Editas Medicine, Inc. (EDIT) Earnings Call Transcript & Summary

Good morning, and welcome to the Editas Medicine Second Quarter 2024 Conference Call. [Operator Instructions]. I would like to turn the call over to Cristi Barnett, Corporate Communications and Investor Relations at Editas Medicine.

Thank you, Britney. 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.

Thanks, Cristi, and good morning, everyone. Thank you for joining us today on Editas' Second Quarter 2024 Earnings Call. With me today are 4 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 disease and to position Editas as a leader 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 monitoring our very strong IP. At the start of 2024, we announced the following 2024 objectives. For reni-cel, we will provide a clinical update from the RUBY trial for severe sickle cell disease and the EdiTHAL trial for transfusion-independent beta-thalassemia in mid-2024 and by year-end 2024. We would complete adult cohort enrollment and initiate the adolescent cohort in RUBY and continued 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 to 22.8 months of follow-up. And the EdiTHAL data set included clinical data from 7 beta thalassemia patients with 4.1 to 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. And all patients have high fetal hemoglobin with levels well above 40% and from 6 months onwards. We also demonstrate fast engraftment with low variability with a mean neutrophil engraftment of 23 days, which may translate to shorten hospital stays for the patients. For cell collection, we have a mean of 2 apheresis cycles with a range of 1 to 4 per patient. Finally, in addition to the clinical data shared with EHA, on the manufacturing front for reni-cel, we have a robust manufacturing process with a low failure rate that continues to improve the experience. This slow rate of manufacturing failure can decrease patient burden and reduce overall cost as we avoid cell recollection and redundant cost of goods sold or COGS. And we are on track to share additional clinical days 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, duration of follow-up to what we've seen in the gene editing medicine field. Before I turn to in vivo, I would 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 delivered 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 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 of regulation, 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 homolog of the beta-globin gene through direct editing of the HPG1-2 promoter site. We are now applying this same approach to in vivo therapeutics by using our indel technology to functionally upregulate the wild-type alleles or functional homolog of target disease genes as we build our differentiated pipeline. Why does the difference between our functional regulation strategy and the knockdown strategy used by other companies matter? Because with our in vivo strategy, we are not competing with existing modalities or technology and 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 an in vivo therapeutic targets in hematopoietic stem cells and other tissues. Third, Editas is well positioned to achieve success with our eco-strategy and pipeline with our established capabilities 4 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. And 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 general 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 quarter 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 payable 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 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 in execution and strong balance sheet, we continue to progress our strategy to deliver differentiated editing medicines to patients with serious genetic diseases and evolved 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 Instructions]. And we will take our first question from Jack Allen with Baird.

Congratulations on all the progress made throughout the quarter. 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 be in a large animal model or a small animal model? And how should we think about the type of experience you're looking to do to [indiscernible] the off-target editing profile for this program?

So Jack, I think you brought up near the end, but let me just restate the question the way I heard it. And then hopefully, 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 might have heard you talk about indications. I'm not sure. So I'm going to ask Linda maybe to address your question.

Yes. Thank you, Jack. You did break up a little bit, so thanks, Gilmore, for elaborating there. 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 POCs 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, biomarker readout and, of course, the tolerability, and we'll be sharing more information, the forum and the timing of announcement of that data at a future time.

We'll take our next question from Samantha Semenkow with Citi.

Just building on the prior question, you're using an LNP strategy in nonviral. Do 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?

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

Yes. 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 which tissues we're doing the nonclinical 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 aspect that you referred to, we'll share the information in the future.

Our next question from Eric Schmidt with Cantor Fitzgerald.

Great. Love the summertime strategy, very efficient. Maybe it will 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?

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

Thank you for the question, Eric. We have announced that in June, we have dosed more than 20 patients, and we are 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 the observational duration of 15 to 18 months, and the total sample size initial submission with 20 patients and with additional 10 patients doing the review. So that's kind of the scope of that. And we have not shared the specifics of the timeline because we have to get final alignment with the FDA, but we are very optimistic that we are collecting the data from -- we are dosing -- closing to the BLA data package we are looking for.

Very helpful. And maybe based on Gilmore's remark, 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.

So Baisong?

Yes, Eric, yes. So we expect to have data from longer duration of follow-up. For those patients, we present at EHA which means we're going to have more than 10 patients that have 1-year exposure and additional patients have a different exposure. And now we also -- at EHA , we presents data for 18 patients, we have since been dosing multiple more patients. So we're going to have more patient data also. So with that, we are excited for the end of the year because we're going to have longer duration, and we're going to have a data package similar to the CASGEVY BLA. So we are looking forward to share data with you all.

We'll take our next question from Terence Flynn with Morgan Stanley.

This is Mia on for Terence. 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 very much, Mia, indeed there are. And let me pass you over to Caren Deardorf, our 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. 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 and 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 3 therapies. In the U.S., we also know that payers are doing case-by-case approval 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 learnings. 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, prepares 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, 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.

We will take our next question from Gena Wang with Barclays.

I will ask 2 questions. First one is what is your average processing from patient enrollment to dose? Any differences between adults and adolescent patients? And the second question regarding your indel technology, you say you were upregulating. Just wanted to make sure that was the knocking down the repressors so that the target gene will be upregulated.

Thank you very much, Gena. What I'm going to do is have Baisong addressed 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?

Yes. 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 3 or 4 months and other 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. Between adult and adolescent, 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 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.

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

Yes. 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, we 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.

We will take our next question from Mary Kate Davis with Bank of America.

I guess looking at your portfolio, how are you looking at the IP licensing opportunities in the future?

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

Yes. 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 nondilutive capital for our company.

We'll take our next question from Brian Cheng with JPMorgan.

It sounds like you may have 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 very much, Brian. I think 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 in 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 the Ad Comm was looking at off-target editing. We actually were very, how should I say, gratified by the Ad Comm last December to see that the data set that we have already generated is a very robust and probably exceeds what was discussed at that Ad Comm. So we feel very good there. We're actually also very pleased with the progress of our manufacturing data. And as I said in my earlier prepared remarks, our ongoing discussions with the FDA really gives a lot of confidence about the progress of multiple data sets beyond just the clinical to bring us towards BLA.

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 how do you think about balancing the risk and reward for your next assets?

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

Yes. 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 we 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.

We'll take our next question from Joon Lee with Truist Securities.

This is Mahdi on for Joon, congrats on the progress. So maybe a 2-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 Gena's question, how many disease you see being amenable to indel mediated functional upregulation?

Thanks, Mahdi, maybe 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 as we talk about our indel functional upregulation, how is that distinguished from the use of LSRs. Linda?

Yes. Thank you for the question. Yes, 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 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, there are many 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.

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. And just 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 differentiated tools in our toolbox as we believe it is a superior editing CRISPR enzyme because of its high efficacy and its high fidelity.

We'll take our next question from Dae Gon Ha with Stifel.

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. 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 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. 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 very much, Dae Gon. So Linda?

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 the remarkable success, we're having with our reni-cel asset. So we are obviously trying to target hematopoietic stem cells in vivo. So 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.

If I may add, Linda, thank you. 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, amenability to functional upregulation is important. We're actually also selecting diseases based on their clinical translatability and 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 a technical clinical regulatory, but actually also commercial success. And then with regard to your second question, what we expect to see from the Beam data set? 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, 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. And 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, our confidence 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 to also remember, as I said earlier, that an additional piece of the data includes our nonclinical, including our off-target editing, which is very robust, as I said, in the package we have generated. And of course, some of that robustness stems from us using AsCas12a as opposed to Cas9 with its differentiated high efficacy, high fidelity characteristics.

We'll take our next question from Luca Issi with RBC Capital.

Congrats on the progress. I have 2 quick ones. Maybe on sickle cell disease, we have seen the U.S. health and human service issuing a negative opinion here on covering fertility preservation for federal insured patients who received 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 focused on your in vivo strategy? Any thoughts there, much appreciated.

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

Luca, thank you for calling that out. Look, we are deeply disappointed by this decision. And we joined the voices of 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 the discrepancy between the commercial patient's 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 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 of 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.

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 our reni-cel, our in vivo progress. We're also very conscious of how we deploy our capital. And I'm going to ask Erick to address that.

Yes. 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 going to 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.

We'll take our next question from Phil Nadeau with TD Cowen.

Two for us. First, on reni-cel and the prospects for clinical differentiation. We're curious to what your most recent thoughts are 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, Gilmore, I think you said the initial indication will be orphan then there will be larger indication perhaps later. Can you give us some sense of what size patient population you think is necessary for a good return on an investment? What's too small, kind of what's the sweet spot for an orphan population?

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.

Yes. Thanks for the question. And as we stated before, in clinical trial, we're looking 3 categories of evidence about differentiation and including hematological parameters and end-organ function and the patient reported outcome. And then the -- in terms of timing of those endpoints and when we see the change, and so for the end-organ function, you specifically mentioned that, it is a relatively new field. But unfortunately, we already see more publications in 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 -- end-organ functions, including pulmonary, cardiovascular, liver, renal and that. And so we -- based on the publication, some of reporting that at 1 year, you see some improvement in it so we're 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 liver. And then the third category is patient report outcome. And we're also very encouraged by the reports and being published in this field then we will be able to see the quality of life change after the treatment. So we're looking forward to seeing more data, and we are very excited to see that our -- the 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 patient data wise. We're very pleased. We're looking forward to share more data at the end of the year.

Thanks very much, Baisong. And then Phil with regard to your second question, which is around -- where do we think that population size or 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 we, at the field and agencies characterize and learn the long-term risk benefit associated with this technology. More importantly than when I turn -- not more importantly, but when I turn to market size, the market size you talked 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 -- 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 and patients. And so when you actually consider those elements, our current estimate is that a range of about 400 million to 500 million is about the market size that would be meaningful and enable us to 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'll take our next question from Jay Olson with Oppenheimer.

This is Cheng for Jay. Just maybe 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?

Just I want to just restate your question because it was a little muffled on the line. I think you were asking was -- will the adolescent cohort be followed for long enough to be part of the label and execution, Baisong?

Yes. Thanks, Cheng. We are very pleased with the progress of adolescent cohort, and we started enrollment of this year, and we already completed enrollment in the matter of months. So very pleased with that. We certainly want to seek for a broader indication of all 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.

We'll take our next question from Yanan Zhu with Wells Fargo Securities.

Great. 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 haploinsufficiency type of indication or are we talking about recessive gene defect here? Secondarily, I wanted to ask about any updated timing for the CAFC patent dispute process?

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

Yes. Thanks very much for your question. So the 2 scenarios you described like both are possible approaches, one can imagine in 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 is 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 1 allele has a mutation -- pathogenic mutation, but there's a wild type of allele that can be upregulated to compensate for the loss of function of the mutated allele. So either scenario is a potential target for us.

Thank you very much, Linda. And I think, Yanan, you asked a second question about update on the CAFC timings. Obviously, the oral presentations occurred in the last quarter in May, and we anticipate a decision probably before the end of the year. 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 2 copies, most copies -- 2 copies of the gene and the context of haploinsufficiency, 1 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. I hope that was helpful.

We'll take our next question from Steve Seedhouse with Raymond James.

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 this support once approved?

So I'm going to split that question into 2 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 mitigating or ensuring that, that impact is not going to be there.

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

Yes. 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'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 therapy and the fertility preservation.

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

So CMS has a section, it's the CMMI model, which is created to be able to explore and launch pilot programs to patient to different areas of need. There are numbers that have been done in oncology over the last years. And 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 or kicked off. And it is voluntary for both manufacturers and for states. So TBD on exactly 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 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 better context.

We'll take our next question from Liisa Bayko with Evercore ISI.

This is Jingming on for Lisa. So there's 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?

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

Yes. Great. Thank you. And we agree in the Middle East and there are other geographies where there is a significant unmet need. As we've said and as we've 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. So we continue to maintain that strategy, and we'll update as appropriate.

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