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

Good morning, and welcome to the Agios Pharmaceuticals Investor Conference Call and Webcast. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Please go ahead.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss top line results from the pivotal Phase III RISE UP trial of mitapivat for the treatment of sickle cell disease. You can access the slides for today's call by going to the Investors section of our website, agios.com. Next slide, please. Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because 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. The next slide shows the agenda for today's call. On the call with me today from Agios, we have Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Next slide, please. We are also joined on the call by Dr. Biree Andemariam, a thought leader in the sickle cell disease clinical community. Dr. Andemariam is a Professor of Medicine and the American Red Cross Endowed Chair in Transfusion Medicine at the University of Connecticut School of Medicine. She is the Founding Director of the New England Sickle Cell Institute and serves as Director of the Connecticut Bleeding Disorder Center. Dr. Andemariam previously served as Chief Medical Officer and on the Board of Directors of the Sickle Cell Disease Association of America. We are pleased to have Dr. Andemariam provide her clinical perspective on the devastating nature of sickle cell disease and the RISE UP Phase III trial results. Following prepared remarks, we will open the call for questions. With that, please advance to the next slide, and I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining today's call. At Agios, everything begins with connection. We partner closely with the rare disease communities we serve to deeply understand their challenges and priorities. This collaboration drives our ability to develop and deliver innovative medicines with the potential to transform lives. As you'll be reminded on this call, sickle cell is a complex and devastating disease. In the U.S., median life expectancy for sickle cell patients is in the late 30s. Despite the staggering statistic, treatment options remain limited. Yet patients continue to advocate fiercely for progress, seeking partners who share their passion and commitment. We at Agios are proud to stand alongside them. On the next slide, you'll see a quote from Cassandra, a sickle cell disease patient and advocate whose words reflect the reality faced by millions of patients worldwide. Her perspective underscores both the severe nature of this disease and the urgent need for new treatment options. As we announced in our press release this morning, the RISE UP Phase III trial of mitapivat in sickle cell disease achieved statistical significance on the primary endpoint of hemoglobin response. And while mitapivat showed a reduction in the other primary endpoint of annualized rate of sickle cell pain crisis, this trend did not achieve statistical significance. On today's call, you'll hear from Dr. Biree Andemariam, who will provide an important perspective on the significant burden faced by patients living with sickle cell disease. Following her remarks, Sarah will do a deeper dive into the Phase III RISE UP trial results, after which Dr. Andemariam will share her clinical insights on the data. Our goal is that by the end of this call, you'll share our conviction in the totality of data and understand the significant potential mitapivat holds in the treatment of sickle cell disease. And with that, please advance to the next slide, and I'll hand the call over to Dr. Andemariam.

Thank you very much, Brian, and thank you, everyone, here at Agios for giving me the opportunity to lay the framework for how sickle cell disease affects the body and how it's deleterious affects and impede the quality of life. First of all, I think it's important for us to remember that sickle cell disease, even though it's a hereditary disorder with a common genetic mutation across individuals, it really has heterogeneous presentation, clinical presentation. And this makes treatments as well as manifestations of the disease very complex to manage. Sickle cell disease affects the red blood cells, specifically the hemoglobin inside of the red blood cell. And since the red blood cells traverse the entire body through circulation, it is a multisystem disorder. And in so doing, as the sickle cells traverse the vasculature, they have the ability to affect virtually every organ system. It's also important to understand the underlying pathophysiology of sickle cell disease. Well, first of all, there's a chronic underlying hemolytic anemia, red blood cells are fragile. They break open easily. The average lifespan of somebody born with sickle cell disease, their red blood cell average lifespan is only 1 to 2 weeks compared to the average person without sickle cell disease where the red blood cells last 3 to 4 months. The other core part of the underlying pathophysiology of sickle cell disease is vaso-occlusion. This is blockage of blood flow at the microvascular level, again, impeding blood flow to all the vital organs. And together, the hemolytic anemia and the vaso-occlusive processes lead to the underlying severe morbidity and cumulative morbidity over the lifespan as well as the early mortality that you raised, Brian. Hemolysis itself, breaking open of red blood cells leads to the release of toxic factors into the intravascular space. This includes free hemoglobin as well as the enzyme arginase. And these and other factors lead to endothelial dysfunction or vasculopathy, a depletion of nitric oxide as well as the activation of a number of inflammatory mediators. And together, this amplifies the risk of vaso-occlusive events. So hemolysis itself leads to vaso-occlusion. So this has been very technical. It's focusing on pathophysiology and biology. It's very complex. But I think we'd be remiss if we didn't also touch on the fact that quality of life in persons with sickle cell disease is very much reduced. And in these people born with this condition, they face a lifetime of having to manage their chronic anemia, keeping in mind that the person living with sickle cell disease has about half the blood volume of someone born without sickle cell disease, and they have to function in society being very anemic and also managing the potential for the development of chronic organ damage over the lifetime as well as managing the vaso-occlusive pain crises that come out of nowhere and make it very difficult to lead fully productive lives. With the next slide, I'd like to just orient us all to what treatment options we have for sickle cell disease. And first of all, what I think you'll appreciate is that we have very few dots on the time line. Sickle cell disease was first reported in the medical literature in 1910, but it wasn't until 1998 that the first drug was approved and that's hydroxyurea, which is the standard of care for all individuals with sickle cell disease. It wasn't until almost 20 years later that the second approved drug for sickle cell disease came on the market, L-glutamine for its ability to reduce vaso-occlusive pain crises. But this has not had much uptake in the community for a number of reasons, including the fact that if you look at the Phase III trial, there was an imbalance in terms of dropouts in the treatment arm compared to placebo. And there's been some difficulty, I think, with understanding and communicating the mechanism of action of L-glutamine. think we were all excited 2 years later when 2 new drugs were approved for sickle cell disease within 2 weeks of each other. 1 being crizanlizumab, which reduced vaso-occlusive crisis and 1 being voxelotor, which was an antihemolytic. And although these did benefit a substantial proportion of individuals living with sickle cell disease. Unfortunately, in a follow-up Phase III study of crizanlizumab, there was no difference compared to placebo, which led to it being withdrawn from the European market. And with voxelotor, as many of us know, after 5 years in the market, it was withdrawn by the manufacturer globally due to some concerns regarding safety and ongoing Phase III studies. So this is where we are in terms of disease-modifying therapy with very few agents and many of us believe that really all we have is hydroxyurea. Just want to touch on the fact that, yes, gene therapies were approved about 2 years ago, but these are complex to give, even though all patients are theoretically a candidate for gene therapy because it does not require a bone marrow donor. Every patient is their own donor. It is hard to access these therapies. They have to be given through authorized treatment centers and require not only hematological expertise, but also bone marrow transplant expertise, and they're also costly. So there's been limited uptake despite some excitement for them becoming on the market. Next slide, please. I'd like to close by just addressing some of the ongoing challenges in treating individuals with hemolytic anemia and vaso-occlusive crisis and sickle cell disease. First of all, with respect to the hemolytic anemia, this is very burdensome to patients. The anemia itself makes it very difficult to function at a high level. There is the ongoing vaso-occlusive risk, endothelial dysfunction as well as end-organ damage that are driven by the underlying hemolytic burden. There are -- and I can tell you, as a clinician, very few options to improve hemoglobin in individuals with sickle cell disease, particularly since voxelotor came off of the market. And really, the mainstay of treatment for anemia is either hydroxyurea for which we only see modest increases in hemoglobin and not in everybody and blood transfusions. And blood transfusions can be very complex, leading to the development of red blood cell alloantibodies that can make it hard to find appropriately matched blood for patients in the future. They also can lead to significant iron overload. And in some parts of the world, particularly those where sickle cell disease is most prevalent, transfusions are not necessarily safe from an infection standpoint or readily available. And in terms of vaso-occlusive crisis, it's important to remember that these are the leading cause of acute morbidity and for people seeking acute medical care, whether that's an emergency department [indiscernible] office or through hospitalization. It's also important to note that right now, the only thing that I as a clinician can do to try to treat somebody that's in the midst of a vaso-occlusive crisis is really [ payload ]. We have nothing that can stop a vaso-occlusive crisis once it's begun. All we do is give patients IV fluids, some oxygen and high doses of opioids until the underlying pathophysiological process dissipates. And this is unacceptable. And some of the existing therapies that we have limitations, as I've mentioned. So I really believe that we are still in a period of time where there's a strong need for physiologically anchored, well-tolerated and predictable therapies for this population. And with that, I'd like to hand the call to Sarah. Next slide, please.

Thank you, Biree. Before I review the results of the RISE UP Phase III trial, I would like to take a moment to review the mechanism of action of mitapivat on the next slide. Mitapivat is an oral allosteric activator of red blood cell pyruvate kinase, which is the enzyme responsible for converting phosphoenolpyruvate to pyruvate and thereby converting ADP to ATP, the main source of energy for the red blood cell. So in activating pyruvate kinase, ATP levels increase and upstream in the glycolytic pathway, 2,3-DPG levels are decreased. In hemolytic anemias, higher ATP improves red blood cell membrane integrity and overall health and thereby reducing hemolysis. And then in sickle cell disease, patients also have higher levels of 2,3-DPG and lowering 2,3-DPG decreases hemoglobin S polymerization, minimizing sickling and microvascular obstruction. These data, which I'll detail shortly, indicate that effectively targeting the last step of the glycolytic pathway, which is important to increasing hemoglobin levels, help achieve upstream benefits, including decreased 2,3-DPG to potentially reduce red blood cell sickling and vaso-occlusion. Next slide, please. Here, you'll see our RISE UP Phase III trial design. As you can see, we conducted a 52-week trial comparing 100 milligram mitapivat twice daily to match placebo with a 2:1 randomization. Patients were stratified based on the number of sickle cell pain crises in the 12 months prior to informed consent and concomitant hydroxyurea use. As we have said previously, we designed this trial with 2 primary endpoints and 5 key secondary endpoints to evaluate objective measures of hemolytic anemia as well as vaso-occlusion. This comprehensive design enables a broad assessment of the potential benefits of mitapivat across multiple aspects of the disease that Dr. Andemariam referenced earlier. Next slide, please. Here, we showed baseline characteristics in the trial. While you can see there was a slightly younger patient population enrolled in the mitapivat arm than in the placebo arm, generally, baseline characteristics were well balanced across the 2 arms. On the next slide, we continue to show disease characteristics, including genotyping, number of sickle cell pain crises observed in the 12 months prior to informed consent, transfusion burden and prior disease-modifying therapy. Again, disease characteristics were well balanced across both arms and highlight that we enrolled a patient population experiencing pain crises and that was not heavily transfused. The next slide reinforces that the patients enrolled in the trial demonstrated characteristics of hemolytic anemia, including measures of hemoglobin, bilirubin, LDH and reticulocyte count. These data depict what we would naturally expect from a sickle cell disease patient population. Moving on from baseline characteristics. On the next slide, we've shown our statistical testing strategy, including the key secondary endpoint hierarchy. As we have said previously, if one or both primary endpoints achieved statistical significance per our statistical analysis plan, the level of alpha would be transferred to key secondary endpoint testing in a hierarchical fashion. Importantly, on the next slide, you can see our patient disposition data. We observed a low discontinuation rate with 85% of patients completing the 52-week double-blind treatment period. And similar to what we've observed in our PK deficiency and thalassemia trials, we saw a very high rollover rate of 99% of patients that completed the trial, they decided to enroll into the open-label extension, which is exceptional. So now moving on to our efficacy results, beginning with the first of our 2 primary endpoints on the next slide. First, I'm going to orient you to the slide format as all of the next slides will have a similar layout. So on the left-hand side of the slide, you'll see a legend, which follows the statistical testing hierarchy. And on the right-hand side, you'll see relevant data tables for each endpoint. So sickle cell patients are anemic and chronic hemolytic anemia leads to poor clinical outcomes, as Dr. Andemariam just highlighted. And therefore, we chose a hemoglobin response as the primary endpoint to be able to assess if mitapivat could improve anemia. In the placebo arm, 2 patients achieved a hemoglobin response, which was defined as at least 1 gram per deciliter increase or more in average hemoglobin concentration from week 24 through week 52 compared to baseline. And in the mitapivat arm, 56 patients achieved that endpoint. Basically being 40.6% of the trial population. So that is a highly statistically significant result on the hemoglobin response. So when we move to the next endpoint, the next primary endpoint, which is the annualized rate of sickle cell pain crisis, we chose that endpoint because, of course, as you heard, sickle cell pain crises are manifestations of vaso-occlusion, and they represent a major cause of morbidity and mortality. And therefore, we chose that as the other primary endpoint. As you can see in the data table here, we observed an annualized rate of 3.05 pain crises in the placebo arm and 2.62 in the mitapivat arm. While we did not achieve statistical significance in the total trial population, we did observe a trend with a 14% reduction in observed crises for mitapivat compared to placebo. The p-value is 0.12. So there is a trend favoring mitapivat versus placebo. So now we're moving on to the secondary endpoints, and we are going to begin with the average in hemoglobin concentration from baseline to week -- from week 24 through week 52. And this is the first key secondary endpoint, which further examines the impact of mitapivat on anemia. So on this endpoint, we show a statistically significant difference of 0.7 grams per deciliter in the average hemoglobin concentration compared to placebo. Again, a highly statistically significant result. And on the next slide, you can see the waterfall plot depicting that average change from baseline hemoglobin concentration from week 24 through week 52, which highlights that the mitapivat patients are clearly responding well and it's very much in line with our other hemolytic anemias. So as Dr. Andemariam highlighted, sickle cell disease anemia is hemolytic in nature. And so our mechanism of action improves red blood cell membrane integrity and health. So therefore, we looked at indirect bilirubin as a marker of hemolysis. And so this slide depicts the endpoint of average change in indirect bilirubin from week 24 through week 52 compared to baseline. So here, you can see that we demonstrated a mean difference of 16.91 micromoles per liter in the mitapivat arm compared to placebo, again, highly statistically significant. Moving on to the next slide. So as fatigue is considered an important symptom in sickle cell disease, we measured fatigue in this patient population. We used the PROMIS Fatigue 13a short form to capture fatigue, and we measured an average change in T scores from week 24 through week 52 compared to baseline in the total trial patient population. So first, more background on the endpoint itself. Scoring is through a normalized T-score and scores that represent fatigue actually can vary depending on the condition. And so when you look at the baseline numbers presented here, 52.72 in placebo and 53.49 in mitapivat, that means that for this disease, the trial enrolled a mildly fatigue patient population. So the patients reported mild fatigue at baseline, and we did not achieve statistical significance on this measure. So because now we are no longer showing statistical significance on the endpoint, we can no longer transfer alpha to the next endpoint, and we can no longer draw statistical conclusions on the next 2 key secondary endpoints. So on the next slide, we report analyzed rate of hospitalizations for sickle cell pain crises and hospitalizations, of course, they often represent the primary driver of health care utilization for patients. So that's why we chose that as the key -- another key secondary endpoint. And in this table, you can see that the analyzed frequency of hospitalizations was 1.81 in placebo versus 1.56 in the mitapivat arm leading to that rate ratio of 0.86, again, representing a 14% reduction in hospitalizations favoring mitapivat. And on the last slide on the key secondary endpoints. So the last endpoint we tested in our statistical hierarchy is the average change in percent reticulocytes. Again, no longer possible to draw statistical conclusions on this endpoint. But we chose reticulocytes because often you see an elevation of reticulocytes in sickle cell disease, and that is truly because it's a compensatory mechanism to address chronic hemolysis. But in addition, the reticulocytes are more adhesive. These are the young red blood cells. They're more adhesive and they're more likely to come together and thereby actively participate in the vaso-occlusive phenomena. And therefore, when hemolysis improves, this can reduce reticulocytes, placing less stress on bone marrow and in turn, reduce also vaso-occlusion. So when you look at this data table, you can see a substantial decrease from baseline in the mitapivat arm compared to placebo. And while we cannot draw statistical conclusions on this endpoint, it's the nominal p-value is 0.001 (sic) [ 0.0001 ], showing that this is a robust data point, and it continues to support the PK activation mechanism. So then when we go to the next slide, we looked at the hemoglobin responders, so the 40.6% of hemoglobin responders in the mitapivat arm. And importantly, in that group, we saw a 1.6 gram per deciliter mean increase from baseline in hemoglobin concentration in mitapivat compared to placebo. And then we continue to look at the sickle cell pain crisis-related endpoints and the PROMIS Fatigue, and this slide highlights that we observed clinically meaningful benefits. So when you look at the hemoglobin responders, we saw an annualized rate of pain crisis of 2.2 compared to 2.98 in the nonresponder group, representing a 26% reduction. Then for the analyzed rate of hospitalizations for sickle cell pain crisis, we observed a 34% reduction for hemoglobin responders compared to nonresponders. And then importantly, when you look at the rate ratio confidence intervals of both of those endpoints, you can see that one is not included. So that reinforces the robustness of these results. And then finally, when we look at the average change in PROMIS Fatigue T-scores in hemoglobin responders compared to nonresponders, we can also see there an improvement of minus 5.19 in the responders versus minus 2.55 in the nonresponders. And the minus 5.19 on average is bigger than the minus 4.1% decrease that was considered clinically meaningful for a meaningful change analysis within this trial. So therefore, we review the data as important findings from the RISE UP trial, suggesting that there are clinically meaningful benefits on sickle cell pain crises related endpoints and PROMIS Fatigue in hemoglobin responders. So finally, we're going to review the safety data, and that data supports the mitapivat's favorable safety profile. So in this overall summary of safety table, you can see that adverse events overall were generally well balanced across mitapivat arm and placebo arms. I remind -- I want to remind you, this is a year-long trial. So it is very normal for almost everybody to report an adverse event. Then when you look at the serious adverse events, there were more events reported in the placebo arm than in the mitapivat arm. And then further down in the TEAEs leading to death, you'll see that there was 1 on placebo and 2 on mitapivat 2:1 randomization, so well balanced there. I want to spend a little bit of time here because, in fact, this data highlights the severe nature of this disease. We had 2 additional deaths in the trial that were not captured as safety event per protocol, but they were part of efficacy endpoints, which leads to a total of 2.2% in the mitapivat arm and 2.9% in the placebo arm of fatal cases. But we also had 2 deaths in the screening period before a patient was even exposed to placebo and mitapivat, again, highlighting the seriousness of this disease. And then on the next slide, we also spent some time highlighting the key summary findings of the liver events analysis. So first, as with other hemolytic anemias in sickle cell disease, patients often have abnormal and fluctuating liver enzymes as part of this -- as part of the underlying disease. And so while we observed liver abnormalities across both treatment arms, any event that met prespecified criteria was reviewed for severity and causality for the likelihood of drug-induced liver injury. And so in the RISE UP trial, we did not observe an imbalance between patients in the mitapivat and placebo arms with lab values meeting lab constellations of concurrent lab values that have the highest sensitivity for drug-induced liver injury. And then upon review of the totality of the data, both by us and by independent hepatologists, there were no similar cases of drug-induced hepatocellular injury as what was observed in the mitapivat thalassemia trials. And therefore, there is no change to the safety profile the way we currently understand it. So in closing, on the next slide, I want to summarize the key takeaways of the Phase III RISE UP trial. So first, mitapivat showed a strong anti-hemolytic profile in the total trial population with a sickle cell pain crises strength. So 40.6% of the patients achieved significant hemoglobin response, and there was a statistically significant improvement in other markers of hemolysis, both on hemoglobin concentration and indirect bilirubin. And then we saw clinically meaningful benefits in hemoglobin responders. So on average, we saw a 1.6 gram per deciliter increase in this group. We saw improvements in sickle cell pain crises-related endpoints with a 26% decrease in the annualized rate of sickle cell pain crises and a 34% reduction in the analyzed rate of hospitalizations for sickle cell pain crises and a reduction in the PROMIS Fatigue T-score. And then we have a favorable safety profile. There were no similar cases of HCI as observed in thalassemia. There was a low discontinuation rate in the double-blind period. And then very importantly, the patients that completed the trial, the 99% of those patients opted to roll over into the open-label extension. So with this data, we intend to submit a marketing application for mitapivat in the U.S. for sickle cell disease after having a pre-sNDA meeting with the FDA in Q1 of 2026. And with that, I want to hand the call back over to Dr. Andemariam to put some clinical perspective on this data package.

Thank you, Sarah. Thank you for the opportunity to do just that. I think that I'm extremely encouraged by these results, particularly the analysis of the hemoglobin responders. Of course, I'm sure there are many people listening that we're hoping that the intention to treat group, that is the entire cohort would have hit on both endpoints. But I think that this is just fine. I think the notion that we were going to be able to develop a treatment for sickle cell disease that can manage the multifaceted pathophysiology of all patients all of the time is just not reasonable. And not every medication has to work in all patients. We don't expect that for other conditions. Why would we expect that for sickle cell disease. But I want to take a deeper dive on what the hemoglobin responder subgroup analysis showed us. 41% of patients in this cohort had a hemoglobin response and your threshold was a hemoglobin response of 1 gram per deciliter or more. But if you look at the mean hemoglobin increase in the responder group, 1.6 grams per deciliter and that was sustained over a year. And to put that into clinical context, we don't have anything else to offer patients that can have us achieve a mean increase of 1.6 grams per deciliter sustained over a year aside from blood transfusions. And what that would translate into is giving someone with sickle cell disease approximately 2 units of blood every couple of weeks per year, which is not sustainable. And blood transfusions, as you know, have multiple downstream clinical consequences, like I said, red blood cell antibodies, the development of iron overload, limited IV access, not to mention that those units could have gone to someone else who almost very desperately needed them. So there's a societal cost there. But I'm very encouraged by what I'm seeing in 41% of the patients. That magnitude of hemoglobin increase being sustained is clinically meaningful. When you look further at other endpoints within the hemoglobin responder group, a 26% reduction in vaso-occlusive crises. That is substantive. I would like people to understand that most of the deaths that occur in individuals with sickle cell disease occur within the context of one of these painful vaso-occlusive crises. So any reduction in the frequency of vaso-occlusive painful crises has a translational benefit in terms of prolonging survival. Health care utilization. We know that health care utilization is high in this population. When looking at costs, there was a study performed published over 10 years ago that looked at acute care costs in America for individuals living with sickle cell disease and acute care costs alone, that is hospitalizations and ER visits across Americans living with sickle cell disease approximated $2 billion per year. That doesn't include their longitudinal care, their pharmacy costs, just going to the ER in the hospital. Look at this. This drug approximated a 1/3 reduction in hospitalizations, which is meaningful on many levels. Now looking at quality of life. The improvement in fatigue in the hemoglobin responder group is fantastic. When you talk to patients, they will tell you that fatigue is their #1 symptom. It gets in the way of everything. And it's directly related to the anemia. So it's not surprising that a drug that works as an antihemolytic and has a substantial increase in the hemoglobin would confer not only reduced vaso-occlusive rate, lower health care utilization as a consequence of reduced vaso-occlusion but also improve the #1 symptom of fatigue. I think what's also important to highlight, and this was near the end of your presentation, Sarah, is that mitapivat is safe in this study. It's well tolerated by the patients. And I think looking forward, if mitapivat were to be available on the market for individuals with sickle cell disease, since it's so safe, I think you could have shared decision-making with your patients, offer it to patients and expect that a substantial proportion would have a hemoglobin response as well as a reduction in vaso-occlusive crisis. And because it's so safe, I think that you could be pretty generous in terms of who you would offer it to. So I think that this is very encouraging. I'm excited by the results, and I hope that those who are listening are as well. So I'd like to hand it back to you, Brian.

Well, thank you very much, Dr. Andemariam, for your clinical context, which is really important to hear following Sarah's very comprehensive review of the data. On the next slide, I want to reinforce the key points that Sarah made in her prepared remarks. First, mitapivat demonstrated a strong anti-hemoglytic profile in the total patient population, as you just heard, with a trend towards reduction in annualized rate of sickle cell pain crisis. Second, we observed a clinically meaningful benefit in hemoglobin responders, which represented 40.6% of patients in the mitapivat arm. And third, mitapivat demonstrated an encouraging safety profile, which, as you just heard from Dr. Andemariam, is an important feature of a potential new disease-modifying agent. Let's go to the next slide. Our corporate priorities are clear. First, we intend to maximize the value of mitapivat. We are roughly 2 weeks from our thalassemia PDUFA goal date of December 7. And I'll add, we've had positive recent labeling discussions with the FDA. We clearly remain excited about the potential to bring this transformative medicine to thalassemia patients in the U.S. And additionally, we will focus on preparing for the potential sNDA filing in sickle cell disease, as you just heard from Sarah. Second, we will continue to advance our pipeline programs. These data validate the mechanism of PK activation, and we look forward to results from the ongoing Phase II trials of tebapivat, our more potent PK activator in lower-risk MDS and in sickle cell disease. We also continue to advance our Phase I programs for AG-236. This is our siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera and AG-181, our phenylalanine hydroxylase stabilizer intended for the treatment of phenylketonuria. Underscoring these first 2 priorities is a commitment to financial discipline with the aim of maximizing shareholder value. To that effect, we will take proactive steps to reduce operating expenses to extend our cash runway and intend to provide an update early next year. Our goal is to become a sustainable rare disease company, and we will continue to work to deliver on that objective. In closing, I want to express my deep gratitude to our employees for their unwavering commitment to our mission and to the investigators and patients whose collaboration made this trial possible. The RISE UP trial represents years of commitment. And with these results, we see a potential path toward delivering a meaningful therapy for sickle cell disease, one that has the potential to create value for patients and stakeholders. With that, I'd now like to open the line for questions. Operator, please open the line.

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

Thank you for the very detailed review of the Phase III data. Maybe for the company and Sarah, first on safety, you mentioned no sign of liver injury, but were there any Grade 2 or Grade 3 increases in liver enzymes? And then for Dr. Andemariam, it sounds like you're quite convinced of the benefits here, though with lack of statistical significance on some of the clinical outcomes, how would you communicate the benefits to your patient with this drug to be approved?

Sure. I'll start with Sarah on the safety question.

Eric, so across the trial in both treatment arms, there are like a variety of different liver enzyme elevations. But as I mentioned, upon selecting very broad net of events to review, both our internal review plus an independent review by hepatologists did not see any drug-induced liver injury in the same way that we saw on thalassemia. So therefore, we feel very confident to say that the safety profile to date hasn't changed.

Thank you. And interesting question, Eric. So Dr. Andemariam, maybe you can comment on, given what you now have seen and discussed, how would you explain the benefits of mitapivat to your patients?

Yes. So thinking forward, if mitapivat is approved and I was having conversations with my patients in clinic, I would say that given sort of an overview of the RISE UP clinical trial results, and I would do this in plain language, which I think I'm very used to doing and I think most doctors are. And I would say, this was given to a number of individuals. And compared to those who were receiving placebo, there was an improvement in their anemia and about 40% of patients who were given this treatment for a year, there was an increase in hemoglobin by almost 2 points. And that would be sort of equivalent to giving you 2 units of blood every few weeks. I would say that in those patients who had a response in terms of their hemoglobin that they translated into reduced episodes of acute vaso-occlusive pain, a reduction in their hospitalizations and improvement in the fatigue symptoms. And so I would say that even though mitapivat didn't necessarily work to improve the anemia in all patients that a 40%, 41% response rate is substantial. And given that it has been shown to be a safe drug that it's worth giving it a try to try to improve the patient [indiscernible] hemoglobin. So that's really how I would guide the conversation. But at the end of the day, it's shared decision-making and the patients will be the ones at the end of the day to make that decision.

Our next question comes from Salveen Richter with Goldman Sachs.

I was just wondering what the registrational path forward is here and what you would tend -- what you think the focus of the pre-sNDA meeting with the FDA will be in the first quarter.

Thanks, Salveen. Sarah, do you want to start with that?

Yes, sure. So from our perspective, when we go to a pre-sNDA meeting, our goal is to highlight the data package that we have obtained in a clinical trial and to highlight our intent to file and make sure that when we do so, that this is in a format that the agency finds good to review. And so that would be here the same goal as any other pre-sNDA meeting that we do prior to submitting. And so here, what we would highlight is that sickle cell disease has a huge unmet need. I think Biree just highlighted it beautifully earlier, why there is such an unmet need and that there are really no treatment options available today, as you just actually mentioned in the previous question that can raise the hemoglobin in such a way that it is building on a consistent data package in other hemolytic anemias as well as it relates to those aspects. And that this clinical trial data package when you actually look at the hemoglobin responders really provides clinically meaningful benefits in that group of patients with reduced reduction on the sickle cell pain crisis-related endpoints and the PROMIS Fatigue. So on the benefit side, there's a very clear clinical compelling story that can be told with this data package. And then the safety side as well, of course, you see serious adverse events and fatal events in this clinical trial patient population, which are consistent with this horrible disease. So on the safety side, it's a clear story to tell as well. So I think from that perspective, in the current landscape and the unmet need, that is how we would present the data package. I don't know if you have anything to ask...

Our next question comes from Ellen Horste with TD Cowen.

I'm on for Marc. I'm wondering if this drug is approved, how long might you treat a patient waiting for a response given that 40% of patients do seem to do really well? I guess, how long would the duration of treatment have to be before you decide this is not benefiting the patient?

I think that's an excellent question for Dr. Andemariam and it's a guest that you're in the room, and you can help give your perspective on that.

Yes. It is an important question, but I think my answer would be really speculative at this point. I think that, as Sarah pointed out, in the intention to treat analysis, there was a statistically significant increase in hemoglobin across the entire cohort that approximated 1 gram per deciliter. And so I think that the -- it's hard to predict what the exact time line of response would be. It's also entirely possible that since this illness is so heterogeneous, that the time to response may be variable between patients. So I think it would be really trial and error with each patient to see whether or not they have that hemoglobin response.

And this might be a good opportunity. And Sarah, you might want to comment, too, that the finding that we talked about in sickle cell disease is, in fact, consistent that we've seen across now 3 different hemolytic anemias. And so we have a similar dynamic with PKD and thalassemia as well. Sarah, anything you want to add?

Right. And so this is the beauty of this package because it's building upon previous data packages as well in different hemolytic anemia and the drug behaves the same way as it has done before, meaning there is a relatively quick onset of action in hemoglobin and then it's a sustained response throughout. And as you know, we already in our PKD label have some language guiding physicians and patients on how to have the discussion around how to assess benefit. So we think that would be something similar. And it's actually very much in line with how Dr. Andemariam just described how to approach it with the patients.

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

Maybe one for the team and then one for Dr. Andemariam. I guess first, one for Brian and Sarah. When you think about potential differentiation with tebapivat versus mitapivat, I guess, do you think a functional benefit is still in the realm of possibility with tebapivat now that you've seen the data from RISE UP? And if so, what's driving that confidence? And then one for Dr. Andemariam. I appreciate the disease characteristics were fairly balanced between placebo and mitapivat arms, which I think speaks to the quality of the study overall. But I guess, how does the 3.05 pain crises on the placebo arm sort of compare to what you'd expect for this patient population broadly? And same thing on fatigue score. Did this, I guess, maybe seem higher than you would expect for placebo?

Yes. Thanks, Alec. Sarah, would you like to start on mitapivat and tebapivat? Starting first with the concept that we believe it's an advantage to have 2 PK activators not 1 as we pursue ever-expanding portions of the population that could benefit from 1 of our PK activators but differentiation options.

Yes. So first of all, I want to bring it back to mitapivat because I do -- it does -- this trial really highlights that a PK activator improves hemolytic anemia. So this is to be anticipated for tebapivat as well because it's a peak activator that it has -- that is of the same thing. However, we do know it's a more potent PK activator and it's currently in a Phase II to really understand how it would influence hemoglobin response. Each drug needs to, of course, work towards its own efficacy and safety profile. And then that data will guide for a big part how we can differentiate. Obviously, here, with this data set, we learned how on the RISE UP trial, we learned that this threshold of 1 gram per deciliter of hemoglobin is confirmed to be an important threshold, an important clinically meaningful threshold. This is already well known across different hemolytic anemias. And then each grant per deciliter that you can improve is associated with better clinical outcomes. So we are really excited about that hemoglobin response that we see. It's 41% of -- so there is like a lot of patients who can still stand to benefit of more potent or more deep hemoglobin responses. We are also very excited that the magnitude of the hemoglobin response is actually leading to these observed clinical benefits in that group. I think this takes away part of the concerns around is too much hemoglobin leading to potentially negative consequences in sickle cell disease. That is not what we see in our data that we see with an improvement of hemoglobin, and you saw the waterfall plot that there is really a clinical benefit in that group. So the data will continue to guide us. And then maybe I can comment also a little bit on the data aspect because the 3.05, if that was expected, what we would see. This was our intent, right? We've always highlighted that we were hoping to enroll a patient population that, on average, have about 3 pain crises in the placebo group. So 3.05 is spot on, I would say. So it does speak to the inclusion and exclusion criteria that these were appropriate and that our assumptions for the whole trial were import -- were correct and appropriate. And then as it relates to the fatigue score, the improvement -- so indeed, like the fatigue reported by patients using this tool highlights that they were mildly fatigued as captured by this tool. But I think it speaks to the complexity of fatigue in this disease. And what you see is an improvement in the placebo group over time and also in the mitapivat intent-to-treat group, which was a little bit more in comparison to placebo. You can see patients improve on the context of having -- being part in the clinical trial. But with that, I would like to actually hand it over to you to comment more on that.

Yes. Thank you, Sarah. And I think this is an important question when we're taking deeper dives into patient-reported outcomes in clinical trials in sickle cell disease, specifically the fatigue score. I think it's important to understand what it takes to be able to take part in a clinical trial. So for patients to be able to take part in a clinical trial, what we do is to go over them what the schedule of events are. And so they have to come in for frequent visits, and they have to meet certain clinical parameters or eligibility parameters. They can't be too sick, they can't be too well. You can imagine that for a patient to be able to commit to frequent visits that they can't have a very significant baseline fatigue level. It would just make it very difficult for them to participate. So I think it's almost like when we conduct these clinical trials, we are selecting for a population that perhaps has more energy than the more representative population. I also really believe that when we give these baseline assessments, patients don't know what it's like to feel better. So I think there can be an underestimate in reporting when we take the baseline fatigue measurements, and then there's not an opportunity to give your answer over again at the end. So that the magnitude or the delta that we're able to measure is minimized artificially.

Our next question comes from Emily Bodnar with H.C. Wainright.

I guess first one, were there any trends in certain baseline characteristics that were more likely to be hemoglobin responders? And then also curious on the blood transfusion comment. What percent of sickle cell disease patients get blood transfusions or have more severe anemia? And do you see that as a subset of patients to maybe focus commercialization on?

Well, thanks, Emily. So we'll start with Sarah on the question about baseline characteristics, any differences with respect to hemoglobin response.

So no, there was not a specific subgroup that was driving the overall efficacy results, which is in line with our other clinical trial experience.

And then a real-world question for Dr. Andemariam about what transfusions.

Yes. So virtually all individuals with sickle cell disease at some point in their life will be transfused. There are a subset of patients who get more frequent transfusions. This includes patients who are either hepat stroke or at risk for stroke or have had other complications like the acute chest syndrome. Sometimes chronic transfusions are used in patients who have frequent vaso-occlusive pain crises as a way to try to reduce that frequency when all else fails. So the -- if you -- for example, if you look at my population, I would say about 10% of my adult patients, so I focus on taking care of adults with sickle cell disease, about 10% of my patients are on chronic transfusions, which means they're getting somewhere between 5 and 10 units of blood every 3 to 6 weeks for life. So the transfusion burden is high. Whether or not that's a subset of patients to target with mitapivat, I think, is a really good question and something that maybe can be explored later.

Yes. Maybe I can comment commercially as well. We -- with the current product profile, we actually see a very compelling commercial opportunity, and that's really driven by the unmet need in the disease that you've seen, the fact that the trial population enrolled a representative sample, and we showed a strong antihemolytic benefit in the responder population. So from a commercialization perspective, of course, we'll need to engage with the FDA and see the label, but the opportunity, it continues to be very, very compelling for us.

Our next question comes from Tess Romero with JPMorgan.

So 2 from us. In your view, does this result qualify as hemoglobin and, which I think you've been talking about for a while. Given the PROMIS Fatigue score did not get met here in the eyes of regulators and this endpoint seemed to rise to the top for KOLs in terms of level of significance. And then my second question is, should we expect the price of PYRUKYND to change on the approval in thalassemia or not?

Sure, Tess. I'm going to go back to Sarah for perspective on hemoglobin and well, she's already recapped a few times how we see the data and the strength of the data, but hemoglobin and then with the responders, what that profile really looks like. And again, we have a KOL in the room. So certainly, Dr. Andemariam can comment on that as well. And then we'll go to Tsveta for the second part.

Yes. Thanks, Tess. So indeed, like from an intent-to-treat perspective, we did not meet statistical significance on the promised fatigue. But this is where you -- when you look at the hemoglobin responders and you've seen that actually you see a robust data on the sickle cell pain crisis-related endpoints and the PROMIS Fatigue score, which goes beyond what was considered clinically meaningful change within the trial. It's really very, very good clinical data for that subgroup of patients. So to us, this is a very, very compelling clinical story. But I'll hand it over to Dr. Andemariam to comment on that.

Yes, I agree. I think you have to look at -- really look at the subgroup of responders, and there's a clear relationship between an increase in hemoglobin, reduction in hemolytic markers, reduction in vaso-occlusive events, whether you measure them by hospitalization or events and entirety and an improvement in fatigue that's clinically meaningful. When you look at the whole cohort, the whole intention to treat cohort, something I think you have to keep in mind with sickle cell disease is that the symptom of fatigue is multifactorial. It's not only related to anemia. It's related to mood issues, whether that's related to depression or anxiety, PTSD, all of these run high in the sickle cell community. A lot of that is related to living with a chronic condition for which there are few available therapies, knowing from the time of childhood that you were probably not going to live as long as your siblings and your peers. There's a fatigue associated with living with sickle cell disease that is sort of psychosocial in nature and not necessarily only due to underlying anemia. That said, the hemoglobin responder subgroup, there seems to be a relationship between that almost 2 gram per deciliter sustained increase over a year of hemoglobin and a clinically meaningful reduction in fatigue, which I'm very excited about. And I think the KOLs that you're talking about will be excited, too.

Yes. And this whole discussion is such a reminder about how complicated sickle cell disease is and the profound unmet need. And of course, test, we would have hoped to have the whole population benefit, but we are inspired by the responder analysis that we've talked so extensively about this morning, and we think it's both the commercial opportunity that Sarah talked about as well as our responsibility for this community to take a step forward and have a thoughtful discussion with the regulators. Sarah, the second part on price whoever work too soon, but...

Absolutely. Too soon, but not too soon for the PDUFA date. So close to 2 weeks to the PDUFA date, and I can tell you that the team is ready and excited to deliver on a very successful launch for thalassemia, pending the FDA approval. From a pricing perspective, of course, we'll have that discussion at the time of approval, but I can tell you, we are very well positioned given the unmet need in thalassemia, the strong product profile that we've demonstrated across the ENERGIZE program. And the fact that thalassemia from a payer perspective is a rare disease. So we don't expect that category to be managed, and we are looking forward to the potential launch coming soon.

And our last question comes from Luca Issi with RBC.

Maybe, Sarah, if I can circle back on maybe prior question, maybe ask a little bit differently. Can you just talk about your confidence that this drug actually gets approved by the FDA at the end of the day? Is your understanding that hitting 1 of the 2 primary endpoints and 2 of the secondary endpoints that are at the top of the hierarchical analysis sufficient to get this over the finish line? Or do you think that the FDA was looking for this trial to hit more than 2 secondary endpoints? Any context there, much appreciated. And then maybe second, on fatigue, if I may, and apologies if I missed it, but can you talk about fatigue when compared to placebo and not maybe baseline? Again, it looks like there was no effect in the ITT population, but there was a benefit in the responder population. So does that imply the fatigue went all the way around in the nonresponder population? Or is that not the right way to think about it?

Okay. So for the first question around the likelihood of approval and all that, you're always going to hear this from me. I'm not going to comment on what the FDA will do or not do or as always, it will be a matter of review. And that is something that happens when you feel you have a data package, and you go talk to the regulators. Ultimately, they do, do their own independent reviews and engage and make their own independent assessment. As we mentioned, we really feel we have a very compelling data package to go and have that engagement with the agency because, again, like we see very consistent data on how mitapivat acts that hemolytic anemia improvement. The clinical context just around the hemolytic anemia improvement was highlighted by Dr. Andemariam very well a couple of times. I think it's really by itself already meaningful in this patient population that if you remember the slides from our presentation, if you look at the treatment options for this horrible disease, it's a very bare landscape. But then to see actually that there is robust data that speaks to clinical benefit in the hemoglobin responders on so-called hard-core endpoints as it relates to sickle cell disease with sickle cell pain crisis-related endpoints and fatigue is really a compelling clinical story to tell. And obviously, we hope the regulator will see it the same way. But as always, it's a matter of review because we're not the FDA, obviously, or any other regulator. So -- but we are looking forward to hopefully collaborating as we've always done in a similar fashion. So in regards to the second question and the complexity of fatigue and placebo and the mitapivat arm, I think I look at this multiple ways. One way was just highlighted by Dr. Andemariam in the context of how fatigue is really multifactorial, very complex in the context of sickle cell disease, and there are more components to fatigue than just physical fatigue. You do also see that patients by this scale report being mildly fatigued. Again, Dr. Andemariam spoke to it as well, like people don't have an opportunity to go back. So when people actually feel better, they can go change their baseline score. So that is a little bit of a problem with these types of tools. But I also think it really does establish the importance of a 1 gram per deciliter increase threshold that is now a very common way to look at a meaningful improvement in hemoglobin for a multitude of reasons. And when you do that, you actually do see you can push past that clinically meaningful threshold in that group. So again, it's like -- it's a compelling clinical story within this data set, and I'm very proud of the data that we delivered with this clinical trial. And most importantly, very grateful to the patients and physicians and our team who have delivered these results.

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

All right. Thanks, Michelle. And again, I want to thank Sarah for the very comprehensive review of the data and to Dr. Andemariam for spending time with us this morning to give us the appropriate clinical context in parallel. And also, thanks, everyone, for listening in. We were pleased to be able to provide an update on the RISE UP trial this morning. This has been years in the making. And I also will remind everybody, we have an action-packed fourth quarter at Agios. As Sarah had noted in her comments, we have, in about 2 weeks' time, our PDUFA date for thalassemia review, which is on December 7. So I'm sure we're going to have plenty to talk about. So thanks a lot, and we definitely look forward to connecting again real soon. Thank you.

Thank you for your participation. You may now disconnect. Everyone, have a great day.