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.
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 2 hours after its completion. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the Safe Harbor Provisions under the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factor section of our most recent annual report on Form 10-K, which is on file with the SEC, as updated by our subsequent filings. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. Now, I will turn the call over to our CEO, Gilmore O’Neill.
Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas Medicine's third quarter earnings call. I'm joined today by four other members of the Editas executive team: Baisong Mei, our Chief Medical Officer, Erick Lucera, our Chief Financial Officer, Linda C. Burkly, our Chief Scientific Officer, and Caren Deardorf, 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 EDIT-301 RUBY trial for severe sickle cell disease, or SCD, by the end of 2023. To provide a clinical data update from the 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, to 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. 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 6 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 8 beta thalassemia patients into our RUBY and Editas 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 2 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 previously shared, we made another important hire as we continue 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 Azzur Devens 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.
In July, we hired Linda C. Burkly 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 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 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 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 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 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 Baisong Mei, our Chief Medical Officer.
Thank you, Gilmore. Good morning, everyone. Let's start with EDIT-301 in development for severe sickle cell disease and transfusion-dependent beta thalassemia. As Gilmore mentioned in his remarks, we continue to enroll in those patients in the RUBY trial for severe sickle cell disease and in the EdiTHAL trial for transfusion-dependent beta thalassemia. As of today, in the RUBY trial, we have enrolled 27 patients, and the 20th patient in the RUBY trial is expected to be dosed in the January 2024 timeframe. In the EdiTHAL trial for transfusion-dependent beta thalassemia, to date, we have enrolled 8 patients. As I shared earlier this year, I have been visiting and continue to visit our RUBY and EdiTHAL clinical trial sites, continuously speaking with our investigators, and I appreciate the enthusiasm and the support from the investigators and study sites.
I'm pleased with the momentum of EDIT-301 in patient recruitment, apheresis, editing, and dosing in both studies. I'm excited to hear from the investigators that patients dosed with EDIT-301 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 exa-cel outcome insightful, and it has reaffirmed the power and potential of this 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 Editas.
More importantly, I'm excited to announce that we will share RUBY and Edit-Cell clinical data in a poster presentation at ASH, as well as in a company-sponsored webinar, both on Monday, December 11. So what we will show? The RUBY dataset will include clinical data from 11 patients. We will present efficacy data, including total hemoglobin, fetal hemoglobin, and the vaso-occlusive events, or VOE. Safety data, including neutrophil and platelet engraftment. The follow-up period of these 11 patients includes 2 patients with at least 12 months follow-up and an additional 4 patients with at least a 5-month follow-up. The other patients will have a 1- to 4-month follow-up period. The Edit-Cell dataset will include clinical data from 6 patients. We will present efficacy data, including total hemoglobin and the fetal hemoglobin, and safety data, including neutrophil and platelet engraftment.
The follow-up period after EDIT-301 treatment includes at least 5 months data from the first two patients treated. The other patients will have 1-4 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 positive initial data from the first patient treated in the Edit-Cell trial. The RUBY dataset covers safety and efficacy data from the first four patients, including 10 months data from the first patient treated and 6 months data from the second patient treated, including total hemoglobin and the fetal hemoglobin. Demonstrating EDIT-301 drives early, robust correction of anemia to a normal physiological range of total hemoglobin in as early as 4 months after EDIT-301 treatment. EDIT-301 drives robust, sustained increase in fetal hemoglobin in excess of 40%.
All four dosed RUBY sickle cell patients remained free of vaso-occlusive events since EDIT-301 treatment. Additionally, all dosed participants, including four RUBY patients and one Edit-Cell patient, showed a successful engraftment within one month of dosing and has stopped red blood cell transfusion. EDIT-301 was well tolerated by patients, and the safety profile of EDIT-301 was consistent with the myeloablative busulfan conditioning and the autologous hematopoietic stem cell transplant. The trajectory of correction of anemia and expression of fetal hemoglobin was consistent across EDIT-301-treated sickle cell patients and beta thalassemia patients at the same follow-up time points. We continue to believe that EDIT-301 can potentially provide robust clinical benefit to patients with severe sickle cell disease and transfusion-dependent 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 hemoglobin expression matters. EDIT-301 uses our proprietary AsCas12a enzyme to edit the HBG1-2 promoter. AsCas12a increases the efficiency of editing and significantly reduces off-target editing when compared to other CRISPR enzymes, including Cas9. Editing HBG1-2 promoter in human CD34 positive cells, resulting 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 patient-reported 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 EDIT-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 Edit-Cell clinical data, next month. Now I will turn the call over to Erick, our 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 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, Editas remains in strong financial position, bolstered by our sharpened discovery focus, June capital raise, 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.
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, 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 one on your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two 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 Cheng with JP Morgan. Please proceed with your question.
Morning, guys. Congrats on the progress and thanks for taking my question this morning. Coming in off the AdCom for exa-cel this week, we saw a lot of focus here on off-target effects and focus on monitoring. Can you give us a look at, or give us a sense of the work that you're doing to address off-target effects? Are you doing whole genome sequencing, and any other insight that you see as potential read-through 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 AdCom. 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 outcome, and I have to say, is that the AdCom represents 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 AdCom represents or 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 you know, chosen to advance our proprietary-owned AsCas12a enzyme, which indeed has higher fidelity and a significant reduction in off-target edits when compared to Cas9.
Thanks, Gilmore. I don't know if you can hear me better now.
Oh, yes, that's better. Much 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. Yeah, thanks, Brian. I mean, without going into details, I don't think it's appropriate at 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. Thanks, Gilmore.
Thank you much. Thanks 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 Semenkow with Citi. Please proceed with your question.
Hi, good morning. Thank you for taking my question. Yeah, just to follow up on, 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 step?
I'm 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 the place to share more details. I don't know, Linda, if you have anything to add.
Yeah, I would just add. This is Linda Burkly, 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. And so we're very confident in our package as we proceed in our path to the BLA. And yeah, in our preclinical data, we are not seeing off-target editing in our preclinical experiments, so we're very confident in our package going forward.
Great. Thank you for taking the question.
The next question is from the line of Joon Lee with Truist Securities. Please proceed with your questions.
Hey, thanks for the update and for taking our questions. You know, 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.
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 of correction of anemia to the normal physiological range, which is by design in our choosing of AsCas12a to edit a gamma globin promoter. I'm going to ask Baisong just to tell you a little more about what we're going to share, at ASH on December eleventh.
Yeah. Thanks, Gilmore. Thanks for question, June. So as I mentioned that in the ASH presentation, we'll have data from 11 RUBY patients and 6 EDIT-301 patients, and we will have longer follow-up period with 2 patients in the RUBY trial with at least 12 months, and then we have additional data from 5 months for the RUBY trial. And go back to your question also on the, on these, AdCom in there, and we are very actually pleased to see, as Gilmore mentioned, that the very successful AdCom and reaffirm, I believe, the technology and also the MOA of using fetal hemoglobin as a target to treat the sickle disease and beta thalassemia.
For differentiation, we are, we are confident that we are fast follower, we have differentiated molecule, 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 with 12-16 gram per deciliter, and for male, it's 13.8-18 gram 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.
Yeah. I think the only other thing is it's, you know, we do note 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. Please proceed 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 are, you know, 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 high conviction targets based on our selection criteria. With regard to your second question. Let's just remind again.
Targeted tissues.
Targeted 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 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 HBG1-2 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 Baisong 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 that's a very. 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, in the liver, but I'll be talking about other tissues as well in the future. Thank you.
Thanks very much, Linda. 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 the door to therapeutics, but the substantial issue there was finding matched donors, where about only 1/10 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 45-50, 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 about 5 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 Gena Wang with Barclays. Please proceed with your questions.
My questions, I think a lot of the questions asked about, the differentiating profile for your, the, EDIT-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 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 to try to develop differentiate profile versus XL?
Thank you very much, Gena. So just wanna just 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 type 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 Baisong comment on the differentiation of our efficacy profile. With regard to the VOEs, I think, you know, understanding a full explanation will 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 EDIT-301, we're looking beyond not just the control of 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, I'll ask Baisong to talk more about that.
Yeah, thanks, Gilmore. Yeah, Gena, yeah, absolutely. We are still very confident that we believe that EDIT-101 is a differentiating molecule. Given what we've seen so far, we have to see that we can actually correct it, have correction of anemia to physiological range of total hemoglobin. And with that, we look into that not only hematological parameter, but end organ function and as well as patient-reported outcome. So we continue to believe that direction will allow us to demonstrate differentiation.
You know, one key thing I think is worth highlighting when we talk about patient-reported 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 those are important elements or specific subdomains of the patient-reported outcomes that we're paying attention to.
Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.
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 hematocrit 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 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 around 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, we also included the nonclinical 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 exa-cel as a benchmark, we've actually seen that the original exa-cel BLA accepted by the FDA included an efficacy data set of 20 patients with 16-month follow-up. An additional efficacy data set of 10 patients was added to that during the review period.
What that actually tells us when you look at our being on track to dose our 20th patient, by January, in the January 2024 time frame, and the continuing robust enrollment that we're seeing in our RUBY study, it really validates our line of sight to creating or generating and 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 that color.
Thank you. Our next question is from the line of Dae Gon Ha with Stifel. Please proceed 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 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 a, 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 the off-target editing is actually happening or not? And then question for Caren, 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 you can comment 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.
So thanks very much, Dae Gon. You know, with regard to the AsCas12a 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 in off-targets with AsCas12a. Secondly, we have a very robust. We don't actually believe that the prevalence of Cas9 would change the requirements for off-target data package generation. Third, 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 tox, you know, 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 off-target. If I could then turn to your question around non- or 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 Caren join us, is that she knows, as you quite correctly pointed out, that space very well. So, Caren, 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.
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.
Yeah, I just-
I'm sorry, Linda, did you have a follow-up?
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, and have not detected off-target editing in that larger number of sickle cell disease patient samples.
Thanks, guys.
Thank you.
Our next question is from the line of Phil Nadeau with TD Cowen. Please proceed with your questions.
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 you'll know kind of 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 robust. I'll pass that to Baisong Mei, who can tell you about his personal experience and conversations with sites and investigators.
Yes. Thanks. Yeah, thanks, Phil, for your question. Really, I've been, you know, continuously visiting study sites. I see really a 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, 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.
So, and indeed, the investigators said that, you know, notwithstanding approvals, this is still an area that they are particularly interested in 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 Mei to talk about that.
Yeah, yeah. Yeah, so this is actually a very important question. We are looking into that, as I mentioned, we're looking into three categories of clinical endpoints for the differentiation. You know, certainly for hematological parameter, you will be taking a shorter time to see. And for the patient-reported outcome, for example, you specifically mentioned the fatigue. And usually, based on my experience in other studies, that when you this kind of clinical, when you kind of see this patient-reported outcome, usually it takes six months, then for the severity, you see something, then usually takes six to one year, you'll see some kind of improvement. But if you monitor longer, you will see a much more impactful compared to the baseline.
So we are very optimistic and confident that we'll be both 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, as well as the kidney. So we'll also see that, looking forward to see the improvement. This area is quite relatively new, but there are publications for allogeneic bone marrow transplant for sickle cell patient. For example, in the brain, blood vessel or blood, the vascular system in brain and also the cardiac system. So there are some reports, relatively limited, see that allogeneic transplant for sickle cell patients could potentially actually improve the organ, improve organ function.
We're looking forward to that direction.
Yeah. And, you know, 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, you know, when you are start applying, new outcomes, measures in clinical trials using potent new medicines that have sort of 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 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.
The next question is from the line of Yanan Zhu with Wells Fargo. Please proceed with your questions.
Hi, thanks for taking my questions. So I was wondering, a focus at the AdCom was 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 work, in your off-target analysis work, are you targeting, again, in single digit sample numbers? Or are you targeting a number significantly higher than that? The next question is about % fetal hemoglobin as a differentiator. I think you talked a lot about total hemoglobin.
I was wondering, you know, based on your data you have reported so far, and also in the 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 complex set of questions, if you will, or a quite diverse set of questions. So with regard to the adequacy of sample, I think the first thing we should do is just remind ourselves that the discussion. So what I would say, the informed discussion at the AdCom demonstrated that you know a robust evaluation of at-risk really showed that from an off-target point of view, the risk management even with the dataset presented to the AdCom was actually very good.
I will say that we are using additional and a multiplicity or orthogonal in silico and in vitro, and indeed some in vivo, that's on the epigenetic 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 will share more detail about that in 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, you know, the experts on the panel, as well as in the sponsor, you know, 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, yeah, I think that was a very good summary, Gilmore. I'm not going to add anything.
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, and but Baisong, I don't know if you want to add to that.
Yeah, yeah.
I'll come back to the third question.
Yes, yeah. Thank you. Thank you again for this question. As Gilmore mentioned, we're very pleased to see the total, the fetal hemoglobin data, as you referred to, actually see patients over 50%. And this is we are excited on that, is 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 BCL11A, we found that we have better fetal hemoglobin expression. But we are in the early stage. We actually to want to see more data to this end, and we're looking forward to see more data ourselves on that.
Thanks very much, Baisong. 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 to Baisong, I'll just remind one thing. While hemolytic hemolysis is a critical part of sickle cell disease, the key driver we feel, we believe, for driving total hemoglobin by design is enhanced erythroid production. Baiso ng, if you want to add to it.
Yeah, that's exactly right, Gilmore. That's what we're going to say. I think what I want to mention that, you know, we are very positive about our hematologic marker data on that. And then the total hemoglobin level is really the two aspects of that. One is hemolysis, one is the erythrocyte process. So I think in our design, we designed to have this molecule have high fetal hemoglobin expression, and then also with the targeting of the HBG1-2 promoter, we have better erythrocyte process and better red blood cell protection, production. So we are looking forward to see more data on that, but we are very pleased with our hemolytic biomarkers.
Great, thanks for the color.
Thanks.
Thank you. Our next question is from the line of Eric Schmidt with Cantor Fitzgerald. Please proceed with your question.
Well, 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, if patients have too much hemoglobin? And if so, what that might be. And then maybe a follow-up for Caren. We saw a couple large pharma gene editing deals this week. Perhaps you could comment on the overall level of interest in potential platform-type collaborations. Thanks.
Thanks very much, Eric. With regard to the total hemoglobin, we believe that correcting, and that's what we've seen, hemoglobin physiological range is of substantial benefit. I think it's. We haven't, you know, we're not going to, 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 with 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 genome 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, you, you know, pharma, I say big pharma, now in a, in a, in a period where we've seen some, somewhat 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, especially through the lens of substantial de-risking of their view, of the value of genome editing as they look to, grow their portfolios. I don't know, if-
Yeah. 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.
Thank you.
Our next question comes from the line of Steve Seedhouse with Raymond James. Please proceed with your question.
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 EHA, and it would comprise or could be summarized in our presentations at the end of the year, because it's actually, you know, 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
commercializing EDIT-301 on our own. Well, we actually look to commercializing EDIT-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-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, 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.
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 we, I can follow up on that.
Thank you.
Thank you.
Our next question is from the line of Luca Issi with RBC. Please proceed with your question.
Well, great. Thanks so much for taking my question. I have two quick ones here. Maybe based on, sounds like you're obviously going to track 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 who also get a broad label that also includes adolescents? So again, any color there, much appreciated. And then the second one, quick, quick one for Linda here. Now, I think you're in 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.
Yeah, thank you for your question. I take your first question, then I pass that. I think we have a plan to dosing adolescent patient, and also for the general clinical programs, we are intending to go to all patients of all ages. So that's kind of work, 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 molecule be a benefit patient from all ages. So that's kind of our intention. I mean, all those things, of course, you know, the label you mentioned, we'll have further discussion and alignment with FDA.
Oh, yeah, thank you for your question. Yeah, that was a very interesting conversation at the AdCom. You know, 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, and this is a method, one of the methods that we use, which is unbiased method, in which the naked DNA is taken from cells and you subject it to cutting with your RNP. And then you do whole genome sequencing, basically, to look for off-target editing, and so this is called Digenome. And so this is one of our methods that we use and look at with our drug product before, before you know, before putting said 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 GUIDE-seq, 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 we're also make us very confident to, 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 Olsen with Oppenheimer. Please just share with your question.
Oh, 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.
Yeah. Yeah. Thanks for that 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 dosed with the EDIT-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 Liisa Bayko with Evercore ISI. Please just share with your questions.
Hi, this is Jingming on for Lisa. Thanks for taking our questions, and congrats on the progress. We have three questions. First, we know that CVC 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, you know, seek alignment on 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.
Hi, this is Erick. Just with respect to any court cases in front of the CVC or anything like that, we'll, we don't really want to comment on those until the final decision is actually rendered, so we'll, we'll just be anxiously awaiting for all that, just like you.
Yeah. So just based on your second question about the middle of next year for the program, and that, you know, two parts of that. One is, as we just shared, that we will have 20 patients dosed by January timeframe next year. Then, by 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. Yeah. Regarding the-
What about for the beta thalassemia?
Yeah, yeah, absolutely. Absolutely, in there. Yeah, so because I saw your question probably cover both, but I just make sure that we cover on that. And the, we actually have very strong momentum for EDIT-301 study also, and then we just shared we actually already have, you know, 8 patients enrolled. And we continue to enroll and dosing patients. But we have not shared what is the goal for next year, how many patients, EDIT-301 patient 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.
We are well engaged with FDA, and we continue having engagement with the FDA, as we just mentioned, that we actually have this RMAT designation, allow us a lot more frequent interaction with the agency, including senior management over there, over the agency. We have not share, have a timeline to share the outcome yet. We'll share that in appropriate time.
Got it. Thank you.
Our next question is from the line of Mani Foroohar with Leerink. Please proceed with your question.
Hi, good morning. This is Lili Nso ngo, online for Manny. 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 EDIT-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 a 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 Erick. 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.
Yeah. So yeah, this is Baisong , for your second part of your question. As we shared, that we will have 20 patient dose by January timeframe of next year, and by middle of next, middle of 2025, then we will have, you know, substantial data packages, probably equivalent to the exa-cel BLA filing, which is accepted by FDA, which have, like, 20 patients in the efficacy data cohort. So they subsequently added additional 10 patient in their addendum with a 4 months additional 4 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.
What exactly the data, FDA data, what exactly the BLA data package will need to align with the FDA? So that we are more, that will have the agreement with the FDA on that, too. You mentioned about post-marketing or the commercialization of these two molecules, and as I shared earlier, that we do not see that recruitment and momentum perspective, and you mentioned about data package, and we actually very excited about the outcome discussion. We feel that these outcomes have further validation of CRISPR technology, further validation of the fetal hemoglobin as a mechanism of action to treat the sickle cell and beta thalassemia. We actually see all those work have a positive impact with EDIT-301.
Thank you. Our final question comes from the line of Terence Flynn with Morgan Stanley. Please proceed with your question.
Great. Thank you for taking our question. This is Max Skor on for Terence Flynn. So, looking to the future a bit, can you expand on your approach to target selection, how you, 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. It's very important that we're delivering medicines that are meeting needs, 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 here to have Caren having joined so that I can partner with her, as well as Baisong, in triangulating this to very much select our targets. I think we're really well positioned now to be selecting these.
We're, 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. Getting to your question about delivery, where our strategy, which Gilmore described in January, is non-viral delivery. So we're prioritizing LNP 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 HBG1-2 promoter with an LNP strategy.
As far as other targets and tissues, of course, LNPs are validated for delivery to liver, 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 continuing interest in forming this space. But we're also interested in other tissues, and so there are many targets out there amenable to ESS technology, and we're excited to move forward, and we'll certainly be sharing information with you as it emerges in the future in 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.