisong. I would like to start with EDIT-103 for reduction autothermal dominant retinitis pigmentosa. EDIT-103 uses 2 adeno-associated virus vectors to knock at the mutant rhodopsin and correct the toxic gain of function, while simultaneously replacing that aberrant gene with a functional one. This approach can potentially address more than 150 gene mutations that cause low ADRP. The program employs a different mechanistic approach than EDIT-101, and we have previously reported highly promising preclinical data.

Last month, during an oral presentation at the European Society of Gene and Cell Therapy Annual Meeting, we highlighted data demonstrating nearly 100% productive editing in nonhuman primates and the generation of over 30% functional adoption gene replacement, which proved to be therapeutically effective in that NHP study. We expect to initiate IND-enabling studies next year following completion of the AAV vector analytical testing.

Moving now to our ex vivo cell therapy programs. Our EDIT-202 iPSC-derived NK cell program for solid tumors is advancing towards IND-enabling studies. This program offers several important key advantages over many existing NK cell approaches. In preclinical models, we've shown that EDIT-202 has potent antitumor activity and substantially increased persistence. We utilize a feed to cell-free system for iNK cell production, thereby mitigating potential risks of introducing exogenous cellular material. Through the development process, we are able to select a fully characterized clone, helping us avoid potential abnormalities and differentiating the iPSCs into NK cells. And finally, the program utilizes our proprietary editing platform, such as our engineered AsCas12a nuclease and sleep knock-in technology, which we believe provides superior editing capabilities in engineered NK cells.

Last month at ESGCT, we presented new preclinical data further supporting the continued development of EDIT-202. The data showed that using SLEEK to knock-in membrane-bound IL-15 and favorable CD16, the EDIT-202 cells had prolonged cytokine independent persistence in vitro as well as up regulated and continuous expression of CD16 after tumor cell exposure, thereby enabling the Editas sales to significantly enhance serial killing of SKOV3 tumor cells. In the SKOV3 intravenous solid tumor model, when combined with an antibody, the EDIT-202 cells resulted in a significant reduction in tumor burden and increased overall survival, demonstrating a 100% not survival rate after 100 days compared to 0% using just the antibody.

As we continue development of EDIT-202, we believe our approach has the potential to create an allogeneic off-the-shelf NK cell therapy medicine with enhanced activity against solid tumors. We plan on presenting additional preclinical data at the Society for Immunotherapy of Cancer Annual Meeting next week.

I'll now hand the call to our Chief Financial Officer, Michelle, to review our financial results.

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 third quarter of 2022.

I'll take this opportunity to briefly review a few items. Our cash, cash equivalents and marketable securities as of September 30 were $479 million compared to $528 million in the prior quarter. We continue to be disciplined with our expense management, and our cash runway extends into 2024.

For the third quarter, we recorded minimal revenue from an outlicense agreement. During the same period last year, we reported $6.2 million in revenue when BMS opted into an additional program under our collaboration. G&A expenses of approximately $16 million were flat compared to the third quarter of 2021. And R&D expenses for the third quarter were $41 million compared with $29 million for the third quarter of last year. This increase was driven by our investment in manufacturing and CMC capabilities to support the ongoing progress of our clinical trials. Overall, Editas remains in a strong financial position as we advance our programs.

With that, I will hand the call back to Gilmore.

Thank you very much, Michelle. I am pleased with Editas' execution over the past quarter. We continue to leverage our best-in-class technology, operational and manufacturing capabilities in our transition into a therapeutics company on the cutting edge of innovation. This transition is underpinned by further enhancement to our gene editing platform, active business development efforts and advancing discussions related to our foundational IP.

We are focused on our goal of building a robust pipeline of assets that maximize the probability of technical, regulatory and commercial success. We look forward to providing clinical updates for our EDIT-101 and EDIT-301 programs in the coming weeks. And in addition, we plan to share more information about our strategic plans in the coming months.

With that, we are happy to answer any questions.

(Operator Instructions) Our first question is from Gena Wang with Barclays.

I have 2 questions regarding the 301 and the 101 data update later this year. Just wondering, for 301, what will be -- you mentioned the 30% fetal globin should be sufficient to show clinical benefit. But given the competitive clinical profile that we've seen so far, would that be sufficient to be competitive? And what will be your goal regarding the fetal globin level.

And then for the EDIT-101, what is considered clinical meaningful and you will collect several different data points. Could you give us a sense like what kind of the magnitude of improvement in terms of [indiscernible] BCVA visual navigation that will be considered clinically meaningful?

Gilmore here. With regard to the 301, as you actually correctly stated what we would see as a minimal threshold to determine that we have a competitive product. We believe that we have a potentially differentiated product based on some of the critical differences in our approach in the use of our AsCas12a enzyme as well as our target to ultimately result in a robust, safe expression of fetal hemoglobin with a durable effect. And we actually, in the future, would hope and plan to see that differentiation declare itself as we move forward.

Nevertheless, we believe that the product will be competitive is because the space -- there is space for actually a number of therapeutic profiles and approaches. And that actually stems around our belief among other things, that over the next few years, this space will evolve slowly. We are confident that the vast majority of the prevent population will remain untreated at the time of our launch, and that will be a result or arise from the -- what we anticipate some slow uptake owing to a number of factors around potential hesitancy, but very importantly, around the evolution of the payer landscape.

With regard to the 101, we have done a lot of work to determine what is clinically meaningful, and we will actually be sharing more details around that as we contextualize the data based on our natural history study. I think it's important to know that we have done a lot of work on this around ensuring that we have reliable parameters for determining real change. And also, it's important to remember that because we're dealing with an inherited disease with early onset of severe visual loss. The determination of clinical meaningfulness will be related to -- and driven by our desire to see improved functional outcomes for patients that would actually change their ability to be mobile and to participate in society.

Our next question is from Greg Harrison with Bank of America.

What is your level of confidence in the potential of the EDIT-101 program. Are you viewing it more as a commercial opportunity in itself or maybe as a proof-of-concept where you could apply the technology to other indications? And maybe you could just elaborate on the earlier comments around the future of the program.

Absolutely. So I think that the EDIT-101 program really has 2 purposes. It was designed, first of all, to develop our experience with applying our technology in humans. And you're actually correct in that statement. I think the second one, as I've highlighted in my opening remarks are that this BRILLIANCE study is designed, amongst other things, to determine what subpopulation or segment of patient population are most likely to respond with a clinical meaningful response to the treatment. And obviously, one of the things that will be necessary is that patient segment or segments be a commercially viable patient population.

Got it. That's helpful.

Our next caller is from Chardan, Geulah Livshits.

This is Cory for Geulah. Wondering if you remain on track to submit a clinical to the FDA to be an alignment on the pivotal trial design and endpoints this year? And what boxhole have left to check the [indiscernible].

I'm afraid the sound was very poor. Could you restate your question? I think I know what you said, but I want to be sure I answered the question.

Yes. Is that better? Yes. So the question was whether you're on track to submit a data package to the FDA to gain alignment on the pivotal trial design in chosen this year and what bottles you have left both check the foam to the FDA to get some feedback.

So Geulah, the sound was very poor, but what make you. I think the question you're asking is, are we on track to submit a clinical data package to the FDA to discuss what a regulatory study would look like for 101. Is that correct?

Right. Yes, that's right.

Okay. Yes. So well, as I say, this month, we will actually be sharing data from our 101 study. And amongst other things, we will be sharing data -- or rather, the objective is obviously to determine is there a population or subpopulation that could actually move forward. Are there outcomes that we can use in a registration trial should we determine that we should go forward based on the size of that self-population and the clinical meaningful of the outcomes.

With regard to our interactions with the FDA, that will be -- that would require, obviously, a go decision. And very importantly, we would only be able to finalize that trial design in negotiation with the FDA should we go forward.

Got it.

Our next question is from Joon Lee with Truist Securities.

For EDIT-103, what's the rate-limiting step for IND and where can we expect that in the clinic? And why are you using Cas9 for that versus Cas12, which you think it sounds like you're excited about. And you're claiming 100% editing in the transduced area, but what is that transduced area? How does it relate to devolve retinal space?

This is Mark. So we are using Cas9 in this particular product because this fits conveniently in a single AAV. And as you know, this is a dual AAV approach where we are knocking down the mutant rhodopsin with the Cas9 nuclease and then replacing it with a codon-optimized human reduction.

In terms of the data, we admit -- in a nonhuman primate study, we typically administer a 100 microliter pipette. So the 30% elevation is the average change in expression within that pipette region. So we take tissue punches from the transduced area versus the untransduced area and make that calculation.

Regarding the IND-enabling studies, as we mentioned in the script, when you move from a research setting to a GLP toxicology study setting, there's more rigor and detail around the analytical testing and requirements, and this is taking a little longer than we had initially anticipated, and that's basically the escalation for pushing out the IND-enabling study start. And typically, we don't give specific time lines on IND submission until we've completed that work.

Our next question is from Matthew Harrison with Morgan Stanley.

This is [indiscernible] for Matthew. So we have 2 questions. One is for the RUBY trial. So do you think the data could be directly comparable to other CRISPR SCD trials? Or do you think there are some differences in patients or other things we should take into account?

The second is about the BRILLIANCE following off your comments. So in terms of potential FDA package submission, should we expect any update in the upcoming clinical trial update in terms of adding endpoint to include for registration trial? Or what specific patient segmentation to enrich in potential registration of trial?

So with regard to the RUBY trial and the EDIT-301 data, we will be reading out the data in December, and we believe that we will be able to share data and plan to share data that will show that we are competitive. As I've said in my previous remarks, we believe that the sickle cell and TDT spaces require and have the potential to accept multiple therapeutics using the CRISPR technology. And we believe that we can actually have and provide a very competitive product for patients.

With regard to the 101 data, we will actually be able to share -- or our plan to share that data set later this month. That is in this month of November. And actually, we'll be able to talk about our next steps forward. Baisong...

Yes. Just to add on that about the RUBY study, Matthew, and also related to Gena's question a bit earlier. So in my comments, about 30% of fetal hemoglobin level is really based on the hypothesis of the clinical observation of the HPFH and it's not our target of the fetal hemoglobin expression level. As Gilmore mentioned, we believe we have a differentiated and competitive product, and we are looking forward to share the data with you later this year.

Okay.

Our next question is from Dae Ha with Stifel.

Congrats on all the progress. A quick clarification on RUBY before I go to BRILLIANCE. On RUBY, I thought I heard 2 patient data by end of year, but I think I heard Baisong say efficacy data from one. So if you can clarify that, that would be great.

In terms of BRILLIANCE, I guess it's more of a 2-part question. So Gilmore, when you say commercially viable, what kind of number range are we talking about when it comes to prevalence? And as it pertains to the efficacy signal that we might see at the presentation later this month, -- earlier this year, ProQR had data that turned out to be completely opposite of what they thought would be considered enriched population for efficacy. So how do you think about sort of handicapping what you see later this month and how that could be predictive of future outcomes in EDIT-101/LCA10 population.

So let me clarify the RUBY. We will be presenting safety data from 2 patients and efficacy data from one patient. Baisong, you may want to expand.

Yes. So just to clarify on that, we have the -- first, we reported the first patient dose during the last update in August. Then these patients, we recently updated, we have dosed a second patient. So the first patient will have a longer duration of observation given that this sickle cell gene editing and gene therapy program, we expect it will take time to see meaningful efficacy data. We will share all the data available for the 2 patients, just we feel the first patient that may be more meaningful from an efficacy perspective. Hopefully, that helps.

And let me turn to the BRILLIANCE question. I think the first question is around the definition of viable. Essentially, when we actually look at these data, with regard to determining the commercial viability of the segment, that would actually -- of the patient population, that will be determined by a number of factors and essentially at the highest level, an intersection of the magnitude and clinical meaningless of the effect size in addition to the population segment size.

With regard to your second question around ProQR, obviously, that was a very unfortunate outcome for patients with this devastating disease. I think it's important to highlight that there are significant differences between their approaches in that we're using an AAV delivered genome editing tool, and they were using an RNA sense-based chemistry. But I think we are very conscious of the importance of robustly being able to segment a patient population in a predictive manner. And we -- as we look at our data and share it with you, we'll be able actually to go into more detail around that.

Excellent. Look forward to it.

Our next question comes from Phil Nadeau with Cowen and Co.

Just 2 from us. First, on RUBY on that first patient that you've mentioned that you're going to have efficacy data from -- I don't believe I heard you say anything about crisis events being part of the efficacy measures. Will you be able to present any data on that or release any data on that? Or is it too early in that patient's evaluation?

And then second, on 202, just what remains before you can enter the clinic with that program.

So I got to ask Baisong to answer the first question and Mark, the second question.

For the RUBY efficacy data, as I mentioned, we will provide safety as well as key hematological parameters. We certainly will report VOC. But as I mentioned earlier, a short-term duration of observation may not be most meaningful, but we set we reported data on that.

Yes, Phil, this is Mark. I think as we perhaps have discussed at the last earnings call. We're completing the -- any animal pharmacology data that's necessary to support the IND-enabling TOX study design and conduct. And as we mentioned in the script, that's planned for some time next year.

Perfect.

Our next question is from Jay Olson with Oppenheimer.

2 questions from us for EDIT-101. Can you remind us if you started dosing the pediatric high-dose group? I think you had previously mentioned that there was an IDMC review of pediatric mid-dose cohort last year? And is there any update you can provide on that?

And then for EDIT-202, can you just talk about the data that you'll be presenting at SITC.

Right. So with regard to 101, I'll have Baisong answer that question and the 202 SITC, I'll ask Mark to address.

Yes. As I mentioned, we did have IDMC meeting as planned -- as we previously scheduled a normal meeting. And at that meeting, the IDMC reviewed all the clinical data and they see a satisfactory safety profile. And regarding your question about how those pediatric cohort, it was discussed at the IDMC. And although they are satisfactory with the safety profile, we commonly continue the study as planned, but they recommend to review additional 3 months of data from the existing patients before starting the high dose cohort in pediatrics.

This will not impact our plan to release the data this month as we just previously mentioned. And it will also -- will not impact our decision about the program. We feel we have adequate data to make a decision about this program.

It's Mark here, Jay. Yes, we're not really in a position to give specifics of SITC data yet given that it's under embargo. As I mentioned in the script, we did present an update at ESGCT, which gave some pretty interesting data on the in vivo comodel and serial tumor killing as 2 examples. So we will -- the data will continue on that track at SITC.

Our next question is from Joel Beatty with Baird.

For EDIT-103, the presentation last month described 100% gene editing and knockout and 30% replacement levels. Could you discuss why 100% editing wouldn't be expected to lead to 100% protein levels and also is 30% enough?

I'm going to ask Mark to answer.

So can you just clarify the second part of that? So the 100% editing is necessary to remove the mutant rhodopsin and so this is an autosomal dominant disease, the 30% replacement. So this is 30% of the codon-optimized rhodopsin, which in a disease setting would be essentially 60% of the endogenous rhodopsin since it's only anemia.

In the NHP model, you may recall, we had reported data showing that we had a knockout only arm as well as a knocked and replace arm, and we were able to correct the phenotype that occurred in the knockout only arm, which is basically loss at photoreceptors with a 30% reduction replacement. So we felt in that particular model system, that was very encouraging data to show that you could overcome loss of rhodopsin.

There are, as you may know, some published data, particularly in thinking of a dog model from the [indiscernible] group, which arrived at a somewhat similar conclusion that around 30% rhodopsin in that particular model was sufficient to correct the phenotype.

Joel, just to be absolutely clear, make sure there's no room for any confusion or misunderstanding. In contrast to LCA10, the 101 on the LCA10, the 103 program is addressing an RP4 disease, which is a domini-herited toxic gain of function, which is why Mark makes the point that you want to have the highest possible efficiency in knocking down that gene that's generating that. Owing to the nature of the approach, we are knocking down both the mutant toxic allele as well as the healthy allele and therefore, are replacing that with a codon-optimized replacement at rhodopsin. And I think you heard Mark give the rationale of why we believe that, that replacement is sufficient.

And maybe just one other comment. I think one reason why we are getting such high productive editing for the RP4 program, is it's a single guy. So we're simply introducing indels, which caused frame shifts in the transcription and therefore, loss of the endogenous reduction. That's different to the 101 program where you have a dual guy. And so the productive editing, which in this case is deletion or reversion is a low percentage.

Great.

Our next question is from Luca Issi with RBC.

Excellent. This is Lisa on for Luca. I have 2 questions. One is on the NK cell platform. We have seen some press lately suggesting that you are the one yard line to partner your oncology pipeline here for the NK program. Just wondering if you have any updates there?

And number two, on sickle cell, given the sickle cell space is very competitive. I was just wondering if you could comment on any additional end points you're thinking about besides pricing. Are you also looking into measures like stroke risk, heart failure or renal failure just in order to help differentiate your product further from others?

With regard to the NK platform, we have talked and have been very open over the past year or so that we are keen to unlock the full potential of our NK platform through partnerships. And with regard to sharing updates, we will look forward to sharing updates, but only when we have any kind of partnership signed and executed.

With regard to 301 and our approach to differentiation, our readout later this year will be that the initial -- our data from the RUBY study going forward. We are actually considering a number of approaches to determining the potential for differentiation of our product. I think you've touched on some of them. There are many others that we are actually considering -- and obviously, those considerations, those outcomes, we are in discussions with our key opinion leaders, experts and ultimately, with regulators in the future, and we'll share more details in the future.

Okay.

Our next question comes from Yanan Zhu with Wells Fargo Securities.

So first on the sickle cell program, I think Baisong, you mentioned that the minimum HPF level of 30%, which is considered clinically meaningful, is not necessarily the target HPF level. Could you elaborate a bit more on the target HPF level?

And secondarily, for this program, where -- could you talk about the value for the sickle cell data update? And also in terms of the length of the follow-up for the first patient, where do you plan to make the data cut in terms of the months follow-up?

For the sickle cell patients regarding the fetal hemoglobin level, as I just mentioned, that our hypothesis of design the molecule was based on the clinical observation of that about HFP patients with sickle cell. So that's how we get to these 30% of patients, right? So that's kind of what we are. It's certainly not our clinical target. We fully weigh this field, and we were looking forward to share our data with you later this year.

With regard to the venue of the update, we are planning to share these data before the end of the year, and we will be letting you know the venue later on.

Then with regard to the length of follow-up and the cut for the data for our 301 disclosure. For the 2 patients, we will have the safety data, as Baisong has outlined. And with regard to efficacy data, hematologic parameters, that data cut would be occurring close to the disclosure, but certainly should be in the early plateauing phase that we would anticipate based on an experience in this space.

Great. And on the LCA10 program, I think I heard for the pediatric mid-dose patients, the data will be safety only. So 2 questions. When would you expect to have at least a 3-month data from the pediatric cohort? And also, for the measurement of BCVA and FST and perhaps also navigation, could the pediatric patients produce -- could those patients perform these tests and provide reliable results?

Yes. You're correct. Our plan is to share safety from the pediatric mid-dose cohort, and we will give clarity on the duration of follow-up at the time of the disclosure and specifics.

And with regard to BCVA and VFN, I may have Baisong comment a bit on that. But it is important to note that one of the reasons that we actually carried out the natural history study was, amongst other things, not just to determine what the long-term or progression of the disease was, but it was actually also understand the behavior of those outcomes that we're using, including BCVA, visual navigation courses in the context of that disease and across multiple age groups.

Baisong, I don't know if you want to add to that.

Yes. Yes, sure. A good question about the endpoint, right, Gilmore mentioned earlier about the purpose of this BRILLIANCE study as well as why we actually conducted the natural history study. So we will be able to use the data from natural history study to contextualize. As you pointed out, for FST visual navigation cost, the challenge is actually not only for the pediatric patients could be for other adult patient 2. So we fully understand that. So we are analyzed testing and retesting variability and all those reliability of the endpoints.

Great.

Our next question comes from Madhu Kumar with Goldman Sachs.

This is Omar on for Madhu. We have 2 questions. So first, how should we think about the internal pipeline development versus external partnering for ex ocular or hemoglobinopathy programs, particularly for oncology cell therapy programs?

And then second, what impact could the inflation reduction or IRA have on indication expansion on pipeline candidates?

With regard to the internal pipeline, as I said a little earlier in my prepared remarks, we are -- we have -- and I've been very excited and happy with the work I've done with the executive team in actually looking across our portfolio as we evaluate our strategy and looking forward to sharing that in the coming months.

But I think the one thing I can say that has been said consistently is that we believe we have a very exciting technology, and we want to find ways to unlock its full potential by appropriate focusing of the pipeline internally as well as seeking powerful and robust partnerships to enable us to expand our bandwidth to fully realize the potential of our technology. But as I say, we will be able to share more about that in the coming months.

And with regard to IRA, thank you for that. We actually -- I know that there has been a bit of presence. Some companies have actually talked about IRA restricting their approaches. I think it's important near-certain looked at that legislation and the regulation around it, and we believe that there is -- and it is designed to enable us to develop new technologies to target difficult and challenging human diseases that have struggled with a very high unmet need. And so we actually feel very optimistic that our technology can operate and innovate -- continue to innovate within the context of the IRA owing to the way the regulation is written.

Our next question comes from Liisa Bayko with Evercore ISI.

I'd just be curious about any read-through or insights you're getting from sort of the progression of Editas through the regulatory process? And then as a kind of a fast follower, maybe you can describe your -- how you see positioning in the marketplace there.

Yes. Obviously, we're very excited along with everyone who's developing therapeutics in this space and very specifically, as this will be an important path finder for genome editing as it moves through the regulatory approval process. In addition, it's worth pointing out that with regard to our exclusive license holding for Cas9, there is an additional upside potential to us beyond just the information that we learn as the regulators share the evolution of they're thinking for this space.

With regard to positioning, we believe that the space because it's new and because of the very high unmet need, tempered by the -- what we would anticipate over the next couple of years might be some hesitancy in uptake and very importantly, the evolution of the payer landscape that we will actually have in a very position with the timing and progression and progress we're making with the 301 program, that the majority of the prevalent patients will actually still be awaiting therapy at the time of our launch. And so with the differences in our approach and our potential to differentiate this additional upside as we see.

So we believe that we have a competitive product and that, as I say, there is space for our product and will be space, substantial space for our product to meet the significant unmet need of patients with both sickle cells and TDT with our 301 product.

Okay.

We have reached the end of our question-and-answer session. Thank you for joining the conference. You may disconnect your lines at this time. Goodbye.