Agios Pharmaceuticals, Inc. (AGIO) Earnings Call Transcript & Summary

Good morning, and welcome to Agios' webcast and conference call regarding the ENERGIZE-T Phase III study. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations and Corporate Communications for Agios.

Thank you, operator. Good morning, everyone, and welcome to Agios webcast and conference call, highlighting the top line data for the ENERGIZE Phase III study. You can access slides for today's call by going to the Investors section of our website, agios.com. On today's call, you'll hear from our Chief Executive Officer, Brian Goff; Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development; Dr. Jeremie Estepp, Medical Director for Agios in thalassemia. And joining for Q&A Cecilia Jones, Chief Financial Officer; and Tsveta Milanova, our Chief Commercial Officer. Before we get started, I'd like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors including those set forth in our most recent filings with the SEC and in any other future filings that we may make with the SEC. And with that, I'll turn the call over to Brian.

Well, thank you, Chris, and good morning, everyone. PYRUKYND is a first-in-class pyruvate kinase or PK activator for adults with PK deficiency. The first disease-modifying therapy for this rare lifelong debilitating hemolytic anemia. Building on Agios' deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, we are also pursuing mitapivat in programs in alpha and beta thalassemia, sickle cell disease and pediatric PK deficiency. Over the last 12 months, our mitapivat development program has been building significant momentum. We announced positive data in the Phase II portion of the RISE UP study in sickle cell disease last June, announced positive data from the Phase III ENERGIZE study in non-transfusion-dependent thalassemia in January. And today, we are thrilled to announce positive data from the Phase III ENERGIZE-T study of mitapivat in transfusion-dependent thalassemia. Importantly, both the ENERGIZE and ENERGIZE-T studies met their respective primary endpoints as well as all key secondary endpoints. Based on these compelling and consistent data, we believe mitapivat is well positioned to become the first therapy approved for all thalassemia subtypes, which includes both alpha and beta thalassemia and both non-transfusion and transfusion-dependent thalassemia patients. And we plan to file a marketing application encompassing data from both ENERGIZE and ENERGIZE-T to the FDA by the end of this year, similar to the approach we took with PKD, which led to a supportive label. With that, I'd like to ask Jeremie Estepp, our Medical Director, who leads the mitapivat development program in thalassemia to review the top line data from the ENERGIZE-T study. Jeremie?

Thank you so much, Brian. I'm really humbled to be here on this auspicious morning representing the ENERGIZE team that includes internal members here at Agios, colleagues and patients and their families from around the globe. As I was preparing to provide the overview of the data, I can't help but be a little bit overwhelmed and humbled, and just joyous with the emotions that I had back in January when we were reviewing our positive ENERGIZE results. And I'm just very thrilled to be able to share positive results of ENERGIZE-T this morning in transfusion-dependent thalassemia, which completes the picture of data that we've generated across the thalassemia subtypes. As a hematologist in my previous life, I have cared for numerous patients and families with hemolytic anemia. And I personally saw the impact of thalassemia firsthand. There is a -- remains a high unmet need in this patient population with very few treatment options and none that are available for alpha thalassemia. So it was an honor for me to have been the Medical Director for both the ENERGIZE and ENERGIZE-T studies. The Phase III ENERGIZE-T study is the first Phase III study to demonstrate efficacy of an oral disease-modifying treatment for transfusion-dependent alpha and beta thalassemia. And it's my pleasure to review those results with you this morning. PYRUKYND, or mitapivat is an oral small molecule allosteric activator of pyruvate kinase. Its novel mechanism of action mitapivat has the potential to correct red blood cell metabolism and improve the overall health and function of thalassemic red blood cells, leading to more effective erythropoiesis, reductions in hemolysis and improvements in how patients feel and function. Mitapivat's mechanism of action also has the potential to address the underlying pathophysiology of all forms of thalassemia. And we have, therefore, advanced two global Phase III studies, ENERGIZE and ENERGIZE-T, together, representing the most comprehensive development program in thalassemia to date to evaluate mitapivat in all patients with thalassemia. Brian, as you mentioned, we announced positive top line data from ENERGIZE study in non-transfusion-dependent thalassemia in January. And as promised, we look forward to presenting a more detailed overview of the results in the preliminary session on European Hematology Association meeting in a couple of weeks. But the focus of today's announcement is ENERGIZE-T in which patients with alpha or beta transfusion-dependent thalassemia, were randomized 2:1 to receive either 100 milligrams of mitapivat or placebo twice daily for 48 weeks, followed by an open-label extension period lasting up to 5 years in which all subjects have the opportunity to receive mitapivat. On this slide, we describe the original number targeted for enrollment for the ENERGIZE-T study of 240 participants. As we noted in our news release, the actual enrollment came in at 258 subjects. The enrollment was balanced globally, and the study enrolled expeditiously similar to the ENERGIZE program, reflecting overall enthusiasm from patients and investigators and highlighting the unmet need identified in these patients. The primary endpoint of the study is transfusion reduction response, which was defined as a 50% or more reduction in transfused red blood cell units with the reduction of at least 2 units transfused of red blood cells in any consecutive 12-week period through week 48 compared with baseline. The primary endpoint is a dynamic assessment of transfusion reduction and we believe is more relevant to clinical practice and how patients could benefit in the real world than a 12-week fixed period. Additionally, key secondary endpoints evaluated three additional measures of transfusion reduction response over longer periods with the goal of showing durability of the effect of mitapivat. We are very pleased to report that the Phase III ENERGIZE-T study of mitapivat indeed met its primary endpoint of transfusion reduction response. On the primary endpoint, treatment with 100-milligram mitapivat twice daily demonstrated a statistic significant reduction in transfusion burden compared to placebo with a p-value of 0.0003. Of the 171 patients randomized to receive mitapivat 52 or 30.4% achieved this transfusion reduction response. Of the 87 patients randomized to receive placebo, 11 patients or 12.6% achieved a transfusion reduction response. And as mentioned, this difference is statistically significant with a p-value of 0.0003. To further characterize the magnitude and durability of effect, three secondary endpoints were additionally assessed, and the treatment with 100-milligram twice daily resulted in statistical improvements across all of them. Specifically, a 50% or more reduction in transfused red blood cell units in any consecutive 24-week period through week 48 compared with baseline, a 33% or more reduction in transfused units in a 36-week period from week 13 through week 48 compared to baseline and a 50% or more reduction in transfused red blood cell units in a 36-week period from week 13 through week 48 compared to baseline. We're incredibly pleased to see mitapivat has statistical significance in all key secondary endpoints, including prespecified endpoints that assess reduction of transfusion burden for a 36th consecutive week period, demonstrating up to 36-week durability of effect for mitapivat, which has not previously been demonstrated by other treatments. Additionally, a higher proportion of patients in the mitapivat treated arm, 9.9% compared to the placebo arm of 1.1%, achieved the secondary endpoint of transfusion independence which we defined as transfusion-free for 8 or more consecutive weeks through week 48. Treatment with mitapivat allowed for some patients to be untethered from the clinic for a meaningful amount of time on par with existing treatment option, but with mitapivat being an oral administrative therapy. This means true freedom from the clinic. Moving on to safety. Overall, during the 48-week double-blind period, incidents of adverse events were similar across the mitapivat and placebo arms and the mitapivat arm, 5.8% of patients experienced an AE leading to discontinuation compared to 1.2% of patients in the placebo arm. Based on the safety and efficacy data observed in ENERGIZE-T, the company will proceed as previously discussed and previously stated with plans of U.S. regulatory submission by the end of the year. And with that, I will turn it over to Sarah Gheuens.

Thanks, Jeremie. Before I put the results in further context, I would also like to take a moment to thank all of the patients who participated, all the investigators and the site staff who have run the study and the entire ENERGIZE-T clinical trial and you Jeremie and the people who have worked also relentlessly in the background to get the database locked, the outputs program deliver the top line results. We couldn't be more proud of today's results, and we couldn't do this without all of you. So as Brian and Jeremie mentioned, our goal from the start of the mitapivat program in thalassemia has been to deliver the first oral therapy approved for all thalassemia subtypes, and we believe we are now poised to do so. So the graph on this slide describes the U.S. thalassemia patient population, and it highlights our Phase III trials were designed to encompass both non-transfusion-dependent patients in orange through ENERGIZE and then the transfusion-dependent patients through ENERGIZE-T in blue. And we have now delivered positive results in both trials, highlighting that mitapivat through its unique mechanism of action can improve hemolytic anemia and thalassemia patients as measured by these two different endpoints supporting each other, a hemoglobin improvement endpoint and a transfusion reduction endpoint and most importantly, that leads to true meaningful change for patients living with thalassemia. So based on the safety and efficacy data generated by these two trials, we are closer to our goal of delivering for the first time of convenience and oral therapy that addresses the underlying pathophysiology of thalassemia and is potentially proved to treat all subtypes of the disease. Going to the next slide, I would like to amplify what Jeremie mentioned by providing also a brief reminder of the top line data we announced on January 3 of this year for the ENERGIZE Phase III trial of mitapivat in non-transfusion-dependent thalassemia patients. So for the primary end point, the study demonstrated a statistically significant increase in hemoglobin response rate, 42.3% compared to patients on placebo, 1.6%. And very importantly, the study also demonstrated statistically significant change in secondary -- in key secondary endpoints, including the average FACIT Fatigue score and the first and only trial to this in NTDT patients. And then on the right, we are very excited to have the opportunity to present more detail on the ENERGIZE study at EHA later this month. which includes a detailed overview of the data by Dr. Ali Taher from the American University of Beirut Medical Center in a plenary session and then also a deeper dive on key quality of life outcomes in a poster presented by Dr. Kevin Kuo from the University of Toronto. So with the positive data now in hand in the Phase III ENERGIZE-T and ENERGIZE studies of mitapivat in patients with alpha- or beta-thalassemia that are transfusion-dependent or non-transfusion dependent, respectively, we aim to submit a marketing application in the U.S. by the end of 2024 based on all available data from both studies. And given the consistent and compelling positive data for both studies, which build on the data we have generated across different programs, we plan to seek a broad label encompassing all subtypes of thalassemia with a potential FDA approval in 2025, following a similar strategy as a strategy applied for PKD. In addition, we also plan to submit marketing applications in Europe and the Gulf Cooperation Council countries, and we aim to provide additional detail on the timing of those applications in the future. And with that, I will turn the call over to Brian.

Well, thank you very much, Sarah. This is a very proud day for Agios. And thank you, Sarah, and your entire team for all of your hard work and also for continuing to deliver on behalf of the patients we wish to serve. With the positive data we now have generated with mitapivat in PK deficiency, sickle cell disease and thalassemia, we are more confident than ever in the potential for mitapivat to become a first-in-class and best-in-class treatment option for multiple indications and to become a multibillion-dollar franchise. To maximize these future potential launches, our commercial organization is laser-focused on building upon the infrastructure established through our current launch in PK deficiency to prepare for a potential U.S. launch of mitapivat in thalassemia in 2025 and for a potential launch in sickle cell disease in 2026. We are truly off to a fantastic start this year with two positive Phase III readouts just since the beginning of the year. And we have more clinical catalysts ahead, including the top line readout from the Phase III ACTIVATE kids-T study of mitapivat in regularly transfused pediatric patients with PK deficiency in the middle of this year. And next year, we're expecting the top line data from the Phase III portion of the RISE UP study of mitapivat in sickle cell disease and the Phase III ACTIVATE study of mitapivat in pediatric PK deficiency patients who are not regularly transfused. Driven by the growing stack of positive data readouts for mitapivat and the potential for two additional first and best-in-class indications for PYRUKYND by 2026, we believe mitapivat is poised to become a multibillion-dollar franchise and to deliver significant value to both patients and shareholders. At the foundation of mitapivat is a differentiated mechanism of action, which leverages PK activation to improve red blood cell health. And as noted in the blue box at the bottom of this slide, just last week, we announced our strong cash balance was further bolstered by the $905 million purchase agreement with Royalty Pharma, which we believe will provide us with the financial independence to prepare for these potential upcoming launches in thalassemia and sickle cell disease and to opportunistically expand our pipeline through both internal programs and disciplined business development. As part of this agreement, which is subject to FDA approval of vorasidenib with a PDUFA date of August 20, 2024. We retained a 3% royalty on U.S. sales above $1 billion annual sales. Also noted in the blue box, we have retained the $200 million milestone from Servier upon approval of vorasidenib as part of our original divestiture. Before we transition to Q&A, I'd like to take a moment to thank the entire team with sincere gratitude to all the patients who participated in the ENERGIZE-T study as well as our employees who continue to do an absolutely fabulous job, including Jeremie and Sarah as well as our collaborators, our study investigators, and our advisers in the patient and clinical communities for their partnership in achieving this remarkable milestone. And with that, we will now open the call for questions.

[Operator Instructions] Our first question comes from Eric Schmidt with Cantor Fitzgerald.

Congrats on yet another positive readout. It's great to see such consistent data sets across these hemolytic anemias, maybe three quick ones, if I can. Are there any secondary endpoints in terms of quality of life and fatigue that you looked at? If so, can you talk about how those have trended? The second question is on the dropout rate. I think there was a 5.8% drop out due to AE, anything in particular there or that's common across that. And maybe third, conversely, we've seen very good persistency and duration of dosing in all these indications. Do you have any indication of the percent of patients or number of patients who are continuing on in the open-label extension?

Eric. And I just want to underscore your comment. We are really pleased that mitapivat just continues to deliver across all the Phase III studies and frankly, Phase II as well as we read out with RISE UP and sickle cell disease last June. I think Sarah is well positioned to take all three of those questions. So do you want to start, Sarah?

Sure. So thanks, Eric. So for the secondary end points, what we have spoken about so far is the secondary endpoint of transfusion independence because we thought that, that provided the most meaningful information right now, and we're looking forward to talk about our other secondary end points at an upcoming medical meeting. In the context of what we have measured, we have some health-related quality of life measurements that they relate in transfusions in the ENERGIZE-T trial, but more to come about that. As you know, we have the patient reported outcome that was positive, statistically significant positive for the ENERGIZE trial, which is very relative to the context, it explains that people in that trial actually felt less fatigue and we are looking forward to give more detail on all of the PROs that were measured in that trial at upcoming EHA. In regards to the dropout rates, we -- the discontinuation rates across the trial were very much in line with what was anticipated. There were -- yes, I think it's good. I think that's a discontinuation. So there was no pattern or trend among these and then in the context of persistency of dosing, we see very similar behavior as like on our other clinical trials.

Our next question comes from Gregory Renza with RBC Capital Markets.

Great. Brian and Agios team. Let me add my congrats on these results and the streak of wins and thanks for taking our questions. Maybe, Brian, just kind of going directly in. When you think about the -- just the clinical meaningfulness of these results, certainly, one that comes up is just how to think about these top line results in the context of, of course, luspatercept. I just wanted to give you and the team an opportunity to maybe just expand on that in the clinical setting, just beyond certainly the oral and IV or injectable dynamics, I should say, and then secondly, just in regards to the placebo response as Jeremie laid out those 11 patients, I'm just curious how you think about those 11 patients who were reported as responders and just putting that into context, please?

Sure. Thanks, Greg. I think I'm going to start with your first question, and then Sarah can take the second on placebo patients. I mean, look, we have set a very high bar based on this study with mitapivat for transfusion-dependent patients and, frankly, across the entire program for thalassemia. So just to regroup on what we reported this morning, ENERGIZE-T demonstrated statistical significance on the primary endpoint. We're very pleased about that. But also on all of the key secondary endpoints, which really point towards duration and durability of the result. And of note, I just want to reemphasize, this is the first study to demonstrate 36 weeks of durability of response. And with respect to your comment about treatment modality, this is an oral therapy with mitapivat. So what that means at the patient level is when we talk about from this study, the fact that 9.9% of the patients achieved transfusion independence defined as 8 weeks or more of no transfusions, it's interesting because what that means with an oral therapy is that not only are the patients independent of transfusions, they are literally independent of the clinic which is the end goal that we're trying to achieve for these patients. So we're very proud of these results. And again, I think in many ways, this sets the bar for everyone else. And Sarah, do you want to take the placebo question?

Sure. Yes. So indeed, the placebo response rate that we observed in ENERGIZE-T was slightly higher if you -- especially if you compare to the luspatercept trial program, but it is within what was expected -- in the expected range for placebo response in this type of study. It was in line with the assumptions we have made when we were designing the study. And so with that, we actually have the result of statistical significance across the primary in all three key secondary endpoints, so clearly demonstrating an improvement in transfusion reduction response. Yes, I'll leave it.

Brian, if I may just one more question. Just as you reiterating the regulatory submission by end of this year. I just wanted to confirm that this is a supplemental NDA or what the plans are as far as those details?

Yes. So yes, confirming that, and we are basically planning to submit all of our clinical trial data plus the data from extension studies and are looking forward to work with the regulatory agencies towards the next steps.

Yes. And I'll just take the opportunity to mention by the end of the year, will be equally exciting for us because we have two corporate goals. One is the submission to the FDA for approval, targeting all thalassemia types with -- based on ENERGIZE and ENERGIZE-T. And again, as a reminder, the other part by the end of the year is we're looking to have a RISE UP Phase III study for sickle cell disease also fully enrolled. So this, 2024 has been very exciting, and it will continue to be so going forward.

Our next question comes from Marc Frahm with TD Cowen.

Congrats on the data this morning. Maybe to Sarah one back in your reported ENERGIZE trial, you didn't make some comments kind of on the relative efficacy in the alpha versus beta-thal subsets. I was wondering if you could maybe you can provide a little bit of commentary there of the kind of relative treatment effect you're seeing across those subsets of thalassemia in this trial. And then the other is with the primary endpoint, I think the kind of headline number is a little bit lower than what Reblozyl achieved in at least the beta-thal subset. But then the transfusion independence data looks at least comparable. And then Brian, very well said, I think, on the kind of relative impact of achieving transfusion independence with an oral therapy versus -- oral versus injectable. So maybe if you could comment on kind of the relative positioning there and maybe what's going on in that maybe the disconnect between the -- what you're seeing in the primary endpoint versus the transfusion-independent endpoint.

Sarah, do you want to start on the alpha?

Well, yes. So the stratification factor for this trial was different. It was non-beta-zero -- non-beta-zero versus beta-zero, beta-zero and again, we have in the subgroup that said, there is none that drives the overall efficacy results. So we're in a very similar position as for ENERGIZE and are pleased with those results. In regards to the -- what the disconnect on the primary endpoint and what we observe on the transfusion independence, this is the mechanism of action of the drug is different. The trials were different, too. It's hard to make a cross-trial comparison because of the different patient population. But clearly, this drug has delivered on its promise of improving red blood cell health and what is exciting for us is that consistent with what we have observed before is that responses can be maintained over a long stretch of time because it truly tries to improve red blood cells health overall. And so that's where we are very excited about our primary endpoint hitting on statistical significance, but we're also extremely excited about our secondary -- or key secondary inputs. Especially the ones that go for a very long duration interval and then, of course, the transfusion independence, which we wanted to highlight to you guys to provide a more complete picture.

And Marc, since you asked about ENERGIZE, I'll just take the opportunity to do a quick advertisement that we were so delighted to have the energized data selected for a plenary session at the European Hematology Association, EHA and that's only in about 2 weeks. That will be on June 15. And then we've already announced that we'll have a webcast the next day on the 16th. So we'll be very happy to discuss those trial results more.

Our next question comes from Christopher Raymond with Piper Sandler.

Congrats from us as well. Really great to see. So maybe just a couple of questions. I know you guys don't have a label yet. But just assuming this is consistent, it's consistent with the data you've had and maybe as broad as hoped. Just looking at the dropout rate, it's very consistent with luspatercept. So I don't know if there's an argument there in terms of differentiation on safety. But I mean, I guess you obviously will have both alpha and beta thal in KOLs that we've talked to have talked about the oral route of administration treatment burden being advantageous for you guys. Just maybe -- is this -- can you contextualize how you think that the treatment decision tree is going to evolve here especially with -- you've got obviously gene therapy approaches that are launching in the space. Any color there? And I've got a follow-up.

Yes, Chris, thanks a lot for the question. I think that from this data -- from this data today with ENERGIZE-T as well as the combined data set with ENERGIZE. Again, we're in a very unique position. This sets a very high bar for what we hope will become foundational therapy for all thalassemia patients. And we've got the two dimensions covered already. We just talked about both alpha and beta-thalassemia patients, which are well represented in our trials. We also now, with the benefit of today's data we have covered non-transfusion-dependent patients, which is about 2/3 of the population in the U.S. as well as remarkably from today's data, the transfusion-dependent patients. And this is oral therapy, which is not necessarily the headline for this product. But in this particular patient population, particularly the transfusion-dependent patients, where the goal is to be free of the clinic. That is a tremendous advantage. And the last thing I'll just say is, keep in mind for this trial, we set the bar high with the primary endpoint of 50% reduction in transfusions. We know from our research and extensive discussions with thought leaders. In fact, we have one -- I have one sitting right next to me with Jeremie Estepp. We know that, that is very significant for patients. And so while we're pleased that others, you mentioned gene therapy continue to make progress on their options for patients to we think of this as foundational therapy potential for a very broad set of patients.

Awesome. Okay. And then maybe as a follow-up, I know you want to probably save much of the detail for EHA, but -- and I think I heard just Brian say that alpha and beta were represented well in the trial, but any differences in terms of response between those patients or anything that we should be thinking about as we think about the full data at EHA?

So the data at EHA will be on ENERGIZE, right? So that is indeed where the stratification factor occurred on alpha- or beta-thalassemia and subgroups will be part of the presentation for our typical presentation. So very similar to how we presented ACTIVATE in pyruvate kinase deficiency. And we've mentioned before as well that none of the subgroups was driving the overall efficacy results. So we talk about what favored in both genotypes.

Thanks, Chris. We'll see you on the 16th.

Our next question comes from Andrew Berens with Leerink.

Congrats on the results side. You obviously had a lot of favorable news recently. A couple for me. I know you're going to present the data at upcoming meeting, but given mitapivat's mechanism of action, I'm particularly interested in any qualitative comments on the metabolic iron parameters in the trial. And then I know Sarah mentioned ENERGIZE had a positive trend in the PRO, but was there actually a PRO and ENERGIZE-T? And then just can you remind us your plans to have commercialize mitapivat outside the U.S.?

So I can maybe take the first two and then hand it over to [ Tsveta ]. So in regards to we did measure iron overload parameters in the trial. And so we'll be looking to present that at a later meeting. We haven't disclosed any data on that yet. But again, like very similar to how we have presented on PKD, you can expect that from us at some point in time as well. In regards to the PRO and ENERGIZE-T, we only have because it's a different set up, right? These patients are regularly transfused. So it's very hard to measure a PRO like what -- how the way we've done it in ENERGIZE. We have looked at some help related quality of life measures as it relates to transfusion specifically. And I'll hand it over to you.

Commercially, obviously, we're super, super excited to see the results of the second ENERGIZE-T study coming together and we are actively preparing. We've been actively preparing for launch, but now across the totality of the thalassemia population and are excited [indiscernible] to provide really the first oral disease-modifying therapy that will be approved across all the thalassemia subtypes. I think the data from the two studies really positions us very well commercially to have a differentiated profile, which will position us as a first-line therapy of [indiscernible] thalassemia subtype. And that's demonstrated not only by the efficacy data that we've seen across the two studies but the impact of quality of life and the possibility of some patients achieving transfusion independence, we see that commercially and very clinically meaningful across all the patients. When it comes to the ex U.S. profile, of course, as we try to expand geographically, we're actively preparing for the launch in the U.S. As Sarah mentioned, we are also submitting regulatory approvals and preparing for European as well as the Gulf Cooperation Countries and we are looking to provide mitapivat for thalassemia patients across the world through partnerships, and we are actively working to secure those partnerships as soon as possible with advancement and the launch of the data.

And you can imagine, just as we had, Andy, with ENERGIZE announced back in January, our partners as they get exposure to this data, that only strengthens those opportunities that we have in GCC and beyond. So we really feel like we're in a great position of strength.

Our next question comes from Alec Stranahan with Bank of America.

Congrats from us as well on the positive readout from ENERGIZE-T. Just a couple of questions. U.S. submission by the end of this year. I guess when would you be equipped to provide guidance on timing of EU submission? And from your interactions with regulators, would you say EMA and FDA are more or less aligned on what they would want to see for approval? And then just lastly, sorry if I missed this from an earlier question, but what was the relative percentage of alpha versus beta enrolled in the study? And in terms of the transfusion independence, I imagine this is maybe something you'll seek to provide that at a later date, but any difference here between alpha and beta on transfusion independence that you're seeing?

So in regards to the first question in U.S. submission versus EU submission. So we do work in a way that we try to provide core documents for all of our regulatory submissions, which we have done before as well. They do -- like each regulator does follow different process and time line. So we work alongside with them. And so our conversations, we have had all conversations that were needed along the development program, and we'll continue to do so because there is now different conversations we will be having moving forward leading up to the submission to and then the ongoing review. In regards to that percentage alpha versus beta in this specific trial. So the stratification factor was not on alpha versus beta but rather alpha is included in the non-beta-zero, beta-zero population. And there, again, we -- there is no -- from those subgroups, one that drives the overall efficacy results. And that is consistent with how that population is -- it's set up because for the regularly transfused patient population, you have less thalassemia patients than what you would see in the non-regularly transfused patient population. And so that's why we chose to have the stratification factors between those two trials differently. To get -- together, those two trials provide data across the whole spectrum of thalassemia. So all of these different genotype plus the transfusion burden.

And the last one on transfusion independence and the split between alpha and beta. I think the simple answer there is we're not going to go further today beyond the 9.9% of the patients achieved transfusion independence, which we just think again is fabulous for patients because that's -- that the ultimate goal is these are the patients that are now non-transfusion dependent. And again, with an oral formulation, that also means they're independent of the clinic, but we're not going to split that out further at this time.

Our next question comes from Salveen Richter with Goldman Sachs.

This is [ Lydia ] on for Salveen. Congrats on the data. Just to expand on some earlier questions, are there any gating factors prior to filing by year-end, particularly to include all subtypes in the label?

So this is -- we're just going to follow regular process and engage with the regulators along the way now that we have the Phase III clinical trial data submit with our -- the difficult structure and engage in the questions and answers because there's always review questions and work with the regulators together. And so the gating factor is us being able to like pull it all together for the agencies to be able to do their review. And that's really...

But again, we have confidence in that as our year-end goal as one of a couple of really important year-end goals, as I mentioned. The other one is full recruitment of the RISE UP Phase III study in sickle cell disease. And I think today's call is just more evidence about the excellence in not just how we design trials and the ambition that we have for patients but the execution. And that's I'm really, really proud of Sarah Gheuens and her whole team and we look forward to that event by year-end of submission.

Thank you. There are no further questions. At this time, I'd like to turn the call back over to CEO, Brian Goff, for closing remarks.

Thanks a lot, Michelle, and thanks again to everyone for the excellent questions, and thanks for listening in. We look forward to speaking with some of you again soon, hopefully from EHA in Madrid. I mentioned we have a webcast that's planned for June 16, following the plenary session that we have that we're expecting on June 15, in Madrid. So thanks again, and hope you have a great rest of the day.

Thank you for your participation. This does conclude the program. You may now disconnect. Good day.