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spk04: Good morning and welcome to Editas Medicine's second 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 Moldover, Investor Relations at Editas Medicine.
spk18: Thank you, Paul. Good morning, everyone, and welcome to our second quarter 2022 conference calls. 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 FCC as updated by our subsequent filing. In addition, Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. Now I will turn the call over to our Executive Chairman, Jim Mullin.
spk11: Thanks, Ron, and good morning, everyone. I'm joined today by several members of the Editas executive team, including Gilmore O'Neill, our chief executive officer, Mark Shearman, our chief scientific officer, Michelle Robertson, our chief financial officer, and Baesong Mei, who I am thrilled to welcome as our new chief medical officer. As you know, on June 1st, Gilmore assumed the role as CEO, and I became executive chairman of the board. Over the past two months, I've partnered closely with Gilmore and the executive team to ensure the seamless changeover of the CEO role. We are very fortunate to appoint a leader of Gilmore's caliber as CEO. During his nearly 20 years of experience in genetic medicine and clinical development, including senior leadership positions at Sarepta and Biogen, he has led some of biotech's most successful clinical programs. Gilmore's drug development experience, proven leadership, passion for genetic medicine, and focus on patients are exactly the right skill set and experience to lever the foundation we've built over the past several years and lead the company towards commercialization. If his first few months are any indication of his leadership abilities, Editas' next few years are undoubtedly poised for success. With that, I'm very pleased to turn the call over to our new CEO, Gilmore O'Neill.
spk02: Thank you, Jim, and good morning, everyone. Let me first say that I am delighted to be here today. As you know, Editas is a forerunner in the development of CRISPR gene editing technology, and I am very happy to have the opportunity to lead the company to create potentially life-changing medicine. I also want to thank Jim for continuing to strengthen the Editas leadership team over the past few years, and I am honored to work alongside such a talented and dedicated group of people. With the addition of our new chief medical officer, we now have a complete and even stronger leadership team in place. Let me start off by giving you my initial two-month assessment. The company's technology is what drew me to Editas. What I have seen since my arrival has reinforced my enthusiasm and given me even more confidence in the company's potential. Editas is transforming from a technology platform company into a therapeutic company that will continue to create, develop, and will commercialize new therapeutic assets. to treat previously untreatable serious diseases. EDITAS has numerous areas of differentiation, including distinct expertise in nucleate enhancements and bioinformatics to drive lead discovery. These enhanced enzymes then coupled with proprietary RNA chemistry to make efficient high-precision edits. And overall, the foundational science that has led to the current pipeline of potential products is impressive. I have found a very creative team of innovators in our discovery group, strong CMC expertise, and promising clinical assets supported by a robust R&D pipeline. With these pieces in place to support our therapeutic pipeline, we now have to focus on clinical execution, which is why I'm so happy to welcome Dr. Baesong Mai as our new chief medical officer to Editas Medicine. Baesong brings substantial translational and registrational trial experiences across several therapeutic areas, including hematology, where specifically he oversaw the global approvals of two drugs for non-malignant blood disorders. He has extensive, and more importantly, a proven track record of both inventing and advancing therapeutics from the bench through clinical development, also leading to multiple global drug approvals. Baesong joins us from Sanofi, where he served as Senior Global Project Head in Rare Disease and Rare Blood Disorders. Prior to Sanofi, based on work at Biogen where I had the privilege of working with him, and I can personally attest to his breadth of knowledge and effective leadership skills. He officially started about two weeks ago, and we very much look forward to his contributions in the months and years ahead. Now, I would like to provide my initial thoughts on our lead pipeline product, starting with our EDIT-301 autologous program for sickle cell disease and transfusion-dependent beta-cholestemia. As many of you know, EDIT301 utilizes a unique mechanism of action that edits the promoter of the gamma-globin gene to disrupt binding of the BCL11A suppressor. In turn, this provides high and durable levels of fetal hemoglobin, or HBF, in a manner that is independent of erythropoietic stress, resulting in reduced sickling and vasoacrusis events in sickle cell patients and resolving anemia and transfusion dependence in beta-cholestemia patients. This is the first time that an autologous ex vivo drug product has been edited using our high-fidelity AS-Cas12A engineered nucleate. We have continued to build momentum with Edit 301 in the past quarter. We dosed the first patient in the Ruby trial for sickle cell disease, and that patient has successfully engrafted. The partial clinical hold was lifted by the FDA, which will allow us to include efficacy data from all treated patients in a future registration package, and we have successfully collected and edited cells of additional sickle cell disease patients. We continue to expand trial sites to help create a steady cadence of patient enrollment, and we remain on track to provide top-line clinical data before year-end. Additionally, we received orphan drug designation for base thalassemia in May, and we remain on track to dose the first TDT patient by year-end. Moving now to our lead in vivo program, EDIT 101 for LCA10, which is a devastating inherited retinal dystrophy caused by autosomal recessive CEP290 mutation. Our ongoing phase one brilliant study has been designed to achieve several objectives. To identify a dose that optimizes the benefit and risk balance of EDIT 101, and that can advance to registration. to identify a segment of LCA10 patients most likely to benefit from therapy in a registrational study using baseline clinical and physiologic characteristics, and to identify the optimal endpoint for use in a registration study. The safety profile has thus far been very encouraging and has allowed us to move up into our high dose and into pediatric patients. And the efficacy data generated to date support proof of concept that gene editing is occurring in retinal photoreceptors. This morning, we announced that we have a dose to pediatric patients in the mid-dose cohort. As of today, we remain on track to provide a clinical update on the BRILLIANS trial later this year, which we expect to include safety and efficacy assessments on all patients who have had at least six months of follow-up evaluation. These data will help identify the most relevant and sensitive endpoints to support registrational trial development. Beyond developing a treatment for LCHM, the EDIT-101 program lays the foundation for subsequent popular drug development programs within our in vivo platform. The proven safety of the capsid, success administration of the editing machinery through subretinal injection, and the delivery of the CRISPR Cas9 enzyme to the photoreceptors have demonstrated that we can effectively edit retinal cells in vivo. For example, our 103, our EDIT-103 program for rhodopsin autosomal dominant RP, leverages all of these elements, and in addition has demonstrated much higher preclinical editing efficiency than EDIT-101 with nearly 100% editing. So even though both the EDIT-101 and EDIT-103 programs use the same AV vector and Cas9 enzyme, the editing efficiency of the EDIT-103 program is substantially greater. Moving to our intellectual property portfolio as a reminder, Broad's patents covering Cas9 are exclusively licensed to EDITAS for therapeutic development. Earlier this year, the Broad Institute prevailed for the third time against the University of California, along with its co-owners, collectively referred to as CBC, in protecting these patents, when the Patent Trial and Appeal Board, or PTAB, ruled in the Broad's favor. As anticipated, CBC filed an appeal with the Federal Circuit, and we remain confident that Broad, and by extension EDITAS, will once again prevail. If that is indeed the case, Editas will retain the sole rights to issue either exclusively or non-exclusively licenses for Brose CRISPR-Cas9 IP for human therapeutics in the United States, which is the dominant market for innovative medicine. And as a reminder, both our ex vivo and cell therapy group platforms use our proprietary AS-Cas12A enzyme, which is not encumbered by any intellectual property dispute. We believe this strong IP position, coupled with our exclusive right to grant future IP licenses to companies desiring to commercialize CRISPR-Cas9 medicine, is a significant value driver for our stakeholders. And with that, I will turn over to our new chief medical officer, Faisal Mahmoud.
spk17: Thank you. Thank you, Guillermo. And good morning. I'm very excited to be speaking with everyone today. And we'll start off by sharing what drew me to Adidas. Firstly, I was impressed by the quality of company science and its leadership in gene editing field. I spent the last several years working in gene therapy and RNA medicine, so I was closely monitoring the evolution of gene therapy and the emergence of CRISPR-based gene editing. I was intrigued by Edita's work and its unique approach to address genetic diseases. Additionally, what inspires me, and I think what inspires most people in this industry, is the opportunity to create a new medicine to make a difference for people suffering from serious genes. Edita's work is highly differentiated from other players in the field, and the opportunity to be a part of a gene editing pioneer is why I'm here. Over the course of my career, I have had the privilege to work in all segments of drug development lifecycle. I entered pharmaceutical industry as a CNC scientist over 20 years ago. While working in CNC, I was leading discovery research team. After transitioning to discovery research, I also had an opportunity to assist in clinical development, which is where I have stayed. I took a leadership role in clinical development with end-to-end responsibility from the first human clinical study to global approval. My experience in CNC and discovery research has been profoundly valuable. and has impacted my work in clinical development. In general, I consider myself to be a direct developer at heart. And my goal is to help Adidas to develop and bring the right medicine to approval for patients who need treatment. I look forward to updating you on our clinical progress on subsequent calls. With that, I will turn the call over to our Chief Scientific Officer, Mark. who will provide an update on our R&D efforts.
spk03: Thank you, Besson. As Gilmore has provided updates on EDIT-101 and EDIT-301, I'd like to begin with EDIT-103 for Rho-ADRP. As a reminder, EDIT-103 is highly differentiated from EDIT-101, with a different approach and superior preclinical data. EDIT-103 uses two adeno-associated virus vectors, to knock out the mutant rhodopsin in order to correct the toxic gain of function while simultaneously replacing that aberrant gene with a functional one. The knockout of the gene in the retinal photoreceptor cell can only occur if the components for the replacement gene are also delivered to and active in that same cell. This mutation agnostic approach can potentially address more than 150 gene mutations that cause RhoADRP. At the ALBO meeting in May, we presented preclinical data that demonstrated nearly 100% productive editing in non-human primates and generated over 30% functional rhodopsin gene replacement, which proved to be therapeutically effective in that NHP study. The data also showed improved photoreceptor organization and improved retinal morphology in the knockout and replace treated group. As we continue to optimize the product, we also think there is potential for further improvement upon that data that we've already presented. We also recently received encouraging FDA feedback on Edit 103 and its expectations as we approach an IND filing. Based on the FDA's input and our ongoing work on the program, we remain on track to initiate IND-enabling studies later this year. Moving now to our cell therapy program. In June, we announced a collaboration with Ematic related to a strategic research collaboration and licensing agreement, pursuant to which we will apply our gene editing technology to gamma delta T cell-adopted cell therapy, an area where Ematic has world-class expertise. We believe that this collaboration will give us the opportunity to develop novel T cell-based therapeutics that enhance tumor recognition. In our cellular therapy collaboration with Bristol-Myers Squibb, we were pleased to announce earlier this morning that BMS has opted into an eight-editing program for alpha-beta-T cell therapeutics. This was their fifth opt-in over the last 12 months, and we are collectively optimistic about continuing the momentum of that partnership. BMS has multiple early programs covering both solid and heme tumors that incorporate editasis technology and use multiple edits to optimally engineered T-cells, both in autologous and allogeneic platforms. The most advanced program from this collaboration is currently in ING-enabling study. The engineered cells demonstrate improved tumor killing and antitumor efficacy compared to wild-type cells, both in vitro and in vivo. We believe that these improved pharmacodynamic and phenotypic characteristics in engineered T-cells open the door for numerous potential clinical applications. For our in-house cellular therapy programs, we are very pleased with the progress we are making with our IPSC-derived NK cell medicine program for solid tumors, with a focus on EDIT202 as our lead program in this area and currently in preclinical development. Using our proprietary engineered AS-Cas12A nucleate technology, we have developed engineered NK cells that have potent antitumor activity and substantially increased persistence in preclinical models which we believe could lead to lower frequency dosing, an important potential advantage for patients compared to many existing NK cell approaches. At the ASGCT annual meeting in May, we presented data demonstrated that an in vivo solid tumor model, edit 202 in combination with an antibody induced significant tumor reduction, tumor burden reduction, resulting in complete tumor clearance in 40% of mice over the course of the experiment. Further, EDIT202 dramatically improved mouse survival over wild-type INK cells in the same model, such that all mice remained alive at the end of the 120-day study period. These impressive data support the development of EDIT202 as a potential allogeneic cell-based medicine for treating solid tumors. One of the key differentiators of this program is our use of a cell-free system to expand and differentiate the edited iPSC into mature NK cells. Most approaches that facilitate the differentiation of iPSC into immune cells involve platforms that typically use feeder cells, introducing inherent risk of exogenous cell fragments getting into the final drug product. In contrast, our INK platform is developed using a feeder cell-free system with defined components for GMP INK cell production. and we are currently in the process of scaling the manufacturing. With that, I'll turn the call over to our Chief Financial Officer, Michelle, to review our financial update.
spk13: 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 in the second quarter of 2022. I'll take this opportunity to briefly review a few items. Our cash, cash equivalents, and marketable securities as of June 30th for $528 million compared to $566 million in the prior quarter. We continue to be disciplined with our expense management and our cash runway as expected to extend into 2024. Revenue for the first half of the year was $13 million compared to $7 million for the same period last year. The increase was primarily attributable to an additional program licensed under our collaboration with DMS. G&A expenses for the first half of the year were $36 million compared to $43 million for the same period in 2021. The decrease was primarily driven by performance awards granted in 2021 that were recognized in the second quarter of 2021. R&D expenses for the first half of the year were $82 million compared to $76 million for the same period last year. This increase was primarily driven by increased manufacturing and clinical investments in employee-related expenses. And lastly, as Mark mentioned, we recently announced a collaboration with Inetis. As part of this collaboration, Inetis has received an upfront cash payment and is eligible for additional payments based on development, regulatory, and commercial milestones. Inetis will also receive royalties on future net sales on any products that may result in this collaboration. Overall, Inetis remains a strong financial position and can continue to advance our program. With that, I'll hand the call back to Gilmar.
spk02: Thank you, Michelle. Again, I want to reiterate how excited I am for the future of Editax. While we have exponentially enhanced our technology capabilities, we are no longer simply a technology platform company. Over the past several years, we have focused on building out our operations and manufacturing teams and have our sights on the end goal, which is commercialization of life-changing medicines for patients. And through very thoughtful clinical development, we are rapidly transitioning to a therapeutic company while remaining on the cutting edge of innovation. Underpinning this transition are further advancements to our innovation technologies, such as our proprietary sleek knock-in gene editing platform. We also continue to be active with business development activity and look forward to advancing discussions related to our foundational intellectual property. Moving forward, we will prioritize assets that maximize the probability of technical, regulatory, and commercial success. This includes current and future programs in our pipeline. So, what is in store for the rest of this year? On the in vivo side, we will be providing a more comprehensive clinical update on our brilliance trial of Edit 101 later this year. That update will focus on safety data, additional POC data for SEP290 editing in the retinal photoreceptors, and the identification of the optimal patient segment and functional visual outcomes for use in future registration studies. Following feedback from the FDA, we plan on initiating IMD-enabling studies for EDIT-103 for Rho-ADRP later this year. And moving to ex vivo, we expect to have initial top-line clinical data for our Ruby study in sickle cell disease later this year, which will include data from the first patient and potentially second patient. And finally, we have begun screening beta-thalassemia patients for the EDIT-301 for beta-thalassemia and anticipate apheresis editing of products as first before the end of the year. We thank all of you for your interest and support, Editas. And with that, we are ready to open up the call for Q&A.
spk04: 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. The confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd 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 key. One moment, please, while we poll for questions. Thank you. Our first question is from Gina Wong with Barclays. Please proceed with your question.
spk06: Thank you for taking our questions. This is Tom for Gina. I have two questions for the six-star defense and medicine for females. So first, I understand it might be earlier, but do you have a rough estimate of the required following up period and trial size for both indications, given the FDA's experience with other more advanced products? And secondly, on the trial, on the enrollment side, would you be able now to dose the next few patients in parallel, or when would you be able to do that?
spk02: Thank you. I'm afraid I couldn't catch your name. But apropos the size of the study, we are closely monitoring what the FDA and other regulatory authorities are guiding to us and to our peers in this space. But we have designed a study to enable us to recruit the patients necessary, and we have the manufacturing capacity to ensure that clinic supply will be available for those numbers. With regards to enrollment, we have in our current protocol a set of criteria for the first couple of patients. where we follow them for approximately 40 days, or rather specifically 40 days, and hold an independent data monitoring review of safety data to initiate the second and third patients. After that, our intention is to move as quickly as is feasible. And this is one of the reasons why I'm so happy that we have our new chief medical officer based on my, with his experience in this space to help us really double down on clinical execution.
spk04: Thank you. Thank you. Our next question is from June Lee with Truist Security.
spk05: Please proceed with your question. Hi. Thanks for the updates and taking our questions. I'm looking forward to the progress with the new additions to the management. I have two questions. On Edit 301, are you able to disclose how quickly the cells engrafted Also, I presume bypassing the need for biologic edits for edit 301 with promoter edits could lead to better efficacy compared to using enhancer edits. Do you think that will show up as a clinical benefit, or is that more of a manufacturing consideration? And lastly, how are you looking to differentiate from excess cells? And I have a quick follow-up.
spk02: Thank you very much, Jun. We have not, we will be planning to disclose our clinical data at the end of the year when we will actually be able to give outcomes around engraftment as well as hematological parameters. With regard to the differentiation, we believe that, as you say, editing the promoter of the gamma globin actually does help increase the durability of expression of fetal hemoglobin. That may be displayed in the hematological parameters over time, but I think as we have said in previous discussions, we anticipate that the clinical benefits of which we believe that would be important will declare themselves over a longer-term follow-up. for patients. I actually could not hear your third question, I'm afraid.
spk05: Oh, no, I think you answered it. So, a quick follow-up on the Gamma Delta. You know, what drew you to Gamma Delta, and are you applying your streak method for the Gamma Delta program? I might have missed that as I was multitasking. Thank you so much.
spk03: Mark. Hey, June, it's Mark here. I can certainly answer that. So, you know, we really like the opportunity that the Gamma Delta T-cell program with Ematix provides us. Many of the technologies that we have used to support the CMS program can be equally applied to the Ematix program. As we had indicated in the earlier press release, you know, they have the opportunity to nominate up to, you know, a number of targets for that program. And we're looking forward to getting that initial list from them. But short answer is yes, we can apply. ES-Cas12a nucleates the technology to that program. Fantastic. Thank you so much.
spk04: Thank you. Our next question is from Dagon Ha with CFO. Please proceed with your question.
spk14: Great. Good morning. Thanks for taking our questions, and congrats on all the progress, and welcome on board, Gilmore. Nice to speak to you again. Two questions from us. Just wanted to follow up on June's question about differentiation. So, Gilmore, when you were talking about differentiation between EDIT301 and CTX001 potentially declaring itself sort of over the longer term. I guess how long of a follow-up would we anticipate before we differentiate or see that differentiation play out given that the market dynamics at that point would be presumably CTX001 being marketed. And then secondly on EDIT301, Mark, just looking back at the strategy you have here using the dual vector, I guess can you walk us through sort of the idea or why it would be superior compared to a single vector utilizing Edit 101 and perhaps as we anticipate the second half update from Brilliance, is there anything that you would be looking to that could be potentially seen as a read-through to Edit 301 as the IND enabling studies get underway? Thanks so much.
spk02: Thanks very much, Dagon. Good to talk again. Let me address the first question around 301 differentiation and the read-through on the clinic. That would be something that we will actually have to determine over the long term. However, we do see the potential of persistence. and durable fetal homologous expression as something that we could see based on hematological parameters in the near term. In the medium to long term, we could see and would anticipate reading those through on the clinical side to maintaining hemoglobin levels at a very favorable level to ensure long-term benefits to patients with regard to end-organ health. and we would see that reading through in both sickle cells and beta-cholestemia in the long term. I will say you addressed market dynamics. I'd like to address that too. While CTX001 may actually be first to market, based on our experience and observation of recent gene therapeutics or so-called one-on-done therapy launches, we anticipate that the pull-through from that CCX001 approval will not actually lead to a large number of untreated patients remain at the time of our launch and commercialization because of the challenges around site capacity. And again, this is what we've seen with other gene or one-and-done therapies, as well as the challenges around negotiating access and reimbursement. So for those reasons, we do believe that that market is there for our product. And then with our differentiation of 301, we believe that this could be the treatment of choice.
spk03: And then I'm happy to answer your question on edit 103. The similarities with 101 are really the AAV5 CAPFID and the FACAS9. And so we know that with subretinal injection, we can effectively transduce human photoreceptors both with our data as well as from other gene therapy programs. But I think pretty much that's where the similarities end. With EDIT103, the reason why we're using a dual vector system is because it's an autosomal dominant disease with a dominant gain of negative function of the mutated rhodopsin. So any therapy has to start by removing that mutant rhodopsin. and then replacing it with a codon-optimized wild-type tumor rhodopsin. And the only way you can do that based on the size of the components is with a dual-vector system. And as you probably remember, we split the components rationally between the two vectors so that only those photoreceptors which take up both vectors, which actually, by the way, is probably all of them anyway, but only those photoreceptors who take up both vectors can actually execute the two-step process of knocking down the endogenous and replacing it. And, you know, lastly, for this particular, for Edit 103, we're targeting rod photoreceptors as opposed to cone photoreceptors for Edit 103.
spk14: Great. Thanks so much. Thanks.
spk04: Thank you. Our next question is from Jay Olson with Oppenheimer. Please proceed with your question.
spk01: Oh, hey, everybody. I want to also welcome the new management team. Thank you for the introduction. And thanks for taking the question. Maybe just on edit 101, can you just comment on the pace of enrollment in the pediatric cohort and any color you can provide there in terms of when you expect to complete dosing in the mid-dose cohort and when is the next IDMC safety review and also any color you can provide on the dosing and expanded cohort, how many patients, and when we should expect to see data or clinical update in the second half of the year. Thank you.
spk02: Thanks very much, Jay. So, let me start at the end and just say that we will be on track to provide clinical data and updates at the end of the year or before the end of the year. Prior guidance has been around the October-November timeframe. And in that data set, we will provide efficacy data from the completed mid and high adult dose cohort from an efficacy point of view. For safety, we will actually have a data cut from all dose patients, as would be good practice. With regard to the IDNC data, The IDMC is scheduled to meet, that is the Independent Data Monitor Committee, is scheduled to meet later this quarter, at which point it will evaluate data, including the two pediatric mid-dose patients. And that meeting would give a decision to enable us to start enrolling in the high-dose cohort. And then with regard to the timing of pediatric enrollment, the approach we initially used was slower than we expected. One of the reasons that I'm here and that Baesong has joined us is to really double down our efforts on clinical execution. We have amended and are actively amending the approach and anticipate that we will be enrolling faster. I do have to say that I don't have complete line of sight yet, but we'll share that with you in the near future.
spk03: Maybe to add one comment on the adult, as you recall, we gave ourselves the option to expand into the mid- and high-dose adults. And, you know, that continues to be a possibility. Obviously, it's reliant upon evaluation of the data as it emerges as well.
spk01: Great. Thanks for taking the question.
spk04: Thank you. Our next question is from Luca Issi with RBC Capital Markets. Please proceed with your question.
spk10: Hi, this is Reena Patel on for Luke at UC. Thank you for taking my question. I just wanted to ask, Mr. O'Neill, given this is your first earnings call, can you talk about the top three reasons why you decided to join the organization and maybe what was the biggest hesitation or concern? And just another on SigelCell, assuming Vertex and CRISPR and possibly Blue get approved ahead of you, how are you thinking about the likelihood of getting approved on a single-arm trial? Can the FDA ask you to run a head-to-head trial?
spk02: So I just, sorry, Reena, thanks for your question. This is Gilmore here. I just want to clarify, I am the one who has just joined the company and based on just the company, Michelle, I'm happy to say, has been with the company for some time as Chief Financial Officer. So forgive me, I just want to be sure that maybe you were addressing the question to me. And what I would say is that what drew me to the company were a number of things, not just the fact and the history of its foundational CRISPR technology, but very importantly, the strength of the science that I saw here, and particularly the... differentiated core expertise in nuclease design and engineering. One nice example of the ASCAS12A evolution, which is a high fidelity, high efficiency enzyme that we have actually now have in the clinic. In addition, the guide RNA, there is a substantial expertise in both chemistry and design for a guide RNA. Other important capabilities also sit within our discovery group, particularly around our quantitative biology, which aids us in our design of guide RNAs. Finally, the CMC capabilities, which are actually impressive with both scale and quality. And more importantly, the concrete examples that we have clinical supply both for delivery of a V as well as autologous edited cells. I did say finally about CMC, but there are other things that drew me as well. The fact that the technology is in the clinic using two platforms, and quite frankly, the cash position, which Michelle described as strong and was actually importantly in joining. So then the other question was around Vertex and CRISPR and what the impact of those approvals might have on our design. You know, how we talk to the FDA and the outcomes of our discussion with the FDA are some things that I would not want to speculate on, but I will tell you that, you know, our trial currently is designed in a way that enables us to look at both hematological parameters as well as clinical parameters both for the sickle cell patient population that we are treating and recruiting as well as the beta-file patient population. And the precedent that we're seeing set gives us some confidence about our approach and obviously as the field evolves, we will be more confident. But I think currently we are very well positioned in our design approach to developing 301. The other thing I do actually want to remind everyone of is that our partial clinical hold was removed by the FDA. Why does that matter? It matters because it enables us to use all the efficacy data in the ongoing trials as part of a marketing application.
spk10: Great. Thank you.
spk04: Thank you. Our next question comes from Rick Bianchowski with SVB Security. Please proceed with your question.
spk08: Hey, good morning. Congrats on all the progress, and thanks for taking our questions. Just two from us. So, my first question is regarding the development of EDIT301 and BetaFAL. Given that there is an upcoming PDUFA date for a competing gene therapy candidate for BetaFAL in the U.S., can you speak to the opportunity, along with some of the challenges, in starting Phase I trials in a treatment setting with an approved gene therapy product? And for my second question, both the Alpha, Beta, and Gamma, Delta T-cell programs have license agreements with outside partners. and the INK Spell program is currently being developed in-house. Gilmour, I was hoping to get your thoughts on the rationale for keeping this program wholly owned and what the right stage of development would be for thinking about whether or not a partnership here would make sense.
spk02: Thanks very much, Rick. So, with regard to Edit 301, The opportunity for basal thalassemia and indeed sickle cell remains strong, we believe. We believe that it has value on its own right. We believe it's a differentiated product. But actually very important, we believe that at the time that we both initiate or whether as we continue, let's say, to recruit patients into our ongoing trials and when we look at the commercial space when we would launch, We believe that owing to the number of the challenges outlined, the uptake and the number of treated patients will actually be relatively slow, certainly for that first approval, because of challenges around access and reimbursement. So we're actually confident that there is value to this program. for those reasons, and also that we will be able to execute and enroll in our ongoing EDITAL as well as RUBI studies. With regard to the partnering, as you pointed out, our partnerships in some immuno-oncology spaces, as Mark has said, the INK program has moved well. We are always interested in partnering or looking at the potential for partnerships. One of the great opportunities and challenges that I have seen with Editas is the broad applicability of its technology. And I think I said when I joined the organization and maintained the position that one very good way to maximize the value of that technology for patients as well as for our other stakeholders is is to maximize and broaden our bandwidth for execution through partnership. And so we are open to looking at partnerships and have said before that we are open to partnerships across a number of our platforms, including the INK platform.
spk04: Thank you. Our next question is from Phil Nadeau with Cowan and Company. Please proceed with your question.
spk09: Good morning. Thanks for taking our questions. A couple on the ocular programs from us. First on Edit 101, I think you're guiding to defining the registrational trial design by the end of the year. It seems to us like you only have a pretty modest experience with the pediatric high dose by that time. So how can you... design the registration trial without that high-dose data? Wouldn't that high-dose data provide important information on the dose necessary to patients and possibly the efficacy endpoints?
spk02: We have not guided to defining a final registration study by the end of the year for the very simple reason that one would have to do that in discussions with regulatory authorities, including the FDA. I should have said, by the way, Phil, thank you for your question. Good to meet you. But we have not given that guidance. What we anticipate doing is looking at that data. We will have a large data set from our mid- and high-dose adult patients, and we'll be able to look at a segment of the patient population because we have seen proof of concept in adult subjects, and we will be also looking at and evaluating and selecting potential endpoints, and we will bring that entire data set to our regulatory engagements. It is important to note that we also have a natural history data set that we'll be looking at that actually also helps us in selecting, designing, and understanding performance and interaction of those clinical endpoints with a broad population that spans the pediatric and adult population.
spk09: That's very helpful. And then second question on edit 103, you disclosed non-human primate data that shows 95% editing and about 37% human protein production in the non-human primates. What data is there to suggest whether that level of protein production is sufficient to rescue the disease?
spk03: Yeah, thanks, Phil. I mean, we're basing that, well, there are two factors that led us to make that statement. One is that in the study itself, in the knockout only arm, we were able to demonstrate a loss of photoreceptors that could be corrected with the knockout and replace approach. And so in that particular experiment, that 30-ish percent rhodopsin was sufficient to rescue those cells, which would otherwise be eliminated in that, you know, from the retina. That's one. The second is that there's a well-published dog model from the UPenn group, Art Tadisian and William Beltran, where they did a knockout and replace experiment with the shRNA and rhodopsin. And in their hands, they showed that about 30% rhodopsin expression was sufficient to rescue photoreceptors in that model system. So those two pieces of information together, we believe, guide us to an approximate level of rhodopsin expression that will be sufficient. What we've also said, though, is that that was the level in that particular experiment. There are still some things that we can change in the way that those experiments are conducted to modify the editing versus replacement levels, and that work is ongoing in the lead up to the IMD and APIN study.
spk09: That's very helpful. Thanks for taking our questions.
spk04: Thank you. Our next question is from Joel Beatty with Bayard. Please proceed with your question.
spk15: Hi. Thanks for taking the question. For Edit 101, have you gotten any FDA feedback on the thought of the use of the natural history cohort as opposed to using a control arm in a registrational trial?
spk02: Thanks very much, Joel. Clearly, the fact that we have a natural history cohort has been a very important point in our discussions internally around our strategy for clinical development. We have not yet had such discussions with the regular authorities, but We will be using both our clinical intervention experience in the brilliance trial as well as a natural history study as we consider the optimal design and prepare for those discussions with the authorities, including the FDA.
spk15: Great. Thank you.
spk04: Thank you. Our next question comes from Yanan Xu with Wells Fargo Securities. Please proceed with your question.
spk16: Hi. Thanks for taking my questions, and I wanted to add my congratulations to Gilmore and Bison for your new appointment. So first question is related to 301. I think you touched upon the differentiation from DTX-001 earlier in the call. I just want to follow up more specifically. whether you expect to see greater hemoglobin, fetal hemoglobin induction with your promoter editing approach compared with CTX001. And also, when you review currently available clinical data for CTX001, where do you see the potential unmet need in those data sets? perhaps 301 could further improve in those areas. And also on 301, how many patients have you defreezed and or manufactured the product for in the Ruby study? And at the year end data update, should we expect just the first patient data? or could we expect more patient data at year-end? Thank you.
spk02: So thanks very much, Yanan. Nice to meet you. Let me start at the end, and I'll work back and also cite and ask Mark to address some of the preclinical data. So we are expecting to and planning to share clinical data from one and possibly two patients at the end of this year, that patient data will include safety as well as engraftment and hematological parameters. With regard to the unmet need, we believe that the differentiation given by our product, and there are two elements of the differentiation. I've highlighted the fact that we anticipate durable, a very durable expression of fetal hemoglobin owing to the promoter of the gamma-globin genes that we've targeted. But in addition, we're using a high-fidelity, highly efficient editing nuclease in the form of AF-Cas12a. And what we believe is that that durable benefit actually has the potential to be an important differentiator simply because it is independent. It drives expression independent of strep erythropoiesis, which is something that could actually become increasingly mitigated over time. And so it would be important to maintain that durable expression of fetal hemoglobin and doing it independently of strep erythropoiesis confers a significant differentiated advantage in the long term. And then with regard to our confidence around the expression of fetal hemoglobin, I'm going to ask Mark to talk a little bit about our preclinical data.
spk03: Yeah, hi, Janan. So early in the program, the preclinical team conducted sort of direct comparisons of the different editing mechanisms, whether the HPG promoter region or the BC11A itself. And we found that the promoter region editing gave slightly higher HBS levels, at least in a preclinical model, but also importantly that we maintain the fidelity of the lineages derived from those cells, whereas with the PC11A approach, there was some linear skewing. So I think efficacy-wise, we believe there could be an advantage, and then long-term safety-wise, also we have some concerns with PC11A, editing a transcription factor which has more than one But, you know, at this point in time, the differentiation will be determined by the clinical data, and that is the data that's emerging.
spk04: Thank you. Our next question is from Steve Steedhouse with Raymond James. Please proceed with your question.
spk12: Good morning. This is Ryan Getzner after Steve. What is your general expectation for neutrophil emplacement and engraftment for patients in the sickle cell study? And have there been any SAEs of note in particular associated with the cell product?
spk02: Thank you. Thanks, Brian. Good to meet you. So our expectation for engraftment of plates and neutrophils, we actually designed our protocol to capture it around day 36. Obviously, it varies across patients, and that has been the experience for both autologous and allogeneic experience in general. But we will be able to share more specifics of that near the end of the year and as the program progresses. The second question, SAEs, we've not actually seen, thank you, we've not actually seen SAEs in this experience to date, but obviously we are aware that the procedure itself, beyond the editing, but in general for engraftment does carry identified risks, and obviously we monitor that very closely. But I think very importantly, we have not seen SAEs at all, and more specifically, have not seen adverse events that would give us concern about the product.
spk12: Got it. Thank you very much.
spk04: Thank you. Our next question comes from Madhu Kumar with Goldman Sachs. Please proceed with your question.
spk07: This is Omari from Madhu. So, the first question Could you give us a sense of what kind of efficacy profile do you need to see at a given one-on-one dose to pursue a registration or trial? And then what venue do you plan to present one-on-one update at, a medical meeting or separately?
spk02: So with regard to our success criteria, what we would want to see is an extension of the POC that we've seen with stability and potentially improvement in some of the adult patients. I think the other determinant of success for the study will be identifying a segment of the patient population that maximizes or has a maximum probability of responding to the therapy and also interacting with a select set of endpoints That will actually also be determined by the phase one study and our interaction or our analysis of that, co-analysis of the natural history study. And with regard to selection of the dose, the phase one study will actually obviously be part of selecting that dose. And as you say, the success criteria for selecting that dose would be determined by seeing maintained stability and improvement in a segment of patients. And we will, we don't actually have a, we are currently evaluating where we would share that data, but anticipate that it's likely to be at a webinar later this year.
spk07: Thank you for answering our questions.
spk04: Thank you. There are no further questions at this time. This does conclude today's conference call. Thank you for your participation. You may now disconnect.
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