Editas Medicine Inc (EDIT) 2023 Q2 法說會逐字稿

Good morning, and welcome to Editas Medicine second quarter conference call. (Operator Instructions)

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, Maria. Good morning, everyone, and welcome to our second 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 Factors section of our most recent Annual Report on Form 10-K 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 for Editas' second quarter earnings call. I am joined today by 3 other members of the Editas executive team, our Chief Medical Officer, Baisong Mei; our new Chief Financial Officer, Erick Lucera; and our new Chief Scientific Officer, Linda Burkly.

I joined Editas 1 year ago tasked with guiding its evolution from platform development company to a commercial therapeutics company. In January of this year, we shared Editas' strategy and a set of objectives for 2023.

The strategy, just as a reminder, comprises of 3 pillars. First, to accelerate the clinical development of EDIT-301, our autologous ex vivo cell therapy for sickle cell disease and beta-thalassemia, and drive toward approval and launch.

Second, to strengthen our discovery organization by dividing it into an advanced technology group and a translational of therapeutics discovery group, and so, sharpen our discovery focus to in vivo editing therapies.

And third, expand our business development activities to partner complementary technological capabilities that could 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.

Our 2023 objectives are, providing a clinical update from the EDIT-301 RUBY trial by the end of 2023, providing a clinical update from EDIT-301 EDITHAL trial for transfusion-dependent thalassemia by the end of 2023; dosing 20 total patients in our EDIT-301 RUBY trial by year-end; hiring a new chief scientific officer with specific expertise aligned to our vision, which we have just done; advancing discovery of in vivo editing of hematopoietic stem cells and other tissues; and leveraging our robust IP portfolio and business development to drive value and complement our gene editing technology capabilities.

So how we executed against the strategy of these objectives in the second quarter? On the leadership side, we made 2 important hires to drive our new strategy. Just last week, we announced that Linda Burkly, a respected scientist and highly experienced and successful therapeutics discovery leader has joined Editas as our new Chief Scientific Officer.

Linda has an outstanding track record of inventing or contributing to the foundations of multiple approved medicines and late-stage clinical candidates. We're looking forward to Linda's leadership as we build on the current in vivo editing work in hematopoietic stem cells and other tissues.

Also, 8 weeks ago, we announced that Erick Lucera, a highly experienced former biotech buy side investor, Chief Financial Officer, and strategic corporate finance executive had joined Editas as our new Chief Financial Officer. You will hear from him later on this call.

As a reminder, under our new target selection criteria, we will select therapeutic targets that 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. Linda will tell you about these developments at a future date.

We remain on track to dose 20 RUBY patients by the end of 2023. And we commenced parallel dosing of patients in our EDITHAL trial in the second quarter of this year. In June of this year, we presented clinical data from our RUBY trial at the European Hematology Association's Annual Scientific Meeting and data from both, our RUBY and EDITHAL trials at our company-sponsored webinar. We remain on track to provide another clinical trial update by year-end for both trials. We would share a further update on enrollment progress in the coming months.

Baisong will share further details regarding the development of EDIT-301 in his remarks, as well as recapitulate the RUBY and EDITHAL takeaways and the clinical data that we provided in June. And as we have previously stated, we plan to engage with the FDA in the second half of the year.

After EHA and our company-sponsored webinar, we raised approximately $117 million in net proceeds from our follow-on issuance of common stock, extending our cash runway into the third quarter of 2025 as we continue our advancement of EDIT-301 towards BLA, prepare for commercial manufacturing of EDIT-301 and build our pipeline to transform the treatment of serious diseases.

As we progress towards our goal of delivering life-changing medicines to patients, we also continue to expand our footprint to support our manufacturing and quality management for clinical supply and for preparation of commercial launch. We recently increased our clean room capacity and are moving to a new Azzur Devens facility. This new facility and increased capacity will support the scaling of EDIT-301 program, manufacturing clinical supply for our RUBY and EDITHAL trials and prepare us for commercial readiness.

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's and Broad Institute's Cas9 patent estates covering Cas9 use in making human medicines. Only a small fraction of these patents are involved in the ongoing USPTO interference proceedings. We remain confident that our IP portfolio provides meaningful value now and in the future.

We are energized by the promising efficacy and safety data that we shared in June, stating that EDIT-301 may be a clinically differentiated one-time durable medicine that can provide life-changing clinical medicine or benefits to patients with sickle cell disease and beta-thalassemia long-term, specifically driving early and robust correction of anemia and sustained increases in fetal hemoglobin.

With our sharpened strategic focus, our world-class scientists and employees and our keen drive in execution, we continue to build momentum to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases. We look forward to updating on our progress in executing our new strategy throughout the year.

Now, I would turn the call over to Baisong, our Chief Medical Officer.

Thank you, Gilmore. Good morning, everyone. I'll start with the EDIT-301 RUBY trial for severe sickle cell disease. As Gilmore stated in his remarks, we continue to dose and enroll patients in RUBY trial. As we have previously shared, we began parallel dosing of patient in RUBY trial earlier this year. And we remain on track to dose total 20 patients in RUBY trial by year-end and to provide additional clinical data by year-end. We will share a further update on enrollment progress in the coming months.

As Gilmore also mentioned, we plan to engage with FDA in the second half of the year. In the EDITHAL trial of EDIT-301 for transfusion-dependent beta thalassemia or TDT, we continue to dose and enroll patients. We commenced the parallel dosing in this trial in the second quarter. We remain on track to provide an additional clinical update from EDITHAL trial by year-end.

As we have done for the RUBY trial, we're also taking multiple measures to accelerate the development of EDIT-301 for TDT and have a strong positive momentum. We have enrolled multiple patients and have -- who we have dosed or who have been competed a apheresis cycle and have a CD34 cells EDITHAL or in the process of pheresis.

Turning to the EDIT-301 clinical data. In June, we shared a promising RUBY clinical data in an oral presentation at the European Hematology Association Congress or EHA, followed by our company-sponsored webinar, where we also have presented a positive initial data from the first patient treated in EDITHAL trial.

The RUBY data from the EHA covers safety and efficacy data on the first 4 patients treated, including 10 months data from the first patient and a 6 months data from the second patient. The data included total hemoglobin and fetal hemoglobin. Excitingly, the data was consistent with the clinical results we shared in last December.

I'd like to take a few minutes to recap some of the RUBY and EDITHAL key takeaways from our presentations in June. This included the following: The 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 infusion.

EDIT-301 drives robust sustained increase in fetal hemoglobin in excess of 40%. All 4 dosed RUBY sickle cell patient remained free of vaso-occlusive events or VOE since EDIT-301 treatment. All dosed patients, 4 RUBY patients and one EDITHAL patient showed successful neutrophil engraftment within 1 month of dosing and have stopped the red blood cell transfusion.

EDIT-301 was well tolerated by patients and the safety profile was consistent with myeloablative busulfan conditioning and autologous hematopoietic stem cell transplant. And the trajectory of correction of anemia and increased expression of fetal hemoglobin was consistent across EDIT-301 treated sickle cell patients and beta-thalassemia patients at the same follow-up time points.

Looking at the data in more detail. RUBY study patient one total hemoglobin reached normal physiological level by 5 months after EDIT-301 infusion and these normal levels persisted during the 10 months follow-up. Patient one's fetal hemoglobin fraction increased to 45.5%, 5 months after EDIT-301 infusion, consistent during the 10 months follow-up. The increase of total hemoglobin and the fetal hemoglobin of RUBY patients 2, 3 and 4 followed the same trajectory as patient one.

For EDITHAL, the first patient experience with EDIT-301 resembled that of 4 RUBY patients. The first EDITHAL patient achieved a fetal hemoglobin fraction of 34.9% or over 4 grams per deciliter in just 1.5 months after EDIT-301 treatment.

We continue to believe that EDIT-301 can potentially provide robust clinical benefit to patients, potentially provide clinical differentiation in the long term.

As we have previously stated, the choice of CRISPR enzyme and the gene editing target to switch on fetal hemoglobin expression matters. EDIT-301 uses our proprietary AsCas12a enzyme to edit HBG1/2 promoter.

AsCas12a increases editing efficiency and significantly reduce off-target editing when compared to other CRISPR nucleus including Cas9. HBG1/2 editing in human CD34+ cells results in greater red blood cell production, normal proliferative capacity and improved red blood cell health when compared to editing of BCL11A.

Based on clinical data so far, we believe that sustained normal level of total 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 has significantly improved quality of life and ameliorate end organ damage.

As I shared last quarter, we have been visiting our RUBY and EDITHAL trial at clinical trial sites and continuously speaking with investigators. I appreciate the enthusiasm and support when we investigated the study sites. I'm pleased with the momentum of any EDIT-301 in patient recruitment, apheresis, editing and dosing in both studies.

I'm excited to hear from the investigators that the patients dosed with EDIT-301 already see positive changes in their lives. We look forward to sharing additional updates as the year progresses including additional RUBY and EDITHAL clinical trial data by year-end.

Now, I'll turn the call over to Erick, our Chief Financial Officer to review our financials.

Thank you, Baisong, and good morning to everyone. Let me first say that I'm excited to be speaking with you today. I came to Editas because I was impressed by the quality of the company's science, its leadership in the gene editing field, its strong IP portfolio, and its highly differentiated work from other players in the field.

I was eager to take this opportunity and join Editas at this pivotal time. We just shared an exciting human data for our elite asset and we're preparing our regulatory and commercialization strategy. I look forward to leveraging my experience to help the company execute our vision to bring innovative medicines to patients and drive shareholder returns.

With that, I'd like to refer you to our press release issued earlier today for a summary of our financial results for the second quarter of 2023. In future quarters, I will give more guidance and for now, I'll take this opportunity to briefly review a few items.

Our cash, cash equivalents and marketable securities as of June 30, were $480 million compared to $402 million as of March 31, 2023. We're expecting -- we expect our existing cash, cash equivalents and marketable securities to fund our operating expenses and capital expenditures into the third quarter of 2025.

Revenue for the second quarter of 2023 was $2.9 million compared to $6.4 million in the same period last year. The decrease is related to a program licensed opt-in from our collaborator Bristol-Myers Squibb that occurred in the second quarter of 2022 that did not occur in the second quarter of 2023.

G&A expenses for the quarter were $17.2 million, which remained slight -- which remained relatively flat from $16.9 million for the second quarter of 2022. The slight increase in expenses is primarily attributable to increased professional services expenses to support PD activities partially offset by a decrease in stock compensation expense.

Research and development expenses this quarter were $29.8 million, representing a decrease from $43.7 million from the second quarter of 2022. The decrease in expenses reflects the focus on execution following the strategic reprioritization of our portfolio, offset by increased activities to accelerate the development of EDIT-301.

Overall, Editas remains in a strong financial position and our sharpened discovery focus coupled with our recent capital raise allow us to concentrate our talent and extend our cash runway further into 2025 which provides ample resources to support our continued progress in the RUBY and EDITHAL, clinical trials of EDIT-301, continue commercial manufacturing preparation and advance our discovery efforts.

As a former investor, I know the value of buy side and sell side knowledge and I look forward to working with the company and hearing from our shareholders as we work to advance our gene-editing medicines.

With that, I will hand the call back to Gilmore.

Thank you, Erick. It has been an exciting year for Editas thus far and a fulfilling first full year for me at Editas. We look forward to continuing our transformation and sharing our progress with you.

As we -- as a reminder, our strategic objectives for the year include providing a clinical update from the EDIT-301 RUBY study by end of this year, providing a clinical data update from EDIT-301 EDITHAL trial for transfusion-dependent thalassemia by the end of 2023, dosing 20 total patients in our EDIT-301 RUBY study by year-end, advancing discovery of in vivo editing of hematopoietic stem cells, other tissues, and leveraging our robust IP portfolio and business development to drive value and to complement our gene editing technology capabilities.

As always, it must be said that we could not achieve our objectives without the support of our patients, investigators, employees and you.

Thanks very much for your interest in Editas and we're happy to answer questions now. Thank you.

(Operator Instructions) The first question comes from Terence Flynn with Morgan Stanley.

Two from me. I was just wondering if you could provide any update on the timelines for your first in vivo program.

And then secondly on the Azzur facility, what's going to be required there from an FDA perspective and do you have to make any changes or do any bridging work to use product from the 2 facilities in the expanded trials?

Thanks very much, Terence, for your questions. Apropos as in vivo, as I've said, our focus is on maximizing the probability of technical and commercial success with clear positive differentiation against the standard of care. The work is continuing to progress and I'm particularly delighted to welcome Linda Burkly here whose leadership is really going to double down and really help us drive this forward. And we'll update you on timelines at an appropriate time when Linda has -- had a chance to really settle in and make her mark.

With regard to the Azzur facility, we anticipate, from a regulatory point of view, obviously, we are engaging or planning to engage with the FDA in this half of the year and are on track to have those conversations and we don't anticipate significant or major work in the transition. Essentially, the processes we have are largely locked down. And as I say, we are engaging with the agencies just to ensure that we are fully aligned on our readiness for commercialization there.

Our next question comes from Samantha Semenkow with Citi.

Now that you have Linda on the team, could you discuss some of the challenges of in vivo delivery to hematopoietic stem cells and how you're thinking about mitigating these challenges going forward?

Thanks very much, Samantha, for your question. I've got to say, Linda has -- let's say has just joined. So I'm going to talk about how she and I -- and Linda, if you want to add anything, please feel free. One of the things is that Linda and I are really highly aligned philosophically on our approach to this. We have made -- we actually have some ongoing work and work is progressing out there. The challenges, obviously, are to deliver the executive functional enzyme and guides to the hematopoietic stem cells.

The good news is that we feel that we have certainly solved 2 of the 3 challenges. The first being that we have human validation of our Cas12a enzyme, thanks to our 301 program, and also we have validated in man in our clinical trials the use of or targeting of the gamma-globin promoter to specific targeting and delivering of those mechanisms to the hematopoietic stem cell. It's something that we're working on currently and we'll be happy to update you more on specifics and progress there at an appropriate time.

Our next question comes from Greg Harrison with Bank of America.

What feedback have you had from physician since the recent update of EDITHAL and 301 program regarding a clinically meaningful data set in sickle cell, especially with respect to hemoglobin response. And what are they looking for from the next update?

Thanks very much, Greg. I'm going to ask Baisong to take that question.

Thanks, Greg. Great question. Absolutely. We received very positive feedback from our investigators as well as patient community. From investigators, they're really to see -- glad to see the consistency of our results and the normalization of the total hemoglobin. And I actually asked a specific important question to one of our investigators. How do you feel is the normalization of total hemoglobin and what's the value he would say. That's absolutely very important and his own patient already told him about the energy that the patient has and the difference they have, and their life change in there too. So that's both from clinical observation and patient likewise perspective.

And related to the data from patient community perspective, after the June presentation, our volume of patient inquiries increased 10x over that period of time after the presentation. So we're very pleased on that too. And we continue to receive inquiries not only in U.S. but also in Canada, and we are helping them to moving through and understand the trial and find eligibility whether they can join us or not. So very, very good.

It's great to hear the progress.

Thank you, Greg.

Our next question comes from Joon Lee with Truist Securities.

Congrats on the progress. Your cash guidance into the third quarter of '25 is pretty specific. What's baked into that guidance? Specifically, does that include preclinical and IND-enabling studies of in vivo programs and/or BLA and pre-commercial activities for EDIT-301?

In fact, is it your intention to commercialize EDIT-301 yourself or would you be looking to a partner to help you with the heavy lifting on the commercial offer?

So I think, Joon, I'll let Erick start.

Yes. With respect to the specific dollars that are included into the cash runway guidance, we are including all of the BLA activities and everything we need to do to prepare for that within the guidance. With respect to IND-enabling studies, we do have some early preclinical research amounts in that, and we'll see what Linda comes up with in the future as to whether or not we'll reallocate some dollars from other programs or not. But that's where we are at this point with respect to guidance and in terms of commercialization of the partner.

Yes, Joon, we actually see commercialization as a nice upside, particularly for making sure we expand our global footprint. And we previously stated that we certainly want to partner ex-U.S. Obviously, as we talk to partners or potential partners, if the terms really line up with where we are to ensure that we can maximize value for patients and shareholders, we could consider co-commercialization in addition to global co-development and commercialization in the United States.

Our next question comes from Gena Wang with Barclays.

Two very quick questions. Regarding the in vivo target, is it fair to say it will be liver targeted and with lipid nanoparticle delivery?

And then regarding the manufacturing, just to follow up. So you do have a Azzur facility and what is your plan for commercial manufacturing capacity in the future? Will you wholly, say in the U.S., try to do a wholly in-house or would you plan to also collaborate with the CDMO regarding the manufacturing commercial supply?

Thanks very much, Gena. Gena, with regard to the in vivo targets, obviously, we've talked about hematopoietic stem cells as an area of particular interest because of our 301 work on human validation or AsCas12a and gamma-globin promoter. The liver is definitely on our list of potential tissues beyond hematopoietic stem cells.

And I think you can reasonably infer with the cessation of our activities of AAV that we're interested in non-AAV technologies and LNPs is certainly an area of interest and one that we have been working on in the past and actually we talked about working on over the past year plus.

With regard to manufacturing, thanks for asking about that. We actually -- with the announcement of our Azzur deal, this is -- essentially enables us to build towards our commercial capacity and readiness for launch. With regard to the more specific elements of around capacity and our prediction, that's something that we are working through and would talk about in the future.

Our next question comes from Dae Gon Ha with Stifel.

Two from me as well. One, with regards to, Baisong, your remark on total hemoglobin as being a differentiation. I guess at what point do you kind of draw the line in the sand and look at that as a differentiator from potential competitors?

And then as a follow-up to that, Vertex last night announced that there will be an AdCom for exa-cel. I guess what are you kind of thinking about in terms of point of contention or debate or discussion as we approach that? And how would you see the AsCas12a targeting HBG promoter as potentially raising another AdCom when you guys go down that line?

Thanks for the question. Regarding the total hemoglobin and related differentiation, we are -- in the current protocol, we're already actively looking to that. And as I outlined previously, we are looking for 3 category of things. One, it comes from hematological and other lab values. The other one -- the second is the -- end organ function; and the third would be patient report outcome and quality of life.

And maybe a few words on the last 2. We -- in the current protocol, we monitor our key organ functions such as cardiovascular, pulmonary and in renal function, we have multiple measures to measure the function. So we believe that the total hemoglobin increase would impact the quality of life and end organ health. So that's why we focus on the end organ function.

And then regarding reported -- patient-reported outcomes, that could be a very important part of that for differentiation. For example, fatigue is the main -- one of the main complaints by sickle cell patients. And that -- and there's already data to show that fatigue can really relate to the anemia on that too. And similarly, for pain, there's also another complaint that patients have, and we also have a closer monitoring of those patient reported outcome and maybe other things, we can share more on.

Yes. Go ahead.

Do you want to add for the differentiation?

No, no. Please. I think that's fine.

Then your second question is about AdCom. And yes, we heard the news about the AdCom, which, of course, this is a novel area that FDA AdCom, which is not a surprise. And we feel that it will help us to learn more about how their data look like and how the expert committee -- its view about or additionally how the FDA feels about it.

And then related to our own mechanism of action, we do not believe the target or AsCas12a cause additional concern from a mechanism of action perspective. As I mentioned before, we're actually -- our targeting of HBG1/2 promoter is mimicking the natural mechanism of the precision fetal hemoglobin -- really the precision of fetal hemoglobin on that. So that's kind of the nature of mutation we are targeting too. And so -- but we're looking forward to see the outcome and the information from the AdCom from the exa-cel.

Our next question comes from Philip Nadeau with Cowen & Company.

Two from us as well. First, in terms of the year-end update on RUBY and EDITHAL, what is your most recent thinking about the number of patients that will be disclosed for both trials and the follow-up for the patients in the disclosures?

Yes. Thanks for the question. Sorry to jump in. Yes, we are on track with those total of 20 patients by year-end. We are not disclosing the specific data to be released at the year-end, but we are on track to provide a clinical update for 4 studies at the year-end.

Great. And then the second question on the interference proceedings that you referenced in the prepared remarks. Can you remind us what are the next steps in those proceedings and when they could conclude?

Yes. Thanks, Phil. The oral -- really, the scheduling of oral presentations is the next step. Those oral presentations have yet to be scheduled. And then what we'd anticipate is a judgment in early to mid-2024. It's worth stating that we are confident that we will prevail as we have before, both in front of the Federal Circuit Appeals Court as well as with the USPTO.

Our next question comes from Yanan Zhu with Wells Fargo.

I wanted to ask about your FDA interaction in the second half of the year. What will be the focus there? Do you think you have enough data to inquire about pivotal path? Do you think the kind of treatment afforded to the competitor in terms of 17 patients forming the basis for a pivotal cohort and the length of follow-up could be similarly afforded to your -- to EDIT-301 as well?

And also, lastly, do you think you have enough differentiation on the total hemoglobin to request a breakthrough designation?

Thanks very much, Yanan, for that detailed question. I'll start. With regard to the FDA interactions that we are planning for this year or this half of the year, we will be talking about multiple elements, including our CMC, as I've said, as well as having a clinical interaction.

With regard to the clinical data, I'm glad that you highlighted where we see Vertex's BLA and the acceptance of an efficacy cohort of 17 patients with about 18 months of follow-up data, which I think is a helpful precedent and certainly an element of guidance that we can actually use.

And then as Baisong has said, the AdCom that will be scheduled towards the end of this year by the FDA, I think, will actually also be very illuminating as we continue in our continuous process of aligning with the agency and understanding how we can come to agreement on what will be ultimately our pivotal path in BLA filing strategy. With regard to differentiation, Baisong, I don't know if you want to add anything.

Yes. Thanks. Yanan, I think your question about differentiation is related to the eligibility for breakthrough designation. We are carefully looking into the regulatory designations and multiple different things in there. And certainly, we are excited by the data we have seen so far, and we'll evaluate the data very carefully and on this path.

And related to your earlier question about 17 patients from the exa-cel, as Gilmore mentioned that, we will know more, especially after the outcome. But it's a good reference for us, and that we still require the final alignment with FDA and what data package is required.

And I think the good thing that I should have, of course, highlighted was that we are on track to dose 20 patients by the end of this year. And so that number is a helpful number for lining up with what we see with the BLA acceptance for exa-cel. Thank you.

Our next question comes from Rick Bienkowski with Cantor Fitzgerald.

Welcome to Linda and Erick. So I wanted to get some clarification on manufacturing. The expanded agreement with the Azzur group seems to be focused on clinical and commercial readiness for U.S. markets given that the footprint is based in Massachusetts. But does the company have any manufacturing capabilities in European markets or would any European-based manufacturing have to come from another potential partner?

Thanks very much, Rick. You're quite right in reminding everyone that we have this exciting new agreement with Azzur as we get ready for BLA and commercial launch. With regard to ex-U.S., I think we'd be consistent in our messaging that we actually would prefer and actually expect a partner to help us with the ex-U.S. from the point of view of expanding our footprint. And obviously, when we talk about that, we talk about in terms of co-development, co-commercialization and all the activities necessary for that.

And I do have one quick follow-up.

Sure.

So one of the areas of development that was highlighted back in January of this year was exploring the use of milder conditioning regimens for stem cell transplant. So my question is, once a milder conditioning regimen is developed, I was curious how this could potentially be folded into clinical trials and what the approval pathway looks like here for use with EDIT-301.

Thanks very much, Rick, for that and reminding us that importance, because, obviously, by creating or by the development of milder conditioning, we see a path to increasing eligibility for sickle cell disease and TD patients, which are very serious diseases. But again, back to milder conditioning, you can extend or expand the milder -- or sorry, the eligible population. We continue to evaluate that, and it's a question really of balancing the reduction of toxicities with engraftment efficacy.

In general terms, we see milder conditioning as something that the transplant sites will use. And as they grow comfortable with it, they will expand it across their used protocols. And that's how we actually would see it enabling autologous ex vivo therapeutics.

Our next question comes from Rich Law with Credit Suisse.

My congrats to both Erick and Linda for joining the company. So the question I have is like can you provide insights to how the partner programs are progressing? So the 11 alpha-beta T cell programs for BMS and the NK cell with Shoreline Biosciences. And when do you expect the program to be disclosed in more details? And then I have a second follow-up question as well.

Sure. Thanks very much, Rich. With regard to the BMS alpha-beta T cells, we're actually happy with the progress. There have been 11 opt-ins, most recently 5 in 2022. 2 of those opt-ins have passed DC and the most advances in IND-enabling studies. Beyond that, it is BMS that is obviously in the driving seat and would actually provide more specifics on the program.

And with regard to Shoreline, we're really delighted to have the opportunity to divest our NK oncology programs to Shoreline. Shoreline is actually happy with where they're going. And I think really any more specific updates would come from Shoreline.

Great. And then the second question I have is following up on the milder conditioning. Would that enable the use of therapy in outpatient setting versus inpatient setting?

So that is actually, I think, at the very key of the milder conditioning because it's -- significantly it's really a combination of reducing the risk to patients, while obviously enabling and still maintaining an optimal transplant engraftment outcome. But yes, that is one key element. And certainly, either we should do it as an outpatient or substantially reduce the need for inpatient monitoring of the patients. And we continue our evaluation of that, because we see it as an important element for expanding the eligible patient population.

Our next question comes from Jack Allen with Baird.

Congratulations to the team on the progress. Maybe first to start on the clinical side, it seems like you made a lot of progress dosing patients with sickle cell disease that are adults. But I was wondering if you had any comments as it relates to your plans to move into younger patients? I know some of your competitors have moved into patients that are 12 to 18 years old. I'd love to hear any thoughts there and then I have one quick follow-up.

Thanks, Jack. I'm going to ask Baisong to take that question.

Yes. Jack, thanks for the question. Absolutely, we are intended to expand this study to all age groups. So we are actively working on that. And with more adult data, we are much more comfortable to go beyond the patient population.

Great. And then maybe on the IP front, you mentioned that the hearings have not been scheduled in this interference case quite yet. But I'd love to hear any thoughts you have as it relates to leveraging our IP and as some of your competitors advance there to potential approval. I guess should we think about essentially a settlement coming before approval or could it come after or I guess, how do you think about conversations surrounding that IP and how you're looking to leverage your strong position there?

I think our key position on our IP is that we really want to ensure that it is used to enable therapeutics for multiple patients with multiple, frankly, in multiple therapeutic areas and indeed, there's a large number of Cas9 products that are in development across both ex vivo and in vivo and across multiple disease areas. As we think about leveraging that from an economic or monetization point of view, we see that, that will vary depending on the stage of development in the disease area. And beyond that, we're not going to discuss individual companies or negotiations.

Got it. One brief follow-up on IP. Can you just remind us as to who has the duty to litigate IP? Is it you or your licensor from that perspective?

So I think we're -- I'm not going to talk about the details of our legal strategy. But the key thing about protection of our IP is that that we will actually protect our IP. Obviously, we want to ensure and we are open for business and very willing to give licenses, but we will protect our IP.

Congratulations on the progress.

Thank you so much.

Our next question comes from Jay Olson with Oppenheimer.

Congrats on the new additions to your team. Can you provide an update on the number of patients enrolled in the sickle cell and thalassemia trials to-date and since you're on track to dose 20 patients in the sickle cell by year-end, do you have a similar dosing goal for thalassemia and if so, how many?

And then separately, can you talk about the ex-U.S. opportunity for sickle cell and thalassemia?

So I'll ask Baisong to address your first question on enrollment.

Thanks, Jay. So we are -- have great momentum, have been rolling patients dosing patients, as I just mentioned. We're on track to dose 20 patients at year-end. And we previously announced, we actually have 20 patients already enrolled in the last quarter we released. So we will provide an update on the enrollment in the coming months and so that -- so we can share more information on that end. And regarding the goal of the number of patient doses for EDITHAL, we have not disclosed the goal for the EDITHAL dosing numbers yet.

And then with regard to the ex-U.S. opportunity, we see actually a substantial and a real opportunity there. And we also see that and believe that the best way to maximize the value for patients and frankly, for us and our shareholders is to seek a partner with a large footprint. And there are a number of partners in that space that are potentially very interesting to us. But as I say, the opportunity is large, and we want to make sure that we optimize the delivery to that opportunity, which is why we're seeking a large partner.

Our next question comes from Mani Foroohar with Leerink Partners.

Obviously, a lot of questions on this call have been around for clinical trial execution, enrollment, et cetera. I want to dig into endpoints if we could. You've discussed earlier on this call, pain and other sort of fatigue, some quality of life issues as an important area of potential differentiation. As clinical trial endpoints, these are pretty notoriously variable and it has some element of subjectivity. What efforts have you made, if any, to ensure comparability between your data on these endpoints and that of your competitors who are likely to have an AdCom approval prior so that we can clearly differentiate -- sorry, clearly demonstrate differentiation, if any.

I'm going to ask Baisong to address that.

Yes. Thanks for the question, Mani. Very good question about endpoints. Maybe I should take a step back a little bit on that. So after I joined Editas in the middle of last year and one thing what we were doing was actually to manage the protocol. We actually changed the primary endpoint as the complete remission of the severe VOE that is consistent with other Phase III clinical trial in a similar setting. So that's kind of the primary endpoint perspective.

Then as I mentioned, there are many endpoints we are looking to, including the end organ functions and the PROs in that too. You have absolutely a very good point about possible variations and especially the PROs in there too. So we're looking into that direction that will be -- we have more data on that and method understanding. But we feel that this is an area that we have publications in the disease by itself. We will have more information about the exa-cel and other data and it will allow us to have an understanding of where we stand for those endpoints.

Great. I guess one quick follow-up. You talked a little bit about how to understand where you guys are on those endpoints. Do you have any emerging components to in the literature or based on experience in PEGASUS data from other companies or your own around what duration of follow-up we would need to be able to compare across trial statistical caveats notwithstanding and kind of provide clear evidence of where you guys are versus where your competitors are? Like how long of a follow-up would we need to clearly differentiate on pain, on fatigue, on quality of life?

Yes, yes. Very good question. That's something we are looking into that too. First of all, we say there are some information already published, for example, in the allogeneic transplant perspective for sickle cell disease. There are publications in multiple different ends on that to see how patients improved after the hematopoietic stem cell transplant for those patients.

And then in terms of specific endpoints, some will take longer and other will take a shorter time. For example, we already see the total hemoglobin increase in a very short time period. So that's kind of probably taking a shorter timewise. And so far, for some quality of life, it may take 6 months or 12 months to go and for the end organ damage, and that's actually a space that we'll continue to learn, there are actually publications, for example, to say from central nervous system and after the allogeneic transplant that see the improvement in hydrodynamic improvement in the blood vessel, in the brain. So there's a lot of studies in this space. But again, we are still in a new territory, we are looking into that. But we are confident that we will see something over the period of time and to see some differentiation.

I think it's also worth reemphasizing, of course, that the biochemical and physiologic differences that we're already describing are certainly generating significant excitement with prescribing and treating physicians and actually also within the patient community as based on and alluded to in the feedback and the follow-up that we've had since presenting very exciting data around the correction of anemia in addition to robust and durable fetal hemoglobin expression at the EHA meeting and in our webinar in June.

Our next question comes from Luca Issi with RBC.

Congrats on all on the progress. Maybe one more of manufacturing. Since you're moving your manufacturing process to a new facility, is it fair to assume that the FDA will ask you to run a clinical bridging study similar to what we've seen from REGENX or do you think that just a analytical comparability study will be sufficient? So again, any color there will be much appreciated.

And then maybe on R&D, pretty material decline in the R&D spend this quarter versus prior quarters. So I wonder if you can provide any additional color on what drove that and how should we think about modeling that line going forward? And then finally, one last one on PD. Any update on partnering with LCA10?

Yes. Thanks very much, Luca. With regard to manufacturing, I think a couple of key points. One is that we are manufacturing within the Azzur space. We're already running our clinical supply in a separate Azzur space. With regard to the details and specifics of what will be required, this is a -- would be part of our alignment and meetings with the FDA, as we have outlined. With regard to R&D spend, I will start and then I'll ask Erick if he wants to actually add any additional color to the spend.

The key thing about the R&D spend, obviously, was that following the rollout of our new strategy where we sharpened our focus on in vivo and are really focused on accelerating our 301 asset, we did actually sharpen and narrow our pipeline. And so that had an impact on spend with the divestiture of our NK assets to Shoreline as well as the cessation of our AAV inherited retinal dystrophy programs. Erick, I don't know if you want to add anything more to that.

No. I think you covered that pretty well. I would just add from a philosophical basis that I think we're all aligned that we want to be focused on high conviction, R&D spend, high conviction assets. We're not really into, "broad R&D pipeline" and "lots of shots on goal". We really want to focus our resources on a few assets that we have high conviction on. And I think that's the philosophy that the team here shares across the board.

And I think that's an important piece of guidance and actually a key reason that Linda has joined us. It's not just about continuing that to advance the work that we have in progress are in vivo, but Linda is very aligned philosophically with myself and the leadership team when it comes to our approach to selecting targets and maximizing the probability of technical and commercial success by clearly selecting targets where we can with our technology differentiate from the standard of care in a meaningful manner.

With regard to the update on LCA10, I will give you a more specific update when -- if we have a taker or a deal. I will tell you there has been some interest. And obviously, we are -- we believe that we saw something, a signal in the patient data set that we analyzed and we hope that another firm or sponsor with a specialty interest in that disorder would actually take it forward.

Our next question comes from Liisa Bayko with Evercore ISI.

I just had -- I wanted to drill down a little bit more on the gentler conditioning regimen program. So like what are you working on in terms of approaching that? What do you think are the most I guess, promising approaches out there? What is your thinking on when something like that could come to market? And I guess, as someone else developed something like that, is that something you think you could fold into your program or how do you think about sort of owning something like that versus someone else within your access to it?

Thank you very much for the question. Well, first, I just want to say that I'm super excited to have joined Editas. I'm so impressed with the foundational technology as well as really the truly excellent of this team.

Coming to your question, of course, the milder conditioning is such a crucial parameter for many therapeutic indications, oncology, so many therapeutic indications as well as, of course, the sickle cell disease. And so it's been sought after to have milder conditioning regimens for many years. And we are, of course, monitoring the landscape and keeping very active eye in all of the various approaches that are out there as well as I've only been here for 7 days, so I'm gearing up to speed on what the team is doing internally. I can boot this over to Gilmore for additional comments. But of course, we are going to be very active in terms of this aspect.

Thanks very much, Linda. And with regard to how we would fold it in, I think your -- I think you've actually touched on it, which is that milder conditioning, as Linda said, is generalizable across multiple elements or I should say, therapeutic areas when it comes to the use of stem cell transplantation. And so we see any advances certainly in systemic therapeutics that impact and can result in milder conditioning, having an impact across expanding the eligibility or the eligible patient population. And obviously, that would have an impact on our therapeutic use.

Obviously, looking beyond milder conditioning, the in vivo target of hematopoietic stem cells is an additional step, which could eliminate the need for any conditioning as well as actually further reduce the burden on patients and health care systems by eliminating the need for harvesting, freezing and collecting CD34+ stem cells.

And the way we would see it rolling in is we would see the development of the milder conditioning therapeutic by whatever is sponsored and adopted at transplant centers in their transplant protocols and then generalizing across multiple therapeutic spaces that use stem cell transplantation.

Our next question comes from Brian Cheng with JPMorgan.

Just one quick one from me on manufacturing. On the Azzur facility, do you have any insights on when this facility could come online? How does that timing potentially fit into the pivotal portion of the ongoing studies? And as you will discuss with the FDA on CMC in the second half this year, are there any specific important items that you need to get aligned with the agency?

Thanks very much, Brian. With regard to online, the timing of this deal and this expansion is really tied to our BLA readiness planning. And so we are happy with the progress with Azzur and the readiness to be online at the time that's appropriate to support our BLA. With regard to FDA alignment, I'm not going to go into the specifics here. But essentially, we just want to confirm and agree with our understanding around the guidance and their interpretation of the guidance and our program as it pertains to a cell therapeutic.

Our next question is from Steven Seedhouse with Raymond James.

This is [Nick] on for Steve. We were wondering if and how you're measuring off-target edits or translocations for EDIT-301 and RUBY or EDITHAL and whether or not you plan to share those data.

Thanks very much, [Nick], for the question. Indeed, we actually have a comprehensive set of assays for looking at off-target edits. We're actually very happy with the data we have seen. Interestingly, we actually saw following our proposed set of assays controls to the agency that many of those remarks were reflected in the guidance that was published after our submissions. But we're actually very happy we're seeing off-target edits.

We believe that it really supports and validates our approach to choose an AsCas12a CRISPR enzyme, which, as you know, is differentiated both for its efficiency as well as its specificity and very low indeed, undetectable off-target editing. So all is actually moving consistently with the selection of that enzyme and its prioritization in our portfolio.

Ladies and gentlemen, we have reached the end of our question-and-answer session, which concludes today's call. Thank you once again for your participation. You may now disconnect.