Good morning, and welcome to the Editas Medicine First Quarter 2024 Conference Call. Please be advised that this call is being recorded at the company's request.

Good morning, everyone, and welcome to our first quarter 2024 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 in the Investors section of our website approximately 2 hours after its completion. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC as updated by our subsequent filings. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements even if our views change. Now I will turn the call over to our CEO, Gilmore O'Neill.

Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas' First Quarter 2024 Earnings Call. With me today are 4 members of the Editas executive team, our Chief Medical Officer, Baisong Mei; our Chief Scientific Officer, Linda Burkly; our Chief Financial Officer, Erick Lucera, and our Chief Commercial and Strategy Officer, Caren Deardorf. We are pleased with Editas' momentum and progress in the first quarter of 2024. Editas' goal is to deliver life-changing medicines to patients with previously untreatable or undertreated genetically determined diseases. And our vision and focused strategy is to position Editas as a leader in In Vivo Programmable Gene Editing. Three pillars underpin our strategy. The first of those pillars is to drive reni-cel, an EdiTHAL cell therapy for hemoglobinopathy and formerly known as EDIT-301 towards BLA and commercialization. The second is to build an in vivo Editing Pipeline. And the third is to increase business development activities with a particular focus on monetizing our very strong intellectual property. At the start of 2024, we announced the following 2024 objectives. For reni-cel, we will provide a clinical update from the RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion-dependent beta-thalassemia in mid-2024 and by year-end 2024. We will complete adult cohort enrollment and initiate the adolescent cohort in RUBY and continue enrollment in EdiTHAL. For our in vivo pipeline, we will establish in vivo preclinical proof-of-concept for an undisclosed indication. And for BD, we will leverage our robust IP portfolio and business developed to drive value and complement core gene editing technology capabilities. So how we executed against this strategy and these objectives in the first quarter. Let us start with reni-cel. First on enrollment. We've been very pleased with the growing patient and health care provider interest in reni-cel. Indeed, we are delighted to share that we have completed enrollment in the adult cohort of the RUBY clinical trial. Additionally, we have enrolled multiple patients and have more in screening in the adolescent cohort of a RUBY study, which was launched at the beginning of this year. And we continue to enroll beta thalassemia patients in our EdiTHAL study. Dosing continues in both the RUBY and EdiTHAL studies. Second, on clinical data. We remain on track to present a substantial clinical data set of at least 18 sickle cell patients with 2 to 21 months of clinical follow-up in the RUBY study in the middle of 2024, and we will share a further update by year-end. We are also on track to present clinical data from the EdiTHAL study of reni-cel in transfusion-dependent beta-thalassemia in the middle of 2024 and again by year-end. Baisong Mei will share more reni-cel data later on in this call. On the manufacturing front, I am pleased to share that we have promoted Greg Whitehead to the role of Chief Technology and Quality Officer, leading our technical development, technical operations and quality departments. Greg has more than 25 years of experience in the biotech industry and extensive cell and gene therapy clinical and commercial development expertise. Now let's turn to in vivo and our pipeline development where we continue to strengthen our in vivo discovery capabilities and continued lead discovery work on in vivo therapeutic targets in hematopoietic stem cells and other tissues. Importantly, we remain on track to establish in vivo preclinical proof of concept for an undisclosed indication by the end of the year. Our internal development efforts are differentiated by leveraging the indel CRISPR technology, which we already used to upregulate gamma globin expression through direct editing of the HPG 12 promoter site in our ex vivo reni-cel program. Our in vivo approach is aimed at functional upregulation of gene expression in genetically defined diseases with a preliminary focus on rare and orphan patient populations. In the medium to long term, we intend to expand to more common genetically determined diseases. Linda Burkly, our CSO, will share more details on our in vivo strategy and progress towards building an in vivo pipeline later on in the call. Finally, what is happening in business development? In March, we signed a 2-year extension to the collaboration with Bristol-Myers Squibb to research, develop and commercialize autologous and allogeneic alpha-beta T cell medicines for the treatment of cancer and autoimmune diseases. We also have options to extend that collaboration for an additional 2 years. To date, Bristol-Myers Squibb has opted into 13 different programs across 11 gene targets to date. 2 programs are currently in IND-enabling studies and 4 programs are in late-stage discovery. And the intellectual property yesterday, oral arguments were held before the U.S. court appeals for the Federal Circuit regarding an appeal of the patent trial and appeal board or PTAB, previous decision favoring Broad Institute in the U.S. patent interference involving specific patents for CRISPR Cas9 editing in human cells between the University of California, University of Vienna and Emmanuelle Charpentier or CVC and Broad. We expect a decision on the case in the second half of 2024. Eric will share more BD and IP details later on in the call. We are energized by our progress in execution this quarter with our sharpened strategic focus, our world-class scientists and employees are keen to drive in execution and a strong balance sheet; we continue to build momentum to progress our strategy to deliver differentiated medicines to patients with serious genetic diseases. Now I will turn the call over to Baisong Mei, our Chief Medical Officer.

Thank you, Gilmore. Good morning, everyone. Let's talk about reni-cel, which is on the clinical development for severe sickle cell disease and transfusion-dependent beta-thalassemia. As Gilmore shared, we are pleased that we have completed enrollment in the adult cohort of the Phase I/II/III RUBY trial and the dosing continues. In the adolescent cohort of the RUBY study, we have enrolled multiple patients and several more patients are in screening. The interest and demand are high. I'm very pleased about how quickly we have moved in screening and enrollment of this cohort. I'd like to thank colleagues and editors and our clinical trial partners for the collaboration and hard work. More importantly, I would like to thank patients, their families, investigators, and the study site staff for their trust and support. In the EdiTHAL trial for transfusion-dependent beta-thalassemia, we continue to move forward with enrollment and dosing. We look forward to sharing clinical data in the middle of this year and also at year-end. As I have shared, I visited and continue to visit our RUBY and EdiTHAL clinical trial sites and speak with the investigators. I appreciate the enthusiasm and support from investigators and study sites. I'm pleased with the momentum of reni-cel patient recruitment and dosing in both studies. I'm excited to hear from the investigators that patients dosed with reni-cel have already seen positive changes in their lives. As we shared on our February earnings call, we aligned with the FDA that the RUBY clinical trial is now considered a Phase I/II/III trial for BLA filing. We also have alignment with the FDA on the study design, endpoints, and sample size. We look forward to future discussions with the FDA and continued collaboration. Turning to clinical data, as Gilmore mentioned, we are on track to present a substantive clinical data set of sickle cell patients with considerable clinical follow-up in the RUBY study in the middle of 2024 and a further update by year-end 2024. What we will show in the RUBY data set includes clinical data from at least 18 sickle cell patients with 2 to 21 months follow-up. The substantive data set will include clinical data from 7 patients with 4 to 12 months follow-up. We will present efficacy data, including total hemoglobin, fetal hemoglobin, and vaso-occlusive events or VOEs for sickle cell patients in the RUBY study, and red blood cell transfusion for transfusion-dependent beta thalassemia patients in the EdiTHAL study, as well as safety data. As a reminder, in December 2023, we shared safety and efficacy data from 11 RUBY patients and 6 EdiTHAL patients. Once again, the data confirms the observation from our prior clinical results, including that reni-cel drove early robust correction of anemia to a normal physiological range of total hemoglobin in sickle cell patients. Reni-cel drove robust and sustained increases in fetal hemoglobin levels in excess of 40%. All RUBY sickle cell patients remain free of vaso-occlusive events following reni-cel treatment. Reni-cel treated sickle cell patients and transfusion-dependent beta thalassemia patients have shown successful engraftment and have stopped red blood transfusions. The safety profile of reni-cel to date is consistent with busulfan and myeloablative conditioning and autologous hematopoietic stem cell transplant. This data reinforces our belief that we have a competitive product, potentially differentiated from other treatments with rapid correction of anemia. Thanks to the decisions our discovery group made early in the program, the choice of CRISPR enzyme and the target to edit for increased fetal hemoglobin expression matters. Reni-cel uses our proprietary AsCas12a enzyme to upregulate the HBG1 and HBG2 promoter. Based on the clinical data thus far, we believe that sustained normal levels of total hemoglobin could be a potential point of differentiation for reni-cel. Now I'll turn the call over to Linda, our Chief Scientific Officer.

Thanks, Baisong, and good morning, everyone. I'm happy to be talking to you this morning to share more details about our in vivo strategy and our progress towards building an in vivo pipeline. I would like to take a moment to remind you why we believe in vivo medicines will be a disruptive transformative development in medical history with the potential to address genetically determined diseases with durable and curative outcomes for patients. First, in vivo medicines may reduce the administration burden of delivering editing medicines to patients in need, which will provide broader access to patients all around the world. Second, off-the-shelf administration may allow for scalable manufacturing and lower costs to produce. Based on these two principles, we believe that in vivo gene editing will provide accessible cures for genetic diseases and, therefore, may be the most disruptive development in medical history. So how will Editas position itself? There are many monogenic diseases that can potentially be cured with a gene editing approach. We have said that we will first target the development of treatments that are clearly differentiated from current standards of care and that will leverage the aspects of CRISPR editing that give it a unique advantage over other therapeutic modalities. Our internal development efforts are differentiated by leveraging the indel CRISPR technology we use to upregulate gamma globin expression through direct editing of the HPG 1 and 2 promoter sites in our ex vivo reni-cel program. Our in vivo approach is aimed at functional upregulation of gene expression in genetic diseases in rare and orphan patient populations, from which we intend to expand to more common diseases. I am also pleased to share several progress updates as we advance our in vivo capabilities towards our long-term vision of being a leader in in vivo programmable gene editing. First and most importantly, as Gilmore mentioned, we remain on track to establish in vivo preclinical proof of concept for an undisclosed indication by the end of the year. Editas is well positioned with established capabilities in the four main components of in vivo gene editing medicine: one, guide RNA; two, editing enzyme; three, messenger RNA; and four, delivery technology, and we are currently evaluating lipid nanoparticles for the delivery of gene editing cargo into multiple tissue types with several companies. Additionally, we are evaluating next-generation delivery technology. Second, our in vivo capabilities with the potential to be used in developing transformative in vivo gene editing medicines are demonstrated by the preclinical data we are presenting at the American Society of Gene and Cell Therapy or ASGCT Annual Meeting in three presentations, taking place on Thursday and Friday of this week. On Friday, in an oral presentation, we will share in vivo preclinical data from mouse studies using lipid nanoparticle-mediated delivery of an optimized guide RNA and engineered AsCas12a messenger RNA. In poster presentations on Thursday and Friday, we will share preclinical data demonstrating AsCas12a guide RNA modifications that enable high potency gene editing in multiple cell types, including in the liver, and improved gene editing outcomes in vivo, enabling the development of in vivo gene editing medicine and research on identifying potent large serine recombinases (LSRs) as the foundation to develop novel in vivo gene editing technologies for whole gene knock-in, expanding potential in vivo gene editing targets for developing medicines. Third, Editas CRISPR-based in vivo gene editing capability has been clinically validated. Notably, in 2020, Editas was the first company to ever treat a human with an in vivo delivered CRISPR-based gene editing medicine, EDIT-101. In fact, earlier this week, the New England Journal of Medicine published a manuscript titled 'Gene Editing for CEP290 Associated Retinal Degeneration,' detailing our former lead development candidate EDIT-101 for the treatment of Leber Congenital Amaurosis type 10 or LCA10. Editas established clear in vivo human proof of concept in 2022, and we are pleased that the results from this groundbreaking clinical trial were published by the New England Journal of Medicine. These progress updates demonstrate Editas' execution on our in vivo strategy and our proven in vivo gene editing capabilities, and I look forward to sharing more details about our in vivo development strategy and our progress towards building an in vivo pipeline later this year. Now I will turn the call over to Erick, our Chief Financial Officer.

Thank you, Linda, and good morning, everyone. I'm happy to be speaking to you, and I'm excited to provide updates on our business development achievements, intellectual property, and financial results for the first quarter of 2024. First, in regard to business development, as Gilmore mentioned, in March, we announced a 2-year extension to the collaboration with Bristol-Myers Squibb to research, develop and commercialize autologous and allogeneic alpha-beta T cell medicines for the treatment of cancer and autoimmune diseases. We also have options to extend the collaboration for an additional 2 years. To date, Bristol-Myers Squibb has opted into 13 different programs across 11 gene targets. Two programs are currently in IND-enabling studies, and 4 programs are in late-stage discovery. As a reminder, for each new experimental medicine that Bristol-Myers Squibb develops and commercializes using opted into genome editing tools, Bristol-Myers Squibb will pay Editas Medicine potential future milestone payments. Following the approval of any products resulting from the collaboration, Editas Medicine is also eligible to receive tiered royalties on net sales. We are pleased that our Bristol-Myers collaboration has proved to be a productive partnership, and we are committed to future collaborations and partnerships that will allow for the continued access and advancement of gene editing. And in IP, as Gilmore mentioned, yesterday, oral arguments were held before the U.S. Court of Appeals for the Federal Circuit regarding the CVC's appeal of the PTAB's decision involving patents for CRISPR/Cas9 editing in human cells. As you know, the Broad Institute has previously prevailed three times against the CVC, twice with the PTAB and once at the Federal Circuit. The Federal Circuit's review will determine whether the PTAB correctly applied the law. It is important to remember that the court will not hear new evidence. An appellate court decision in the Broad's favor would reaffirm Editas' position as the exclusive licensor of the patents covering Cas9 used in human medicines in the U.S. It's also important to remember that only a small fraction of the IP we licensed from the Broad is involved in the ongoing U.S. PTO interference proceedings. We expect a decision on the case in the second half of 2024. We remain confident that the Broad will once again prevail. Our IP portfolio of foundational U.S. and international patents covering Cas9 and Cas12 used in human medicines is a source of meaningful value, as we believe that globally, there are more than 100 Cas9, Cas12a programs in development worldwide, with the majority being developed by 10 companies. We believe these potential deals represent a potential material source of non-dilutive capital, as evidenced by our deal in the fourth quarter of 2023 that extended our cash runway by 2 quarters. We look forward to future discussions. And now I'd like to refer you to our press release issued earlier today for a summary of our financial results for the first quarter of 2024. I'll take this opportunity to briefly review a few items for the quarter. Our cash, cash equivalents, and marketable securities as of March 31, were $377 million compared to $427 million as of December 31, 2023. We expect our existing cash, cash equivalents, and marketable securities, together with the near-term annual license fees and contingent upfront payment payable under our license agreement with Vertex to fund our operating expenses and capital expenditures into 2026. Revenue for the first quarter of 2024 was $1.1 million compared to $9.9 million for the same period in 2023. The decrease relates to the January 2023 one-time sale of the company's wholly owned oncology assets and related licenses. R&D expenses this quarter increased by $11 million to $49 million in the first quarter of 2024. This increase relates to additional clinical and manufacturing costs that support the continued progression of the company's reni-cel program. The increase is also attributable to one-time payments related to sublicense and license obligations. Editas will continue to incur these types of payments as we and our collaboration partners advance certain license programs in the gene editing space. G&A expenses for the first quarter of 2024 were $19 million, which decreased from $23 million in the first quarter of 2023. The decrease is primarily attributable to one-time professional service expenses related to the 2023 strategic initiatives and business development activities, as well as reduced legal and patent costs. With our BD and IT activity and a cash runway into 2026, Editas remains in a strong financial position. We have ample resources to continue the advancement of our reni-cel program, support the progression of our in vivo capabilities, develop our pipeline and leverage our strong IP position for additional business development and licensing opportunities. With that, I will hand the call back to Gilmore.

Thank you, Erick. We are proud of our progress in the first quarter of 2024 and we look forward to continue to accelerate the momentum in 2024. As we continue to evolve from a development-stage technology platform company into a commercial-stage gene editing company, we look forward to continuing our transformation and sharing our progress with you. As a reminder of our 2024 strategic objectives for reni-cel, we will provide a clinical update from the reni-cel RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion-dependent beta-thalassemia in mid-2024 and year-end 2024. We have now completed the adult cohort enrollment and have started enrolling patients in the adolescent cohort in RUBY. We will also continue enrollment in EdiTHAL and dosing in both trials. For our in vivo pipeline, we will establish in vivo preclinical proof of concept for an undisclosed indication. And for BD, we will leverage our robust IP portfolio and business development capabilities to drive value and complement core gene editing technology capabilities. As we shared today, we are making significant progress on all three pillars of our strategy this quarter, including reni-cel, in vivo and business development, including intellectual property. We entered 2024 with great momentum, and I am proud of the Editas team's significant progress towards becoming a commercial stage company and on developing clinically differentiated transformational medicines for people living with serious previously untreatable diseases. As always, we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners, and you. Thanks very much for your interest in Editas, and we're happy to answer questions. Thank you.

We will now be conducting a question-and-answer session.

I'm wondering about your in vivo pipeline and the proof of concept that you're expecting by the end of this year. What would be the bar for success that you're looking for in this program?

Thanks very much, Samantha. I'm going to ask Linda to address that.

We are looking for proof of concept for high efficiency delivery and editing for our targeted interest in vivo in this preclinical POC that will give us confidence in our ability to target the target of interest. We are going to be sharing more information on this at a future date. Thank you for the question.

Congrats on the progress. An interesting update on your disclosure is the plan to identify large serine recombinases, which implies sort of a new approach to many of your peers are also developing. Does the size of the recombinases, mediated insertion allow for inserting a coding sequence for dystrophin, for example, and are you able to comment on whether DMD is out of the question regarding your in vivo aspirations?

Thanks very much, Joon. I'm going to have Linda take that.

We're excited about the LSR technology that we're disclosing here. We are identifying many different novel LSRs. We're not disclosing at the moment the size of the integrations that can be accommodated by the large serine recombinases, but we have quite a few novel LSRs that we have identified and are further characterizing.

Looking at the reni-cel program here, how are you guys looking at the midyear update compared to the year-end update here? As follow-up time progresses, what should we look for from treated patients in terms of safety and efficacy moving forward?

Baisong is going to take that one.

So in this midyear release, we expect to have at least 18 patient data for the RUBY study. And within the 18 patients, four of them will have longer, 12 to 21 months of exposure, and seven will have 5 to 12 months of exposure, and another seven will have 2 to 5 months exposure. With that, we feel this data is very meaningful to see the direction not only the increase of total hemoglobin normalization of total hemoglobin and increase of fetal hemoglobin, but also the durability of the study and the impact from an efficacy perspective, for example, severe vaso-occlusive events. For the EdiTHAL study, we will have patients from at least 7 of those patients with 4 to 12 months of exposure, which also will be very meaningful. That is compared to the December release where we had 11 RUBY patients and 6 EdiTHAL patients. So that substantial more data will help us to understand this group better.

Congratulations to the team on the progress. I'm going to stay with the reni-cel program. I was hoping you can provide some color on dosing of the pivotal cohort. I know you've commented on the adult cohort being fully enrolled, but have all those patients received therapy, and any other comments you can provide as it relates to the size of the cohort that you've agreed to with regulators would be very helpful.

Thanks very much, Jack. I'll answer the first part and then pass it to Baisong to provide maybe give a little more color to regulatory interactions. We have obviously completed the adult enrollment, which we're very excited about, not least because that is in the context of 2 approved therapies. So it really is a very concrete reflection of the enthusiasm that Baisong has found and described, indeed increasing enthusiasm about our program with his visits to sites and conversations with investigators, health care providers, and indeed with patient advocacy groups. We have scheduled many of those patients already for dosing, and we'll give you further updates on the progress of dosing at a later date. And with regard to the regulatory color, I think Baisong, you might want to share a little more there.

Yes. For regulatory, as we shared, we have alignment with the FDA that the RUBY study is a Phase I/II/III study for BLA filing. We also have alignment on the sample size, duration, and study design of that. So we continue to have collaboration with the FDA on further discussions about this program.

If I may, very quick 2 questions. First, should we read into your ASGCT presentation for in vivo indications such as glaucoma? And second, I know you mentioned also a little bit about the current approved genomic therapy for sickle cell. We still have a 10% patient relapse with VOE events. What do you think are the key factors that we should look into for the potentially differentiated durability with hopefully 100% control?

I'm going to ask Linda to handle the first part of your question around the ASGCT and then Baisong can talk about durability and what we're seeing today.

Primary open-angle glaucoma is obviously an area of very high unmet need. And while we conducted those studies because of that, we are not currently pursuing that indication, but we were able through those studies to demonstrate intensive preclinical proof of concept and showcase our in vivo capabilities with respect to three components: our ability to deliver lipid nanoparticles in vivo with our gene editing cargo, our proven capability of our proprietary enzyme, AsCas12a, to edit in vivo and our guide modifications to enhance gene editing potency. So these capabilities really position us well for delivering in vivo gene editing medicines, and we're really pleased with the ASGCT disclosures.

I will take up on the question about the VOE relapse for sickle cell patients. First, I would say, I want to congratulate the entire field for the effort of treating sickle cell disease, including the recent approval of the two molecules. I think what we see is that with the continued effort of all of us, we will continue to improve and transform the treatment for sickle cell disease patients. With reni-cel, we are still continuing to collect the clinical data. As I mentioned, we expect this to be a competitive but differentiated molecule and with normalization of the total hemoglobin correction of anemia. We are looking forward to see our own data on the VOE as we reported; thus far, we have seen all those patients dosed with reni-cel are free of VOE events.

This is CJ on for Mani. Ours is following the agreement with Vertex last year, just how are you thinking about future IP monetization opportunities?

I'm going to ask Erick to address that question.

Obviously, as we said in the transcript, we view the future potential royalty monetization and licensing activities as an integral and very important source of non-dilutive capital. As you know, these are foundational IP patents that apply to just about everybody's projects in Cas9 and Cas12. We expect to have conversations with those folks as soon as we can.

Can you just remind us what's your latest thinking around the timing of holding discussions with regulators on sickle cell? And just given the data that you're going to present midyear, any updates and color on the timing of holding a productive conversation with regulators would be appreciated.

I'm going to ask Baisong to talk about that sort of I think your two questions really, which is about what the data are in the middle of the year and how they integrate with our discussions with regulators.

Yes. So Brian, as I mentioned, we are very pleased with the data we're going to release in the middle of the year, which is substantive and also gives us good direction on how much we will get and to have, for example, a data set to have equivalent to the BLA filing, right? So that's one part of that. We're very happy to see the amount of data and the patient outcome from the data. The other thing is about the regulatory engagement. As I mentioned, we already have alignment on this Phase III study to support the VOE, and we have continued engagement with the FDA. We have not disclosed all the details of the interaction yet. But as a reminder, we have unmet designation, which allows us to have frequent interaction with the agency, but also with high-level interaction with the agency. This, of course, helps give us the opportunity for potential priority review and rolling submission. So we're very excited about the direction. We'll continue to have engagement and collaboration with the FDA.

Congrats on the progress. Are you able to give the approximate number of patients who are enrolled in the RUBY trial with sickle cell disease? And then it sounds like you've been able to make pretty good progress in enrollment in that study despite the availability of commercial cell therapies. I was just wondering if at centers that have both experimental and commercial cell therapy available, maybe Baisong could talk a little bit about what's driving the decision to use the Editas product over others.

Baisong can update you on where our clinicaltrials.gov set us a target for the cohort in our trial and then obviously, build on his perceptions of why we're doing so well with enrollment even in the context of commercial therapies being available.

We are very pleased with the momentum by the enrollment in both the EdiTHAL cohort and the adolescent cohort. For the EdiTHAL cohort, we shared that in February we enrolled 40 patients; now we have enrolled slightly more than 40 patients. Therefore, we closed the adult cohort enrollment. For the adolescent cohort, we started at the beginning of this year, and we have already enrolled multiple patients and have modified experience. We're very pleased with that. As I mentioned, I'm on the road all the time to visit our investigators and the study sites, and they really feel that, one is actually there, I believe the reni-cel based on the MOA, based on the data we have continued to share on that. I also give credit to the entire field working on that with the two gene therapy approved for sickle cell, which has also increased interest in the direction of gene therapy for sickle cell disease. So that's how we see, over the last year or so, we see really great momentum for reni-cel enrollment, especially after we release our data.

Congrats on all the progress. Can you talk about the timing of the collaboration extension with Bristol? Was there some new data that triggered the new collaboration? And is there any color on what new data Bristol may have seen?

What I want to do is ask Erick to address the question about the BMS. What I do want to say is I can address the conditioning, which is that just at our last earnings, we talked that we are going to continue monitoring the space. We have significant context of the academic and nonacademic worlds around the field. But we have actually really deployed our efforts and resources internally to focusing on our in vivo pipeline, including developing hematopoietic stem cells. The rationale for that being that we see that where a milder conditioning therapy is actually approved, it would be used universally and adopted universally in transplant centers across multiple indications, including stem cell transplantation and hemoglobinopathies. And with that, I'm just going to pass to Erick just to talk about the BMS deal.

Regarding the timing of the renegotiation of the extension, we recently issued a press release that provides an update. As for the data from Bristol-Myers, they have just completed a portfolio review, and we are pleased to note that all our collaborative projects are progressing well. Specific details about these programs are best left to them to discuss. I would emphasize that during their most recent R&D Day last September, which was their first in several years, they showcased six products in their pipeline that utilize our technology. For more information on our collaboration, I recommend checking their R&D disclosures from that meeting. We are very enthusiastic about our partnership with Bristol-Myers, which has endured through multiple mergers and portfolio reviews.

Given the association between total hemoglobin levels and organ function, do you plan to utilize any quantitative endpoints basically assessing organ function in the RUBY trial? And if so, what might those look like? And when could we maybe expect initial data?

I'm going to ask Baisong to address that question.

We certainly have measurements for the end-organ function. We look into several major organ systems to monitor the function improvement. For example, we monitor liver function, not only with different lab values. We're looking to pulmonary function to check the respiratory system. We also have cardio echo and other measures you're talking to measure the cardiovascular system as well. So we are looking forward to see more data on that and give us more understanding of how end-organ function may behave after treatment. Just a reminder that we also, of course, look into not only sickle cell but also other areas in terms of the anemia, how that impacts function and how the correction of anemia may be able to improve that function post-treatment. And in sickle cell specifically, over the last couple of years, we already see more publications about end-organ function given after the allogeneic transplant to treating sickle cell patients; we are very excited about that.

First on the differentiation of total hemoglobin normalization. I was wondering, have you had feedback from sickle cell treaters on that differentiation and whether there's any hesitancy or push back that perhaps the current level of hemoglobin achieved by the marketed product is sufficient? How much of that kind of thinking is out there? And on the in vivo side, I was wondering, are you focused on first-in-class targets or perhaps not first-in-class targets, but hoping to have a differentiation on specificity and transduction efficiency, etc.?

So I'm going to ask Baisong to talk about the differentiation of total hemoglobin, and then I'll ask Linda just to talk about our approach to first-in-class or clear differentiation and where we would see that with our approach to functional regulation.

I mean, certainly, we talked about the investigators as well as the KOLs and sickle-cell treaters for our differentiation and how we may be able to see with the position of this molecule. And when we're talking to those hematologists and sickle cell treaters, they see our data. And when hematologists just mentioned that it is better if you have a 16-gram per deciliter versus 10 grams per deciliter of total hemoglobin. They also mentioned the enthusiasm of our study, and there are quite a few knowledgeable hematologists who see the difference among several molecules. When the investigators said that he was waiting for our trial and did not participate in others. Those are the anecdotal examples of that. As I mentioned earlier, we certainly want to look forward to seeing the clinical data.

Yes, in vivo our in vivo approach is aimed at functional upregulation of gene expression in genetically determined diseases, and this strategy positions us very well to be differentiated from others in terms of our targets and our target editing strategies. What this means is that we can go after targets that others can't go after. From an indication perspective, we can go after indications that perhaps others can't go after, and so we could have a first-in-class strategy. Also within a given indication, we could devise a targeting strategy that would be best in class, if you will. So we can have first-in-class strategies as well as best-in-class opportunities. I hope that answers your question.

Congratulations on all the progress. I have a quick question about reni-cel and the filing strategy. What is your vision for the BLA? Are you planning to file for adults and adolescents at the same time or one after the other? Any insight on that would be appreciated. Additionally, could you discuss the opportunity for sickle cell disease in the Middle East? Vertex seems quite enthusiastic about that market, so I’m curious about your strategy to potentially enter that market. Are you still considering partnerships? Would you be able to access that distributor? Any thoughts on this would be appreciated.

So I'll ask Baisong just talk about our regulatory strategy as far as we have shared it. And then Caren can talk about just how we're looking at and thinking about the Middle East and frankly, in the context of the rest of the world.

We are very pleased with the interaction with the agency and continued interaction with the agency about the reni-cel for the RUBY study as a Phase III study to support BLA and all the front of the Phase III study, we have alignment on that, and we have continued conversations with the FDA on this route. We have not shared the specifics about the date of the BLA or the indication of adult or adolescent. But as we shared, we are very pleased with the enrollment for both the EdiTHAL cohort and the adolescent cohort. So that gives us a great position for this molecule.

Thanks for the question about the Middle East, and certainly just the populations outside the United States. There are absolutely a number of geographies where there is a significant population of sickle cell patients and really high unmet need in beta-thalassemia as well. What I'd say is our continued drive to execute in the U.S. and move reni-cel forward with differentiation just continues to support the opportunity for us to partner at the appropriate time, and that's certainly something that we've said we are open to and we'll certainly provide more color in the future as appropriate.

This is Nick on for Steve. We actually had a longer-term question. To what extent can you leverage the infrastructure that Vertex is already building out for Casgevy? And will EDIT-301 be able to plug into the existing authorized treatment centers once launched?

I'm going to ask Caren to address that.

First, I'd say that I'm really pleased to see some of the initial progress for the other therapies and being able to get patients started. We always anticipated that it would be a dipping many centers starting to dip their toe as they build the infrastructure and they gain the confidence, so to answer your question, absolutely. We've always said that in this kind of market of the complexity of the ex vivo being a fast follower is absolutely an advantage. We also, on our own, have a really strong base of over 20 clinical sites in the U.S. with very strong enrollment, and relationships that we're leveraging and those relationships and the guidance they're giving us will be really pivotal for us as well. But this is a field that will benefit from the increase in education with patients, which Baisong mentioned also helps with our enrollment and just building the infrastructure, but we are engaged on the KOL, the patient advocacy as well as on the payer front to ensure that we're prepared.

Quick follow-up here. I just wanted to look on reni-cel one more time and ask when we might hear a little bit more about the differentiation as it relates to the treatment process. Have you provided any color on the number of apheresis cycles and how editing efficiency of the AsCas12a may allow you to be more efficient in manufacturing the process?

So I'm going to ask Baisong to provide color.

We have not shared specifics about the number of cycles involved in apheresis. Since I joined, we have been collaborating with both our internal and external apheresis teams. Our current focus is on enhancing the apheresis cycle and providing support to the study sites for the process, which is important because it alleviates the patient burden and ensures a smooth manufacturing process. We are very pleased to see the progress in this area. Additionally, we hope that this clinical experience will be very beneficial for our commercialization efforts.

Kind of similar to the last question, you previously talked about optimizing the vein to vein process. Would you be able to walk us through how this process would provide advantages both from an operational logistics perspective?

I'll ask Baisong to address that.

Yes, happy to do so. We are working together to optimize this process by getting the study sites to improve this process from multiple factors. One of the factors just mentioned is bio-apheresis. The other factor is the logistics, and we provide support on that. The third factor is actually patient condition; as we know, we are treating patients with severe sickle cell disease. Before the reni-cel treatment, they can have multiple VOE events per year, which can impact the study process.

Mani, this is Caren. I would just add that, again, in the fast follower position, one of the things that gives us the opportunity to do is to really understand how the first two therapies are commercialized, what's working, what's not working, what they need to see differently, and really making sure that Editas sets ourselves up as the partner of choice. We're working very hard on that, and we'll certainly talk about that at a later time.

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