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

Good morning, and welcome to Agios webcast and conference call regarding the ENERGIZE 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, VP Investor Relations and Corporate Communications for Agios. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Agios webcast and conference call, highlighting the top line data of 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 will 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 and 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 any other future filings that we may make with the SEC. And with that, I'll turn the call over to Brian.

Well, thanks a lot, Chris, and good morning, everyone. I hope everyone had the opportunity to recharge a bit over the last week. And I must say we are thrilled to begin 2024 by announcing positive results from the Phase III ENERGIZE study of mitapivat in non-transfusion-dependent thalassemia. Non-transfusion-dependent thalassemia represents over half of thalassemia cases and while this disease often leads to damage to multiple organ systems and significantly reduces patient quality of life, there are currently no approved oral therapies. With the positive data that Jeremie and Sarah will discuss over the next few minutes, we believe that mitapivat has the potential to become the first oral therapy approved for non-transfusion-dependent thalassemia and we look forward to continuing to advance our ongoing and fully enrolled Phase III study in transfusion-dependent thalassemia with the goal of ultimately delivering the first therapy approved for all adults living with thalassemia. So with that, I'm going to ask Jeremie Estepp, who leads the mitapivat development program in thalassemia to review the top line data from the ENERGIZE study. Jeremie?

Thanks so much, Brian. It's so amazing to be here today. And before I jump into the data, I just want to take a personal second to note that for me personally before joining Agios almost 3 years ago, I was a practicing pediatric hematologist here in the U.S. where I regularly treated patients with both sickle cell disease and thalassemia and observed firsthand the impact that these diseases had on their life, the unmet need and the challenges that they face and it's just a privilege to be here to represent the ENERGIZE program team and our community partners and the patients that participated in the studies to provide a review of the results of the first positive Phase III study of an oral treatment for non-transfusion-dependent thalassemia. So as a reminder, thalassemia is a group of genetic disorders that impacts both alpha and beta globin generation and results in the production of excess globin chains. These excess globin chains then precipitate causing red blood cell toxicity and leading to ineffective erythropoiesis and hemolysis. And importantly, while patients with non-transfusion-dependent thalassemia do not require regular transfusions for survival, they do suffer from chronic anemia, significant complications related to damage of nearly all their organ systems, a reduction in their quality of life and premature mortality, and treatment options are limited across the thalassemia subtypes, and there are currently no oral treatments approved for non-transfusion-dependent thalassemia. The glycolytic pathway is a key target in pathway for red blood cells because that's the pathway that provides the required ATP needed for normal erythrocyte red blood cell health. And by enhancing ATP production, mitapivat has the potential to correct the red blood cell metabolism and improve the overall health and function of thalassemic blood cells, leading to a more effective erythropoiesis, a reduction in hemolysis and improving our patients overall feel and function. Based off this hypothesis, 2 global Phase III randomized controlled trials of PYRUKYND and thalassemia were developed that encompass a broad range of thalassemia patients. Mitapivat's mechanism of action has the potential to address the underlying pathophysiology in all forms of thalassemia, including Alpha- and Beta-Thalassemia and we're, therefore, advancing 2 global Phase III studies to evaluate mitapivat in these subtypes, the only Phase III study to evaluate thalassemia and all of the groups. The first of these studies, which is the focus of today's announcement is ENERGIZE depicted on the left, in which patients with alpha or beta non-transfusion-dependent thalassemia were randomized 2:1 to receive either 100 milligrams of mitapivat or placebo twice daily for 24 weeks, followed by an open-label extension period of lasting of up to 5 years. On this slide, we described the original number targeted for enrollment for the ENERGIZE study of 171. As we noted in our news release, the actual enrollment came ahead at 194 subjects. The primary end point of this study was hemoglobin response rate defined as an increase of at least 1 gram per deciliter in average hemoglobin concentrate from week 12 to week 24 compared to baseline. The key secondary endpoints include changes from baseline and average FACIT-Fatigue Score and average hemoglobin concentrations, and Sarah Gheuens will speak to on the complementary ENERGIZE-T study which is evaluating mitapivat in patients with transfusion-dependent thalassemia in just a few minutes. So we are very pleased to report that the Phase III ENERGIZE study of mitapivat met its primary endpoint of hemoglobin response. On the primary endpoint, treatment with mitapivat demonstrated a highly statistically significant increase in hemoglobin response rate compared to placebo with a p-value of less than 0.0001. Of the 130 patients randomized to receive mitapivat, 55 of them or 42.3% achieved a hemoglobin response of at least 1 gram per deciliter and average hemoglobin concentration from weeks 12 through weeks 24 compared to baseline. Of the 64 patients randomized to receive placebo, 1 patient or 1.6% achieved a hemoglobin response. As mentioned, this difference was highly significant with a p-value of less than 0.0001. Turning to the secondary endpoints. Treatment with 100 milligrams mitapivat also resulted in statistically significant improvements in both the key secondary endpoints, which included a change from baseline in average hemoglobin concentration from weeks 12 to 24 and a change from baseline and average FACIT-Fatigue subscale scores from weeks 12 to 24. Overall, during the 24-week double-blind period, incidents of adverse events were similar across mitapivat and placebo arms with 4 subjects or 3.1% in the mitapivat arm experiencing adverse events leading to discontinuation and there were no AEs in the placebo arm leading to discontinuation. Based on these data, we're very inspired and hopeful for the potential of mitapivat to become the first oral therapy approved for all adults living with non-transfusion-dependent Alpha- or Beta-Thalassemia and we look forward to presenting more detailed analysis from this study and upcoming medical meetings. And with that, I will turn it over to Sarah Gheuens.

Thank you, Jeremie. And before I dig in further in ENERGIZE-T, I want to say thank you very much to all of the patients who participated, to all of the investigators who have run this study but also a very special thanks to you and to the whole ENERGIZE team because it truly takes a village to get these studies to be completed and the results today, we couldn't be more happy. So with that, I think today's data truly underscore the potential for mitapivat to become a foundational therapy in non-transfusion-dependent thalassemia, was highlighted as well in Dr. Taher's quotes in release today. And I would like to spend the next few minutes outlining our next path forward for a broader [indiscernible] program in thalassemia. So today, treatment options for thalassemia are limited. So for instance, when you look at the distribution here on the slide, in the U.S., there are approximately 60% of thalassemia patients including those with non-transfusion-dependent disease that have no approved treatment options. So building on the data that we reported today, our goal is to deliver a convenient oral therapy that addresses the underlying pathophysiology of thalassemia and is approved to treat all types of the disease. We aim to build on this momentum as we continue to advance ENERGIZE-T. So Jeremie has spoken today about ENERGIZE, which is on the left. So now we're focusing on the right-hand side of the slide. So ENERGIZE-T, the second arm of the mitapivat development program. And that study is evaluating mitapivat in transfusion-dependent patients. It's evaluating the same dose of 100-milligram mitapivat versus placebo and is enrolling individuals with both Alpha- and Beta-Thalassemia but the primary endpoint here is reduction in transfusion burden, defined a 50% reduction in transfusion burden in any 12-week rolling period in the 48-week trial duration. Secondary endpoints include additional measures of transfusion reduction in safety. So looking ahead, we are hoping to have a potential [indiscernible] thalassemia, and our regulatory strategy is to do this with one single filing encompassing the data of ENERGIZE and ENERGIZE-T as we seek a broad indication for all adult thalassemia patients in the U.S. We have moved up our time line for the data readout for the Phase III ENERGIZE-T study to the middle of this year rather than our previous projection of second half of 2024 and this translates into a potential approval for all forms of thalassemia in the U.S. next year. And with that, I will turn over the call back to Brian.

Well, thanks a lot, Sarah, and Jeremie to you as well. This is certainly a proud day for the organization. Today's positive Phase III readout in thalassemia is obviously an important addition to the growing body of evidence suggesting that mitapivat has the potential to transform the treatment of a range of hematologic diseases. And these include PK deficiency, where we are already launched with a brand name PYRUKYND, sickle cell disease, and you may recall that we just reported positive Phase II data at ASH last month. And of course, thalassemia, where we're discussing some very exciting Phase III data today. So as we advance our late-stage mitapivat development program across multiple rare hematologic diseases, and these are shown in orange on this slide. We also continue to progress programs in additional rare diseases with high unmet need, and these include lower risk MDS, phenylketonuria, or PKU, and polycythemia vera or PV. Perhaps most importantly, in addition to today's readout, we expect 4 more Phase III readouts of mitapivat by the end of next year. And so we're obviously in the midst of a very exciting time at Agios. So these include the Phase III ENERGIZE-T study in transfusion-dependent thalassemia and we've now updated our timing guidance to have this readout in the middle of this year. The Phase III ACTIVATE-Kids and ACTIVATE-KidsT study in pediatric PK deficiency next year and the Phase III RISE UP study in sickle cell disease also next year. With these anticipated readouts, we have the potential for an approval in thalassemia next year and approvals in both pediatric PK deficiency and sickle cell disease in 2026. Today's positive Phase III data combined with 4 additional Phase III readouts by the end of next year, really position Agios for significant growth over both the near and long term. The data for mitapivat across multiple hematologic diseases continues to be consistent. Our current launch in PK deficiency has strengthened the capabilities that we believe will need for multiple potential launches in larger patient populations over the next few years, and we remain in a strong cash position to complete our ongoing programs and potentially expand our portfolio through disciplined business development into 2026. Now before we transition to Q&A, I would also like to take a moment to extend my sincere gratitude to all of the patients who participated in the ENERGIZE study, as well as our employees who continue to do a fabulous job, and you just heard from 2 of our finest Jeremie and Sarah as well our collaborators, our study investigators and our advisers in the patient and clinical communities for their partnership and achieving this milestone. So with that, we will now open the call for questions.

[Operator Instructions] The first question comes from Tess Romero with JP Morgan.

Good morning, Brian and team. Nice to see this positive result here. I'm looking forward to seeing you all next week at our conference. So a couple of questions from us here. Can you remind us how the patient demographics and baseline characteristics in ENERGIZE compared to the prior Phase II trial? And how should we think about the proportion of Alpha-Thalassemia patients that were enrolled in this study versus the prior trial here? And thinking back, as I recall, I think -- not -- I think the response rate in the Phase II was over 80%. And then as you think about the kind of around 43% that you saw here, what do you think the main reasons could be for that kind of coming in? And anything else you would sort of mention about helping us put that response rate that you saw in the context? And looking forward to next week.

We are as well. Thanks a lot, Tess. So I'm going to let Sarah get going on your questions.

Thanks, Tess, and looking forward to next week as well. So in regards to the population, the comparison, so this is the non-transfusion-dependent patient population trial ENERGIZE. So that was the similar population as we had in Phase II. In Phase II, we also allowed for different genotypes to come into the trial. So similar to this trial, we have Alpha- and Beta-Thalassemia patients participating in the trial. In regards to further details on the distribution and patient baseline characteristics, we will present all of that information at an upcoming medical meeting, but we can already say that the patient population in the trial is reflective of the general patient population for thalassemia globally. So we are very pleased with that. In regards to your second question, response rate of Phase II versus Phase III. Just want to remind that in the Phase II, this was really a proof of concept. So we looked at hemoglobin increase at a different time period just for 1 time point before reaching week 12. Here, we have put a different bar on the hemoglobin response, meaning that we were looking for a maintenance of response. So we averaged out hemoglobin over week 12 to week 24 to get to the Phase III endpoint. And that, of course, leads to a more stringent hemoglobin response rate. We are, however, extremely pleased with this result both the primary endpoint of 43%, but then also all of the key secondary endpoints. And we truly believe this is creating a package that is allowing us to speak to the benefit risk profile of this drug.

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

And congratulations on the data. Can you talk a little bit about your sense of the urgency to treat these patients with non-transfusion-dependent disease relative to the transfusion-dependent patients and any differences in uptick you might expect between those groups? And then on the commercialization front, what does this mean for your plans for European commercialization of mitapivat in this indication and in PKD? And at what point would you move to build an infrastructure in Europe or seek a partner there?

Yes. Thanks a lot, Greg. I think -- so we'll do it in 2 parts. And it's perfect that Jeremie is here as a -- someone with significant clinical experience in thalassemia, I think he should comment on that question. And then that, I can pick up on the commercial question.

Yes. So with respect to treatment urgency for NTV, I think that the urgency is a fair amount importance -- the most recent treatment guidelines for thalassemia from [ Tiff ] have highlighted that non-transfusion-dependent thalassemia patients with hemoglobins of less than 10 grams per deciliter on average or at a high risk of developing the long-term complications of end organ damage and reduced quality of life and premature mortality. So I think that the academic field is really transitioning towards the idea that we really need to be quite a bit more aggressive with respect to treating these patients. The other thing to highlight about the urgency that I think that the program itself highlighted was this program was in approximately 20 countries across the globe and routinely beat the metrics with respect to site activation, with respect to how quickly we were able to screen patients, how quickly we were able to enroll them into the studies and I think that, that speaks to the urgency that the community itself has identified with respect to the urgency and the need for non-transfusion-dependent thalassemia patients. And with that, I'll turn it over to Tsveta for the second half of the question.

Perfect. And thanks for the question. We are obviously very excited to see the positive results today. As both Brian and Sarah mentioned, over 50% of the thalassemia patients around the globe are non-transfusion dependent patients. In the U.S., they have no treatment approved for non-transfusion-dependent thalassemia and globally, there is no oral therapy approved for those patients. So we are excited to be actively preparing for the launch. When you think about the U.S., there are about 8,000 patients with thalassemia in the U.S. And we are preparing for the launch on 2 dimensions, both utilizing some of the capabilities we've built through PK deficiency but also very much recognizing that it's going to be a very different launch with thalassemia. And one of the primary reasons for that is the thalassemia patients are actually diagnosed and known to the health care systems. There is a newborn screening for thalassemia, there are established ICD-10 codes, and that gives us the opportunity to actually focus our educational efforts on the unmet need and the burden of the disease which just Jeremie outlined in the areas where we know the physicians actively managing and monitoring non-transfusion-dependent thalassemia patients. We've communicated also several times that the global prevalence of thalassemia is quite unique. There is high prevalence in the Gulf region, in the [ GCC ] countries. And just as a comparison to remind you, 8,000 patients with thalassemia in the U.S., there are 70,000 patients with thalassemia in the Gulf region. So we are actually now especially with the positive data momentum, actively looking to identify partners for commercializing PYRUKYND globally for thalassemia, the GCC region but also in other regions across the globe, and we'll be moving as quickly as possible there now with the positive data behind us.

Our next question comes from Chris Raymond with Piper Sandler.

Congrats from us as well on this positive readout. Maybe 2 questions. I think I wanted to follow up on the comparison between the Phase II and the Phase III. So I guess this may come out when you present the full data. But just thinking about the different measurements that you guys used, we -- I think the Phase II looked at response week 4 to 12. This is week 24. Is there like a tapering off, I guess, of response? Is there some sort of trajectory that we should be thinking about in terms of long-term effect? I guess that's first and foremost. And then second question is, when we think about the ENERGIZE-T study at midyear that you have, just looking at Reblozyl, it confers a less than 10% placebo-adjusted benefit. Is that the bogie to do better than Reblozyl in transfusion-dependent thal patients? Or is there some other way to think about it?

So thanks for the question. So in regards to your first question, the drug behaves like it typically has behaved. So we -- I mean, we don't see a tapering of the effect or the maintenance of the response. I think the best data set to look at is our Phase II in which we have continued to follow patients for multiple years now. And you can see that the hemoglobin response is maintained, and that is consistent with how we -- how the drug behaves across the different indications. So this is truly -- the different response rate is truly a reflection of a different endpoint being used and the number of measurements being done, and that's really it. So, we are very pleased with how the drug behaves. The drug behaves exactly as we know it to behave. And so -- yes, no tapering of the said drug. In regards to your second question, it's obviously not a head-to-head comparison to luspatercept program. It's a very different mechanism of action. The way we have defined our primary endpoint is also different than how Reblozyl have defined their primary endpoint. So we are now just very eagerly awaiting the readout of that trial and are looking forward to report those results midyear.

Yes. And maybe I'll just add on that, in overall, the way we see that mitapivat can be positioned in this patient segment with thalassemias, First of all, as a reminder, what we're going after is all subtypes of thalassemia. So it's Beta-thalassemia, of course, where there's been a lot of focus from others, but also importantly Alpha-thalassemia that has literally no approved therapeutic option. And then the reason this is such an important day for thalassemia from our perspective is here you have data showing both hemoglobin improvements, of course, but also feel and function, which we look for consistently across all of our hematologic pursuits with mitapivat and the PRO data, we think, is particularly inspiring. So it's really the totality of data that we're looking to bring to the table with our regulatory package. And then lastly, and given the data that we have, this is more of an incidental point, but the fact that this is oral therapy versus subcutaneous every 3 weeks, we think that's obviously very beneficial for patients from an access and ease-of-use standpoint. But again, going back to the point that Jeremie made, I think, look, no further than the fact that this trial recruited so efficiently and we certainly have the ENERGIZE-T study fully enrolled that usually that's a great indicator about the product profile and how both investigators and patients see it.

The next question comes from Andy Berens with Leerink.

Congrats from me on the successful trial. Obviously, a good way to start the new year. Two questions -- two questions. You already gave us some color on the difference between the Phase II results and what you presented today. Just wondering if you could give us any more idea about who responded or didn't respond that could predict who may get benefits eventually from treatment? And then one regulatory question. We see the FDA stat back from responder analyses and communicate a preference from a more holistic view of efficacy. It seems like most of those cases have been with more subjective end points but just wondering if you think the agency will be more focused on mean changes in the cohort versus the responder analysis, is that the primary endpoint?

Thanks, Andy. So in regards to the question from the difference between Phase II and Phase III, I'm going to try to give you a little bit of a different flavor here. But our study, the Phase III study truly delivered on its pre-specified primary endpoints, meaning, it was an intent-to-treat analysis, meaning that the mitapivat patients, people who responded and not responded, everybody was being looked at and compared to placebo. What I can tell you is that the pre-specified sub group analysis, all favored mitapivat as well in comparison to placebo around our stratification factor. So there was not a specific group driving this result, which is also very good news. And then in regards to the average changes of hemoglobin, that is a key secondary endpoint. So that is part of our data package. Again, this is an intent-to-treat. So it will include nonresponders and responders, which is a very typical way to -- to provide your clinical trial results for regulatory review.

The next question comes from Salveen Richter with Goldman Sachs.