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spk10: Good morning, and welcome to Edisys 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 Mulder, Justice Relations at Edisys Medicine. Please go ahead, sir.
spk05: 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 investor 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 statements, even if our views change. Now, I will turn the call over to our CEO, Gilmer O'Neill.
spk08: Thanks very much, Ron, and good morning, everyone. I'm joined today by several members of the Editas executive team, including Baesong Mai, our chief medical officer, Mark Sherman, 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. EDIT301 utilizes a unique mechanism of action that edits 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 in sickle cell sufferers and reduction in anemia in TDT patients. I would also note that our EDIT301 program uses our proprietary AS-Cas12A engineered nuclease, which our preclinical data suggests results in higher fidelity and higher efficiency editing than Cas9. As a reminder, the initial patient dosing with EDIT301 represents the first time that an autologous ex vivo drug product was edited using our AS-Cas12A engineered nuclease. In the RUBI 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 RUBI trial by year end. These data would include efficacy data from the first treated sickle cell disease patient, as well as safety data from the first two treated patients. In the EDIT-VAL Phase 1-2 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 or blindness, and talk about the Phase 1-2 Brilliant Study. The Brilliant Study is designed to achieve several objectives. to 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 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-dosed 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. In order to move forward to a registrational study, we would need to see a meaningful treatment benefit for a commercially viable patient segment. Baesong will provide further details in his remarks. Beyond the BRINIANS trial, on the safety side, the EDER1-1 program lays the 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 EDER1-1, 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 sub-license 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 PTAP and once at Federal Circuit, against parties collectively known as CBC. As anticipated, the CBC 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. An appellate 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 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 CAS 9 license for commercialization. We believe that our strong IP position relates to CAS 9 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 CAS 9, including several in late-stage clinical development. We look forward to providing additional updates. I will now turn the call over to Baithong, our chief medical officer, to review the details of our clinical programs. Thank you, Gilmore.
spk06: Let's start with ADI-301. As Gilmore noted, we recently dosed a second sickle cell disease patient in the SPACE-1-2 Ruby study. Beyond the first two patients dosed with ADI-301, we also have completed a phrasis and successfully edited 3034 positive cells from several additional patients. The Ruby Studies Independent Data Monitoring Committee, or IDMC, is expected to review the available data this month. Once the committee has endorsed the 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 RUBI trial in a future registration package. So what to expect from the RUBI data release by end of this year? We plan to provide an update on safety and tolerability from both dose 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 counts of every three sites with measurable fetal hemoglobin, known as F-cells. Taking a step back, EDIT301 is targeting the gamma globin promoter, mimicking the natural 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 four to five months after dosing. If we can achieve these objectives, This would meaningfully increase our confidence in Edit301 being a differentiated and competitive product. By using our engineered ACE Cas12A with a high editing efficiency and specificity, by targeting the promoters of gamma globin gene 1 and 2, we expected these would deliver robust fetal hemoglobin expression, suppress the vessel occlusive crisis, 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 I-II ADITHEL trial of ADDIS301, the study is designed to assess the safety, tolerability, and the preliminary efficacy of ADDIS301. The first patient in the study has been enrolled and completed the freezes. We have completed editing of the CD34 positive 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 brilliant studies IDMC recently met as part of some normally planned meetings. We're pleased that edit 101 has maintained a satisfactory safety profile. Following its review of the available clinical data, the IDMC recommended a continued brilliant study and has endorsed continued enrollment in all active cohorts. As Gilmour mentioned, we are on track to provide an update on available clinical results from the brilliant study this month. The update will include available safety data on 12 adults and two pediatric patients, and efficacy data on adult patients. The adult efficacy update was including one year of data from adult mid-dose cohort and six months data from the adult high-dose cohort. The BRILLIAN 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 that are including full field sensitivity, functional outcome including visual navigation course, visual function outcome including best corrected visual acuity or BCVA. and the measures of visual quality of life, including 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 want to thank our patients, investigators, and the staff members at the study sites 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.
spk07: Thank you, Baishong. I would like to start with EDIT-103 for rhodopsin 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 row 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 non-human 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 completion of the AAV vector analytical testing. Moving now to our ex vivo cell therapy programs, our EDIT202 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 EDIT202 has potent antitumor activity and substantially increased persistence. We utilize a feeder 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 when differentiating the iPSCs into NK cells. And finally, the program utilizes our proprietary editing platform, such as our engineered AS-Castroire nuclease and sleek 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 EDIT202, The data showed that using SLEEC to knock in membrane-bound IL-15 and cleavable CD16, the EDIT202 cells had prolonged cytokine-independent persistence in vitro, as well as upregulated and continuous expression of CD16 after tumor cell exposure, thereby enabling the edited cells to significantly enhance serial killing of SCO3 tumor cells. In the SCO3 intravenous solid tumor model, when combined with an antibody, the EDIT202 cells resulted in a significant reduction in tumor burden and increased overall survival, demonstrating a 100% mouse survival rate after 100 days compared to 0% using just the antibody. As we continue development of EDIT202, 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.
spk01: 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 at 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. DNA 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 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 Gilmour.
spk08: Thank you very much, Michelle. I am pleased with Edith's execution over the past quarter. We continue to leverage our best in class technology, operational and manufacturing capabilities in our transition into a therapeutic 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 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.
spk10: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate that your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions. Our first question is from Gina Wang with Barclays. Please proceed with your question.
spk12: Thank you for taking my questions. I have two questions regarding the 301 and the 101 data update later this year. Just wondering, for 301, what will be, you know, you mentioned that 30% fetal globing should be sufficient to show clinical benefit, but given the competitive clinical profile, what we've seen so far, would that be sufficient to be competitive? What would be your goal? regarding the phytoglobin level. And then for the added 101, what is considered clinical meaningful? And you will collect several different data points. Could you give us a sense, like, what kind of a magnitude of improvement in terms of a LOCMAR BCVA visual navigation that would be considered clinical meaningful?
spk08: Thank you very much, Gina. Gilmore here. With regard to the 301, 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 AS-Cas12A 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, as is because the space, there is space for actually a number of therapeutic products profiles and approaches, and that actually stems around our belief, among other things, that over the next few years, the space will evolve slowly. We are confident that the vast majority of the prevalent population will remain untreated at the time of our launch, and that that will be a result or arise from what we anticipate some slow uptake owing to a number of factors around potential hesitancy, but very importantly around the evolution of the pear 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 inherent 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.
spk13: Thank you.
spk10: Our next question is from Greg Harrison with Bank of America. Please proceed with your question.
spk18: And 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? And maybe you could just elaborate on the earlier comments around the future of the program.
spk08: Absolutely. So, I think that the Edit 101 program really has two 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 brilliant 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 that patient segment or segments be a commercially viable patient population.
spk18: Got it. That's helpful. Thanks for taking the question.
spk10: Our next caller is from Chardon, Julia Lipschitz. Please proceed with your call.
spk09: Hi, this is Chloe for Gula, and thanks for taking the questions. We're wondering if you remain on track to submit a clinical to the FDA to be in alignment on a pivotal trial design and choice of endpoints this year, and what boxes you have left to
spk08: Thank you, Judah. 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.
spk09: Yeah, sorry. Is that better? Yeah, so the question was whether you're on track to submit a data packet to the FDA to gain alignment on the pivotal trial design in terms of endpoints this year, and what boxes you have left to check before you can submit that package to the FDA and get some feedback.
spk08: So, Julia, this sounds very poor, but what I'm actually going to think, 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.
spk09: Yeah, that's right.
spk08: Okay. Yeah. So, well, as I say, this month we will actually be sharing data from our one-on-one 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 with 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 subpopulation and the clinical meanings of the outcomes? With regard to our interactions with the FDA, 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.
spk13: Got it. Thank you.
spk10: Our next question is from June Lee with Truro Securities. Please proceed with your question.
spk03: Hey, thanks for taking our questions. For edit 103, what's the rate limiting step to IND and when can we expect that in the clinic? And, you know, why are you using Cas9 for that versus Cas12, which you think it sounds like you're excited about? And, you know, you're claiming 100% editing in the transduced area, but what is that transduced area? How does it relate to development retinal space? Thank you.
spk07: Thanks, June. 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 code and optimized human rhodopsin. In terms of the data, In a non-human primate study, we typically administer a 100 microliter BLEB. So the 30% elevation is the average change in expression within that BLEB 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, You know, 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, you know, this is taking a little longer than we had initially anticipated. And that's basically the escalation for pushing out the start IND enabling study start. And typically we don't give specific timelines on IND submission until we've completed that work.
spk10: Our next question is from Matthew Harrison with Morgan Stanley. Please proceed with your question.
spk19: Hi. Thanks for taking our questions. This is Wenjian online for Matthew. So we have two 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 adding update in the upcoming clinical trial update in terms of adding endpoint to include for registration or trial, or what specific patient segmentation to enrich in potential registration or trial?
spk08: Thank you very much. So with regard to the Ruby trial and 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 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 have and provide a very competitive product for patients. With regard to the 101 data, we will actually be able to share or plan to share that data set later this month. That is in this month, November. and actually we'll be able to talk about our next steps forward.
spk06: Yeah, just to add on that about the Ruby study, Matthew, and also related to Gina's question 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're looking forward to share the data with you later this year.
spk13: Okay, thanks.
spk10: Our next question is from Dane Ha with Spiegel. Please proceed with your question.
spk20: Hey, good morning. Thanks for taking our 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 end of year, but I think I heard Baizong 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 two-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, you know, 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 slash LCA10 population? Thank you.
spk08: Thanks very much, Jaegon. So let me clarify the ruby. We will be presenting safety data from two patients and efficacy data from one patient, based on you may want to expand. Yes.
spk06: So just 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 those second patients. So the first patient will have a longer duration of observation, given that these 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 two patients, just we feel the first patient data may be more meaningful from efficacy perspective. Hope that helps.
spk08: Thanks very much, Baesong. And let me turn to the brilliant 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 a segment, that will actually, of the patient population, that would be determined by a number of factors, and essentially at the highest level, an intersection of the magnitude and clinical meaning 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 AV-delivered genome editing tool and they were using an RNA antisense-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 as we look at our data and share it with you, we'll be able actually to go into more detail around that.
spk20: Thank you. Excellent. Look forward to it. Thanks.
spk10: Our next question comes from Asil Nadu with Cowan & Co. Please proceed with your question.
spk16: Morning. Thanks for taking our questions. Just two 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?
spk08: Thank you. So I'm going to ask Baesong to answer the first question and Mark the second question.
spk06: Thanks, Phil. For the Ruby efficacy data, as I mentioned, we will provide safety as well as key hematological parameters. We certainly will report a VOC, but as I mentioned earlier, a short-term duration of the observation may not be most meaningful, but we certainly will report the data on that.
spk07: Yeah, Phil, this is Mark. I think as we perhaps have discussed at the last earnings call, we're completing any animal pharmacology data that's necessary to support the IND-enabling tox study design and conduct. And as we mentioned in the script, you know, that's planned for sometime next year.
spk13: Perfect. Thank you.
spk10: Our next question is from Jay Olson with Oppenheimer. Please proceed with your question.
spk02: Oh, 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 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 CITSE? Thank you.
spk08: Right, thanks very much, Jay. So with regard to 101, I'll have Bae Song answer that question and the 202 CITSE I'll ask Mark to address.
spk06: Yeah, thanks for the question. 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 cohorts, it was discussed at IDMC, and although they are satisfactory with the safety profile, we recommend to continue the study as planned, but they recommend to review additional three months of data from the existing patient 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 not impact our decision about the program. We feel we have adequate data to make a decision about this program.
spk07: Yeah, hi, it's Mark here. Yeah, we're not really in a position to give specifics about the CITC 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 SCO3 model and serial tumor killing, two examples. So the data will continue on that track at CITC.
spk13: Thank you, Mark.
spk02: Thank you very much.
spk10: Our next question is from Joel . Please proceed with your question.
spk17: Thanks. For edit 103, the presentation last month described 100% gene editing and knockout and 30% replacement levels. Can you discuss why 100% editing wouldn't be expected to lead to 100% protein levels and also is 30% enough?
spk08: Thank you, Mark. I'm going to ask Mark .
spk07: Can you just clarify the second part of that? So the 100% editing is necessary to remove the mutant rhodopsin, 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 one allele. In the NHP model, You may recall we had reported data showing that we had a knockout-only arm as well as a knockout and replace arm. And we were able to correct the phenotype that occurred in the knockout-only arm, which is basically loss of rod foot receptors with the 30% rhodopsin 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, I'm thinking of a dog model from the Yupeng group, which arrived at a somewhat similar conclusion that around 50% rhodopsin in that particular model was sufficient to correct the phenotype.
spk08: So, thanks very much, Mark. Joe, just to be absolutely clear, you know, make sure there's no room for any confusion or misunderstanding. In contrast to LCA10, the 103 or 101 of the LCA10, The 103 program is addressing an RP4 disease which is a dominant inherited 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 we're replacing that with a codon-optimized replacement, a rhodopsin. And I think you heard Mark give the rationale of why we believe that that replacement is sufficient.
spk07: 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 guide. So we're simply introducing indels, which cause frame shifts in the transcription and therefore loss of the endogenous rhodopsin. That's different to the 101 program where you have a dual guide. And so the productive editing, which in this case is deletion or aversion, is a lower percentage.
spk13: Great. Thank you.
spk10: Our next question is from Luca Isi with RBC. Please proceed with your question.
spk15: Oh, excellent. Thanks for taking our questions. This is Lisa. I'm for Luca. I have two 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 endpoints you're thinking about besides crises. 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? Thanks for taking the question.
spk08: Thanks very much, Yifeng. 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 differentiation, our readouts later this year will be that 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.
spk13: Great.
spk10: Thanks for taking our questions. Our next question comes from Ian Zu with Wells Fargo Securities. Please proceed with your question.
spk04: Hi. Thanks for taking my questions. So first on the SQL Shell program, I think, Bison, 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, could you talk about the venue 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 month of follow-up? Thanks.
spk06: I thank you, Yanen, for the question. For the sickle cell patient, regarding the fetal hemoglobin level, as I just mentioned, that, you know, our hypothesis of design these molecules was based on the clinical observation of that about HFP patient 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're fully aware of this field. and we were looking forward to share our data with you later this year.
spk08: Thanks very much, Beto. With regard to the venue for 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. And with regard to the length of follow-up and the cut for the data for our 301 disclosure, For the two patients, we will have the safety data, as Baesong has outlined, and with regard to efficacy data, hematologic parameters, that data cut will 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.
spk04: Great. Thanks for clarifying. the color. And on the LCA10 program, I think I heard for the pediatric mid-dose patient, the data will be safety only. So two questions. When would you expect to have at least a three-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? Thanks.
spk08: Yeah, thanks very much, Yanen, for those follow-up questions. 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 based on 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 to 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, based on, I don't know if you want to add to that.
spk06: Yes, sure. That's a good question about the endpoints. Gilmore mentioned earlier about the purpose of the Sabrina 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 or visual navigation course, the challenge is actually not only for the pediatric patient, could be for other adult patients too. So we fully understand that. So we are analyzing testing and retesting variability and all those reliability of the endpoints. Yep.
spk04: Great. Thanks, and thanks Gilmore for all the color.
spk10: Our next question comes from Madhu Kumar with Goldman Sachs. Please proceed with your question.
spk14: Hi, this is Omar from Madhu. We have two questions. So first, how should we think about the internal pipeline development versus external partnering for exocular or hemoglobinopathy programs, particularly for oncology cell therapy programs? And then second, what impact could the Inflation Reduction Act or IRA have on indication expansion on pipeline candidates?
spk08: Thanks very much for your questions, Amari. With regard to the internal pipeline, as I said a little earlier in my prepared remarks, 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 the IRA, thank you for that. We actually, I know that there has been a bit of press and some companies have actually talked about IRA restricting their approaches. I think it's important and we have certainly 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 you know, 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.
spk13: Thank you. Thank you.
spk10: Our next question comes from Lisa Beko with Evercore ISI. Please proceed with your question.
spk11: Hi, thanks for taking the question. I'd just be curious about any read-through or insights you're getting from sort of the progression of Exacell through the regulatory process. And then as a kind of a fast follower, maybe you can describe how you see positioning in the marketplace there. Thanks.
spk08: Yeah, thank you very much, Lisa, for your question. Obviously, we're very excited along with everyone who's developing therapeutics in this space, and very specifically as this will be an important pathfinder 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 their 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 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 be 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, there's 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 cell and TDT with our 3-in-1 product. Thank you.
spk13: Okay. Thank you.
spk10: 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.
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