Earnings Call Transcript - EDIT Q3 2023

Operator, Operator

Good morning, and welcome to Editas Medicine's Third Quarter Conference Call. All participants are now in 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 Cristi Barnett, Corporate Communications and Investor Relations at Editas Medicine.

Cristi Barnett, Corporate Communications and Investor Relations

Thank you, Rob. Good morning, everyone, and welcome to our third quarter 2023 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 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 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.

Gilmore O'Neill, CEO

Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas Medicine's third quarter earnings call. I am joined today by four other members of the Editas executive team, Baisong Mei, our Chief Medical Officer; Erick Lucera, our Chief Financial Officer; Linda Burkly, our Chief Scientific Officer; and Caren Deardorf, our Chief Commercial and Strategy Officer. We are pleased with Editas' momentum and progress in the third quarter, and I look forward to sharing these details. Before that however, let's take a quick step back to provide perspective. Editas' goal is to deliver life changing medicines to patients with previously untreatable or undertreated diseases. I joined Editas in June 2022 to help realize this goal, tasked with guiding the company's evolution from a platform development company to a commercial therapeutics company. As many of you know, in January of this year, we shared Editas' decision and strategy to position Editas as a leader in programmable gene editing. As a reminder, three pillars underpin our strategy. First, to accelerate the clinical development of EDIT-301, our autologous ex vivo gene edited medicine for severe sickle cell disease and transfusion dependent beta thalassemia and drive it towards approval and launch. Second, to sharpen our discovery focus to in vivo editing therapies. And third, expand our business development activities to partner complementary technological capabilities that can advance our in vivo pipeline development in addition to out-licensing our robust IP and knowhow to maximize the use of CRISPR-based medicines. At the start of 2023, we outlined the following 2023 objectives. For EDIT-301 to provide a clinical update from the EDIT-301 RUBY trial for severe sickle cell disease or SCD by the end of 2023. To provide a clinical data update from EDIT-301 EdiTHAL trial for transfusion dependent beta thalassemia or TDT by the end of 2023 and to have dosed 20 total patients in the RUBY trial by the end of 2023. For in vivo medicine development hire a new Chief Scientific officer with specific expertise aligned to our vision and to advance the discovery of in vivo editing of hematopoietic stem cells or HSEs and other tissues. And for business development to leverage our robust IP portfolio and business development capabilities to drive value and to complement our core gene editing technology capabilities. So how have we executed against this strategy and these objectives in the third quarter? Let's start with EDIT-301. First, on clinical data, we will present a company sponsored webinar in tandem with a poster presentation at ASH both on December 11 that is next month. We plan to share clinical data from 11 sickle cell patients in the RUBY trial and six beta thalassemia patients in the EdiTHAL trial. Baisong will share more details about our presentation later on the call. Second, on enrollment, we have enrolled 27 sickle cell and eight beta thalassemia patients into our RUBY and EdiTHAL studies, respectively, and screening continues at a good pace. Third, on dosing, we now expect to dose the 20th patient in the RUBY trial in the January 2024 timeframe due to individual patient schedules. And finally, for 2024 data disclosures, we remain 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. Baisong will share further details regarding our December data readout and clinical progress of EDIT-301 in his remarks. On the regulatory front, we are also pleased that just two weeks ago, the FDA recently granted us a Regenerative Medicine Advanced Therapy, or RMAT designation to EDIT-301 for the treatment of severe sickle cell disease. Advantages of the RMAT designation include all the benefits of the Fast Track and Breakthrough therapy designation programs, including, but not limited to, intensive FDA guidance on efficient and expedited drug development, possible rolling review, and priority review of the BLA. With respect to commercial plans, as we've previously shared, we made another important hire as we continued to gain momentum in pursuing a leadership position in hematopoietic stem cell medicines for hemoglobinopathies. In late September, we announced that Caren Deardorf, a highly experienced and successful therapeutics commercial leader has joined Editas as our new Chief Commercial and Strategy Officer. Caren has a proven ability to translate early discovery and clinical assets into robust business strategies with disciplined portfolio prioritization and value creation. Additionally, she has led multiple successful U.S. and global product launches. Caren's expertise and track record make her the ideal leader to help Editas reach this goal for patients. To further enable commercialization, as previously shared in July, we will increase our clean room capacity when we move our CMC team into the new AsierDevons facility in early 2024. With this increased capacity, we ensure our ability to scale EDIT-301 manufacturing both for clinical supply for our RUBY and EdiTHAL trials, as well as to prepare us for commercial readiness. In a step forward for the gene editing industry and patients alike, we were delighted to see the recent exa-cel AdCom, the very focused review by FDA and the AdCom confirmed our confidence in the robust nature of our own off-target assessment. The patient testimonials in addition were incredibly moving and powerful and demonstrate the significant need for new and transformative medicines for the treatment of sickle cell disease. Turning now to in vivo and our pipeline development. As stated earlier this year, our drug discovery group began lead discovery work on in vivo therapeutic targets in hematopoietic stem cells and other tissues. And in July, we hired Linda Berkley as our Chief Scientific Officer to spearhead these efforts. Linda looks forward to sharing more at the appropriate time. As a reminder, under our new target selection criteria, we will select therapeutic targets that will allow our genome editing approach to differentiate maximally from the current standard of care for serious diseases. The target selection criteria will work to identify targets that maximize the probability of technical, regulatory and commercial success. Now, let's turn to business development. In August, we shared that we entered into an agreement with Vor Bio providing a non-exclusive license for ex vivo Cas9 gene edited HSC therapies for the treatment and/or prevention of hematological malignancies. Under this agreement, Editas received an upfront payment and will be eligible for future development, regulatory and commercial milestone payments as well as royalties on medicines utilizing the related intellectual property. Turning to our intellectual property position. As a reminder, Editas holds a large portfolio of foundational U.S. and international patents and is the exclusive licensee of Harvard University and the Broad Institute's Cas9 patent estate covering Cas9 use in developing human medicines. Only a small fraction of these patents are involved in the ongoing U.S. PTO interference proceedings. As the exclusive licensee, we are uniquely positioned to issue exclusive and non-exclusive sublicenses for Cas9 to any company seeking to use these enzymes to make human medicines, including in vivo and ex vivo uses. Our recently announced licensing deal with Vor Bio further bolsters our confidence that our IT portfolio provides meaningful value now and in future. To conclude my remarks, we are energized by the promising efficacy and safety data we shared in June, signaling that EDIT-301 may be a clinically differentiated, one-time durable medicine that can provide life changing clinical benefits to patients with sickle cell disease and beta thalassemia in the long term. Specifically driving early and robust correction of anemia and sustained increases in fetal hemoglobin. With our sharpened strategic focus, our world-class scientists and employees, and our keen drive in execution, we continue to build momentum to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases. I will now turn the call over to Baisong, our Chief Medical Officer.

Baisong Mei, Chief Medical Officer

Thank you, Gilmore. Good morning, everyone. Let's begin with EDIT-301, which is being developed for severe sickle cell disease and transfusion-dependent beta thalassemia. As Gilmore mentioned, we are currently enrolling and dosing patients in the RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion-dependent beta thalassemia. As of now, we have enrolled 27 patients in the RUBY trial, with 20 patients expected to be dosed by January 2024. In the EdiTHAL trial, we have enrolled eight patients to date. I have been visiting our RUBY and EdiTHAL clinical trial sites, engaging with our investigators, and I appreciate their enthusiasm and support. I'm pleased with the progress we are making in patient recruitment, apheresis, editing, and dosing in both studies. I've heard from the investigators that patients treated with EDIT-301 are experiencing positive changes in their lives. We plan to engage with the FDA in the latter half of the year. Additionally, we found the recent exa-cel AdCom insightful, reaffirming the power and potential of gene editing technology. As a physician, I look forward to the transformative impact gene editing could have on treating serious diseases and enhancing patient lives. As a drug developer, I’m eager to see the first medicine approved, with more to follow from other companies, including Editas. I am also excited to announce that we will present RUBY and EdiTHAL clinical data at ASH and in a company-sponsored webinar on Monday, December 11. What we will show includes the RUBY data set, which features clinical data from 11 patients. We will share efficacy data covering total hemoglobin, fetal hemoglobin, vaso-occlusive events, and safety data on neutrophil and platelet engraftment. The follow-up period for these patients includes two with at least a 12-month follow-up and four with at least a five-month follow-up. The remaining patients will have a one to four-month follow-up period. The EdiTHAL data set will similarly present data from six patients, including efficacy and safety markers. Two patients will have at least five months of follow-up, while the others will follow a one to four-month timeline. In June, we previously shared promising RUBY clinical data during an oral presentation at the EHA Congress and also presented positive initial data from the first patient treated in the EdiTHAL trial. The RUBY data set included safety and efficacy information from the first four patients, showing that EDIT-301 can drive significant correction of anemia within a normal physiological range of total hemoglobin as early as four months after treatment. All four RUBY sickle cell patients have remained free of vaso-occlusive events since treatment with EDIT-301, and all participants, including four RUBY patients and one EdiTHAL patient, demonstrated successful engraftment within one month of dosing, discontinuing their red blood cell transfusions. EDIT-301 has been well-tolerated by patients, and its safety profile aligns with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. The trends in anemia correction and fetal hemoglobin expression have been consistent among both sickle cell and beta thalassemia patients at similar follow-up times. We firmly believe that EDIT-301 could provide substantial clinical benefits for patients with severe sickle cell disease and transfusion-dependent beta thalassemia, potentially creating long-term clinical differentiation. We look forward to presenting additional clinical data and longer follow-up results in December. As previously stated, the selection of CRISPR enzyme and the target for editing to activate fetal hemoglobin expression are vital. EDIT-301 utilizes our proprietary AsCas12a enzyme to edit the HBG12 promoter, enhancing editing efficiency and minimizing off-target effects compared to other CRISPR enzymes, such as Cas9. Editing the HBG1 and HBG12 promoters in human CD34 cells results in increased red blood cell production, better proliferative capacity, and healthier red blood cells compared to targeting BCL11A. We assess differentiation across three endpoint categories in clinical trials: hematological parameters, organ function, and patient-reported quality of life outcomes. Based on the available clinical data, we believe sustained normal hemoglobin levels could differentiate EDIT-301. Maintaining a normal total hemoglobin level is a crucial clinical outcome for patients, significantly enhancing quality of life and reducing organ damage. We look forward to sharing more data, including from the RUBY and EdiTHAL trials, next month. Now, I will hand the call over to Erick, our Chief Financial Officer.

Erick Lucera, Chief Financial Officer

Thank you, Baisong, and good morning, everyone. I'm happy to be speaking with you today and with one quarter under my belt at Editas; I'm even more impressed by the quality of our science, our leadership in the gene editing field, the strong intellectual property portfolio, and our highly differentiated work from other players in the field. I was excited to join this summer and I continue to be impressed with what I see. With that, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the third quarter 2023, and I'll take this opportunity to briefly review a few items. Our cash, cash equivalents and marketable securities as of September 30 were $446 million compared to $480 million at June 30, 2023. We expect our existing cash, cash equivalents and marketable equity securities to fund our operating expenses and capital expenditures into the third quarter of 2025. Revenue for the third quarter of 2023 was $5.3 million, which primarily relates to the upfront payment under the non-exclusive Cas9 license to Vor Bio in August 2023. R&D expenses this quarter were $41 million, essentially flat from the third quarter of 2022, which reflects various offsetting expenses, including decreases in R&D spend related to our reprioritization and targeted focus on our EDIT-301 program, offset by increased spending and pre-commercialization efforts, including medical affairs and patient advocacy. G&A expenses for the third quarter of 2023 were $15 million, which decreased from $16 million for the third quarter of 2022. The decrease in expense is primarily attributable to decreased headcount expenses, including stock compensation and reduced legal costs. Overall, Editas remains in a strong financial position bolstered by our sharpened discovery focus, June capital raise, and recent out licensing deal. Our cash runway into the third quarter of 2025 provides ample resources to support our continued progress in the RUBY and EdiTHAL trials of EDIT-301, continue commercial manufacturing preparation, and advance our discovery and research efforts. As I've shared before, I'm a former buy-side investor and I know the value of buy-side and sell-side knowledge. I look forward to hearing from our shareholders as we work to advance our gene editing medicine. We value your feedback. And with that, I'll hand the call back to Gilmore.

Gilmore O'Neill, CEO

Thank you, Erick. As we continue our momentum and the execution of our goals, it remains an exciting year for Editas. We look forward to continuing our transformation and sharing our progress with you. As always, it must be said that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners and you, the investment community. Thanks very much for your interest in Editas and we're happy to answer questions. Thank you.

Operator, Operator

Thank you. We will now begin the question-and-answer session. Our first question comes from Brian Cheng with J.P. Morgan. Please go ahead with your question.

Brian Cheng, Analyst

Good morning, everyone. Congratulations on your progress, and thank you for allowing me to ask my questions. Can you provide an update on the development of off-target stack and services? Specifically, I'd like to know about the work you're doing regarding off-target. Are you involved in whole genome sequencing, and do you have any insights that might contribute to your path to approval? Thank you.

Gilmore O’Neill, CEO

Brian thanks very much. I'm afraid it was incredibly difficult to hear you with the background noise and I know you're suffering from some connection problems there. I think I heard you talk about off-targeting, so I'm assuming you're referring to this week's transform. Yes. And so let me just go with that and then we can follow-up if it's incorrect. But, as you know, I think you referred to the AdCom, and I have to say that the AdCom represented an incredibly positive and exciting moment for this week. It was a great day for sickle cell warriors where patients now can think about not battling a disease, but actually living a life. It was a significant milestone for CRISPR genome editing as that AdCom represents sort of almost a penultimate step towards approval for the first CRISPR-based medicine. What struck us in the very focused discussion of the AdCom was the positive tone, but actually also as we listened to the commentary, it really substantially strengthened our confidence in the very robust data package that we've generated about off-target editing. I hope I've answered your question, because with off-target editing is what I heard. I think the only other thing I want to emphasize, of course, is that we have chosen to advance our proprietary owned AsCas12a enzyme, which indeed has higher fidelity, and it's a significant reduction in off-target edits when compared to Cas9.

Brian Cheng, Analyst

Thanks, Gilmore. I'm not sure if you can hear me better now.

Gilmore O'Neill, CEO

Yes, that's better. That's better.

Brian Cheng, Analyst

Okay. Okay. Yes. So I'm just wondering if there was a lot of focus specifically on off-target effects. So I'm just wondering if there is any work that you're doing now that is different than the gene editors, players that are in the market that are different to make sure that the regulators will be happy with the way that you're monitoring these off-target effects. Thank you so much.

Gilmore O'Neill, CEO

Yes. Thanks, Brian. I mean, without going into details, I don't think it's the appropriate time to go into details. We are doing more than was discussed at the AdCom, and that's where our confidence about the robustness of our data package comes from. I hope that answers your question.

Brian Cheng, Analyst

Yes, that was very helpful. Thanks so much.

Operator, Operator

Our next question comes from the line of Samantha Semenkow with Citi. Please proceed with your question.

Samantha Semenkow, Analyst

Hi, good morning. Thank you for taking my question. Yes, just to follow-up on the last question, Gilmore, and you sort of touched on this, the difference between Cas12a and Cas9. Can you just talk a little bit more in detail about what you're seeing as the different off-target risk and how you'd be able to show that to regulators when you get to that stuff?

Gilmore O'Neill, CEO

Indeed. Happy to. Let me just preface again with the sort of high level that in published data we have and others have shown a substantial reduction in off-target editing when comparing AsCas12a versus the Cas9 enzyme. With regard to the data package that we have generated and continue to generate off-target, it is substantial. I'm not sure that we are in a place to share more details. I don't know, Linda, if you have anything to add.

Linda Burkly, Chief Scientific Officer

Yes, I would like to reinforce what Gilmore just mentioned. We are employing various distinct methods, in addition to what was previously discussed regarding outcomes. Therefore, we have strong confidence in our package as we advance towards the BLA. Additionally, our preclinical data indicates that we are not observing off-target editing in our experiments, which further strengthens our confidence in our package moving forward.

Operator, Operator

The next question is from the line of Joon Lee with Truist Securities. Please proceed with your question.

Joon Lee, Analyst

Hey, thanks for the updates and for taking our questions. Based on all that's been presented during the AdCom, where do you see room for clinical differentiation and is that something that we can expect to see at ASH? Specifically, can you comment on your platelet engraftment, reticulocyte count and markers of hemolysis? Thank you.

Gilmore O'Neill, CEO

So I think the key thing is that we are very excited already by the clinical data that we have presented and what we see as a competitive fast follower with potential for differentiation. And what we've seen to-date was a consistent highest level correction of anemia to the normal physiological range, which is by design, choosing ASCs 12a to edit a gamma globin promoter. I'm going to ask Baisong to tell you a little more about what we can share at ASH on December 11.

Baisong Mei, Chief Medical Officer

Thank you, Gilmore. Thank you for the question, Joon. As I mentioned in the ASH presentation, we will present data from 11 RUBY patients and six EdiTHAL patients, with a longer follow-up period for two RUBY trial patients who have been monitored for at least 12 months. Additionally, we have more data from the RUBY trial collected over five months. Regarding the AdCom, we are very pleased with the successful outcome as Gilmore highlighted. We believe in the technology and the mechanism of action using hemoglobin as a target to treat sickle cell disease and beta thalassemia. For differentiation, we are confident that we are fast followers with a differentiated molecule, and we are happy to report that we have data showing the ability to correct anemia. For reference, the normal total hemoglobin levels for females range from 12 to 16 grams per deciliter, and for males, it is 13.8 to 18 grams per deciliter. We are pleased to see our patients reaching the normal range and look forward to sharing more data during the ASH presentation and our webinar next month.

Gilmore O'Neill, CEO

Yes. I think the only other thing is we do note that we've had very successful engraftment timelines. It's too early to say more than that in the space. And I think we're also very happy with where our hemolytic markers are.

Operator, Operator

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

Greg Harrison, Analyst

Hey, good morning. Thanks for taking the question. Just thinking, when should we expect an update on the in vivo editing efforts? How do you think the commercial opportunity is there relative to ex vivo in sickle cell? And then, what other indications or tissues do you think are attractive candidates for your in vivo technology?

Gilmore O’Neill, CEO

Thank you, Greg. Regarding future updates, our company is committed to making promises and engaging in discussions that we are confident we can fulfill. Over the past year, we have been working diligently. Linda has been with us for only about three months, and we want to ensure she has ample time to connect with our medical and commercial team, now led by our new Chief Commercial and Strategy Officer. It’s important for us to select and focus on high-conviction targets based on our criteria. As for your second question, let’s revisit that.

Greg Harrison, Analyst

Targets and tissues.

Gilmore O’Neill, CEO

We have made progress, and Linda may discuss targets and tissues.

Linda Burkly, Chief Scientific Officer

Yes, thank you for the question. We're very excited to develop an in vivo HSC program based on the success of our targeting approach for sickle cell disease and TDT, moving the targeting of the HBG12 low to an in vivo approach. We're well-positioned for this, given the emerging success we've seen in the clinic, as Baisong has described. We're working hard on the delivery strategy for in vivo HSC, both internally and with potential external partners, and I'm very excited about this direction. As for other tissues of interest, we'll discuss those in the future, as we're interested in delivering for them as well. Thank you.

Gilmore O’Neill, CEO

Thanks very much, Linda. And then, with regard to the third part of your question, you asked about the commercial opportunity for in vivo. Essentially, what you can actually see is a strategy that we're driving, which progressively expands the number of patients and a fraction or proportion of the patient population that can actually use the tissue or use these treatments allogeneic opened a door to therapeutics. But the substantial issue there was finding matched donors where about only about one-tenth of patients can find a matched donor. By going to autologous ex vivo, we've increased that tenfold. By going to in vivo and thus eliminating the risks and burdens of conditioning, we can actually further expand the patient population and address the unmet need that extends into patients who while not described as severe, it's worth remembering that the median survival for this disease in a developed healthcare system like that of the United States is about 45 to 50. As again was impressed upon us at the AdCom by those incredibly moving testimonies from patients and their parents and family members. And indeed, in economies with no healthcare system, it's an 80% mortality by five years of age. So there is a substantial unmet need and in vivo will massively increase the commercial the eligible patient population.

Greg Harrison, Analyst

Great. That's helpful. Thanks again, and looking forward to the update.

Operator, Operator

Our next question is from the line of Gena Wang with Barclays. Please proceed with your question.

Gena Wang, Analyst

My questions, I think a lot of questions asked about the differentiating profile for the EDIT-301. So maybe I wanted to ask in a way actually it was surprising we saw VOE event happen so early during exa-cel AdCom. I'm wondering what is your thoughts there and then for your efficacy clinical profile, what kind of say factors you can pay attention to in order to monitor this event and try to develop differentiate profile versus exa-cel.

Gilmore O'Neill, CEO

Thank you very much, Gena. So doesn't want to just recapitulate your questions to be sure I get it all. You want to talk about the differentiation of our EDIT-301 product for as we're focusing on severe sickle cell disease. You were interested in or surprised to see VOEs reported in some patients post-treatment at the AdCom. And I think you're interested in also understanding what are the elements that we're monitoring for differentiation in our efficacy profile. What I will start and then pass, I can start and then I'll have Baisong comment on the differentiation of our efficacy profile. With regard to the VOEs, I think understanding a full explanation will be hard for us at this point. There were many elements of the data that were not presented, which is not surprising in a very truncated presentation. But obviously looking at the correlation of fetal hemoglobin expression, the other factors that can drive VOEs, et cetera, is something that we obviously afford to get with more data being able to understand. I think what does stand and remains true is that the upregulation of fetal hemoglobin actually has a substantive impact on controlling VOEs. Now, as we look to differentiation for EDIT-301, we're looking beyond not just the control of the VOEs, but actually correcting other elements of the disease. And with that, and with a particular focus on the correction of anemia to normal physiologic range and its impact, and I'd say Baisong to talk more about that.

Baisong Mei, Chief Medical Officer

Yes. Thanks, Gilmore. Gena, yes, absolutely. We are still very confident that we believe that EDIT-301 is a differentiated molecule, given that what we've seen so far, we have to see that we can actually have a correction of thalassemia to physiological range of total hemoglobin. And with that, we look into that not only hematological parameters but also organ function and as well as patient report outcomes. So we continue to believe that direction will allow us to demonstrate differentiation.

Gilmore O'Neill, CEO

One key thing I think it's worth highlighting when we talk about patient report outcomes is that fatigue is a significant complaint. In fact, again, we heard it at the patient testimonials, lack of energy, fatigue, not just the hospitalizations and pain, but fatigue and loss of energy. And so those are important elements or specific sub-domains of the patient-reported outcomes that we're paying attention to.

Operator, Operator

Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.

Jack Allen, Analyst

Great. Thanks so much for taking my question and congratulations to the team on the progress made throughout the quarter. I wanted to ask a little bit about the RMAT discussions. To what degree was the differentiation on total hemoglobin discussed in the RMAT? And then, I believe during the prepared remarks, you mentioned a more substantial data set expected in mid-2024. During the RMAT discussions, did you have any conversations around what could be viewed as a pivotal data set here? And I'd love to hear your thoughts if so.

Gilmore O'Neill, CEO

Thank you for your question, Jack. I think it's too early to discuss the specifics of our conversations with the FDA. However, I appreciate you mentioning RMAT because the FDA has reviewed clinical data, including hematological parameters, which notably involve the correction of anemia. Additionally, it included a non-clinical package to illustrate how this correction occurred by design. Another point regarding RMAT, as we mentioned earlier, is that it boosts our confidence in the review process's timeliness due to the various mechanisms available, such as frequent engagement with the agency and the potential for priority review and rolling submission. Regarding the substantive data set, if we consider exa-cel as a reference, the originally submitted BLA was accepted with efficacy data from 20 patients followed for 16 months, and a further efficacy data set from 10 additional patients was included during the review. This context is encouraging as we aim to dose our 20th patient around January 2024 and observe strong enrollment in the RUBY study. It supports our outlook for presenting a substantial data set with robust follow-up by mid-2024 that highlights the correction of anemia and fetal hemoglobin expression, which aligns with our goal for a BLA by 2025.

Operator, Operator

Thank you. Our next question is from the line of Dae Gon Ha with Stifel. Please proceed with your question.

Dae Gon Ha, Analyst

Hey, good morning, guys. Thanks for taking the questions. Maybe I'll briefly go back to the off-target editing and then a BD one for Caren. On the off-target editing, I guess Gilmore, you talked a lot about the differentiation of AsCas12a versus the Cas9 being used. Just curious, does that, in your view, think you need a little bit more characterization work on the molecular side, given that Cas9 is being a little bit more prevalently used on the CRISPR/Cas based medicine field? And maybe as an offshoot of that, I think there were also discussions around how exa-cel ran all these analyses in a more theoretical manner, but didn't really test the treated patients' blood samples pre and post. So can you confirm if you guys are doing the pre and post testing of the blood samples to see if off-target editing is actually happening or not? And then, question for Caren, to an earlier question about BD and expansion opportunity, you talked about the in vivo HSC delivery, but I don't know if that was intentional or not, but I didn't hear you talk about non-genotoxic conditioning, so I don't know if you can comment on a little bit more on that. Do you see that as part of your armamentarium going forward? Perhaps your magenta experience can speak to that. Thanks so much.

Gilmore O'Neill, CEO

Thank you, Dae Gon. Regarding AsCas12a compared to Cas9, the first key point is that we have published data, both from our team and other laboratories, demonstrating a significant reduction in off-target effects with AsCas12a. Additionally, we do not anticipate that the prevalence of Cas9 will alter the requirements for generating off-target data packages. Our data package so far is very strong, and as Linda mentioned, we are employing multiple orthogonal evaluations, both in silico and in vitro. This also includes our non-clinical in vivo evaluations, which extend beyond what was presented at the AdCom. All of this enhances our confidence. Lastly, we are currently testing the drug products. Now, regarding your question on non-genotoxic conditioning, this area continues to be of interest to us. We have conducted internal work and are keeping an eye on the external landscape. One of the advantages of having Caren on board is her extensive knowledge in this area. Caren, would you like to add anything?

Caren Deardorf, Chief Commercial and Strategy Officer

Yes. Thank you. Thanks for the question and just want to comment how excited I am to be here with the Editas team to help move these therapies forward. Now, you bring up a really important point, something that's important to all of us and will absolutely be part of the evolution of this market space and treatment modality. I think the benefit today is that the risk benefit for severe sickle cell and TDT does remain very strong with the current offering. But we take it very seriously, and we're doing a lot of important work to try to make sure we are part of moving forward to evolve this to be an overall better treatment.

Linda Burkly, Chief Scientific Officer

I just wanted to add to what Gilmore had said, like to affirm that we do test, we have tested drug product lots from a larger number of sickle cell disease patients to confirm the and have not detected off-target editing in that larger number of sickle cell disease patients with samples.

Operator, Operator

Our next question is from the line of Phil Nadeau with TD Cowen. Please proceed with your question.

Phil Nadeau, Analyst

Good morning. Congrats on progress, and thanks for taking our questions. Two from us. First, in terms of continued recruitment in the clinical trials, do you assume any change in the rate that you'll be able to recruit patients following what seems likely to be the approvals of the first two genomic medicines for sickle cell disease by the end of the year? That's the first question. And then, second, a follow-up on differentiation. How long a follow-up do you think you'll need to determine whether fatigue or the hemoglobin levels are truly differentiated? Is that something that kind of relatively quickly, or will that take months, if not years of follow-up to determine? Thanks.

Gilmore O'Neill, CEO

Thanks very much, Phil. With regard to recruitment, no, we do not expect any change. We believe that our enrollment will continue to be robust. I'll pass that to Baisong, who can tell you about his personal experience and conversations with sites and investigators.

Baisong Mei, Chief Medical Officer

Thanks, Phil, for your question. Really that I've been continuing to visit and study sites, I see really very strong momentum and feedback about it and we actually have many patients on our list for this trial. So we actually do not see the impact. So we continue to see the positive momentum. And not only now, but I will see it for next year and we will continue to see the momentum on that.

Gilmore O'Neill, CEO

And indeed, the investigator has said that notwithstanding approvals, this is still an area that they are particularly focused with regard to our therapy and the trials. You asked the other question about differentiation and with regard to the time to actually see differences in total hemoglobin and then what some of the more downstream clinical impacts would be around fatigue or other outcomes. And I'm going to ask Baisong to talk about that.

Baisong Mei, Chief Medical Officer

This is a very important question that we are examining. As previously mentioned, we focus on three categories of clinical endpoints for differentiation. For hematological parameters, we expect to see results relatively quickly. Regarding patient-reported outcomes, such as fatigue, my experience with similar studies indicates that for severe disease, noticeable improvements typically start to appear around six months, and with continued monitoring over six months to a year, we anticipate observing significant positive changes compared to baseline. We are optimistic about this. The second category involves evaluating end organ damage, including the cardiac, pulmonary, liver, CNS, and kidney systems, and we are eager to see improvements in these areas as well. Although this field is relatively new, there have been publications on allogeneic bone marrow transplants for sickle cell patients that suggest potential enhancements in organ function, particularly in the brain and cardiac systems. We look forward to exploring these potential benefits.

Gilmore O'Neill, CEO

Yes. Phil, one of the things I would say is that, you know Baisong and I have been around the block long enough as drug developers to know that when you start applying new outcomes measures in clinical trials using potent new medicines that have sort of have an unprecedented potency in disease, your ability to absolutely firmly predict the absolute time point, the number of patients, et cetera, needed to actually demonstrate that benefit can vary and require additional work. So while we are very enthusiastic about the work that we're doing here, we also are pragmatic and experienced enough to know that we will see hematologic parameters quickly. We may see end organ functional physiologic parameters in a slightly longer-term and then with regard to other outcomes, some of that will be, as I say, we're optimistic, but we have to just temper that with the realism that it may take somewhat longer.

Phil Nadeau, Analyst

That's very helpful. Thanks again and congratulations on the progress.

Gilmore O'Neill, CEO

Thanks very much.

Operator, Operator

The next question is from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.

Yanan Zhu, Analyst

Hi, thanks for taking my questions. I was curious about the focus at the AdCom regarding the number of patient samples tested for off-target effects and whether that number is sufficient to assess the risk for patients with specific genetic variants. In your off-target analysis, are you working with single-digit sample sizes, or are you aiming for a significantly larger number? My next question pertains to percent fetal hemoglobin as a potential differentiator. You discussed total hemoglobin extensively, but based on the reported data and your abstract at ASH, it seems that three out of your first four patients had over 50% fetal hemoglobin. I'm interested in your confidence that this will be replicated in additional patients and whether it could serve as a distinguishing factor. Lastly, could you share your thoughts on whether there's a correlation between total hemoglobin levels and hemolytic markers? Specifically, is there a link at the patient level where higher total hemoglobin corresponds with better hemolytic marker results? Thank you.

Gilmore O'Neill, CEO

Thanks very much, Yanan. So I'm going to try and choreograph a set of answers to a complex set of questions, if you will, or quite a diverse set of questions. So with regard to the advocacy sample, I think the first thing we should do is just remind ourselves that the discussion the very what I would say the informed discussion at the AdCom demonstrated that a robust evaluation of at risk really showed that from an off-target point of view, the risk management, even with the data set presented at the AdCom was actually very good. I will say that we are using additional and a multiplicity of orthogonal in silico and vitro and need some in vivo that's on the iconic state, but in silico and in vitro assessments, which go well beyond what was shown at the AdCom in our data package. I'm not going to go into the specifics of the numbers of patients just to say it's more and obviously we share more detailed about that at an appropriate time in the future. I think the other thing about the variants again, I just want to reaffirm I thought actually that the discussion by the geneticists at the AdCom was very illuminating. I thought both parties, the experts on the panel as well as in the sponsor, really articulated very clearly how the nature of variation, the nature of common ancestry for all humanity, and how we can really manage and identify variants and the risks associated with that. I think it was a very robust discussion and again, it gave us great confidence in our management of risk and the data package that we're generating there. Linda, I don't know if you wanted to answer that.

Linda Burkly, Chief Scientific Officer

No. I think that was a very good summary. I think that was a very good summary, Gilmore. I'm not going to add.

Gilmore O'Neill, CEO

Thanks very much, Linda. With regard to the percentage of fetal hemoglobin as a differentiator obviously we're excited by the data we show its early days yet. And what is clear from the experience described for people who have coincident inheritance of hereditary persistence of fetal hemoglobin with sickle cell disease or indeed thalassemia is that the higher the level of fetal hemoglobin or percentage or fraction fetal hemoglobin, the greater the benefit certainly for sickle cell disease. I'd say it's 30 days for us, but Baisong, I don't know if you want to answer that.

Baisong Mei, Chief Medical Officer

Yes, yes.

Gilmore O'Neill, CEO

I'll come back to the third question.

Baisong Mei, Chief Medical Officer

Thank you for the question. We are very pleased to see the fetal hemoglobin data showing over 50% in patients, and we are excited about this outcome. This is due to our rational design approach for EDIT-301. We compared targeting the HBG12 promoter with BCL11A, and we found that our approach yields better fetal hemoglobin expression, although we are still in the early stages. We look forward to seeing more data on this.

Gilmore O'Neill, CEO

Thanks very much, Baisong. I think your final question was around the correlation between total hemoglobin and hemolytic markers. I think that is an interesting question before hand it to Baisong I'll just remind one thing. While hemolysis is a critical part of sickle cell disease, the key driver we believe for driving total hemoglobin by design is enhanced erythroid production. Baisong if you want to add?

Baisong Mei, Chief Medical Officer

Yes, that's exactly right, Gilmore. That's what we're going to say. I want to emphasize that we are very positive about our agnostic marker data on that. The total hemoglobin level is related to two aspects: hemolysis and the HBG12 process. In our design, we ensured that this molecule promotes high fetal hemoglobin expression, and by targeting the HBG12 promoter, we achieve better processing and improved protection of red blood cells. We are eager to see more data on this and are very pleased with our hemolytic biomarkers.

Operator, Operator

Thank you. Our next question is from the line of Eric Schmidt with Cantor Fitzgerald. Please proceed with your question.

Eric Schmidt, Analyst

Good morning. Thanks for taking my questions and congrats on the progress. Maybe the first, the HbF production levels are obviously quite impressive. Is there a total hemoglobin above which you start to grow concerned in sickle cell disease that patients have too much hemoglobin? If so, what that might be? And then maybe a follow-up for Caren. We saw a couple of large pharma gene editing deals this week. Perhaps you could comment on the overall level of interest in potential platform-type collaborations. Thanks.

Gilmore O'Neill, CEO

Thank you very much, Eric. Regarding total hemoglobin, we believe that correcting it to the normal physiological range offers significant benefits. It's difficult to predict a threshold that could be considered too high. There has been some conflicting data about the risks associated with polycythemia in a broader patient population. However, we are confident in the data we are collecting regarding total hemoglobin and our ability to normalize it. You also mentioned recent gene editing deals announced this week. It's encouraging to see major pharmaceutical companies showing increased enthusiasm for the genome editing field during a time when we've witnessed some challenging deals. This week has been particularly positive for the CRISPR genome editing sector, marking a key step toward approval for a first CRISPR-based therapy. It's promising to observe the pharmaceutical industry reassessing the value of genome editing with a focus on significantly reducing risks as they aim to expand their portfolios.

Caren Deardorf, Chief Commercial and Strategy Officer

Yes. Thanks, Eric. It's Caren. What I would add is I think Editas is so well-positioned right now, having refocused the portfolio, we are in a great place to be able to move our own programs forward and are very excited by the continued interest and it opens the door for partnering should that be the right path for us.

Operator, Operator

Our next question comes from the line of Steve Seedhouse with Raymond James. Please proceed with your question.

Steve Seedhouse, Analyst

Good morning. Thank you. Two quick ones. First, are lymphocyte and neutrophil counts at baseline and post-transplant something that you are going to share in either the poster or the associated presentation at ASH? And then separately, is it your intent at Editas to commercialize EDIT-301 on your own? Thanks.

Gilmore O'Neill, CEO

Thanks very much for this question. With regard to neutrophil engraftment data, that is something that we actually did present at our EHA, and it would comprise or could be summarized in our presentations at the end of the year, because it's actually a measure of engraftment is part of the safety monitoring that we do in our studies. And then with regard to your second question, which was around commercializing 301 on our own. Well, we actually look to commercializing 301. We're actually building towards that because that we believe that's important. We have indicated previously that we're interested in an ex-U.S. partner with a large footprint. Obviously, the details of any such partnership and how that might expand, would really depend very much on those negotiations. It's something that we would share upon any kind of agreement, but only then.

Steve Seedhouse, Analyst

Gilmore, just to clarify, I was asking about lymphocyte and neutrophil counts like longitudinally post-transplant, just because in the exa-cel data they don't recover to baseline. So I'm just curious if that's something you plan to share and it'd be interesting to know whether it's different or the same given the different genomic target and different editor.

Gilmore O'Neill, CEO

So well, we have not seen, we've been actually very happy with our counts. We're actually very happy with our counts to-date. But what I can follow-up on that.

Operator, Operator

Our next question is from the line of Luca Issi with RBC. Please proceed with your questions.

Luca Issi, Analyst

Great. Thanks so much for taking my question. Two quick one here, maybe based on sounds like you're obviously on track with those 20 patients by January 2024. Are you enrolling any adolescents? Just trying to understand if there is a scenario where your initial label will just include adults versus some of your peers would also get a broad label that also includes adolescents. So got any color there much appreciated. And the second one, quick one for Linda here. I think during the AdCom earlier this week, one of the potential suggestions to further characterize off-target editing risk was to actually do whole genome sequencing in 20 patients before and after the genetic manipulation. So I just wonder if that's something that you're contemplating to do. Thanks so much.

Baisong Mei, Chief Medical Officer

Yes. Thank you for your question. I take your first question and I pass that. I think we have a plan to dose adolescent patients and also for the general clinical program, we are intended to go to patients of all ages. So that's kind of what because this disease is essentially starting with genetic disease start from a very young age. So we intend to actually be able to have this molecule benefit a patient from all ages. So that's kind of our intention I mean, all those things of course, the label you mentioned will have further discussion and alignment with FDA.

Linda Burkly, Chief Scientific Officer

Thank you for your question. It was a very interesting discussion at the AdCom. One of our methods discussed was a biochemical approach applied to naked DNA. This unbiased method involves extracting naked DNA from cells, cutting it with our RMP, and performing whole genome sequencing to check for off-target editing. This technique is known as digenome. We use this method as a robust criterion to evaluate our drug product before administering it to patients. This contributes to our confidence in our methodology, alongside the other methods we utilize, including in silico and guide seek. That's what I'm able to share at this moment, but there are many other elements to our strategy that bolster our confidence regarding the off-target editing package we are developing.

Operator, Operator

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

Jay Olson, Analyst

Hey, congrats on the progress and thank you for taking the question. Maybe just another question on read across from the exa-cel AdCom since there was some discussion about long-term monitoring and surveillance of these patients. Can you just share your thoughts and plans to follow EDIT-301 patients long-term in a post approval setting? Thank you.

Gilmore O'Neill, CEO

Yes. Thanks for your question, Jay. So we certainly will have a long-term follow-up for patients. And so that study is designed to actually follow the patient up to 15 years for anybody who actually doses with EDIT-301. And that's also consistent with the regulatory requirements. So that's absolutely our plan.

Operator, Operator

Next question is from the line of Liisa Bayko with Evercore ISI. Please proceed with your question.

Jingming Chen, Analyst

Hey, this is Jingming on for Liisa. Thanks for taking our questions and congrats on the progress. So we have three questions. First, we know that CDC has filed an appeal to the Court of Appeals. When do we expect to hear the decision for that? And then, second, as I know you mentioned that more substantial data set for sickle cell is coming in the middle of 2024. Just wondering when should we expect more substantial data set for the TDT patients. And then the third is, you mentioned that in the second half you plan to engage with the FDA to seek alignment or regulatory path for EDIT-301. We are wondering, will you inform the Street on the result of the discussion? And if so, what's the timing for that? Thank you.

Erick Lucera, Chief Financial Officer

Hi, this is Erick. Regarding any court cases in front of the CDC, we prefer not to comment on those until a final decision is made. We will be waiting just like you for that outcome.

Baisong Mei, Chief Medical Officer

Yes. This is Baisong responding to your second question regarding the program in the middle of next year. We will have dosed 20 patients by January, and by mid-year, we will have substantial follow-up data for those patients. Additionally, we will continue dosing more patients throughout the year, providing us with a significant amount of data on sickle cell disease by that time.

Jingming Chen, Analyst

I want to ask for the beta thalassemia?

Baisong Mei, Chief Medical Officer

Yes, absolutely. I believe your question covered both topics, and I want to ensure we address that. We have strong momentum for the EdiTHAL study, and as we mentioned, we currently have eight patients enrolled and are continuing to enroll and dose patients. However, we haven't disclosed the specific goal for next year regarding how many EdiTHAL patients will be dosed, but we will provide that information at the appropriate time. Regarding your question on FDA engagement and outcomes, we are actively engaged with the FDA, and we have the RMAT designation, which allows for more frequent interactions with the agency, including senior management. However, we do not have a timeline to share the outcome just yet, but we will communicate that when the time is right.

Operator, Operator

Our next question is from the line of Mani Foroohar with Leerink. Please proceed with your question.

Lili Nsongo, Analyst

Hi, good morning. This is Lili Nsongo on for Mani. Thank you for taking our question. I just wanted to ask if you could potentially give us an update on the progress of the manufacturing scaling for 301, both for clinical development and for potential commercialization. And then on the other side, second question in terms of the package for BLA. So we're just timing. I think you had mentioned potential package readiness by 2025. By then we might have post marketing data from potentially two gene therapy programs. I was wondering if you and how you would see that impacting potential pivotal design. Thank you.

Erick Lucera, Chief Financial Officer

Hi, this is Erick. I'll take the first question with respect to the manufacturing, scaling timing. As a reminder, we're very confident in what we're doing and making the investments in manufacturing for the commercial launch. We haven't specifically commented on the scale or timing, but just reiterate our confidence in everything we're doing on a manufacturing standpoint.

Baisong Mei, Chief Medical Officer

Yes, this is Baisong. To address the second part of your question, we anticipate having 20 patient doses by January next year, and by mid-2025, we expect to have substantial data, likely comparable to the BLA filing accepted by the FDA, which includes data from about 20 patients. They then added another 10 patients with an additional four months of data. We believe we will be ready to submit an FDA-equivalent package with similar data by the middle of next year. However, the exact details of the BLA data package will need to align with the FDA's requirements, which will aid in our agreement with them. Regarding the post-marketing and commercialization of these two molecules, we have noted a lack of recruitment momentum. We are very optimistic about the outcomes discussed and believe they provide further validation for CRISPR technology and the use of fetal hemoglobin as a mechanism to treat sickle cell disease and beta thalassemia. We see all this work positively impacting EDIT-301.

Operator, Operator

Thank you. Our final question comes from the line of Terence Flynn with Morgan Stanley. Please proceed with your question.

Unidentified Analyst, Analyst

Great. Thank you for taking our question. This is Matt Gahr on for Terrence Flynn. So, looking to the future a bit, can you expand on your approach to target selection, how we should think about your pipeline evolving going forward? Also, as you think about tissue-specific delivery for your future in vivo programs, how are you thinking about the advantages and disadvantages to investing in AAV and/or LNP? Thank you.

Linda Burkly, Chief Scientific Officer

Thank you for your question. Our approach to target selection focuses on applying criteria that differentiate us from the standard of care. It is crucial that we provide medicines that address unmet patient needs not currently met by existing treatments. We will seek targets where we have strong confidence and a high likelihood of success both technically and commercially. I am excited to have Caren join the team, allowing me to collaborate with her and Baisong to effectively select our targets. We are well-positioned to make these selections. I'm particularly enthusiastic about the emerging data supporting the in vivo sickle cell disease TDT target. Regarding delivery, as Gilmore outlined in January, our strategy is centered on non-viral delivery, with a focus on LNP delivery. We are working both internally and with external partners to develop an approach for in vivo HSC targeting for our HBG12 promoter using LNPs. LNPs are already validated for delivering to the liver, which is an area of interest for us, and recent industry deals indicate ongoing pharma interest in this sector. However, we are also exploring other tissues, as there are numerous targets suitable for Editas technology. We look forward to advancing these initiatives and will share information as it becomes available in the future. Thank you.

Operator, Operator

Thank you everyone. This will conclude today's conference. You may disconnect your lines at this time. We thank you for your participation.