Earnings Call Transcript - EDIT Q3 2022

Operator, Operator

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 Moldaver, Investor Relations at Editas Medicine. Please go ahead, sir.

Ron Moldaver, Investor Relations

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 update. A replay of today’s call will be available on the Investors section of our website approximately two hours after its completion. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company’s future expectations, plans and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC 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 statement, even if our views change. Now, I will turn the call over to our CEO, Gilmore O’Neill.

Gilmore O’Neill, CEO

Thanks very much, Ron, and good morning, everyone. I am 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 adds 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 complications as well as a 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 AsCas12a engineered nuclease. In the RUBY Phase 1/2 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 two treated patients. In the EDITHAL Phase 1/2 study for transfusion-dependent beta thalassemia, we have completed apheresis and CD34+ 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 result in early severe visual impairment or blindness. I will talk about the Phase 1/2 BRILLIANCE study. The BRILLIANCE study is designed to achieve several objectives. We determine the safety of delivering EDIT-101 to retinal photoreceptors, identify a subpopulation of LCA10 patients characterized by baseline molecular, clinical or physiological parameters who are most likely to benefit from therapy, and identify a dose that optimizes the benefit-risk balance of EDIT-101 as well as the optimal endpoints to consider for a registration study. An update on the BRILLIANCE trial will be provided this month through a press release and company-sponsored webinar. 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 one-year natural history study of 26 LCA10 patients with mutations in the CEP290 gene will be used to contextualize the BRILLIANCE data. 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 laid the foundation for subsequent potential drug development programs that utilize our AV-based in vivo platform in inherited retinal diseases. Thus far, we have demonstrated 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 US. With our exclusive license, the granting of a sublicense on either an exclusive or non-exclusive basis is at our discretion. As you know, earlier this year, the Broad Institute prevailed for the third time, twice with the PTAB, and once at Federal Circuit against parties collectively known as CDC. As anticipated, the CDC appealed the most recent PTAB decision and the Federal Circuit will review the ruling to determine whether the law 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. A panel court decision in the Broad's favor would reaffirm Editas's position as the exclusive licensor of the Cas9 therapeutic patents in the US. Thus, all companies that are developing a product utilizing Cas9 and that plan to commercialize that product in the US will need a license from Editas. It is important to also remember two things about EDIT-301 on the IP front. First, it uses our proprietary AS Cas12a 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 relating to Cas9 human therapeutics in the US 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.

Baisong Mei, Chief Medical Officer

Thank you, Gilmore. Let's start with EDIT-301. As Gilmore noted, we recently dosed a second sickle cell disease patient in the Phase 1/2 RUBI study. Beyond the first two patients dosed with EDIT-301, we have also completed apheresis and successfully added 334 test positive cells from several additional patients. The RUBI 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 an expansion of our trial sites. We will be able to include efficacy data from all treated patients in the RUBI trial in the future registration package. So what to expect from the RUBI data released by the 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 cell construct erythrocytes, with measurable fetal hemoglobin known as F cells. Taking a step back, EDIT-301 is targeting the gamma-globin promoter, limiting the nature mechanism of Hereditary Persistence of Fetal Hemoglobin or HPFH. In sickle cell patients with HPFH, when fetal hemoglobin level is at least 30%, the patients usually have no vessel occlusive complications or end-organ damages. Therefore, as a threshold, we're aiming to achieve fetal hemoglobin levels of at least 30% in four to five 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 high editing efficiency and specificity by targeting the promoters of gamma-globin genes 1 and 2, we expect this will deliver robust fetal hemoglobin expression, suppress vaso-occlusive crises, and provide long-term clinical benefit to those living with sickle cell disease. Moving to our development efforts in transfusion-dependent beta thalassemia in our Phase 1/2 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 apheresis. We have complete editing of the CD34+ cells to be infused back into the patient, and we are scheduling the dosing date for this patient. Let me turn over to EDIT-101 for LCA10. The BRILLIANCE study's 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 continuing the 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 two pediatric patients and efficacy data on adult patients. The adult efficacy update will include one year of data from the adult mid-dose cohort and six months of 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 measure psychophysical outcomes including full-field sensitivity, functional outcomes including visual navigation course, and visual function outcomes including best-corrected visual acuity or BCVA, as well as measures of visual quality of life that include National Eye Institute VFQ-25 instruments. I'm happy with the progress that we are making in improving the execution of our clinical program, and we want to thank our patients, investigators, and the staff members at the study site for their contributions 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.

Mark Shearman, Chief Scientific Officer

Thank you, Baisong. I would like to start with EDIT-103 for redoxin autosomal-dominant retinitis pigmentosa. EDIT-103 uses two adeno-associated virus vectors to knock out 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 RHO-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 & Cell Therapy annual meeting, we highlighted data demonstrating nearly 100% productive editing in nonhuman primates and the generation of over 30% functional rhodopsin gene replacement, which proved to be therapeutically effective in that NHP study. We expect to initiate IND-enabling studies next year following the 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 feeder cell-free system for NK 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 in differentiating the iPSCs into NK cells. Finally, the program utilizes our proprietary editing platforms, such as our engineered AsCas12a nuclease and sleep knock-in technology, which we believe provide 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 cleavable CD16, the EDIT-202 cells had prolonged cytokine-independent persistence in vitro as well as regulated and continuous expression of CD16 after tumor cell exposure, thereby enabling the edited cells to significantly enhance serial killing of SKOV-3 tumor cells. In the SKOV-3 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% survival rate after 100 days compared to 0% using just the antibody. As we continue the 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.

Michelle Robertson, Chief Financial Officer

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 will take this opportunity to briefly review a few items. Our cash, cash equivalents, and marketable securities as of September 30th 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 out-license 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.

Gilmore O’Neill, CEO

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 at the cutting edge of innovation. This transition is underpinned by further enhancements 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. 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, Operator

Thank you. We will now conduct a question-and-answer session. Our first question is from Gena Wang with Barclays. Please go ahead with your question.

Gena Wang, Analyst

Thank you for taking my question. I have two questions about the 301 and 101 data update later this year. For the 301, you mentioned that 30% fetal-globin should be sufficient to show clinical benefit. Given the competitive clinical profile we've seen so far, will that be enough to be competitive? What is your goal regarding the fetal-globin level? For the EDIT-101, what is considered clinically meaningful? You will collect several different data points, so could you provide an idea of what magnitude of improvement in terms of logMAR BCVA visual navigation will be deemed clinically meaningful?

Gilmore O’Neill, CEO

Thank you very much, Gena. Gilmore here. With regard to the 301, as you correctly stated, that is our 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 robust, safe expression of fetal hemoglobin with a durable effect. We actually hope and plan to see that differentiation declare itself as we move forward. Nevertheless, we believe that the product will be competitive as is because there's a considerable space for numerous therapeutic profiles and approaches, and that essentially stems from our belief that over the next few years, this space will evolve slowly. We are confident that the vast majority of the present population will remain untreated at the time of our launch, which should result from expected slow uptake and several factors, including potential hesitancy and particularly the evolution of the payer landscape. With regard to the 101, we have done significant work to determine what is clinically meaningful, and we will be sharing more details around that as we contextualize the data based on our natural history study. It's also 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 and driven by our desire to see improved functional outcomes for patients that actually change their ability to be mobile and to participate in society.

Gena Wang, Analyst

Thank you.

Operator, Operator

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

Greg Harrison, Analyst

Thanks for taking the question. 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? Could you elaborate on the earlier comments around the future of the program?

Gilmore O’Neill, CEO

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

Greg Harrison, Analyst

Got it. That's helpful. Thanks for taking the question.

Gilmore O’Neill, CEO

Thanks.

Operator, Operator

Our next caller is from Chardan, Geulah Livshits. Please proceed with your call.

Unidentified Analyst, Analyst

Hi. This is Chloe for Geulah. Thanks for taking the question. I was wondering if you remain on track to submit a clinical package to the FDA to align on the pivotal trial design and for feedback this year.

Gilmore O’Neill, CEO

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

Unidentified Analyst, Analyst

Yes. Is that better? The question was whether you're on track to submit a data package to the FDA to gain alignment on the pivotal trial design this year and what is still pending?

Gilmore O’Neill, CEO

Yes. As I said, this month, we will actually be sharing data from our 101 study. Among other things, we will be sharing data to determine if there is a population or subpopulation that could actually move forward. Are there outcomes that we can use in a registration trial should we decide to go forward based on the size of that cell population and the clinical meaningfulness of the outcomes? Our interactions with the FDA would obviously be necessary for a go decision. Very importantly, we would only be able to finalize that trial design in negotiation with the FDA should we decide to proceed.

Unidentified Analyst, Analyst

Got it. Thank you.

Operator, Operator

Our next question is from Joon Lee with Truist Securities. Please proceed with your question.

Joon Lee, Analyst

Hey, thanks for taking our questions. For EDIT-103, what's the rate-limiting step for IND, and when should we expect that in the clinic? Why are you using Cas9 for that versus Cas12, which sounds like you're excited about? You’re claiming 100% editing in the transduced area, but what is that transduced area? How does it relate to the overall retinal space? Thank you.

Mark Shearman, Chief Scientific Officer

Thanks, Joon. This is Mark. We are using Cas9 in this particular product because it fits conveniently in a single AAV. 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 rhodopsin. In terms of the data, we admit in a non-human primate study, we typically administer a 100 microliter blood. The 30% elevation is the average change in expression within that leg region. We take tissue samples 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. This is taking a little longer than we had initially anticipated, and that's basically the explanation for pushing out the start of the IND-enabling study. Typically, we don't give specific timelines on IND submission until we've completed that work.

Operator, Operator

Our next question is from Matthew Harrison with Morgan Stanley. Please proceed with your question.

Unidentified Analyst, Analyst

Hi, thanks for taking our question. This is Gunjana for Matthew. We have two questions. One is for the RUBY trial. 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 matters we should take into account? The second is about the BRILLIANCE following your comments. In terms of potential FDA package submission, should we expect an update in the upcoming clinical trial update regarding endpoints to include for the registration trial or what specific patient segmentation to enrich in a potential registration trial?

Gilmore O’Neill, CEO

Thank you very much. Regarding the RUBY trial and the EDIT-301 data, we will be reading out the data in December. We believe that we will be able to share data and plan to share data that would show that we are competitive. As I 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 provide a very competitive product for patients. Regarding the 101 data, we will share, or plan to share that data set later this month, in November. We will be able to discuss our next steps moving forward. Baisong Mei, would you like to add?

Baisong Mei, Chief Medical Officer

Just to add on that about the RUBI study, Matthew, and also related to the previous question. The 30% fetal hemoglobin level is based on the hypothesis of clinical observation of the HPFH, and it's not our target for the fetal hemoglobin expression level. As Gilmore mentioned, we believe we have a differentiated and competitive product, and we are looking forward to sharing the data with you later this year.

Unidentified Analyst, Analyst

Okay, thanks.

Operator, Operator

Our next question is from Dae Gon Ha with Stifel. Please proceed with your question.

Dae Gon Ha, Analyst

Hey, good morning. Thanks for taking my questions and congrats on all the progress. Quick clarification on RUBY before I go to BRILLIANCE. On RUBY, I thought I heard two patient data by the end of the year, but I think I heard Baisong say efficacy data from one. If you can clarify that, that would be great. In terms of BRILLIANCE, I guess it's more of a two-part question. When you say commercially viable, what kind of number range are we talking about when it comes to prevalence? How do you think about handicapping what you see later this month and how that could be predictive of future outcomes in the EDIT-101/LCA10 population?

Gilmore O’Neill, CEO

Thanks very much, Dae. So, let me clarify the RUBY. We will be presenting safety data from two patients and efficacy data from one patient. Baisong, would you like to expand?

Baisong Mei, Chief Medical Officer

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

Gilmore O’Neill, CEO

Thanks very much, Baisong, and let me address the BRILLIANCE question. The definition of viable for the patient population will be determined by several factors, including the magnitude and clinical meaningfulness of the effect size in addition to the size of the population segment. Regarding your second question about ProQR, that was an unfortunate outcome for patients with this devastating disease. It’s critical to highlight that there are significant differences between their approaches, and we’re using an AV delivered genome editing tool, while they were using RNA antisense-based chemistry. We're conscious of the importance of robustly being able to segment a patient population in a predictive manner. As we analyze our data and share it with you, we will provide further detail.

Dae Gon Ha, Analyst

Excellent. Look forward to it. Thanks.

Operator, Operator

Our next question comes from Phil Nadeau with Cowen & Co. Please proceed with your question.

Phil Nadeau, Analyst

Good morning. Thanks for taking my questions. Just two from us. First, on RUBY, regarding the first patient for efficacy data, 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 is it too early in that patient's evaluation? Then, on 202, what remains before you can enter the clinic with that program? Thank you.

Gilmore O’Neill, CEO

I'm going to ask Baisong to answer the first question and Mark, the second question.

Baisong Mei, Chief Medical Officer

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

Mark Shearman, Chief Scientific Officer

Yes, Phil, it’s Mark. As previously discussed at the last earnings call, we're completing the necessary animal pharmacology data to support the IND-enabling toxicology study design and conduct, which we mentioned is planned for sometime next year.

Phil Nadeau, Analyst

Perfect. Thank you.

Operator, Operator

Our next question is from Jay Olson with Oppenheimer. Please proceed with your question.

Jay Olson, Analyst

Hey, thanks for taking the questions. Two 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 the 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? Thank you.

Gilmore O’Neill, CEO

Thanks very much, Jay. Regarding 101, I'll have Baisong answer that question, and for the SITC, I'll ask Mark to address.

Baisong Mei, Chief Medical Officer

Yes, thanks for the question. Yes, as I mentioned, we did have an IDMC meeting as planned, as part of the regular schedule. At that meeting, the IDMC reviewed all clinical data and found a satisfactory safety profile. Regarding your question about the high-dose pediatric cohort, it was discussed at IDMC. They were satisfied with the safety profile and recommended continuing the study as planned but suggested reviewing an additional three months of data from existing patients before beginning the high-dose cohort in pediatrics. This will not impact our plans to release data this month as previously mentioned.

Mark Shearman, Chief Scientific Officer

Hi, it’s Mark here, Jay. We're not really in a position to give specifics about the SITC data yet, as it’s under embargo. As I mentioned in the script, we presented an update at ESGCT, which showed significant data on the in vivo CRISPR model and tumor killing as examples. The data will continue along that track.

Gilmore O’Neill, CEO

Thank you, Mark.

Jay Olson, Analyst

Thank you very much.

Operator, Operator

Our next question is from Joel Beatty with Baird. Please proceed with your question.

Joel Beatty, Analyst

Thanks. 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 if 30% is enough?

Gilmore O’Neill, CEO

Thank you, Mark. I'm going to ask Mark to answer that.

Mark Shearman, Chief Scientific Officer

So, could you clarify the second part of your question? The 100% editing is necessary to remove the mutant rhodopsin as this is a dominant disease. The 30% replacement refers to the codon-optimized human rhodopsin, which in a disease setting would essentially be 60% of the endogenous rhodopsin, since it's only one allele. In the NHP model, we’ve reported data showing we could correct the phenotype in the knockout-only arm with only a 30% replacement. Thus, we felt this was encouraging data showing that you could overcome the loss of rhodopsin. There are some published data, particularly a dog model, which arrived at a similar conclusion, showing that around 30% rhodopsin was sufficient to correct the phenotype.

Gilmore O’Neill, CEO

So, thanks very much, Mark. Joel, just to be clear, the 103 program is addressing an RP4 disease, which is an inherited toxic gain of function. This is why Mark points out the importance of achieving the highest efficiency in knocking down the gene generating that. We are knocking down both the mutant toxic allele as well as the healthy allele and thus replacing it with a codon-optimized replacement rhodopsin. You heard Mark give the rationale of why we believe that replacement is sufficient.

Mark Shearman, Chief Scientific Officer

Additionally, the high productive editing rate for the RP4 program is likely due to it being a single guide. We’re introducing indels that cause frame shifts in the transcription, resulting in loss of the endogenous rhodopsin. This differs from the 101 program with a dual guide, where the productive editing percentage is lower.

Joel Beatty, Analyst

Great. Thank you.

Operator, Operator

Our next question is from Luca Issi with RBC. Please proceed with your question.

Unidentified Analyst, Analyst

Hello everyone. Thanks for taking my question. This is Lisa on for Luca. I have two questions. One is on the NK cell platform. We have seen some press lately suggesting that you are on the verge of partnering your oncology pipeline here for the NK program? Just wondering if you have any updates there. Second, regarding sickle cell, given this space is very competitive, are you looking into additional endpoints besides CRISPR measures? Are you also considering measures such as stroke risk, heart failure, or renal failure to help differentiate your product from others?

Gilmore O’Neill, CEO

Yes. Thanks very much, Lisa. Regarding the NK platform, we've been very open about wanting to unlock the full potential of our NK platform through partnerships. When it comes to sharing updates, we will do so when we have any partnership signed and executed. With regard to 301 and our approach differentiation, our readouts later this year will provide the initial data from the RUBY study. Going forward, we are considering various approaches for determining the potential for product differentiation, and you've highlighted some of them. There are many others we are considering and, of course, those outcomes are being discussed with key opinion leaders, experts, and ultimately with regulators as we move forward. We will share more details in the future.

Unidentified Analyst, Analyst

Great. Thanks for taking our questions.

Operator, Operator

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

Yanan Zhu, Analyst

Hi. Thanks for taking my questions. First on the sickle cell program, I think Baisong mentioned that the minimum HbF level of 30%, which is considered clinically meaningful, is not necessarily the target HbF level. Could you elaborate a bit more on the target HbF level? Additionally, where do you plan to share the sickle cell data update, and in terms of the follow-up length for the first patient, where do you plan to make the data cut?

Baisong Mei, Chief Medical Officer

Thank you, Yanan, for the question. Regarding fetal hemoglobin levels, as I mentioned, our design was based on the clinical observation of HPFH, so that's how we derived the 30% level. It’s certainly not our clinical target. We’re aware of the competitive landscape and are looking forward to sharing our data with you later this year.

Gilmore O’Neill, CEO

Thanks very much, Baisong. Regarding the venue for the update, we plan to share it before the end of the year but will confirm the exact venue later. Regarding the length of follow-up and the data cut for our 301 disclosure, we will have safety data as outlined, with hemoglobin levels and other parameters being cut close to disclosure, during the early plateauing phase based on our experience in this field.

Yanan Zhu, Analyst

Great, thanks for the color. For the LCA10 program, I think I heard for the pediatric mid-dose patients, the data will be safety only. When do you expect to have at least three months' data from the pediatric cohort? Also, for the measurement of the BCVA and FST, could the pediatric patients perform these tests and provide reliable results?

Gilmore O’Neill, CEO

Yes, you're correct. Our plan is to share safety data from the pediatric mid-dose cohort. We will clarify the duration of follow-up during the disclosure. Regarding BCVA and VFN, I’ll have Baisong comment. It's important to note that the Natural History Study was conducted to determine long-term disease progression and behavior of outcome measures across different age groups.

Baisong Mei, Chief Medical Officer

Yes, that’s a good question. As previously mentioned, we will be utilizing data from the Natural History Study to contextualize outcomes for the BCVA and Visual Navigation Course. The challenge lies in obtaining reliable results not just from pediatric patients but across all patients. We're fully aware of this and are analyzing test-retest variability and reliability of endpoints.

Yanan Zhu, Analyst

Great, thanks Baisong and Gilmore for all the color.

Operator, Operator

Our next question comes from Madhu Kumar with Goldman Sachs. Please proceed with your question.

Unidentified Analyst, Analyst

Hi, this is Mario here on for Madhu. We have two questions. First, how should we think about the internal pipeline development versus external partnering for ocular or hemoglobinopathies programs, particularly for oncology cell therapy programs? Secondly, what impact could the Inflation Reduction Act or IRA have on indication expansion for pipeline candidates?

Baisong Mei, Chief Medical Officer

Thanks very much for your questions, Mario. Regarding the internal pipeline, we have been pleased with the work of the executive team in evaluating our strategy and are excited to share that in the coming months. We believe we possess a very exciting technology, and we want to unlock its full potential by appropriately focusing our pipeline internally while actively seeking powerful partnerships to expand our bandwidth for realizing that potential. As for the IRA, we recognize the press surrounding it, but we feel optimistic about our technology continuing to develop new treatments for challenging diseases that have a significant unmet need.

Gilmore O’Neill, CEO

Thank you.

Operator, Operator

Our final question comes from Liisa Bayko with Evercore ISI. Please proceed with your question.

Liisa Bayko, Analyst

Hi. Thanks for taking the question. I’d be curious about any insights you're gaining from the progression of cell therapy through the regulatory process. As a fast follower, could you describe how you see the positioning in the marketplace?

Gilmore O’Neill, CEO

Thank you very much, Liisa, for your question. We're very excited, just like everyone else developing therapeutics in this space, especially as this serves as a vital pathfinder for genome editing as it moves through the regulatory approval process. Regarding our exclusive license for Cas9, there is added upside potential for us along with gaining insights as regulators evolve their thinking in this space. We believe that because of the unmet need, this market holds growth potential tempered by regulatory hesitance and the evolution of the payer landscape. We are well-positioned with our progress in the 301 program, potentially meeting the substantial unmet need for patients suffering from sickle cell disease and TDT with our 301 product.

Liisa Bayko, Analyst

Okay. Thank you.

Operator, Operator

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.