Editas Medicine - Q2 2024

Transcript

Operator (participant)

Good morning, and welcome to the Editas Medicine Second Quarter 2024 conference call. All participants are now in a listen-only mode. There will be a question-and-answer session at the end of this call. Please note, this call is being recorded at the company's request. I would like to turn the call over to Cristi Barnett, Corporate Communications and Investor Relations at Editas Medicine.

Cristi Barnett (SVP of Corporate Communications and Investor Relations)

Thank you, Brittany. Good morning, everyone, and welcome to our second quarter 2024 conference call. Earlier this morning, we issued a press release providing our financial results and recent corporate updates. A replay of today's call will be available in the Investors section of our website approximately 2 hours after its completion. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of the Safe Harbor Provisions under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC, as updated by our subsequent filings. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. Now, I will turn the call over to our CEO, Gilmore O’Neill.

Gilmore O’Neill (President and CEO)

Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas' Second Quarter 2024 Earnings Call. With me today are four other members of the Editas executive team: Our Chief Medical Officer, Baisong Mei, our Chief Financial Officer, Erick Lucera, our Chief Scientific Officer, Linda Burkly, and our Chief Commercial and Strategy Officer, Caren Deardorf. Because it is summertime, we're going to keep today's prepared remarks brief and leave more time to take your questions. Let me start by saying that we are pleased with Editas' momentum and progress in the second quarter of 2024 as we pursue Editas' goal to deliver life-changing medicines to patients with previously untreatable or undertreated genetic diseases, and to position Editas as a leader in in vivo programmable gene editing. Three pillars underpin our strategy.

The first of those pillars is to drive reni-cel, a gene-edited cell therapy for hemoglobinopathies, formerly known as EDIT-301, toward BLA and commercialization. The second, to build a differentiated in vivo editing pipeline, and the third, to increase business development activities with a particular focus on monetizing our very strong IP. At the start of 2024, we announced the following 2024 objective: For reni-cel, we would provide a clinical update from the RUBY trial for severe Sickle Cell Disease and the EdiTHAL trial for Transfusion-Dependent Beta Thalassemia in mid-2024 and by year-end 2024. We would complete adult cohort enrollment and initiate the adolescent cohort in RUBY and continue enrollment in EdiTHAL.

For our in vivo pipeline, we would establish in vivo preclinical proof of concept for an undisclosed indication, and for BD, we would leverage our robust IP portfolio and business development to drive value and complement core gene editing technology capabilities. So how have we executed against this strategy and these objectives in the second quarter? Let's start with reni-cel. First, we shared RUBY and EdiTHAL clinical data in June at EHA 2024, the European Hematology Association's annual congress. The RUBY data set included 18 sickle cell patients with 2.4 months-22.8 months of follow-up, and the EdiTHAL data set included clinical data from seven beta thalassemia patients with 4.1-12.8 months of follow-up. These data from the RUBY trial support our continued belief that reni-cel will be a best-in-class product for sickle cell disease.

So why do we think this? All patients treated in the RUBY trial are free from vaso-occlusive events post-reni-cel infusion. All patients have robust correction of anemia, with a mean total hemoglobin level within the normal range for both genders at greater than 14 grams per deciliter. All patients have high fetal hemoglobin, with levels well above 40% from 6 months onwards. We also demonstrate fast engraftment with low variability, with a mean neutrophil engraftment of 23 days, which may translate to shortened hospital stays for patients. For cell collection, we have a mean of 2 apheresis cycles, with a range of 1 apheresis cycle-4 apheresis cycles per patient. Finally, in addition to the clinical data shared at EHA on the manufacturing front for reni-cel, we have a robust manufacturing process with a low failure rate that continues to improve with experience.

This low rate of manufacturing failure can decrease patient burden and reduce overall costs as we avoid cell recollection and redundant cost of goods sold, or COGS. We're on track to share additional clinical data for both the RUBY and EdiTHAL trials by the end of this year, 2024. Second, RUBY enrollment and dosing continues to be strong. Indeed, we have now completed enrollment of the adolescent cohort. As a reminder, we completed the adult cohort enrollment in the first quarter of this year. We are manufacturing drug product and scheduling adolescent and adult dosing concurrently. We also continue to progress EdiTHAL and are pleased to announce completion of the adult cohort enrollment and continue to dose patients.

Finally, based on our continued and collaborative conversations with the FDA, we still expect our future BLA package to be similar in number of patients and duration of follow-up to what we've seen in the gene editing medicine field. Before I turn to in vivo, I'd also like to state that we are very focused on the best use of capital as we develop reni-cel and map to the future. As part of that focus, we frequently evaluate opportunities, including the potential for partnering reni-cel, to most efficiently drive reni-cel towards commercialization, ultimately deliver it to patients in need. Now let's turn to our in vivo pipeline, where we continue to strengthen our in vivo discovery capabilities and drive lead discovery work on in vivo therapeutic targets in hematopoietic stem cells and other tissues.

Importantly, we remain on track to establish in vivo preclinical proof of concept for an undisclosed indication by the end of the year. We want to take a moment, rather, I want to take a moment to reiterate our in vivo strategy to develop a pipeline of gene editing medicines for patients with serious genetic disease. As a reminder, our internal development efforts are differentiated from established modalities, and we are not pursuing the same gene editing approach as others. First, our strategy is to use our indel technology for functional upregulation of gene expression to address loss of function or deleterious mutations. Let me be clear: Our strategy is not the knockdown strategy that others in gene editing are pursuing.

And it is worth highlighting that we have already demonstrated that our indel technology can drive functional gene upregulation, thus creating differentiated experimental medicines, as in our ex vivo development of reni-cel. With reni-cel, we leverage our indel CRISPR technology to upregulate the expression of the gamma globin gene, a functional homologue of the beta globin gene, through direct editing of the HBG1/2 promoter site. We are now applying the same approach to in vivo therapeutics by using our indel technology to functionally upregulate the wild type alleles or functional homologue of target disease genes as we build our differentiated pipeline. Why does the difference between our functional upregulation strategy and the knockdown strategy used by other companies matter? Because with our in vivo strategy, we are not competing with existing modalities or technologies in development that are based on knockdown strategies.

Second, our indication selection strategy targets rare and orphan diseases that we believe will allow us to be the first or best in class for a given indication. We expect to move into diseases with larger patient populations in the future. Our lead discovery work is in in vivo therapeutic targets in hematopoietic stem cells and other tissues. Third, Editas is well positioned to achieve success with our in vivo strategy and pipeline with our established capabilities in the four main components of in vivo gene editing medicines. One, our guide RNA modifications that enable high-potency gene editing in multiple cell types, including in the liver, and improved gene editing outcomes in vivo. Two, a superior editing enzyme in AsCas12a. Three, our messenger RNA.

Four, delivery technology, where we are currently evaluating lipid nanoparticles for delivery of gene editing cargo into multiple tissue types with multiple companies, as well as evaluating additional next-generation delivery technology. I look forward to sharing more details about our in vivo pipeline later this year and our in vivo proof of concept. Finally, 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 2024. I take this opportunity to briefly review a few items for the quarter. Our cash, cash equivalents, and marketable securities as of June 30 were $318 million, compared to $377 million as of March 31, 2024. As you will note, our burn rate was slightly higher this quarter than the past.

This higher rate is due to increased external research and development expenses, primarily related to clinical and manufacturing costs related to the accelerated progression of our reni-cel program. We expect our existing cash, cash equivalents, and marketable securities, together with the near-term annual license fees and the contingent upfront payment, payment under our license agreement with Vertex, to fund our operating expenses and capital expenditures into 2026. Before we turn to Q&A, as always, it must be said that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, corporate partners, and you. We are energized by and proud of our progress and execution this quarter.

With our sharp and strategic focus, our world-class scientists and employees, our keen drive and execution, and strong balance sheet, we continue to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases, and evolve from a development stage technology platform company into a commercial stage gene editing company. Thank you very much for your interest in Editas. We are happy to answer questions now. Thank you.

Operator (participant)

At this time, if you would like to ask a question, please press star and one on your telephone keypad. You may remove yourself from the queue at any time by pressing star two. Once again, that is star and one if you would like to ask a question, and we will take our first question from Jack Allen with Baird. Your line is open.

Jack Allen (Senior Research Analyst)

Great. Thank you so much for taking the questions, and congratulations on all the progress made throughout the quarter. I apologize for any background noise here. I'm traveling today. But I wanted to ask about the preclinical proof of concept from the in vivo program that's expected later this year. I was hoping you could just elaborate a little bit more as it relates to what kind of data you look to put out, will it be in a large animal model or a small animal model? And how should we think about the types of experiments you're looking to do to elucidate the off-target editing profile for this program?

Cristi Barnett (SVP of Corporate Communications and Investor Relations)

So, Jack, I think you broke up near the end, but let me just restate the question in the way I heard it, and then hopefully, you know, if you need to correct this, let us know. So essentially, you just want to have an understanding of the data that we will have for our in vivo POC, the size or the species, that we will use in vivo. And I think you want to talk about, I think I may have heard you talk about indications. I'm not sure.

Linda C. Burkly (EVP and Chief Scientific Officer)

Yeah.

Gilmore O’Neill (President and CEO)

So I'm gonna ask Linda maybe to address your question.

Linda C. Burkly (EVP and Chief Scientific Officer)

Yeah, thank you, Jack. You did break up a little bit, so thanks, Gilmore, for elaborating there. So yes, we are on track to establish preclinical POC in vivo for this undisclosed indication by end of year. We've not yet disclosed the species in which we're working, but our evaluation process is going to entail evaluating the biodistribution to the site of interest, the efficiency of editing, the level of target modulation measured, for example, by a biomarker readout, and of course, the tolerability. We'll be sharing more information, the forum, and the timing for our announcement of that data at a future time.

Jack Allen (Senior Research Analyst)

Great. Thank you so much for taking the question.

Gilmore O’Neill (President and CEO)

Thanks, Jack.

Operator (participant)

Thank you. We'll take our next question from Samantha Semenkow with Citi. Your line is open.

Jack Allen (Senior Research Analyst)

Hi, great. Good morning, and thanks for taking the question. Just building on the prior question, you're using an LNP, 'cause that's your strategy, non-viral. Would you expect to have an LNP targeted for the tissue of interest for the proof of concept readout indication optimized this year? Or would you need to further optimize after the proof of concept is in hand? Thank you.

Gilmore O’Neill (President and CEO)

Sam, thank you very much for your question. I, I'll have Linda take that.

Linda C. Burkly (EVP and Chief Scientific Officer)

Yeah, thank you, Sam. Thank you for the question. We are evaluating LNPs with different partners because we are interested in targeting different tissue cell types for different disease areas of interest. We haven't yet disclosed, you know, which tissues we're doing the non-clinical clinical POC targeting in, and we'll be sharing that information at a future time when we disclose the data. So in terms of the targeting aspects that you refer to, we'll share that information in the future.

Operator (participant)

Thank you. Next question from Eric Schmidt with Cantor Fitzgerald. Your line is open.

Jack Allen (Senior Research Analyst)

Oh, great. Love the summertime strategy. Very efficient. Maybe it'll continue into the fall and winter. We'll see. In terms of my questions, first, with the adolescent reni-cel cohort now completed in terms of enrollment, can you start to estimate your timeline to a BLA?

Gilmore O’Neill (President and CEO)

Thank you, Eric. I'm going to have Baisong take that question for you.

Baisong Mei (CMO)

Thank you for that question, Eric. We, we have announced that in June, we have dosed more than 20 patients, and we're continuing to dosing patients, so that is moving along very well. And then we continue to consider the Casgevy approval as our benchmark, so that in terms of sample size, in terms of efficacy sample size, as well as observation duration of 15-18 months, and the total sample size, initial submission with 20 patients and with additional 10 patients during the review. So this is kind of the scope of that. And we have not shared the specifics of the timeline because we have to get a final alignment with the FDA, but we are very optimistic that we are collecting the data from which we are dosing close to the BLA data package we are looking for.

Jack Allen (Senior Research Analyst)

Okay, thank you. Very helpful, and maybe Baisong or Gilmore, can you talk about what we hope to learn at the late 2024 update on the program? But as Gilmore mentioned, at this point, we know a fair bit about reni-cel's profile.

Gilmore O’Neill (President and CEO)

Baisong. So Baisong.

Baisong Mei (CMO)

Yeah. Yeah, thanks, Eric. Yeah. So we expect to have data from longer duration of follow-up for those patients we present at EHA, which means we're gonna have more than 10 patients have 1 year exposure, and additional patients have a different exposure. And then we also at EHA, we present data for 18 patients. We have since been dosing multiple more patients, so we're gonna have more patient data also. So with that, we are very excited for the data end of the year because we're gonna have longer duration, and we're gonna have a data package similar to the Casgevy BLA, so we are looking forward to share data with you all.

Jack Allen (Senior Research Analyst)

Thank you very much.

Operator (participant)

Thank you. We'll take our next question-

Baisong Mei (CMO)

Thanks, Eric.

Operator (participant)

- from Terence Flynn with Morgan Stanley. Your line is open.

Jack Allen (Senior Research Analyst)

Good morning, this is Mia on for Terence. Thanks for taking our question. So recognizing it's still early in the launches of Casgevy and Lyfgenia, but are there any learnings thus far that you hope to utilize for a future reni-cel launch? Thanks.

Gilmore O’Neill (President and CEO)

Thanks very much, Mia. Indeed, there are, and let me pass you over to Caren Deardorf, our Chief Commercial and Strategy Officer.

Caren Deardorf (Chief Commercial and Strategy Officer)

Great. Thanks, Mia, for the question. First, we really want to say that we're encouraged by the Vertex update of the 20 patients in cell collection, which is a nice bump up from the 5 in Q1, and we really see that as an acceleration that we have anticipated, because we understand that there are multiple steps in the process to get a patient dosed. We anticipate that they probably have a number of additional patients in the earlier enrollment phase before cell collection, including getting payer reimbursement. We anticipate significantly more uptake over the coming quarters as we look at both companies. We know from our own enrollment and the excitement in our trial, that there is a lot of patient and physician interest, and so that will continue as there's more exposure to our three therapies.

In the U.S., we also know that payers are doing case-by-case approvals with few rejections. We know that patients are able to get access and that policies will be in place over time. As a reminder, we really believe that our fast follower timing is an advantage, which gets to your question about the learning. And that really allows us to be able to optimize our own launch plan. And another key component is that we understand the time it takes for centers to get up to speed, for payers to put policies in place. All of that, we anticipate, will come together around the time that reni-cel might launch.

We are already seeing a decrease in the amount of time for onboarding between Bluebird and Vertex, and anticipate that onboarding cycle from our own conversations and research will be significantly shorter at the time of our launch. So we are really encouraged, and we know how much it takes behind the scenes, and we're just really glad to see patients moving closer to dosing. Thank you for the question.

Jack Allen (Senior Research Analyst)

Great, thank you.

Operator (participant)

Thank you. We will take our next question from Gena Wang with Barclays. Your line is open.

Jack Allen (Senior Research Analyst)

Thank you. I will ask two questions. First one is, what is your average process time from patient enrollment to dose? Any differences between adults and adolescent patients? And a second question regarding your indel technology. You say you will do upregulating. Just wanted to make sure that was the knocking down the repressor so that the target gene will be upregulated.

Gilmore O’Neill (President and CEO)

Thank you very much, Gena. What I'm going to do is have Baisong address your question about the process time or the vein to vein time, or enrollment to infusion time for adolescents versus adults. And then I'll pass over to Linda, and I'll restate your question just so we all remember. Baisong?

Baisong Mei (CMO)

Yeah. Thank you, Gena, for your question. From the enrollment to dosing, it varies quite significantly among patients, and some are going to be very short, like three or four months, and others can be up to 10 months or even longer, because some patients have VOE in the middle and during the process before dosing, of reni-cel. From the between adult and adolescent, and, and, we see now is that we have very robust enrollment, and that screening process was going faster than we had for adult, and the apheresis process also going very smoothly. And that's probably also related to that the adolescent patients in a better health condition compared to older adult patients.

Gilmore O’Neill (President and CEO)

Thanks very much, Baisong. And then, Gena, you asked a question just to clarify how we're using indel technology to functionally upregulate genes and specifically, the interdiction of the regulator.

Linda C. Burkly (EVP and Chief Scientific Officer)

Yeah. Thank you, Gena, for the question. So our functional upregulation strategy is not, is different. It is not a knockdown strategy, so we, as per your question, would not be knocking down the repressor. If we use the reni-cel example as a paradigm, in that case, we are creating an indel to disrupt the binding site for the repressor, and that way we are upregulating gamma globin expression. So using that as an example, we could do a similar type of thing for another target of interest. There are other ways that one can create indels to upregulate gene expression. This is the approach that we are taking that is differentiated from a knockdown approach. Thank you for the question.

Jack Allen (Senior Research Analyst)

Thank you.

Operator (participant)

Thank you. We'll take our next question from Mary Kate Daly with Bank of America. Your line is open.

Jack Allen (Senior Research Analyst)

Good morning. Thank you so much for taking my question. I guess looking at your portfolio, how are you looking at the IP licensing opportunities in the future? Thank you.

Gilmore O’Neill (President and CEO)

Thanks very much, Kate. I'm going to ask our CFO, Erick Lucera, to address that.

Erick J. Lucera (CFO)

Yeah, thanks for the question. We believe we have a very strong foundational position with respect to the IP license that we have from Harvard, MIT, and the Broad. We are very open to having conversations with a range of companies, in terms of getting a structure in place that is, sort of bespoke and works for both us and them. We believe there's a high double-digit number of programs out in development, and a good number of those, about half, are with 8 to 10 different companies. So, we look forward to having conversations with folks, and, as you can see, we've had some pretty good success in the last few years, as evidenced by some of the licenses that we've already put in place.

So very excited to have that as a potential source of non-dilutive capital for, for our company.

Jack Allen (Senior Research Analyst)

Thank you.

Operator (participant)

Thank you. We'll take our next question from Brian Cheng with J.P. Morgan. Your line is open.

Jack Allen (Senior Research Analyst)

Hey, guys. Thanks for taking our questions this morning, and happy summer. It sounds like you may have had, you know, additional discussion of the agency this past quarter. Just curious, other than the clinical data, what other additional items have you discussed? And just based on Casgevy package at the time of the BLA, I would assume that you can potentially file sometime next year. So outside of the clinical package, that we're waiting for mature data, what other additional data or gating factor do you need to line up between now and then? In other words, any color on your readiness towards the filing? Thanks.

Gilmore O’Neill (President and CEO)

Thanks very much, Brian. I think you did. There's sort of a complex question, in that you're asking about the multiple data sets that are required to actually go filing. First of all, let me be very clear that we have not actually shared an estimate or given guidance to when we would file the BLA. I think that's very important, just to state. The second is that we are very happy from the clinical data point of view and the generation, how we're actually progressing towards really meeting or matching up with the benchmark set by the Casgevy approval, with, of course, the additional data that we are generating from a differentiation point of view.

The additional data sets obviously include the preclinical, and we know that a key focus of the agency when you consider outcome was looking at off-target editing. We actually were very how should I say gratified by the outcome last December to see that the data set that we've already generated is a very robust and probably exceeds what was discussed at that outcome. So we feel very good with that. We're actually also very pleased with the progress of our manufacturing data. And as I said in my earlier prepared remarks, you know, our ongoing discussions with the FDA really gives us a lot of confidence about the progress of multiple data sets into, you know, beyond just the clinical to bring us towards BLA.

Jack Allen (Senior Research Analyst)

Okay. And maybe just one more follow-up. On the in vivo side, is that going to be first in class or best in class approach? Just curious if how do you, you know, think about balancing the risk and reward for your next assets? And thank you.

Gilmore O’Neill (President and CEO)

Thank you very much, Brian. I'm going to have Linda address that.

Linda C. Burkly (EVP and Chief Scientific Officer)

Yeah. Thanks, Brian, for the approach, the question. I think the differentiated approach is for going after functional upregulation is really important. I think from an indication standpoint, because of the fact that we can go after targets that others may not be able to go after using a knockdown strategy, and that is established modalities or other technologies in development can't go after that target, that really gives us the ability to be first in class. We can also envision editing strategies that would yield a better outcome than other approaches that are going after that particular indication, giving us best in class. So we can either have first in class or best in class opportunities here.

Jack Allen (Senior Research Analyst)

Great. Thank you.

Operator (participant)

Thank you. We'll take our next question from Joon Lee with Truist Securities. Your line is open.

Jack Allen (Senior Research Analyst)

Hi, good morning. This is Mehdi on for Joon. Congrats on the progress, and thanks for taking our question. So, maybe a two-part question. Could you please provide any additional color on your in vivo editing approach, as you previously talked about LSRs, and they usually require a landing site insertion first? So, any color there would be appreciated. And then, to follow on Joon's question, how many disease you see being amenable to indel-mediated functional upregulation? Thank you.

Gilmore O’Neill (President and CEO)

Thanks very much, Mehdi, for your questions. Let me start. I'll have Linda address both questions, and I'll restate the second question. Obviously, your first question was, you know, as we talk about our indel, functional upregulation, how is that distinguished from the use of LSRs? Linda?

Linda C. Burkly (EVP and Chief Scientific Officer)

Yes. Thank you for the question. Yeah, the LSR technology that we disclosed at ASGCT, we're very excited about that. That is a technology that may enable us in the future to have large gene insertions, and so this would be gene replacement approach. This is something that we're working towards. What we're doing in the shorter term now is functional upregulation of gene expression, and this is increasing the expression of a gene in order to compensate for a loss of function or a deleterious mutation in a patient with a serious genetic disease. So, if that answers your first question, I think then you asked a question about how many diseases are amenable to indel.

And there are many, obviously, genetic diseases caused by loss of function or deleterious mutations, and there are many ways in which they are regulated by various regulatory elements, and so there should be many, many opportunities here for functional upregulation of those targets.

Gilmore O’Neill (President and CEO)

If I may add, thank you very much, Linda. I think one of the key things is that as we know from the human genome, only a small quantity of the genome actually encodes proteins. There's a large amount, the vast majority of the genome actually is non-coding, and much of that comprises regulatory elements that actually control the expression of genes. And as Linda very eloquently put it, this is what we're actually trying to target. Just so we're absolutely clear, we are talking about indel using our CRISPR technology in general, and very specifically in the very near term, leveraging our AsCas12a, which as we highlight, is, we believe, one of the key differentiation tools in our toolbox, as we believe it is a superior editing CRISPR enzyme because of its high efficacy and its high fidelity.

Jack Allen (Senior Research Analyst)

Thank you.

Operator (participant)

Thank you. We'll take our next question from Dae Gon Ha with Stifel. Your line is open.

Jack Allen (Senior Research Analyst)

Hey, good morning, guys. Thanks for taking our questions and congrats on the progress as well. Maybe first question for Linda. Going back to the in vivo, recognizing you're going to be disclosing, so I don't want to probe too much, but at least help us appreciate it a little bit more. Is this—Are you guys kind of driven by the limitations of LNP-mediated delivery in terms of what cell types and what organ types you can go into? Or is this more dependent on how big of a size market you have potential of, first indication as well as the potential subsequent indications that can come after this first one? And then second question, maybe high level, Gilmore or Baisong, you know, year-end, we're also expecting Beam's first data set coming out of Beam 101.

You talk about reni-cel being best in class, so I was just wondering, what kind of data set would keep you more confident about that notion going into that ASH presentation? Thanks so much.

Gilmore O’Neill (President and CEO)

Thanks very much, Dae Gon. So, Linda.

Linda C. Burkly (EVP and Chief Scientific Officer)

Thank you, Dae Gon. So to your first question, yes, in terms of the LNP, the delivery obviously is critical for getting POC. So we've shared our interest in targeting hematopoietic stem cells, and this is obviously to translate this, the remarkable success we're having with our reni-cel assets. So we are obviously trying to target hematopoietic stem cells in vivo. We've also, though we haven't disclosed all of the disease areas that we're interested in, and other than HSCs, we have mentioned that we are interested in targeting the liver, and so there are validated LNPs for targeting liver. So there is a pragmatic approach here based on delivery.

Gilmore O’Neill (President and CEO)

If I may add, Linda, thank you. You know, it is not just the delivery tool that we are leading with an LNP that actually determines how we select our targets. Obviously, delivery is an important element. Obviously, amendability to functional upregulation is important. We're actually also selecting diseases based on their clinical translatability, in that we want to ensure that we can actually get obvious clinical signals in our human proof of concept. And obviously then, obviously, we also further filter that by ensuring that we are truly differentiated to ensure or maximize the probability, not just of technical, clinical, regulatory, but actually also commercial success.

Then with regard to your second question, you know, what do we expect to see from the Beam data set? You know, frankly, obviously, we're looking forward to seeing it. It is always good to see continued pursuit of therapeutics within a clinical space for which there is an enormous, enormous unmet need in the context of sickle cell disease and transfusion-dependent thalassemia. It's very hard. I can't speculate on what Beam would show. I look forward to hearing it, hearing it, and we all look forward to hearing it. But I will tell you that we are very happy with the differentiated profile that we are developing for reni-cel.

It's important to point out that we are very happy with the biological profile, the hematological profile, the clinical profile, all of which are very strong. And in addition, as we've alluded to, we are confident in the evolution, in the current state of, and the continued evolution of our manufacturing from the success rates is very gratifying. So overall, we actually feel very good. And of course, it's important though to remember, as I said earlier, that an additional piece of the data includes our non-clinical, including our off-target editing, which is very robust, as I said, in the package we've generated.

Of course, some of that robustness stems from us using AsCas12a as opposed to Cas9, with its differentiated high efficacy, high fidelity characteristics.

Jack Allen (Senior Research Analyst)

Great. Thanks so much.

Gilmore O’Neill (President and CEO)

Thank you.

Operator (participant)

Thank you. We'll take our next question from Luca Issi with RBC Capital. Your line is open.

Jack Allen (Senior Research Analyst)

Oh, great. Thanks so much for taking my question, and congrats on the progress. I have two quick ones. Maybe on sickle cell disease, we have seen the U.S. Department of Health and Human Services issuing a negative opinion here on covering fertility preservation for federally insured patients who receive gene therapy for sickle cell disease. So just wondering, what is your take on that? And then maybe second, Gilmore, bigger picture, you seem very excited about the in vivo upregulation strategy here. Is there a version of the world where you just partner reni-cel, both U.S. and ex-U.S., instead of building a commercial infrastructure and just focus on your in vivo strategy? Any thoughts there are much appreciated. Thanks so much.

Gilmore O’Neill (President and CEO)

Thanks very much, Luca. So I, I'm going to pass your first question to Caren around the HHS decision.

Caren Deardorf (Chief Commercial and Strategy Officer)

Yeah. Luca, thank you for calling that out. Look, we are deeply disappointed by this decision, and we join the voices of, you know, Vertex, Bluebird, really the whole field, in this decision, which seems very out of touch with the severity of sickle cell and the unmet need. And it just continues to drive a discrepancy between the commercial patients' ability to access therapies and have companies cover the fertility preservation, as you know, and Medicaid patients. So we are very disheartened. We also know that there are a lot of voices who are within Congress and within the industry and other organizations, including the patient advocacy groups, who have a very strong voice.

And our hope is that all of us together will be able to really raise this issue, and, you know, have it reversed in the coming time. We believe that things will sort themselves out. We are disappointed for the patients who are seeking treatment today. Our belief in our own timing as fast follower is a lot of these unfortunate decisions will be figured out at the time that we're ready to come to market. But thank you for calling it out. It is really an out of touch decision. And we will hope for the best and do our part.

Gilmore O’Neill (President and CEO)

Thanks very much, Caren. And then, Luca, to your second question around... I think it sort of stems from our prepared remarks, how why we're extraordinarily excited by reni-cel in vivo progress. We're also very conscious of how we deploy our capital, and I'm gonna ask Erick to address that.

Erick J. Lucera (CFO)

Yeah, Luca, just following up. As we've said for many years, our intention was to look for partners outside of the U.S. And I can tell you, as someone who invested in biotech for 15 years and has been doing business development and CFO for about 15 years, you never know where those discussions may go. But what we can assure you is that we're gonna do the right thing in terms of what's in the best interest for getting our products to as many patients as possible, and driving shareholder returns to the best level possible.

Jack Allen (Senior Research Analyst)

Great. Thanks so much.

Operator (participant)

Thank you. We'll take our next question from Phil Nadeau with TD Cowen. Your line is open.

Jack Allen (Senior Research Analyst)

Good morning, thanks for taking our questions, two from us. First on, on reni-cel and, and the prospects for clinical differentiation, we're curious what your most recent thoughts are on the, on the time to see that clinical differentiation on things like end organ damage. Is it possible that we could start to see strong signals of that in the ASH presentation? And then second, on the in vivo development program, gamma, I think you said the initial indication will be orphan, and then there'll be larger indications, perhaps later. Can you give us some sense of what size patient population you think is necessary for a good return on an, an investment? What's too small? Kinda what's the, what's the sweet spot for an orphan population? Thanks.

Gilmore O’Neill (President and CEO)

Thanks very much, Phil. So I'll have Baisong talk about the differentiation and how we see that evolving. And then I will take your question on how we think about the size of the population.

Baisong Mei (CMO)

Yeah. Yeah, thanks, thanks for the question. And, as we stated before, in clinical trial, we're looking three categories of evidence about differentiation, and including hematological parameters and end organ function, and the patient-reported outcome. And then the, then the-- in terms of timing of those endpoints and when we see the change, and, so for, for the end organ function, you specifically mentioned that it is relatively new field, and but fortunately, we already see more publications in the allogeneic transplant for treating sickle cell disease. They have presented encouraging data that after allogeneic transplant, you can see the end organ function improvement, including cardiovascular, central nervous system, and so on and so forth. And in our clinical trial, we monitor multiple organ and organ functions, including pulmonary, cardiovascular, liver, renal, and, and that.

Based on the publication, some are reporting that at one year you see some improvement already, so we are very encouraged by that. But other parameters, for example, the hematological parameter, will give us more opportunity to directly measure that change, for example, we're talking about the correction in anemia. And then the third category is patient-reported outcome, and we are also very encouraged by the reports and being published in this field, that we will be able to see the quality of life change after the treatment. So we're looking forward to see the more data, and we are very excited to see that our data from all our patients are very consistent. Now, we report 18 patient data.

We see that the same direction and the same trajectory in terms of the patient data-wise. We're very, very pleased. We're looking forward to share more data at the end of the year.

Gilmore O’Neill (President and CEO)

Thanks very much, Baisong. And then, Phil, with regard to your second question, which is around where do we think that a population size for an orphan indication, where we're sort of focusing our initial foray in vivo, lines up for optimal ROI? A couple of things. First of all, the reason that we're actually focusing on rare orphan, the main reason, obviously, is that as we bring in new technology to patients, we want to actually maximize the probability of technical and regulatory success, while, you know, we at the field and agencies characterize and learn, the long-term risk benefit associated with this technology. More importantly, that when I turn, or not more importantly, but then I turn to market size.

The market size we're talking about is really based on patients, the patient numbers with indication versus the price. And obviously, price will be determined by a number of factors, including the amount saved by what we're talking about are potentially or largely curative therapies with high potency. I mean, this is what we want. One of the things we're really excited about our technology is we're talking about using this technology, not just because it's new and cool, but because it has the potential to deliver high potency, large effect sizes in patients.

And so when you actually consider those elements, you know, our current estimates that a range of about $400 million-$500 million is about the market size, that would be meaningful and enable us to, you know, drive growth, and as we grow and evolve into treating larger populations, as we build that safety characterization in a number of smaller orphan-sized populations. I hope that's-

Jack Allen (Senior Research Analyst)

That's very helpful. Yeah, that's very helpful. Thank you.

Operator (participant)

Thank you. We'll take our next question from Jay Olson with Oppenheimer. Your line is open.

Jack Allen (Senior Research Analyst)

Hey, this is Chen on the line for Jay. Thanks for taking the question. This may be on reni-cel. By the time you file a BLA, I'm just curious, do you think the follow-up in the adolescent cohort is long enough so the label may cover both adult and adolescent patients? Thank you.

Gilmore O’Neill (President and CEO)

Thanks very much, Jay. I just want to restate your question because I—It was a little muffled on the line. I think you were asking, will the adolescent cohort be followed for long enough to be part of the label and inclusion?

Jack Allen (Senior Research Analyst)

Yes, that's correct.

Gilmore O’Neill (President and CEO)

Okay.

Jack Allen (Senior Research Analyst)

Yeah, that's correct. Thank you.

Gilmore O’Neill (President and CEO)

Please, Baisong.

Baisong Mei (CMO)

Yeah, thanks, Chen. We are very pleased with the progress of adolescent cohort, and we started the enrollment of this year, and we already completed enrollment in a matter of months, so we're very pleased with that. We certainly want to seek for broader indication of all age age cohorts, and we already have alignment with FDA about the clinical trial for all the age cohorts. So that's where we very much are looking forward to that.

Jack Allen (Senior Research Analyst)

Okay, thank you so much.

Operator (participant)

Thank you. We'll take our next question from Yanan Zhu with Wells Fargo Securities. Your line is open.

Yanan Zhu (Senior Equity Research Analyst)

Oh, great. Thanks for taking our questions. So for the in vivo program, are you trying to upregulate the gene, the disease-causing gene itself, or are you trying to upregulate a different gene to compensate for the loss of the disease-causing gene? In other words, are we talking about a haploinsufficiency type of indication, or are we talking about recessive gene, you know, gene defect here? Secondarily, wanted to ask about any updated timing for the CAFC patent dispute process. Thank you.

Gilmore O’Neill (President and CEO)

Thanks very much, Yanan. So, with the first question, I'm going to, you know, start by saying that you have actually described, or you've actually, you nailed both elements of the upregulated strategy, but I'll let Linda just expand on that. And then, I'll restate the second question, and we'll address that.

Linda C. Burkly (EVP and Chief Scientific Officer)

Yeah, thanks very much for your question. So the two scenarios that you described, like both are possible approaches. One can imagine in a loss of function homozygous recessive state, upregulating a pathway gene that can compensate for the loss of the mutated gene. So that's the case with the reni-cel example, where beta globin in TDT is, there's no expression of beta globin, or in sickle cell disease, it's a deleterious mutation, and so it's not functioning properly, and we upregulate gamma globin to compensate in both of those cases. One can also imagine a scenario of haploinsufficiency, where you have one allele has a mutation, a pathogenic mutation, but there's a wild type allele that can be upregulated to compensate for the of the loss of function of the of the mutated allele. So either scenario is a potential target for us.

Gilmore O’Neill (President and CEO)

Thank you very much, Linda. I think, Yanan, you asked a second question about update on the Casgevy timings. Obviously, the oral presentations occurred in the last quarter in May, and we anticipate a decision probably before the end of the year.

Yanan Zhu (Senior Equity Research Analyst)

Great. Very helpful.

Gilmore O’Neill (President and CEO)

May I just. I was just wondering if I could translate haploinsufficiency into lay terms, for those who might not have done molecular biology or genetics. By haploinsufficiency, everyone carries two copies of a gene, and in the context of haploinsufficiency, one gene is not functioning, which results in a reduction in the total dose of protein that's available, to the person, resulting in disease, so-called insufficiency or haploinsufficiency. And the strategy that Linda is describing, that we're pursuing to manage that, is that you drive up expression of the normal copy, to actually approach or get to the same dose of overall protein, that would be required for normal health. Hope that was helpful.

Yanan Zhu (Senior Equity Research Analyst)

Great. Thanks, O'Neill, and thanks, Linda.

Operator (participant)

Thank you. We'll take our next question from Steve. Steve Seedhouse with Raymond James, your line is open.

Speaker 10

Hi, good morning, and thank you for the question. This is Nick on for Steve. Had a quick follow-up to Luca's first question, actually. Are you able to speak to the importance and demand for fertility support in your own clinical trials experience for SCD? Also curious of your thoughts on the potential market impact if you're not able to provide the support, once approved. Thank you.

Gilmore O’Neill (President and CEO)

So I'm going to split that question into two parts. I'm going to ask Baisong to talk about our experience in our clinical trial, and then I'll have Caren to talk about the impact, and very importantly, how we anticipate, you know, mitigating or ensuring that that impact is not going to be there.

Baisong Mei (CMO)

Yeah. Yeah, thank you for the question, Nick. We, in clinical trial setting, we do provide fertility support, which is critical for patients, especially this patient population, that it is important for them to have that support to be able to go through the, the chemotherapy and conditioning process. You know, I want to let Caren to emphasize the importance of that in the commercial setting.

Caren Deardorf (Chief Commercial and Strategy Officer)

Yeah. Thanks, thanks for the question. So we do see this as a very important component of support to sickle cell patients in the context of the gene editing transplant. In terms of impact on the market, what I will say is that for the Medicaid population, within the CMMI model that we've all discussed and we hope and anticipate will get started sometime in 2025, there actually is a carve-out there, so that within the model, which we don't know how many states will be included, but that does cover Medicaid patients, and the fertility preservation is able to be included in that. And then in the commercial setting, it is, it's fine.

So the decision that HHS or the IG made does not affect commercial and also, again, CMMI, which we are encouraged and very hopeful that that will move quickly. And I am hopeful that there will be enough pressure and enough parties that will move to eventually change this. So by the time we're launching, I can't promise, but I don't anticipate it will be a huge market impact. And even in the coming years, I think that there are other opportunities for patients to be able to receive the gene editing therapies and the fertility preservation.

Gilmore O’Neill (President and CEO)

Caren, it might be worth just pausing for a second and just taking people through the acronyms and the sort of the structure of...

Caren Deardorf (Chief Commercial and Strategy Officer)

Yeah, sorry.

Gilmore O’Neill (President and CEO)

No, no, no.

Caren Deardorf (Chief Commercial and Strategy Officer)

Yeah.

Gilmore O’Neill (President and CEO)

It's just that, you know, what CMMI is.

Caren Deardorf (Chief Commercial and Strategy Officer)

So CMS has a section, it's the CMMI model, which is created to be able to explore and launch pilot programs to patients, to different areas of need. There are a number that have been done in oncology over the last years. They created a specific cell and gene therapy program, of which the sickle cell disease area was highlighted, and the program was initiated earlier this year, kicked off, and it is voluntary for both manufacturers and for states, so TBD on exactly, you know, who is involved in it. But the opportunity is there, with a lot of funding, for federal CMS, through the CMMI model, to be able to negotiate with manufacturers on behalf of a lot of states. So it takes out some of that work and that variability.

Again, it is a promising program that needs to be moved forward quickly, but within it, there was a waiver on the Anti-Kickback Statute around providing the fertility preservation. So hopefully that gives a little bit better context.

Gilmore O’Neill (President and CEO)

Thanks very much, Caren. Thanks, Nick.

Operator (participant)

Thank you. We'll take our next question from Liisa Bayko with Evercore ISI. Your line is now open.

Jingming Chen (Equity Research Analyst)

Hi, this is Jingming on for Lisa. Thanks for taking our question. There's a large number of patients in the Middle East, and can you please comment on how you plan to target this region? Do you plan to execute global launch yourself, or will you need a partner considering the complexities? Thank you.

Gilmore O’Neill (President and CEO)

Thanks very much, Jing. I'm going to have Caren address that question.

Caren Deardorf (Chief Commercial and Strategy Officer)

Yes. Great. Thank you. We agree, in the Middle East, and there are other geographies where there is a significant unmet need. As we've said and as was stated earlier, we continue to consider partnering for anything outside of the United States and any way that we can improve and accelerate access of therapies like reni-cel to patients in need. We continue to maintain that strategy, and we'll update as appropriate.

Gilmore O’Neill (President and CEO)

Thank you very much, Caren.

Jingming Chen (Equity Research Analyst)

Great.

Operator (participant)

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