Editas Medicine, Inc.

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 Christy Barnett, Corporate Communications and Investor Relations at Editas Medicine.

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 investor section of our website approximately two hours after its completion. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for 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 filing. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. Now, I will turn the call over to our CEO, Gilmore O'Neill.

Thanks, Christy, and good morning, everyone. Thank you for joining us today on Editas Medicine's third quarter earnings call. I'm joined today by four other members of the Editas executive team. Baesong Mai, our chief medical officer, Eric Lucera, our chief financial officer, Linda Berkley, our chief scientific officer, and Karen Dierdorf, our new 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' vision, 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 know-how 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 EDIT301 Ruby trial for severe sickle cell disease, or SCD, by the end of 2023, to provide a clinical data update from EDIT301 Edithal trial for transfusion-dependent basothalassemia, 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 HSCs, 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 11th, 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 EDIT trial. Baesong 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 Edifal 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 substantial clinical data set of sickle cell patients with considerable clinical follow-up in the Ruby study in the middle of 2024. Baesong will share further details regarding our December data readout and clinical progress of EDIT301 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 EDIT301 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 previously shared, we made another important hire as we continue to gain momentum in pursuing a leadership position in hematopoietic stem cell medicines for hemoglobinopathy. In late September, we announced that Karen Dierdorf, a highly experienced and successful therapeutics commercial leader, has joined Editas as our new Chief Commercial and Strategy Officer. Karen 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, Karen'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 Azure Devon 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 Edital 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 XSL 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 Vorbio, 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 past nine patent estates covering Cas9 use in developing human medicines. Only a small fraction of these patents are involved in the ongoing USPTO interference proceedings. As the exclusive licensee, we are uniquely positioned to issue exclusive and non-exclusive sub-licenses 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 Vorbio further bolsters our confidence that our IP portfolio provides meaningful value now and in the future. To conclude my remarks, we are energized by the promising efficacy and safety data we shared in June, signaling that EDIT301 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 sharp and strategic focus, our world-class scientists and employees, and our keen drive and 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 Bae Song, our Chief Medical Officer.

Thank you, Guillermo. Good morning, everyone. Let's start with EDI-301 in development for severe sickle cell disease and transfusion-dependent beta thalassemia. As Guillermo mentioned in his remarks, we continue to enroll and dose patients in the RUBI trial for severe sickle cell disease and in the EDI-301 trial for transfusion-dependent beta thalassemia. As of today, in the RUBI trial, we have enrolled 27 patients, and the 20th patient in the RUBI trial is expected to be dosed in the January 2024 time frame. In the EDI-CELL trial for transfusion-dependent beta thalassemia, to date, we have enrolled eight patients. As I shared earlier this year, I have been visiting and continue to visit our Ruby and EDI-CELL clinical trial sites, continuously speaking with our investigators, and I appreciated the enthusiasm and the support from the investigators and study sites. I'm pleased with the momentum of EDI-301 in patient recruitment, of freezes, editing, and dosing in both studies. I'm excited to hear from the investigators that patients dose with Eddie three one have already seen positive changes in their lives. As we have previously shared, we will engage with FDA in the second half of the year. On a related note, we found the recent XSL outcome insightful and it is reaffirmed the power and potential of these gene editing technology. As a physician, I'm excited for patients living with serious diseases that gene editing has the potential to transform the treatment of the diseases and ultimately patient lives. As a drug developer, I'm eager to see the first medicine approved and swiftly followed by more medicine from other companies, including Adidas. More importantly, I'm excited to announce that we will share Ruby and Edithel clinical data in a poster presentation as well as in the company-sponsored webinar, both on Monday, December 11th. So, what we will show. The RUBI dataset will include clinical data from 11 patients. We will present efficacy data, including total hemoglobin, fetal hemoglobin, and vaso-occlusive events, or VOEs. And safety data, including neutrophil and platelet engraftment. The follow-up period of these 11 patients includes two patients with at least 12-month follow-up and an additional four patients with at least a five-month follow-up. The other patients will have a one to four-month follow-up period. The ADECL dataset will include the clinical data from six patients. We will present efficacy data including total hemoglobin and fetal hemoglobin, and the safety data including neutrophil and platelet engraftment. The follow-up period after EDI3-1 treatment includes at least five months' data from the first two patients treated. The other patients will have one to four months' follow-up period. As a reminder, this past June, we shared promising Ruby clinical data in an oral presentation at the European Hematology Association Congress, or EHA. Followed by our company-sponsored webinar, we also presented possible initial data from the first patient treated in the EDI3-1 trial. The RUBI dataset covers safety and efficacy data from the first four patients, including 10-month data from the first patient treated and six-month data from the second patient treated, including total hemoglobin and the fetal hemoglobin. Demonstrating AD301 drives early, robust correction of anemia to a normal physiological range of total hemoglobin in as early as four months after AD301 treatment. ADD301 drives robust sustained increase in pre-homoglobin in excess of 40%. All four-dosed Ruby sickle cell patients remained free of vessel occlusal events since ADD301 treatment. Additionally, all dosed participants, including four Ruby patients and one ADD cell patient, showed successful engraftment within one month of dosing and has stopped red blood cell transfusion. ADD301 was well-tolerated by patients, and the safety profile for ADD3-01 was consistent with the myeloid-tubulescent and conditioning and autologous hematopoietic stem cell transplant. And the trajectory of correction of anemia and expression of freedom globin was consistent across ADD3-01-treated sickle cell patients and penicillin-sumate patients at the same follow-up time point. We continue to believe that EDD3-1 can potentially provide robust clinical benefit to patients with severe sickle cell disease and transfusion-dependent beta-thalassemia, potentially provide clinical differentiation in the long term. We look forward to our presentation of additional clinical data and a longer follow-up in December. As we have previously stated, the choice of CRISPR enzyme and the target to edit it to switch on fetal microbe expression matters. Edit 301 used our proprietary ASCAS12A enzyme to edit the HBG12 promoter. ASCAS12A increases the efficiency of editing and significantly reduces off-target editing when compared to other CRISPR enzymes, including Cas9. Editing HBG12 promoter in human CD34 positive cells resulted in greater red blood cell production and with normal proliferative capacity and improved red blood cell health when compared to editing of BCL11A. We look at the differentiation in three categories of endpoints in clinical trials, hematological parameters, end organ function, and the patient report outcome or quality of life. Based on the clinical data so far, we believe that sustained normal level of hemoglobin could be a potential point of differentiation for EDI-301. As a reminder, a sustained normal total hemoglobin level is an important clinical outcome for patients, as the correction of anemia can significantly improve quality of life and ameliorate the end-organ damage. We look forward to sharing additional data, including Ruby and EDI-CELL clinical data, next month. Now I will turn the call over to Eric, our Chief Financial Officer.

Thank you, Besson, 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 30th were $446 million compared to $480 million at June 30th, 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 CAS 9 license to VORBIO 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 in 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, EDITOS remains in strong financial position, bolstered by our sharpened discovery focus, June capital raise, recent out licensing deal. Our cash run right into the third quarter of 2025 provides ample resources to support our continued progress in the Ruby and EDITFL 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 Gilmar.

Thank you, Eric. 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, investment community. Thanks very much for your interest in EDItas, and we're happy to answer questions. Thank you.

Thank you. We'll now be conducting a question and answer session. If you'd like to ask a question at this time, please press star 1 on your telephone keypad and a confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we poll for questions. Thank you. Our first question comes from the line of Brian Chang with JP Morgan. Please proceed with your question.

Good morning, guys. Congrats on the progress, and thanks for giving my question. How many off-the-accom for active style this week? We saw a lot of focus here on off-target effects and for the proof of monitoring. Can you give us a look at the work that you're doing to address off-target effects? Are you doing whole genome sequencing? And any other insights that you see of potential reach to your path to approval? Thank you.

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 ad comp. Yeah, and so let me just go with that, and then we can follow up if it's incorrect. But, you know, I think you referred to the ad comp. represent an incredibly and drove a great excitement for this week. It was a great day for sickle cell warriors, you know, 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 outcome represents almost a penultimate step towards approval for the first CRISPR-based medicine. What struck us in the very focused discussion of the outcome 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 AF-Cas12A enzyme, which indeed has higher fidelity and a significant reduction in off-target edits when compared to Cas9.

Thanks, Gilmour. I guess my – I don't know if you can hear me better now.

Oh, yes, that's better.

I guess my question – oh, okay, okay. Yeah, so I'm just wondering if – you know, there were 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.

Yeah, thanks, Brian. I mean, without going into details, I don't think it's appropriate this 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 was the question.

Yeah, that was very helpful. Thanks, Gilmore.

Thank you very much, Brian. It sounds like you're on a plane, so have a good trip. Okay.

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

Hi, good morning. Thank you for taking my question. Yeah, just to follow up on the last question, Gilmore, and you sort of touched on this, the difference between CAS 12A and CAS 9. 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 step?

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 AF-Cas12a 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.

Yeah, I would just add, this is Linda Berkeley, CSO. Yeah, I would just add and echo what Gilmore just said, that we're using multiple orthogonal methods, additional methods as compared to what we heard at the ADCOM. We're very confident in our package as we proceed in our path to the BLA. In our preclinical data, we are not seeing more target editing in our preclinical experiments. we're very confident in our package going forward.

Great, thank you for taking the question.

The next question is from the line of June Lee with Truist Securities. Pleased to see you with your questions.

Hey, thanks for the update 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 ASHE? Specifically, can you comment on your platelet engraftment, reticulocyte count, and markers of hemolysis? Thank you.

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, you know, potential for differentiation and what we've seen to date with a consistent, you know, highest level correction of anemia to the normal physiological range. which is by design in our choosing of AS-CAS12A to edit a gamma-globin promoter. I'm going to ask Baesong just to tell you a little more about what we can, about what we're going to share at ASH on December 11th.

Yeah. Thanks, Guillermo. Thanks for the question, Jun. As I mentioned that in the ASH presentation, we'll have data from 11 Ruby patients and six EDIFEL patients, and we will have a longer follow-up period with two patients in the Ruby trial with at least 12 months, and then we have additional data from five months for the Ruby trial. And go back to your question also on these EDICOM in there, and we are very actually to see, as Gilmo mentioned, the very successful outcome and to reaffirm, I believe, the technology and also the MOA of using fetal hemoglobin as a target to treat sickle disease and beta-thysemia. And we, with differentiation, we are confident that we are fast followers, we have differentiated molecules, and we are very pleased to see that we presented data that we'll be able to correct the anemia. And in our case, the normal total hemoglobin for female was 12 to 16 grams per deciliter. And for male, it's 13.8 to 18 grams per deciliter. And we're pleased to see our patients going to the normal range. And we're pleased to share more data during the ASH and webinar presentation data next month.

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

Excellent. Thank you so much.

Thanks. Thank you very much.

Our next question is from the line of Greg Harrison with Bank of America. Pleased to see you with your questions.

Hey, good morning. Thanks for taking the question. Just thinking, when should we expect an update on the in vivo editing efforts? And 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?

Thanks very much, Greg. With regard to future updates, This is a company who philosophically wants to make promises and make discussions that we believe that we can absolutely deliver on. We have been doing work over the last year. Linda has only been here about three months, and we want to ensure that she has the time to, again, engaging with our medical and commercial team now led by our new Chief Commercial Strategic Officer, the ability to make sure that we choose and progress against high conviction targets based on our selection criteria. With regard to your second question, let's just remind again. Targets and tissues, yes, forgive me. So we have actually, you know, advanced work. In fact, Linda, I might ask you to talk about target tissues.

Yeah, thank you. Yeah, thank you for the question. So, of course, we're very excited to... to develop an in vivo HSC program based on the success of our targeting approach for sickle cell disease and TDT. And so moving the targeting of the HBG12 locus to an in vivo approach. And so we're very well positioned for that, considering the emerging success that we're seeing in the clinic that Baesong has described. And so we're working very hard to come up with the delivery strategy for in vivo HSC. And we're doing that both internally and through potential external partners. And so I'm very excited about that avenue. And then in terms of other tissues of interest, We'll be talking about those in the future. We are interested in the liver, but I'll be talking about other tissues as well in the future. Thank you.

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 the 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 match donors, where about only about one-tenth of patients can find a match 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.

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

Our next question is from the line of Gina White with Barclays. Please proceed with your questions.

I think there are lots of questions asked about the differentiating profile for the EDI-101. So maybe I wanted to ask, you know, in a way, actually, it was surprising we saw a VOE event happen so early during XSL Adacom. 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 differential profile versus Excel?

Thank you very much, Gina. So just to recapitulate your questions to be sure I get it all, you know, 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. I think you're interested in also understanding what are the elements that we're monitoring for for differentiation in our efficacy profile. What I will start and then pass, I can start and then I'll have Besson comment on the differentiation of our efficacy profile. With regard to the VOEs, I think, you know, understanding a full explanation would be hard for us at this point. There were many elements of the data that, you know, 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 look forward 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 EDIT301, we're looking beyond not just the control of VOEs, but actually correcting other elements of the disease. And with that, and with the particular focus on the correction of anemia to normal physiologic range and its impact, that's based on to talk more about that.

Yeah, thanks, Guillermo. Yeah, Gina, yeah, absolutely. We are still very confident that we believe that L3-1 is a differentiating molecule. Given that what we've seen so far, we have to see that we can actually have correction of anemia to physiological range of total hemoglobin. And with that, we look into that not only hematological parameter but an organ function and as well as patient report outcome. So we continue to be in that direction will allow us to demonstrate differentiation.

You know, one key thing I think is 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. you know, lack of energy, fatigue, not just the hospitalizations and pain, but fatigue and loss of energy. And so these are important elements or specific subdomains of the patient report outcomes that we're paying attention to.

Our next question comes from the line of Jack Allen with Baird. Pleased to see you with your question.

Great. Thanks so much for taking my question, and congratulations to the team on the progress nature of 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 RMET? And then I believe during the prepared remarks, you mentioned a more substantial data set expected in mid-24. During the RMET discussions, did you have any conversations around what could be viewed as a pivotal data set here? And I'd love to hear any thoughts, if so.

Thanks very much, Jack, for your question. You know, I think the first thing is it's premature to go into the details of discussions about the FDA. However, I am glad that you highlighted RMAT because, indeed, the FDA does and did review clinical data, including, you know, hematologic parameters, which, as you quite correctly pointed out, include the correction of anemia. And as we said, it also included the non-clinical package to demonstrate how that happened by design. I think the other point about the RMAT, obviously, as we said in the prepared remarks, is that it essentially increases our confidence in the timeliness review through the various mechanisms that are available to us, both with high frequency engagement with the agency going forward, as well as the possibility of a priority review and rolling submission. You asked about the substantive data set, and I think What I would say is that if you look to XSL as a benchmark, we've actually seen that the original XSL-BLA accepted by the FDA included an efficacy dataset of 20 patients with 16-month follow-up. An additional efficacy dataset of 10 patients was added to that during the review period. But that actually tells us, when you look at our being on track to dose our 20th patient, by January, in the January 24 timeframe, and the continuing robust enrollment that we're seeing in a Ruby study, it really validates our line of sight to creating or generating and present, being able to present in the middle of 2024 a substantive data set with, you know, robust follow-up around a period that shows the correction of anemia and fetal hemoglobin expression. and validates line-of-sight to a BLA into 2025. Great.

Thanks so much for the call.

Thank you. Our next question is from the line of Dagon Ha with CIFOL. Pleased to see you with your questions.

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 Karen. On the off-target editing, I guess, Gilmore, you talked a lot about the differentiation of ASCAS 12A 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 XSL 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 Karen. You know, 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, like, you can comment on a little bit more on that. Do you see that as part of your armamentarium going forward? Perhaps your Magenta exchange can speak to that. Thanks so much.

So, thanks very much, Jaegon. You know, with regard to the AS Cas12 versus Cas9, I think the first takeaway is that we have published data from ourselves and other labs showing that there is a differentiated, significant reduction of targets with AS-CAS12A. Secondly, we have a variable. We don't actually believe that the prevalence of Cas9 would change the requirements for off-target data package generation. our data package that we've generated to date is very robust. And as Linda said, we're using multiple orthogonal both in silico and in vitro evaluations, also including, by the way, our nonclinical talks in vivo, but evaluations that go beyond what we saw presented and discussed at the adcom. So again, all of that adds to our confidence. And then finally, We are actually testing the drug product. So, that's kind of the old target. If I could then turn to your question around non-genotoxic conditioning. This is an area that remains of interest to us. We have done internal work. We're also monitoring the external landscape. One of the things, one of the additional benefits of having Karen join us is that she knows, as you quite correctly pointed out, that stays very well. So, Karen, I don't know if you want to add further commentary.

Yeah, 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.

Excellent.

Thanks so much.

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.

Thanks, guys. Thank you. Our next question is from the line of Phil Nadeau with TD Cowan. Please proceed with your question.

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 of a follow-up do you think you'll need to determine whether fatigue or the hemoglobin levels are truly differentiated? Is that something that you'll know relatively quickly, or will that take months, if not years, of follow-up to determine? Thanks.

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 Baesong, who can tell you about his personal experience and conversations with sites and investigators.

Thanks, Phil, for your question. Really, I've been continuously visiting study sites. I see really very strong momentum and feedback about it. And we actually have many patients on our list for these trials. So we actually do not see the impact, but 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.

And indeed, the investigator has said that, you know, notwithstanding approvals, this is still an area that there are particular incidents with regard to our therapy and the trials. You asked another 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. I'm going to ask Baesong to talk about that.

This is actually a very important question. We are looking into that. As I mentioned, we look into three categories of clinical endpoints for the differentiation. You know, certainly that for hematological parameter, you will take a shorter time to see. And for the patient report outcome, for example, you specifically mentioned the fatigue. And usually, based on my experience in other studies, that when you kind of see this patient-reported outcome, usually it takes six months for the CBTD to see something. Then usually it takes six to one year you will see some kind of improvement. But if you monitor longer, you will see much more impactful compared to the baseline. So we are very optimistic and confident that we will be able to see something in that direction for patient-reported outcome on that. And the other category I mentioned is also for the end organ damage, and we actually look into the cardiac, pulmonary, liver, and CNS, and as well as the kidney. So we'll also see that, looking forward to see the improvement. These areas are relatively new, but there are publications for allogenic bone marrow transplant for sickle cell patients, for example, in the brain, blood vessel, the vascular system in brain, and also in cardiac system. So there are some reports, relatively limited, see that allogenic transplant for sickle cell patients could potentially actually improve the organ function. So we're looking forward to that direction.

Yeah. Phil, one of the things I would say is that, you know, Baesong and I have been around the block long enough as drug developers to know that, you know, when you start applying new outcomes, measures, in clinical trials using potent new medicines that 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 be useful. vary and require additional work. So, you know, 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. That's very helpful.

Thanks again, and congratulations on the progress.

Thanks very much.

Our next question is from the line of Yanan Zhu with Wells Fargo. Let's just see what's your question.

Hi. Thanks for taking my questions. So I was wondering, a focus at the adcom was of the adequacy of the number of patient samples tested for off-target and whether that's enough to characterize the risk in certain patients with genetic variants. I think I was wondering, in your off-target analysis work, are you targeting again, single digit sample numbers, or are you targeting a number significantly higher than that? The next question is about percent fetal hemoglobin as a differentiator. I think you talked a lot about total hemoglobin, but I was wondering Based on the data you have reported so far and also in abstract at ASH, it seems like you had three patients of your first four patients who had greater than 50% fetal hemoglobin. I was wondering about your confidence of that being replicated in additional patients and also that being a differentiator. And lastly, I was wondering about your thoughts on whether there is a correlation between total hemoglobin and hemolytic markers and whether you can comment on your thoughts there, i.e. higher, maybe at a patient level, whether a higher total hemoglobin is correlated with better hemolytic marker observations. Thank you.

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 a quite diverse set of questions. So with regard to the adequacy sample, I think the first thing we should do is just remind ourselves that the discussion, the very, so what I would say, the informed discussion at the ADCOM demonstrated that, you know, a robust evaluation of at-risk really shows that from an off-target point of view, the risk management, even with the data set presented to the adcom, was actually very good. I will say that we are using additional and a multiplicity of orthogonal in silico, in vitro, and indeed some in vivo. That's on the on-clinic side, 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'll share more detail about that at an appropriate time in the future. I think the other thing about the variants, again, I just want to reaffirm that 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 want to add to that.

No, I think that was a very good summary. I think that there was, yeah, I think that was a very good summary. Thank you.

Thanks very much, Linda. With regard to the percentage of fetal hemoglobin as a differentiator, you know, obviously we're excited by the data we've shown. It's early days yet. And, you know, 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 of fetal hemoglobin, the greater the benefit, certainly for sickle cell disease. I'd say it's early days for us, but based on it, what do you want to add to that?

Yeah, yeah. Come back to the third question. Yes, yeah, thank you. Thank you for this question. As Gilman mentioned, we're very pleased to see the total, the data as you referred to actually see patients over 50%. And this is, we are excited on that. It's also because this is a rational design approach for edit 301. We compared that this approach, of the targeting the HBG1-2 promoter with HBG1-2 promoter versus BCR11A, we found that we have better fetus hemoglobin expression. But we are in the early stage. We actually want to see more data to this end, and we're looking forward to see more data ourselves on that.

Thanks very much, Baesong. I think your final question was around the correlation between total hemoglobin and hemolytic markers. I think that's That is an interesting question. Before handing the base on, 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.

Yeah, that's exactly right, Guillermo. That's what we're going to say. I think what I want to mention that, you know, we are very positive about our hemolytic marker data on that. And then the, so the total hemoglobin level is related to aspects of that. One is hemolysis, one is the SRE process. So we, I think in our design, we designed to have this molecule have high fetal hemoglobin expression. And also, with the targeting of the HPG1-2 promoter, we have better X-ray process and better red blood cell production. So, we are looking forward to seeing more data on that, but we are very pleased with our hemolytic biomarkers.

Great. Thanks for the cover.

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

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? Do patients have too much hemoglobin? If so, what that might be? And then maybe a follow-up for Karen. 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. Thanks.

Thanks very much, Eric. With regard to the total hemoglobin, we believe that correcting, and that's what we've seen, hemoglobin physage range is of substantial benefit. I think it's hard to speculate about a level that is too high. Indeed, there has been an experience in general with polycythemia in sort of a broader patient population with some conflicting data about the risks of same. But as I say, we feel very confident about the data we're getting in regard to our total hemoglobin and the way that we are correcting it to normal physiological ranges. I think you asked a question about some recent, you know, gene no editing deals just this week that are announced. You know, what I would say, is that what is striking about it is it is great to see pharma, I say big pharma, now in a period where we've seen some a dearth of deals leaning in and increasing their excitement around the genome editing space. In other words, what I would say is this has been a very good week for CRISPR genome editing space with both that sort of critical near to final step towards approval for a first CRISPR-based therapy and to see now pharma actually looking essentially to the lens of substantial de-risking, in their view, of the value of genome editing as they look to grow their portfolios. I don't know if... Yes.

Thanks, Eric. It's Karen. What I would add is I think EDItos 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.

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

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.

Thanks very much for that question. With regard to neutrophil engraftment data, that is something that we actually did present at our e-hub. 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 we believe that's important. We have indicated previously that we're interested in an ex-US 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.

Gilmore, just to clarify, I was asking about lymphocyte and neutrophil counts, like longitudinally post-transplant, just because in the XSL 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.

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 anyone can follow up on that. Thank you.

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

Oh, great. Thanks so much for taking my question. I have two quick ones here. Maybe based on, it 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 where your initial label will just include adults versus some of your peers. You'll also get a broad label that also includes adolescents. Again, 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. I just wonder if that's something that you're contemplating to do. Thanks so much.

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

Oh, yeah, thank you for your question. Yeah, that was a very interesting conversation at the ADCOM. One of our orthogonal methods, and this also came up at the ADCOM, was the method of using a biochemical method applied to naked DNA. This is a method, one of the methods that we use, which is unbiased method. in which the the naked DNA is taken from cells and you subject it to cutting with your RMP and Then you do whole genome sequencing basically to look for off-target editing. And so this is called di genome And so this is one of our methods that we use and look at with our drug product before before you know, before putting that drug product into patients. So, I think this is one of the robust criteria that we, you know, one of the robust methods that we use in our approach. So, I think that's basically one of the reasons that we are confident in our approach to, in addition to the other methods that we use in Silico and GuideSeq that were described I guess that's basically what I'm prepared to share at this moment, but there are many other aspects to our approach that also make us very confident about our approach to the off-target editing package that we're preparing.

Got it. Thanks so much.

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

Oh, hey, congrats on the progress and thank you for taking the question. Maybe just another question on read across from the XSL ad comms 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.

Yeah. Thanks for the question, Jay. 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 does with the EDI-301, and that's also consistent with the regulatory requirements. So that's absolutely our plan.

Great. Thank you.

The next questions are from the line of Lisa Baco with Evercore ISI. Please just share with your questions.

Hey, this is streaming on for Lisa. 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. I'm just wondering when should we expect more substantial data set for the TBT patients? And then the third is you mentioned that in the second half, you plan to engage with the FDA to, you know, seek alignment or regulatory path for 301. We are wondering, will you inform the street on the results of the discussion? And if so, what's the timing for that? Thank you.

Hi, this is Eric. Just with respect to any court cases in front of the CVC or anything like that, we don't really want to comment on those until the final decision is actually rendered. So we'll just be anxiously awaiting for all that, just like you.

Yeah, so this is based on for your second question about the middle of next year for the program. And, you know, two parts of that. One is, as we just shared, that we will have 20 patients dose by January timeframe next year. Then by the middle of next year, we will have substantial follow-up for the 20 patients. And we'll also have continued dosing patients over the course. So we'll have a lot of data over the middle of next year for sickle cell disease.

Regarding the... What about for the beta thalassemia?

Yeah, yeah, absolutely, absolutely. And I got in there, yeah, because I saw your question probably cover both, but I just make sure that we cover on that. And we actually have very strong momentum for edithelial study also, as we just shared. We actually already have, you know, eight patients enrolled, and we continue to enroll in dosing patients. And, but we have not shared what is the goal for next year, how many patients, how many patients were dosed yet. We will share that in appropriate time. And your third part of your question is about, you know, FDA engagement and outcome. And so we are, we are, we're well engaged with FDA and we continue having engagement with FDA as we just mentioned that we actually have these RMAT designation allow us a lot more frequent interaction with the agency, including senior management over there, over the agency. But we have not a timeline to share the outcome yet. We'll share that at an appropriate time.

Got it. Thank you.

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

Hi, good morning. This is Lillian Sango, online for MAMI. 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 with the timing, I think you had mentioned potential package readiness by 2025. By then, we might have post-marketing data from potentially two gene therapy program. I was wondering if you and how you would see that impacting potential pivotal design. Thank you.

Hi. This is Eric. I'll take the first question with respect to the manufacturing, scaling, and timing. You know, 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.

So, yeah, this is based on for your second part of your question. As we shared that we will have 20 patient dose by January time from next year and by middle of next year. middle of next, middle of 2025, and then we will have, you know, substantial data packages probably equivalent to the access BLA volume, which is accepted by FDA, which have like 20 patients in the efficacy data cohort. So they subsequently added additional 10 patients in the addendum with the four months, additional four months data afterwards. So we expect that we will be able to file the FDA equivalent package to, we will have equivalent data package by middle of next year. But what exactly the FDA data, what exactly the DOA data package will need to align with FDA. So that we are, that will have the agreement with FDA on that too. And you mentioned about post-marketing or the commercialization of these two molecules. And I shared earlier that we do not see that recruitment momentum perspective. And you mentioned about data package. And we're actually very excited by the outcome discussion. And we feel that these outcomes have further validation of CRISPR technology, further validation of the phytohemoglobin as a magnet of action to treat sickle cell amphetisemia. So, we actually see all those who have a positive impact of ADD301. Thank you.

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

Great. Thank you for taking our question. This is Max Gore on for Terrance 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.

Yeah, hi. Thank you very much for your question. So as far as target selection, our approach is really to apply criteria so that we are well differentiated from standard of care. very important that we're delivering medicines that are meeting needs that the patients have that are not already met by existing therapeutics. And so we're going to look for targets in which we have high conviction as well as targets that have high probability for technical as well as clinical and commercial success. And so I'm very excited to have Karen having joined so that I can partner with her as well as Baesong in triangulating this to very much select our targets. I think we're really well positioned now to be selecting these where, as I said, Before, I think we're very excited about the in vivo sickle cell disease, TDT target, because we already have emerging data supporting that target. And getting to your question about delivery, where our strategy, which Gilmour described in January, is non-viral delivery. prioritizing LMP delivery amongst the non-viral deliveries and working internally as well as through external partners to derive an approach for in-vivo HSC targeting for our HBG12 promoter with an LMP strategy. As far as other targets and tissues, of course, LMPs are validated for delivery-deliver, so We're interested in that and I think we're well positioned there as well with our technology and especially with the recent deal that we saw announced and just showing the interest, continuing interest in pharma in this space. But we're also interested in other tissues. And so there are many targets out there amenable to Edis-S technology and we're excited to to move forward and we'll certainly be sharing information with you as it emerges in the future at an appropriate time. Thank you.

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