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

Good morning, everyone, and thank you for joining the Agios EHA Investor Event. [Operator Instructions] Also, I want to note that a copy of the slide deck is available on the Agios Investor Relations section of the Agios website. I will now turn the call over to Jackie.

Thanks, Steve. I think we're going to show our forward-looking statements real quick first. Thanks, everybody, for joining us this morning or this afternoon, depending on what time zone you're in. We appreciate your interest in our story. So here is today's agenda. I'll be very brief with my opening remarks, and then I'll turn it over to our Chief Medical Officer, Dr. Chris Bowden, who will go through mitapivat's mechanism of action for you. And he will also speak about the burden of pyruvate kinase deficiency, and you'll find that one of our abstracts and presentations for EHA is exactly on that topic, and it's part of the overall story of why we think mitapivat's going to be an important treatment option for patients with PKD. We also then have 2 stellar physicians with us this morning: Dr. Andreas Glenthøj, who will speak about PKD and specifically the ACTIVATE and ACTIVATE-T trials; and Dr. Kevin Kuo, who, I think, has been with us before and will speak about thalassemia and our Phase II data. And Chris will probably introduce them a little bit more later. So thanks, guys, for being with us this morning. And then we'll come back. Chris will summarize very rapidly, and then we'll have a Q&A. So we're excited to be here today at EHA with our newly focused strategy at Agios for a whole host of reasons, not the least of which because we've got some exciting data to present and, we think, a very compelling story to tell around mitapivat and what it may be able to do for of PKD, thalassemia and sickle cell disease patients. But we're now 6 months post our announcement of our strategic pivot to focus only on genetically defined diseases and sell our oncology business to Servier. That process has gone very well in terms of the transition of our oncology people and assets. And we think that the business proposition for you as well as maybe more importantly, the focus and differentiation that we can bring to patients in the future for Agios is extremely exciting because of the combination of the backbone scientific platform that we have in cellular metabolism and now bringing that to focus on genetically defined diseases, with the first wave of those being for indications for patients with serious hemolytic anemia. So we're very excited about our future to bring relatively even greater differentiated proposition to patients with this focus and our core science. We have been studying PK activation for quite a long time. If we go all the way back to our research efforts and now 6 years in the clinic with PK activation. We've been doing this for longer than anyone else has. We are leaders and pioneers in this area, and we look forward to sharing what we think is a very robust set of data in the EHA presentation. So with you today and over the course of the next few days with the meeting. We've had patients at the center of everything that we do at Agios for the entirety of our existence. We brought that to IDH mutant cancer patients here. Some of you have interacted with Tamara in events that we've had related to genetically defined diseases in PKD. We're bringing that same sense of urgency to helping these patients who have these chronic diseases that they deal with over the entire course of their lives, and they've had far greater implications, I think, than most of us are fully able to appreciate, and I hope that you'll learn a little bit more about that today. So that science of cellular metabolism, our focus on patients has not changed and will continue to do that over time. With mitapivat, we actually see that we have a pipeline within a drug, and we also believe that we have a broader pipeline across the mechanism of PK activation of both PKR as well as some other areas of PK activation that you'll hear about from us over the course of time. But we are going to do amazing things for PKD patients in the first instance with mitapivat. And then we will be able to take this drug into greater and greater numbers of patients as we just move from PKD to thalassemia to sickle cell disease with a mechanism of action that we think is going to be very important for all 3 of these indications. And we're very excited about -- this is our anchor product and other things that we're going to be bringing along through the pipeline. So with that, there's a handful of key takeaways for you today. I'm going to turn it over to Chris in just a second, and we'll also come back and summarize some of the key points. But I do want to emphasize that we've been doing this for longer than anyone else and in a more broad way than anyone else. So we understand this mechanism extremely well. You're going to hear about the ACTIVATE and ACTIVATE-T data. And then if you look at the other abstracts and presentations that we have at EHA, you're going to see a very compelling story, I think, around the burden of disease of PKD, all of the things that mitapivat can do to help address that, the cost of this disease over the course of a patient's lifetime and the impacts that mitapivat is having on patients' quality of life. It's a very compelling story. And then you'll see the details on the Phase II data for thalassemia, where we're extremely excited to be initiating the pivotal program in that indication this year and moving that forward in both alpha and beta thalassemia patients where no other company has generated clinical data for the alpha thalassemia patients. So with that, I will turn it over to Chris Bowden and subsequently to our physician guests. So thank you very much.

Thanks, Jackie. And from me, good morning and good afternoon and good evening from -- wherever you are around the world. It's for us and for me, a pretty exciting day to be able to really talk about the data from our pivotal studies in pyruvate kinase deficiency. I joined Agios in 2014 and as someone who at that time had spent the majority -- not all of it, the majority of my time developing drugs in the oncology space, where we, for the most part, we're looking to shut down mutated enzymes because they were kinases that had gone awry. The concept of an -- a rare hemolytic anemia that you could design a drug that would activate what is now an underperforming enzyme on the basis of inherited mutations was really exciting. And so now 7 years later, with the help, assistance and expertise from a whole group of people, both in Agios and as well as investigators and brave patients, we're here and this is a really exciting day. And for those of you who've been following our story for a while, when we're talking about PKR activation in mitapivat that we're focusing in on the red cell. And the red cell is a marvel of evolution when it's -- it picks up oxygen from the atmosphere in the heart, and it has to be able to fit through the -- as a single cell through your capillary. And then hemoglobin can grab onto the oxygen, where that holds on to it and circulates into the heart where it gets shot out through the aorta and has to -- red cell has to withstand amazing sheer forces and high velocities. And then yet again, so it has to be pliable and flexible and then travel down to the peripheral tissues where it can offload its oxygen. So your carrying high concentrations of oxygen is a tough job as it is. And hemoglobin allows it to do that, squeezing through capillaries is another amazing challenge. And what's particularly interesting for red cells and has turned out to be the issue that leads to problems in the chronic hemolytic anemias that we're studying is that the way red cell -- mature red cells generate energy is through a single and efficient process that you see outlined in the top right of this slide, and that's glycolysis. And that allows red cells to dispense with mitochondria when they grow up. That also can create an Achilles' heel of sorts. So if you go to the next slide, in the red cells of patients with hemolytic anemia, they have insufficient ATP, and we tend to think about that with our collaborators as either an absolute increase -- absolute decrease or insufficiency or relative insufficiency of ATP. But regardless, what happens in that state is that the cell can't repair or handle some of the cellular damage that comes from reactive oxygen species. Because when there's oxygen in that cell, high concentrations, it can cause some damage. And in the case of sickle cell disease, the problems with ATP can also lead to -- red blood cell changes that are classic and associated with sickle cell disease, which is that sickling. If you go to the next slide, Steve, so the decrease, that lack of ATP, and the impact on the longevity of those cells, you can see in the middle. So for individuals who don't have one of these 3 chronic hemolytic anemias, they can expect their red cells to live approximately 120 days. But the shortened life span that you can see, whether this was PK deficiency, thalassemia or sickle cell disease, is on the order of 80% to 90% reduction. And it's that anemia and the hemolysis in the shortened red blood cell lifespan that can lead to fatigue, iron overload and potentially serious complications. And our experts here have been working with and developing new treatments in taking care of patients with these diseases for a long time and can certainly elucidate on that much further. One thing that we want to -- we make a point of and I want to highlight again is at the bottom of the slide, and that it's that issue of this absolute reduction and insufficiency of ATP versus relative. And I tend to think about this in the context of pyruvate kinase. So in PK deficiency, you have a mutated pyruvate kinase whereas in thalassemia and sickle cell, pyruvate kinase is wild type, and it's pretty -- it's functional, although there have been some interesting new discoveries. And in thalassemia and sickle cell disease, you have a relative insufficiency. So there, by activating the wild-type enzyme, we hope to improve the health of the cell. And in pyruvate kinase deficiency, it's almost like we're repairing pyruvate kinase and thereby elevating ATP. If you go to the next slide, as always, the understanding of the role of pyruvate kinase and how it can be activated and improve outcomes in some chronic hemolytic anemias requires some knowledge of the glycolytic pathway that you see on your left. And this is a several stage biochemical pathway that's been -- that's very well characterized, where glucose is converted into pyruvate. And there are several steps along the way. The important component and the important -- the take-home message for pyruvate kinase is it's the last step in this cascade and it catalyzes the reaction of PEP that you see to pyruvate. Phosphoenolpyruvate is PEP. And in doing so, that's where ATP energy is generated and that has favorable effects on reducing reactive oxygen species damage and other very important components of maintaining membrane integrity. The other important component with the pyruvate kinase is when you activate it or get it to function normally as you can increase flux through the pathway and reduce 2,3-DPG levels. And regulating those 2,3-DPG levels can govern the ability of oxygen binding to hemoglobin. And that's a -- can be a very important component that you heard us talk about in terms of thinking about the potential for mitapivat in individuals with sickle cell disease. Next slide. And mitapivat is really at the center of our efforts to transform these hemolytic anemias by increasing red blood cell health and longevity by increasing ATP, potentially reducing 2,3-DPG and reducing sickle cell -- sickling in patients with sickle cell disease. We've done a lot of work here in a number of different disease models. We have some data at this meeting for the first time talking about mitapivat having potential in hereditary spherocytosis, an area of great interest for Drs. Kuo and Glenthøj. So we see a lot of application for mitapivat in its ability to activate PKR and to address -- fundamentally address chronic hemolytic anemias for a number of different diagnoses. Next slide, please. And today, Dr. Kuo is going to talk about thalassemia. And Dr. Glenthøj will proceed him and presenting our data on -- in adults with pyruvate kinase deficiency. And this was the first disease that we started to target when we began developing mitapivat a number of years ago. And one important component of that has been to work in collaboration with investigators, hematologists who have been studying this rare disease as well as with other health care providers and patients to really elicit the burden of the disease because when I came in to Agios knowing very little about it, we were looking at mostly single cell -- single-institution publications, which were very helpful in terms of setting the foundation. But it was clear that we were going to have to do a lot more work to wrap our arms around what our investigators and collaborators were telling us was a very serious disease, but we have to continue to build that clinical data set. And if you go to the next slide, it has been a journey to take this component, which is the pathophysiology of disease. And if you look at the panel on your left, and we know that the chronic and ongoing hemolysis leads to anemia, hyperbilirubinemia and iron overload, was really wrapping our arms around and carefully describing those acute and long-term comorbidities and complications of the disease was one very important component of developing and describing that disease burden. On the right, the other component of this that I just want to speak to is that we know and discovered relatively early on that those mutations in the PKLR gene led to either reduced activity of the enzyme or reduced stability, sometimes both. And some -- a lot of work has been conducted to understand relationships between genotype and clinical phenotype. So if you go to the next slide, this is the figure that you've seen many times that we talked about, and I'm not going to go into all these different consequences. But what I want to point out is that when you look at the man on your right, the baseline and retrospective data from the natural history study, which was sponsored by Boston Children's Hospital, and the first international natural history study for pyruvate kinase deficiency really put a lot of detail and really brought much more understanding about the serious complications that can start in infancy. The chronic fatigue and reduced quality of life that individuals with pyruvate kinase deficiency can experience and the consequences of chronic hemolysis in all the organ systems that can be impacted and to really characterize this heterogeneous disease and the short and long-term complications. Next slide, please. This is -- and here's the product of that. Here, so you see in front of you a number of different publications over the years, whether it's related to the burden of disease from the natural history study, the consequences of iron overload making the diagnosis and the burden of disease. This component I was talking about earlier, which is relationships between genotype and phenotype. And we continue to develop the story through now our PEAK Registry as well as additional and extended collaborations with investigators, who are becoming the world of people who understand and can diagnose the disease is expanding. And so we're going to continue to develop this story because it's an important one. Next slide, please. Here's one example of some work that I found fascinating that came out of the natural history study. And on your left, you see it was demonstrated in the natural history study that in patients with pyruvate kinase deficiency, who were not receiving regular transfusions, iron overload was demonstrated, whether it was through looking at elevated ferritins or liver iron content by MRI scanning. And another important observation that you see on the right was that patients were demonstrated to have iron overload by MRI even when they didn't have a significantly elevated ferritin level. And that has had some impact on recommendations for how clinicians should think about monitoring patients for iron overload. And this is a finding that's coming about again from these collaborations that started with the natural history study and gave us a patient database that we could then start to conduct these studies on over -- across a wide spectrum of both ages and severities of disease. Next slide, please. Another finding that was published at this year's ASH meeting, virtual ASH meeting, we looked at mortality among veterans with the diagnosis of pyruvate kinase deficiency. And this is a real-world study where we tapped the U.S. Veterans Health Administration database. And what you see on your left is a Kaplan-Meier curve, which looks at a cohort of individuals from that database who do not have pyruvate kinase deficiency versus the 18 patients in the veterans database with pyruvate kinase deficiency. And you can see on your right, that is a pretty long follow-up period and that the median time until death is 10.9 years in the pyruvate kinase deficiency cohort and 17 years, much longer in those individuals from that database without pyruvate kinase deficiency. So this suggests that the burden of this disease is both impactful at the individual patient level in terms of signs and symptoms, but also may decrease their life span as well. Next slide. So that -- those are 2 examples of data that we've published in the past. And now at EHA this year, we continue to build on this story. And you see here 4 areas. So at the top, first is that osteopenia and osteoporosis are serious complications that have to do with bone health and presents early in life for patients with pyruvate kinase deficiency. In conjunction, we continue to follow patients on the DRIVE PK study who have been treated with mitapivat, and they do not experience progression of bone mineral density by DEXA scanning despite that mild aromatase inhibition effect of mitapivat. For the first time, we're publishing data on the burden of disease from the perspective of the economic burden. And you can see there, that poster outlines greater than USD 3 million in lifetime cost. Pediatrics is an area of interest for us, whether it's in pyruvate kinase deficiency, where we've conducted the first pediatric analysis from the Agios-sponsored PEAK Registry and indeed, demonstrates a high disease burden early in life for many children who were born with the disease. And that's why we'll be launching our trial next year in children with pyruvate kinase deficiency. And then last but not least has been the enormous efforts. And again, my gratitude and hats off to the investigators who've collaborated to work to standardize the diagnosis, reduce logistical burdens and really allow proper identification. We have some interesting posters at this meeting as well. So with that, if you proceed to the next slide, I'd like to introduce Dr. Andreas Glenthøj from Denmark. I met Andreas a number of years ago. He contacted us because he was aware of our program and had been working with Kevin and others. And it's been a great experience to work with him in terms of developing this trial, but Andreas also has been instrumental in helping us think about other ways to apply mitapivat in other chronic hemolytic anemias. So Andreas, let me turn it over to you, and thank you for being here today.

Well, thank you very much, Chris, and thank you for those very kind words. It's also been a pleasure to work on this program, which I find quite instrumental in improving the quality of life in these patients. I'd like to present 2 different trials, the ACTIVATE trial and the ACTIVATE-T trials, both are pivotal Phase III trials of mitapivat in patients with pyruvate kinase deficiency. The first one, the ACTIVATE-T trial, is for patients who are not receiving regular blood transfusions. And the second one, the ACTIVATE-T trial, is for patients who are receiving regular blood transfusions. So I will start with the Phase III trial, the ACTIVATE trial, which is a randomized, multicenter, double-blind, placebo-controlled study of mitapivat in adults with pyruvate kinase deficiency not receiving regular transfusions. Next slide, please. These are just the disclosures of the authors. Next slide. So Chris also mentioned the burden of disease, and we can walk through the comorbidity and long-term complications of these patients. But what I really want to stress in this regard is that these patients -- I know all adult patients with pyruvate kinase deficiency have been diagnosed. And what I find common for them is the reduced quality of life. Most of them complain about chronic fatigue from early childhood, from infancy. Many of them have received blood transfusions, spent a lot of time at the hospital getting these blood transfusions. Some of them get surgery, have their spleen removed, which may improve their anemia. But still after that, they can still suffer from debilitating fatigue, making them unable to perform normally as other children and as other adults. So it's more difficult for them to complete an education, to take care of their jobs or their families or perform small to normal activities. So the current strategies we have, which is blood transfusions and splenectomy are clearly insufficient. So in that regard, new targeted therapies, such as mitapivat, is more than welcome from the patient perspective. Next slide. So this is sort of similar to the slide that Chris shared before. What I want to focus on is on the right, where we can see the pill, mitapivat, which is 1 oral pill taken twice daily, which does not alleviate the consequences of the disease, but targets the molecular defect of pyruvate kinase deficiency. So we're targeting the enzyme, which is deficient, which should in theory be both more elegant and also have the potential to correct the entire disease and not just specific consequences of the disease. In the Phase II trial, the DRIVE PK study, we saw that half the patients, they actually responded to treatment. So 50%, 26 of 52 patients actually achieved a hemoglobin response while getting this therapy. We saw some mild side effects, but as the study was nonrandomized with -- not with a placebo arm, we are unable to discriminate it from placebo. So as the next slide shows, we can see that this is the Phase III study, which addresses these problems. We have a screening phase, a dose escalation period and a fixed dose period. And in the screening period, patients are randomized 1:1 between the active drug between mitapivat and placebo. In the dose escalation period, we identified the maximum tolerated dose or the optimal dose of the individual patient. That being said, the 50-milligram dose, which was the highest dose here, was actually the lowest dose in Phase II trial, which was found to be just as good as 300 milligrams, which was the highest dose in the Phase II trial. So the patient received that in the fixed dose period. And after that, we looked at the efficacy outcomes, which is the next slide. So the primary endpoint in this study was a hemoglobin response defined as at least 1.5 gram per deciliter increase in hemoglobin concentration compared to baseline. The key secondary endpoint was the average change in hemoglobin concentration from the baseline. And there were also other important secondary endpoints, such as the average change in the markers of hemolysis and the changes in the markers of hemopoietic activity. And from a patient point of view, we also included PROs, patient-reported outcomes, addressing quality of life and the impact on their daily lives in these novel tools developed by Agios. Next slide. So this is just a statistical testing strategy. I won't spend too much time on that. But just that being said, there was a 90% power to identify change in the primary endpoint. And after that, we went for the secondary endpoints. Next slide. So 102 patients were assessed. And we randomized 80 patients, half of them to mitapivat and half of them to placebo. And what I find very notable is that none of the patients discontinued during the trial period. So all 80 patients progressed and was analyzed in the full analysis set. Yes, next slide. And you can see that the demographics shows a well-balanced population between mitapivat and placebo. The mean age was 36, 37 years. Most patients were female, white and from either Western Europe or North America. Next slide. The baseline characteristics shows a high disease burden. You can see that the hemoglobin level is, of course, low, 8.6, 8.5. And the ferritin is high, indicating iron overload in many of these patients. Also, there is a high hemolytic burden, as assessed by the bilirubin, LDH, haptoglobin and reticulocytes, the so-called hemolysis markers of these patients. Most of the patients had received a prior splenectomy, a prior cholecystectomy. Some of them had received iron chelation therapy and ultimately, the DEXA scores showed that they were osteopenic in their range. Next slide. So this is the most important slide of the study. On the right, you have the placebo arm of the study. Each bar is 1 patient. And on the left, you have the active drug on the mitapivat arm. 40 patients in each. And notably, no patient in the placebo group has a hemoglobin response. If you look on the left, you'll see that 16 out of the 40 patients in the mitapivat arm, they have a hemoglobin response of at least 1.5 gram per deciliter. This is, of course, highly significant, and shows that the study met the primary endpoint. Next slide, please. So this is the key secondary endpoint, which is the average change in hemoglobin from baseline. And as you can see, patients in the mitapivat arm, they -- during the dose escalation period, they go up in the hemoglobin concentration whereas the placebo arm stays the same. And notably, in the fixed dose period, the patients actually sustain their hemoglobin response, which is, of course, very important since this could be a lifelong treatment for the patients. This was also highly significant. Next slide, please. So if we look at the markers of hemolysis because that's the other thing. Pyruvate kinase deficiency is more than just what your hemoglobin level is and having a lot of hemolysis and very active bone marrow producing new red blood cells can also be stressing for the patient and be contributing to the fatigue. So what we saw here was also a reduction in hemolysis when we evaluate the bilirubin. That goes down, you can see the blue line on the left. It goes down in the mitapivat group but stays the same in the placebo group. The same is the case for the LDH. And if we progress through the next slide, we see that haptoglobin, which is fully suppressed in patients with pyruvate kinase deficiency or at least most of them, it becomes measurable again in the patients responding to mitapivat and also in the patient in the mitapivat group overall. Reticulocytes are reduced, indicating that these patients who get mitapivat, they actually need to produce less in the bone marrow and that is a good sign. That means that they have less [ boluses ] and minor need to produce new red blood cells compared to baseline. All of these were highly statistically significant. Next slide, please. So this response was seen across all predefined study subgroups. So regardless of baseline hemoglobin, age, sex, race, splenectomy, cholecystectomy, we saw in this forest plot, there was improvement in the mitapivat group. Next slide. And from the patient perspective, this was a new thing to have patient-reported outcome tools. And Agios developed 2 tools, the daily diary and the impact assessment tool. In both cases, we saw a high internal consistency. There was an excellent retest reliability. And overall, these tests a lot of important parts of patient lives, how tired they are, how much jaundice they have, bone pain, shortness of breath, energy levels in the daily diary completed every day. And then in the impact assessment, which is weekly, we have more -- which activities they are able to perform, how much extra rest they need. In either case, a higher score would indicate a higher disease burden. So if we take the next slide. We see that the mitapivat group experiences significantly better improvement in both assessment tools, both the daily diary and the impact assessment tools compared to placebo. So the patients, importantly, experienced to have an improved quality of life, which does fit that they experienced a better hemoglobin level when having a blood sample or drawn. Next slide, please. So the safety profile was excellent. We see there were adverse events as there is in any study, but it's pretty well balanced between the placebo group and the mitapivat arm. There were serious treatment-emergent adverse events in both groups. And in the mitapivat group, there was one of them that was considered related to the study drug, which was musculoskeletal pain. But none of these led to dose reduction, to interruption, to discontinuation or to death. Next slide, please. If we look at the most frequently reported adverse event in the ACTIVATE study, we saw a balance between the placebo arm and the mitapivat arm. And actually, when we look at the Phase II study, the DRIVE PK study, which was published 2 years ago in the New England Journal of Medicine, we saw nausea, headaches and initial insomnia as important adverse events that were thought to be perhaps related to mitapivat. But all of these are more frequent in the placebo arm than in the mitapivat arm. So that is quite striking and demonstrate that this drug was fairly -- or very well tolerated, actually. Next slide, please. So to walk you through it, mitapivat demonstrated sustained improvement in hemolytic anemia in regular -- nonregular-transfused patients with pyruvate kinase deficiency. 40% of the patients achieved a hemoglobin response, whereas 0% achieved that in the placebo group, this was highly significant. It was -- it occurred early in treatment, and it was sustained over time. This was also what we saw in Phase II trial, where the long-term follow-up of 42 months shows that the hemoglobin improvements are sustained for a very long time. And we've seen no patients where it has declined during treatment. So it was also considered -- seen across all predefined subpopulations. And if we look at the secondary outcomes, there was an average change to the better in hemoglobin concentration. There was an improvement in hemolysis markers and in markers of hemopoietic activity. We also saw that the patients reported that they had an improved quality of life, as seen in the patient-reported outcome forms. And notably, it was very well tolerated and the safety profile was consistent with previous studies, and no adverse event led to discontinuation of study drug. So let's move on to the next study. Next, please. So this was the ACTIVATE-T study. Next slide, please. So this is also a Phase III study, but this was an open-label study across 11 different countries, if I remember correctly, where we looked at patients who were receiving regular transfusions. There was no placebo arm because it was thought that this would not be ethically correct to do so. So all patients received the active drug. Next slide, please. These are just the disclosures. Next slide. Well, this is some of the same. Of course, the comorbidities and long-term complications are pretty similar between patients. There are differences between the transfused patients and the nontransfused patients. I won't go into details here. But what is common in these patients is regardless of regular transfusions, these patients suffer from poor quality of life. chronic fatigue, which hinders their normal daily lives. So there's still a great need for novel treatments such as mitapivat. Next slide, please. Next slide. So this is the setup of the ACTIVATE-T trial. There's still a screening phase and individualized dose escalation period where we find the optimal dose of mitapivat in the individual patients, and we have a fixed dose period. The patients had to have at least 6 transfusion episodes, so 6 times they go to the hospital or the outpatient unit to get a transfusion in the prior year. Next slide. And the primary efficacy endpoint of this study was an achievement of transfusion burden reduction. And that should be at least 33% compared to the historical transfusion burden. Secondary efficacy endpoint included a number of transfusion episodes, how many became transfusion-free and how many achieved a hemoglobin concentration within the normal range. Exploratory efficacy endpoints were the changes in markers of hemolysis and changes in the patient-reported outcome tools that I just went through in the ACTIVATE study. Next slide, please. So 33 patients were assessed and 27 patients were treated with mitapivat in the ACTIVATE-T trial. 6 patients discontinued and 1 was lost due to follow-up. But in the full analysis set, all 27 patients who received at least 1 dose of mitapivat were included. Next slide. The median age was 36. Most patients were female, white and from Western Europe. Next slide, please. So this slide demonstrates that the patients both had a high disease burden and a high transfusion burden. As seen on the left, the hemoglobin level is low and probably influenced by transfusions. Ferritin levels are high, indicating these patients are likely, very likely to have iron overload. Most patients have received a prior splenectomy, cholecystectomy and had received iron chelation therapy. As seen in the ACTIVATE study, most patients -- or on average anyway, were in the osteopenic range. If we look at the transfusion data, there was a mean of 9.7 transfusion episodes in the prior year. And here, they got a mean of 16.6 transfusion over a year. Next slide. So this is the most important slide of the study. This is a waterfall plot with each bar is a patient. And the blue bars, 10 patients achieved a transfusion reduction of at least 33%. This corresponded to 37% of the patients. This was highly statistically significant. Notably, 9 of these patients had more than 50% reduction in their transfusion burden. And if we look on the right, there was 1 patient who discontinued. And this patient actually had a transfusion response of more than 50%, but did not complete the first 12 weeks in the fixed dose period and was, therefore, considered a nonresponder anyway. Next slide. 6 of the patients became transfusion-free. That corresponded to 22% of the patients. And if we go to the next slide. 3 patients actually achieved a hemoglobin concentration within the normal range. So this is quite notable that 22% of the patients who had probably received, for most of their life or all their lives, transfusions were able to become transfusion-free by taking 1 tablet twice daily. Next slide. So to summarize this, the patients had a reduction in transfusion episodes of almost 40% and a reduction of the red blood cell units transfused by 37%. That's, in our opinion, very good. Next slide, please. If we take 1 individual patient, this is a 68-year old woman who started in the trial. She started in the dose escalation period. And here, you can see on the top, the red line, which is her hemoglobin level that increases over the dose escalation period and stays high in the fixed dose period. Her markers of hemolysis, LDH, bilirubin, reticulocytes and haptoglobin, they all improved during the dose escalation period and stays better during the entire fixed dose period. Next slide, please. So this forest plot is quite similar to the one seen in the ACTIVATE trial. And it demonstrates that the improvements were seen across all predefined study [ subpopulations ], including age, sex, race, mutation category, transfusion burden and splenectomy. Next slide, please. We also use the PKD daily diary and impact assessment tools to assess disease burden of baseline and at the time point during the study. If we take the next slide, we can see that at all time points during the study, there were improvements in the scores reported by the patients. Next slide, please. Mitapivat very well tolerated and this was consistent with previously reported data. There were serious adverse events reported, 3 of them, but none of these were considered related to the study drug and none of these led to discontinuation, interruption of study drug or to death. Next, please. So to summarize this, the ACTIVATE-T trial was the first clinical study to assess mitapivat in patients with pyruvate kinase deficiency who were receiving regular transfusions. And we saw that 37% of the patients achieved a transfusion reduction response, 22% of the patients actually became transfusion-free and 11% of the patients even achieved normal hemoglobin concentrations in the study. Importantly, from a patient perspective, we saw improvements in quality of life measures with the novel patient-reported outcome tools developed for pyruvate kinase deficiency. And finally, mitapivat was well tolerated and the safety profile was consistent with previously reported data, including the data of the randomized ACTIVATE trial I just discussed also. So next slide, please. So first of all, I would like to thank the patients for volunteering to participate in this study. And also to all the coinvestigators around the world, who spent quite a lot of time working to get the study completed. And thanks to Agios for a very good collaboration. Thank you very much.

Thank you, Andreas. Let me now turn it over to Dr. Kuo, who comes to us from the Princess Margaret Hospital in Toronto. Dr. Kuo has been another really important and influential collaborator for us, given his long-time expertise in hemolytic anemias from the get-go as well as his experience with patient-reported outcomes and other areas. So thank you again, Kevin, for coming today and for presenting the Phase II thalassemia study. So I'll turn it over to you.

Well, thank you, Chris, for the generous introduction, and good morning, everyone, and good afternoon to some. We're now going to switch gears to thalassemia, which is another hemolytic condition. Now you may be surprised that I'm calling thalassemia a hemolytic condition because we usually think of thalassemia as an underproduction anemia, where there's either qualitative reduction or quantitative -- qualitative change in the hemoglobin leading to the anemia. But it's actually more than just anemia and I'll show you on the next slide. Well, it's estimated that there's 18,000 to 23,000 patients in both the U.S. and EU, majority of patients in the world actually reside in South Asia and Southeast Asia as well as the Middle East. Next slide, please. So here, what we have is that the hemolysis creates a toxic reactive species -- previous slide, I'm sorry. So what I mean by having the 2 -- more than just anemia is that there are both the effects of the hemolysis as well as ineffective erythropoiesis. The hemolysis creates toxic reactive oxygen species, free iron, depletion in the nitric oxide, inflammation and damages to a blood vessel, and this leads to what we see on the right-hand panel here, the strokes, the silent strokes, the pulmonary hypertension, the gallstones, the splenomegaly, the venous blood clots as well as leg ulcers. Now on the other hand, there's also an effect from erythropoiesis, which then leads to the bone deformations, the osteoporosis, the extramedullary hematopoiesis. But the ineffective erythropoiesis also drives the iron overload, even in the absence of transfusion. And so this is what we see on the left panel here, left side of the figure. And iron overload, if left untreated, can lead to heart failure, irregular heart rhythms, sudden death, liver cirrhosis, things like diabetes, infertility, hypogonadism, hypothyroidism, hypoparathyroidism and iron overload in both the heart and liver. These are the things that we commonly see in the clinic. And so when we see our patients, they -- we take a multisystem approach because they come in with these whole set of comorbidities, again, regardless of whether they transfused or not. Next slide, please. And next slide. Sorry, this -- go back to the previous. Sorry, previous. Yes. Okay. Sorry, about that. Yes. So going back to this, I'm just going to talk a bit about the mechanism again because what we see here when we talk about [ mutations ] just in anemia is that we see an imbalance in both the alpha- and beta-globin ratio. So if you're talking about beta thalassemia, you're talking about a relative reduction in the beta-globin, so you have an excess in alpha. Now conversely, in alpha thalassemia, you have a reduction in alpha, which leads to an excess in beta. Now this imbalance, these excess globins will precipitate and aggregates, and this leads to the oxidative damage, which then leads to hemolysis and ineffective erythropoiesis which then leads to anemia. But in addition, ineffective erythropoiesis, as I've shown in the previous slide, leads to dysregulated iron metabolism, which then leads to iron overload, but this also further drives the oxidative damage that we see. Next, please. And next. So on behalf of our coinvestigators and collaborators, I'll be presenting on the results of the Phase II open-label, multicenter study of the pyruvate kinase-activated mitapivat in adults with nontransfusion-dependent alpha and beta thalassemia. Next slide, please. Here, we have the study schema. The primary objective of the study is to evaluate the efficacy of the mitapivat in nontransfusion-dependent thalassemia patients. 20 patients from 4 sites in the U.S., U.K. and Canada all have the following conditions with beta thalassemia with or without alpha-globin gene mutations, hemoglobin E beta thalassemia or alpha thalassemia with a hemoglobin of 10 grams per deciliter or less and with being nontransfusion-dependent defined as 6 or less red cell units transfused in the preceding 24 weeks and none in the 8 weeks prior to the study drug starting. And these patients are enrolled in the study. Following screening, patients were entered into a 24-week core period where they received an initial dose of mitapivat of 50 milligrams twice a day. And at week 6, there is an option of a dose increase to 100 milligrams twice a day based on safety and tolerability. Now after the 24-week core period, patients may enter an optional 10-year extension period. The primary endpoint is defined as an increase in hemoglobin by at least 1 gram per deciliter from baseline between weeks 4 and 12. Secondary and exploratory endpoints include sustained or delayed hemoglobin response, markers of hemolysis, erythropoietic activity as well as safety. Next slide, please. Here, we present the results from the core period. 19 out of the 20 patients completed the core treatment period. And the median age were 44 years and half of the population was Asian. The 5 patients with alpha thalassemia and 15 patients of beta thalassemia were enrolled and the genotype breakdown is shown on the right-hand panel here. The median hemoglobin increase was -- sorry, the median hemoglobin at baseline was 8.43 grams per deciliter. Next slide, please. The primary endpoint is hemoglobin response during weeks 4 and 12, and this was met in 80% of the patients. And all 5 of the alpha thalassemia subgroup met the primary endpoint, while 11 under the 15 patients with beta thalassemia also met the primary endpoint. Next slide, please. The secondary endpoint to sustain hemoglobin response, which is defined as meeting the primary endpoint and also at least 1 gram per deciliter increase in hemoglobin of at least 2 readings between weeks 12 and 24, was met in 65% of the 20 patients, with all 5 of the alpha thalassemia subgroup meeting the secondary response. Now the mean hemoglobin change from baseline between weeks 12 and 24 was 1.3 grams per deciliter and were comparable between the alpha and the beta subgroups. Next, please. And here, the figure shows that the increase in hemoglobin started as early as 4 weeks and is sustained over the core treatment period. The mean hemoglobin change is now shown in the diamonds. Mean time to hemoglobin increase of at least 1 gram per deciliter amongst the responders was 4.5 weeks. And the hemoglobin increase was maintained to have a dose increase to 100 milligrams twice a day at week 6 and is sustained for the remainder of the 24-week core treatment period. Next, please. And here, we have both markers of hemolysis and in erythropoiesis, and both has shown improvements and they were consistent with the hemoglobin increase. The indirect bilirubin in the LDH shows decline in both alpha and beta thalassemia patients and the erythropoietin approached the upper limit of normal in both groups by week 6. And so these results are consistent with the proposed mechanism of action for mitapivat. Next, please. Preliminary analysis of the ATP from the blood from these patients shows that there's a mean increase of up to 87% in thalassemia patients, and this is consistent with mitapivat's mechanism to enhance glycolysis. These observed increase in ATP is similar to the previously observed with mitapivat in the multiple ascending dose studies in healthy volunteers. Next, please. Now overall, 17 or 85% of the patients experienced a treatment-emergent adverse event during the core period. And the most commonly reported TEAE were initial insomnia, a dizziness and headache, but no other TEAE were reported by more than 20% of patients. Now the most common AE that is reported in 2 or more patients are shown in this table here. The safety profile is consistent with previous studies of mitapivat in healthy volunteers as well as patients with pyruvate kinase deficiency, as shown previously. And all of these AEs were either Grade 1 or 2 and majority were self-limiting. Next, please. And here, we shown that 5 or the 25% of patients experienced at least Grade 3 TEAE with 1 each of renal impairment, arthralgia, initial insomnia, anemia and positional vertigo. And there were no significant changes in measures of bone health within this core treatment period. Next, please. So in conclusion, this is the first clinical study evaluating pyruvate kinase activation as a therapeutic option in both alpha and beta thalassemia. It's the first drug trial aimed at evaluating the treatment of thalassemia. And I really must emphasize this, there has been no treatment at all since the discovery of alpha thalassemia other than supportive care, as you know, with transfusions or more of, I would say, even more of a palliative nature, but this is now the first time we're ever able to put a clinical trial in alpha thalassemia. And the study met its primary endpoint and demonstrated a sustained hemoglobin response as well as improvement in hemolysis and ineffective erythropoiesis in patients with alpha and beta thalassemia. And mitapivat was well tolerated, and the safety profile was consistent with previous studies. 17 patients continued on to the extension period of the study. And as of 29th of April of this year, 16 patients remained on the drug. So mitapivat through activation in a wild-type PKR may represent a very novel therapeutic options for patients with both alpha and beta thalassemia. We currently have 2 pivotal Phase III trials, the ENERGIZE for the NTDT and the ENERGIZE-T for the TDT for patients with both alpha and beta thalassemia, and they'll be initiated later this year. And I'd like to thank, first of all, the patients as well as to Agios for the support of this trial as well as Onyx.

Thank you, Dr. Kuo. Thank you to all of our presenters, and we are right on time. So if you can just advance one slide, Steve? Jackie told you what we were going to tell you. We just walked through that. And just want to make a couple of comments in terms of summarizing this very exciting EHA meeting for us as well as some key upcoming milestones. So I hope that you're coming away with a strong -- an increasingly strong impression of mitapivat's activity and potential for clinical benefit in adults with pyruvate kinase deficiency and thalassemia. We are very -- feeling very good about this package of trials and the work we've been doing over a number of years now. And in fact, we're getting -- we're very close to pressing the button on regulatory filings in the United States and in Europe. Darrin's team is hard at work in commercial preparations for our potential launch. In terms of looking -- other forward-looking measures, we will launch 3 Phase III trials this year, 2 in thalassemia, the ENERGIZE and the ENERGIZE-T for individuals with both alpha and beta thalassemia One study for individuals who are not regularly transfused, one for regularly transfused, patients with a diagnosis of thalassemia and a Phase II/III study in sickle cell disease. And as I spoke earlier, we are also continuing development and putting our package together to initiate a trial in children with pyruvate kinase deficiency next year and with our eyes on thalassemia and sickle cell after that. So with that, I will stop and turn it back to Jackie to help us through the Q&A and direct us.

Yes. I think Steve may jump in and help me as well. But otherwise, Steve, I'm just going to go down the chat. Is that the best way to do this?

Yes. Jackie, that sounds good. Looks like we have a question from Mike King at H.C. Wainwright. I guess this is for Dr. Glenthøj. Do you believe the dose of mitapivat is adequate? Would you be willing to explore higher doses in your patients? And do you believe 24 weeks is an adequate time for you to assess the benefit of mitapivat and PKD?

Well, to take it one at a time. I think the dose of mitapivat is adequate. We saw in the Phase II trial that 300 milligrams were not superior in efficacy compared to 15 milligrams. So in that regard, yes. Would it have any concerns trying a higher dose? Not really. We see in Kevin's study that there, 100 milligrams twice daily is well tolerated. So I wouldn't have any problems giving a higher dose. There could be other potential benefits of giving higher dose mitapivat in just the hemoglobin concentration. And for instance, it does reduce the bilirubin concentration, which is quite central for many of these patients. They also complain about being quite yellow, which especially for young people is quite debilitating socially. So overall, I think it is adequate, but I wouldn't have any safety concerns giving a higher dose once it's approved and I'm able to adjust myself. So over time, 24 weeks, is that enough? Well, it's enough to assess that it works, and we have a long-term follow-up study of 5 years. So we are working on that, but I don't see any reason why it should stop working. But of course, as in any trial, the long-term follow-up is important.

Indeed. Andreas, can -- if we could explore this a little further for both you and Kevin. And when you look at the individuals for -- that are not regularly transfused and then you hold them in one place and then you take the individuals from ACTIVATE-T, do you see beyond 24 weeks, tangible improvements that would indicate improving clinical benefit because you're tampering down hemolysis or other measures? So maybe, Andreas, can you comment on that?

Well, yes. And to be honest, I know the patients I've treated the best. But yes, we have seen patients where the responses are more slow. And especially in the transfused patients, of course, there is an improvement over time because at first, they are influenced quite a lot by the transfused units. Also, I have seen patients where the bilirubin goes down after a very long time, more than 24 weeks. So in that regard, there could be additional benefits by long-term treatments. Of course, also the long-term outcomes and complications, I suspect that they will have less complications when we correct the underlying defect. So there's additional benefits hidden there that we will elucidate when we have the long-term follow-up, yes. But -- and if we look at the Phase II trial, we have the long-term follow-up now, I think, 42 months. And the hemoglobin response is sustained. And so it seems very positive, and I look forward to seeing the Phase III patients with that long follow-up.

Kevin? Thanks, Andreas. Can you give us your perspective there?

On PKD or thal?

In pyruvate kinase deficiency. You've got experience now with patients being on the drug [indiscernible]. So talk a little bit about that. And thalassemia as well, this whole aspect of -- we talk about hemoglobin, but you have always educated us that there's this hemolysis component above and beyond hemoglobin going up.

Absolutely. It's a process that matters more than the endpoint here, it's the process that's deadly to these patients. But to speak to the pyruvate kinase deficiency first, essentially, we do -- [ at least subjectively ], from my experience of our patients who have been on mitapivat is that you do see this sort of long-term improvement in the quality of life. And I'm sure, Andreas, you have seen that as well in your patients on long-term follow-up. And I think we need to continue to collect these data because I think they are instrumental in sort of exploring the long-term positive effect of mitapivat in our populations.

And I can complement that. Seeing patients, it's quite touching sometimes. Some of the patients in the ACTIVATE-T study who have been receiving transfusions all their lives and were not able to perform at work or anything like that, I had a patient who was actually crying because she -- it's the first time, she had a pretty normal hemoglobin level and she didn't feel the fatigue. She had tried to get transfusions prior to that, and we tried to push her hemoglobin level up, but that was not doing the job. The whole process of less hemolysis, as Kevin mentions, is instrumental to this. We even have some patients where we tried to exchange transfuse them to remove their deficient red blood cells, to remove the hemolysis component and that seems to be working excellently. And this drug targets exactly that, making sure that -- well, at least the good responders, don't [ hemolysize ] as much anymore, so yes.

Andreas, you probably have heard this story before, but I'm just going to tell it again for the benefit of others. This is exactly what we see in the thalassemic population. I'm just going to give you 2 examples. One is a mother of a 5-year old and a 3-year old. And during lockdown, of course, it's very difficult because all the kids are on virtual learning and you have to watch a 3-year old plus a 5-year old. And she used to have to take maps before being on mitapivat. And this is a thalassemic patient, she used to have to take naps in the afternoon, and she would get her mother-in-law to take care of the kids, like there was no way that she could get up, she told me. And now being on mitapivat, she can go the entire day without having to stop. I mean she is so thankful to be on it and so like she just wants to stay on it forever. And then I have another patient who tells me that he works in construction. And it's been difficult for him because, again, he would get the fatigue and he would try to workout. He has worked out all his life. And he always thought that he doesn't have enough strength, that's what he once blamed it on. And he would work for like 30, 45 minutes, and then he would need to stop, like because [indiscernible] Now he says he can go on for 1 hour and 45 minutes and just keep going in terms of his workout. And he's gaining weight. Andreas, I'm sure you've seen this as well, right? I mean, like I hate to say it. I mean most PKD patients are scrawny like me and same as with thal. But I mean, it's the first time they were actually seeing them gaining weight and [indiscernible] they're happily complaining that they're gaining weight.

You can consider this like running a marathon. All the time, your bone marrow is producing cells 5, 7x faster than it should be doing and now this is corrected.

That's right.

Those are some very powerful patient-reported outcomes. And then well, Steve, let's get ready to go to the next question. Mike King, I would also point out, we studied higher doses in the DRIVE PK study and we actually demonstrated that responses at higher doses, we could maintain them when we brought patients down to the area of around 50 milligrams. And so the dose discussion is always an interesting one because we segregate pyruvate kinase deficiency from the other disease of sickle cell and thalassemia and potentially hereditary spherocytosis and others where we're activating wild type, where we tend to have a different discussion. So more -- Mike, we can talk about that. But why don't we move on to the next question?

Great. Our next question is from Anupam Rama at JPMorgan. For PKD, the burden of disease slide showed 17% of patients with osteopenia or bone [indiscernible] and there was a poster about the burden of osteopenia at EHA as well suggesting earlier onset of disease. How do you think about mitapivat's impact here and also the mild aromatase observed?

Let me ask Andreas to...

Well, I think, Chris, Kevin and I can answer it. But in short, we followed them with DEXA scans, and we didn't see any change over the study period. So there was no decrease in bone mineral density there. We are following it in the long-term follow-up, but we have no suspicion that mitapivat will contribute to reductions. What we don't know yet is if this is an intrinsic feature of pyruvate kinase deficiency. We don't know what will happen when we treat these patients long term, whether we will improve this. But we haven't seen any signal that the aromatase inhibition when we're using 50 milligrams has any negative effect on bone mineral density. You're welcome to supplement, Chris or Kevin?

Yes, Andreas. I mean the -- it's the same observation in the thal trial here.

Andreas and Kevin, just to follow your thread out a little farther, Andreas. You think there's the potential that over time as you ameliorate hemolysis in that marrow, which you say is running a marathon, starts to calm down, we could see improvements in bone mineral density if calcium is supplemented, people are exercising. Do you think that's a possibility?

Yes. I'm very cautious as an investigator, but correcting the underlying genetic defect, it does make sense that we ameliorate all the comorbidities and complications seen in pyruvate kinase deficiency. So I think there is the potential to see improvement, but we don't know yet. But yes, very -- I very much hope so, and it will be very interesting to follow.

Yes. From a company perspective, we always knew that we would be obtaining DEXA scans in these individuals over a long period. For both reasons, for the safety aspect of the drug, but also, we thought there was the potential opportunity that if we really had a major impact that we might see it improve over time. Steve, do you want to go to the next question?

Next question comes from Mark Breidenbach with Oppenheimer. Compared to patient populations between ACTIVATE and the DRIVE PK studies in terms of the types of PKR mutations represented in the study populations, should we expect a future product label in PKD to exclude some specific mutations? And then he has a follow-up after that.

Why don't I take that one because you're asking a labeling question. And then I think I'll ask our experts to comment a little bit about the genetics. We haven't -- in contrast to what we did at the DRIVE PK trial, when we finally -- we got to publish that, in the supplement, there's extensive information on genotype and outcome. And we are going to get through that. That takes a while to do all that, and that will be forthcoming. So we don't have that level of detail yet. The -- we did -- our label is going to be in adults who have a diagnosis of pyruvate kinase deficiency. That's the label that we're going for. And with these 2 trials, we think we encompass that. Now the eligibility criteria for the trial states that you have to have at least 1 missense mutation. And we are expecting that there will be some -- there may be some language to that effect, whether it's in the clinical trial section or what have you. So that's how we're [ approaching it from ] the company and regulatory perspective. Maybe now to shift the perspective, I can ask -- start with you, Andreas. Given what you know and your experience with the drug, how comfortable do you see the DRIVE PK patients? And what is your view around if access were not an issue for treating a double nonmissense patient based on the data that you have?

Well, first of all, since the safety profile is, in my opinion, excellent, I would have no problems testing this in patients. And we have very little data on the specific mutations. The best we have is the Amish mutation, but I would be comfortable testing any patient. And since the response is pretty quick, I think that for now, I would be comfortable testing it in patients to see whether it works. And if there's no effect, we can always stop it again. So I wouldn't really be concerned about testing in double nonmissense-mutated patients. That being said, of course, we will adjust our expectations when telling a patient about this and say, well, the chances are maybe small. But on the other hand, if it works in a specific patient and could transform their lives, it's worth a try because the current treatment strategies are insufficient. Then there's the other thing, effect is more than just hemoglobin. So in the Phase II trial and also in the Phase III trials, we focused on the hemoglobin response. But actually, I have patients also in long-term follow-up who did not have a hemoglobin response, but really appreciates being on the drug because, for instance, they feel less fatigue anyway or they feel less -- they feel the positive benefits of having a lower bilirubin level. So they're less jaundiced, less yellow. And that can be important for many patients, they look less sick. So from -- if I didn't have to look at the label given or ask anyone, I would be comfortable treating any patient to see if there was a benefit since the current options are insufficient. And this is definitely worth a try, and it's a good try.

Yes. Kevin?

Yes. I completely agree with Andreas. I mean to me, hemoglobin is merely a very convenient surrogate marker, which we can hang our hat on as a trial endpoint. But at the end of the day, again, it's what -- the journey of hemolysis is what complicates and kills these patients. This is not -- it's not necessarily hemoglobin. We have a lot of patients -- not a lot, but we have some patients who have relatively decent hemoglobin in the 8 to 9 or even 10 range. And yet, they have wicked, wicked hemolysis leading to all the complications that Andreas has described. And this is where I see patients suffer the most, is that this dose was very, very high hemolytic rate because we have to remember that hemolysis consumes nitric oxide, releases reactive oxygen species, which then lead to vasculopathy as well as creating thrombosis and so forth. And so if we can even just suppress the hemolysis, I think it will be worthwhile to try these patients. And let's not forget as well that the division between missense and nonmissense is actually very crude analysis of the ways in which the patients will respond.

And we also have other indications -- sorry, we also treat other hemolytic anemias, such as paroxysmal nocturnal hemoglobinuria, where we see patients where we give eculizumab or ravulizumab to patients. And sometimes, the hemoglobin level does not improve, but hemolysis, it disappears pretty much. And these patients have a lower risk of thrombosis and have an improved quality of life despite having the same hemoglobin sometimes. So I think it's fair to say that the point of hemolysis is much more important than hemoglobin levels.

So thank you to both of you. It's a really interesting question that came from the audience, and it shows the perspective of Agios to go and present a data package to regulators that we think has a good probability of being approved. And then it's the various ways the clinicians who are actually using the drug or thinking about using it. And then in the middle of that are the access providers and the systems that make those drugs available so that just gives us a really good sense of the various sundry perspectives that will be coming soon. Next question, Steve?

Yes. Just a quick follow-up for Mark, then we'll move on. For the Phase II thalassemia study, if there was any observed correlation between baseline hemoglobin level and magnitude of hemoglobin response in the Phase II thalassemia study population.

We haven't seen such a correlation, but I think the numbers are simply too small for us to tell.

Great. Next question is from Marc Frahm at Cowen for Dr. Glenthøj. Do you -- who do you think are the best candidates for mitapivat? Would you keep patients on the drug long-term if hemoglobin directionally improves to any extent or only if they hit the thresholds of the hemoglobin response from infusion independence?

Well, I think the best candidates for mitapivat would be any patient who demonstrates a response after he's tested mitapivat. So in that regard, I think I would give the chance or the option for any patient that I would be allowed to test the treatment on. I would keep the patients on drug long-term because I think in theory, correcting the underlying molecular defect makes sense. And since we're not correcting their genes, the response would disappear when we stop the treatment. So I would keep them unless there was any specific reason, any safety issues, and we haven't seen that in the safety profile. So I don't think it's a threshold for how much I would give them or dose adjust. I would give the maximal dose that didn't give higher than normal hemoglobin. If I could turn them in the normal range, that would be great. If I can only achieve a little less, that's still good, yes.

And to Andreas' point, I think, as I said before, the hemoglobin is just a very convenient path for us to hang our endpoints. And I think what's important is how the patient -- his clinical outcome, right? And it's how the patient is feeling. And we've clearly demonstrated in the PRO improvement. And so what I would do in addition is to administer PRO at baseline as well as on follow-up of these patients, so that I can provide an objective evidence that there is a clinically meaningful outcome here, demonstrating clinically meaningful outcome in the particular patients. I think it will be helpful for, at least in countries like Canada, for example, in Denmark, where we rely on public reimbursement. We can actually demonstrate an objective improvement in the patients' lives with PROs.

Okay.

And then just one more for Marc. For Darrin or Chris, can you update us on your PKD patient identification efforts? How many patients have been identified as you're testing of previously unexplained anemia patients continuing to track with historical [ Spanish ] data.

Yes. I'll take it. This is Darrin. So the -- as we've shared previously, we've reported identifying 1000-or-so patients. We continue to identify more patients, and we expect that to accelerate through the balance of this year and into the launch. We've just -- we're just about finished with training our new field team, our hemolytic anemia specialists who will start engaging with physicians towards the end of June and into early July. We've also, this week, initiated our patients -- our PKD, or pyruvate kinase deficiency, focused patient support model, which is offering additional disease education support for diagnosed patients. So all these efforts, along with the testing program, Anemia ID and other disease education efforts continue to buoy us -- buoy our efforts in -- or bolster efforts rather, in terms of increasing patient identification. And as we've shared also the -- our experience with 23andMe around their new report as well, which has also reached out to a fair number of patients who are at least carriers of one of the mutations and several who actually are homozygous for the mutation as well.

And I can supplement a bit.

Thanks, Darrin.

There's an abstract at EHA showing the European effort to identify more patients where we look at the patients in Denmark and EU countries under [indiscernible] And I think that's a great academic interest in also identifying more patients. So there will be many more patients identified. We can see great differences between countries. And there's no reason to think that there are less patients in France and in Denmark. On the contrary, there should be just as many.

Right.

Before we jump to the next question, Steve, I just want to quickly go back or make a comment about the last thing we were discussing, which is -- gets to this aspect of treatment success or failure. And what you're hearing today, just I want to stress to the audience is trials that we run as a team, as a group, they have an endpoint. And that is how success or failure is often described. But what Drs. Glenthøj and Kuo are telling you, as experts who treat lots of these patients, is that there's some pretty significant nuance there. And the questions you're asking are very interesting as they really start to get into how the drug is going to be used. And so I just wanted to stress that because I'm looking at Peter's question, which was, will you keep patients on who don't have a very significant hemoglobin rise that show clear evidence of reduction of hemolysis? And I think what you heard in the previous exchange was that Drs. Glenthøj and Kuo would be looking at that very carefully. Steve, next question? We've got time for a few more.

Yes. Let me just go back to the beginning real quick [indiscernible] From [indiscernible] how are you looking at the ex U.S. ex [indiscernible] opportunity for mitapivat in thalassemia? Are the pivotal trials global, including patients across geographies? And any plans to conduct trials in China?

So I can...

Let me take...

Sorry. Go ahead.

Go ahead, Darrin. Just from the trial, the ENERGIZE trials, they're global. And we see the unmet need as being all over the world. And one thing I've learned a lot from -- in become -- having more exposure to this disease is the burden of alpha thalassemia in Asia, for example. So yes, we're across geographies. With regard to your specific question around China, we're going through our feasibility now, and we'll be able to provide a detailed list of countries where we're running the trial in the future as we get closer to operationalizing. Darrin, did you want to jump in?

Sure. I'll add just a little bit to it. So as you heard from Dr. Kuo, the majority of the need is outside of the major -- what we refer to as the major markets, right, North America and the EU. So while the numbers are substantial between the EU and the U.S., there are more than 100,000 beta thal patients just in a number of markets like Saudi Arabia, Israel, Greece, Brazil, China, not to mention even greater parts of Southeast Asia. So the opportunity outside of the major markets rivals that of the U.S. and the EU substantially.

[ We'd like to hear ] some follow-on questions around this, I see. Right now, we're not experiencing COVID delays. We hope that the United States continues to provide doses of vaccine all over the world, and we do whatever we can, and other countries have stepped up and make that happen. And we've got some -- we'll have some further disclosures around time lines. Would we file the 2 together, TDN, NTD? For ENERGIZE, if they came in at the same time, and they were both positive, for sure. So Steve, back to you. I don't know who's next in the queue after that.

Yes. Next question is from Michael Schmidt. In thalassemia, how will mitapivat be competitively positioned relative to luspatercept?

Luspatercept, yes. So the -- we're -- right now, we're assuming from a base case comparable efficacy in the nontransfusion-dependent and transfusion-dependent populations. What we're hearing from the community is a fairly -- and particularly now as the familiarity amongst physicians has increased with luspatercept a good deal, that the -- some of the nonclinical aspects of the mitapivat profile resonated a good deal with physicians. Specifically the route of administration, obviously being an oral compared to subcu injection, which is required to be delivered in office. And so from a patient's convenience and compliance perspective, we think that confers advantage to mitapivat. At the end of the day, it will come down to actual data. But we're encouraged based on what we've seen so far in the Phase II and based on the profile that we expect to see coming out of the Phase III. It should be -- it should -- we think we're well positioned to compete effectively relative to luspatercept. I'll just also note that, look, the -- there's continued unmet need for this overall population. More options for these patients are clearly needed. Not even luspatercept is hitting -- is addressing the need in more than half of that patient population. So the opportunity for new treatments to be able to offer hope to these patients is substantial.

And if I may add, Darrin.

Yes, go ahead. Thank you.

Sorry, Chris. Yes. If I may add, Darrin, don't forget that we are also the first to study in alpha thalassemia.

Absolutely, absolutely.

Whereas [ it's not ] for luspatercept, it's only focused on beta.

Beta thal, correct.

[ And just going ] into their mechanism of action, too, right, completely different mechanism of action.

And actually, if I can just echo both Kevin and Darrin, I think, what the patients are telling me at least, they're interested in getting treatments that can give them fewer visits to the hospital. They travel a long way, many of the patients to go to the hospital to get specialized blood care, but having to go there every 3 weeks or how -- or at least regularly, just for the injection and then having the time when to get transfusions on top of that, it's not always helpful. It's an excellent drug, but I don't think that -- what they really want is something to make sure that they don't need to go as much to the hospital.

Okay. Let's move on to Peter Lawson from Barclays. Are there -- are the observed hemoglobin increases sufficient enough to reduce transfusion burdens in patients with severe disease? And would you keep patients on mitapivat with improved hemolysis even if hemoglobin levels didn't increase?

So let me -- Peter, I think the component around keeping patients on who may not -- who have tangible, clinically evident improvements in hemolysis, I think we heard both Drs. Kuo and Glenthøj say that in access permitted, they -- if patients are feeling better and they're seeing other parameters, it's not just about hemoglobin. So let me now turn over to our experts. The second question that you asked is, are the observed hemoglobin increases sufficient? This is in PKD to reduce transfusion burden in patients with severe disease. Andreas, we'll start with you.

Well, I can speak to the ACTIVATE-T study and the subpopulations we had there, we saw response in all subpopulations. So we don't have any data to support that it shouldn't work in severe disease. And if we look at transfusion burden, which would be sort of an indicator of this is very [indiscernible] since they need a lot of blood transfusion. The patient I had with the highest transfusion need, she is now transfusion-free. So I think that's an excellent example of it's impossible to say upfront. But I wouldn't be reluctant in any way to treat patients with a high disease burden. On the contrary, I would feel the need would be even greater to test it there. And even a small response in a severe patient would still be very welcomed.

Yes.

So I would draw from my experience with DRIVE PK as I had participated in DRIVE PK, the Phase II study of PKD with mitapivat. And in that study, my patients, I felt that there was a deep decrease in reduction in so far as that these patients often have sudden dips in the hemoglobin because of rapid hemolysis from like a viral infection or some sort of stress or inflammation. And what I found with mitapivat is that once they're on it, it sort of prevents these sudden dips. So I had a patient where she would get like 5 or 6 -- like not 5, but like, I'd say, 2 to 3. Yes, 2 to 3 transfusions a year because of these viral infections. Actually, you got 5 to 6 with viral infections, but then 2 or 3 out of them would require transfusions. And the mitapivat really prevented these sudden drops.

[indiscernible] interesting.

And this is just not -- this is not just a Canadian phenomenon. We -- I also have patients who report that these infections, normally, when they get the flu, they're out for 2 weeks, where all their friends, they spend much less time being sick when getting a normal viral infection. And they really feel an improvement here, even though they might not feel a major improvement on an everyday basis. And still, when they do the patient-reported outcomes, we can also see that when they're actually scoring themselves, they do feel improvements, but they just -- always -- they -- it's difficult for them to objectivize it because you don't feel the change from day 1, you might just when looking back, see, well, this is actually an improvement. So therefore, the approach are very important. And I think that it will also be important when we start to give it to patients outside of a clinical trial. I agree with Kevin there.

Yes. I mean these patients, really, a lot of them tell me that they really didn't know how crappy their lives were until they actually see a change in it.

So Kevin, is the same clinical scenario potentially applicable in thalassemia? Have you seen it? Because sometimes, when we looked at the individual patient data, we'd see these dips and we -- it's relayed or we see it in database, herpes simplex infection, things like that. So they're so sensitive. Have you observed that in the thal study at all?

It's exactly same. It mirrors that as well. I think in some -- in many ways, the thalassemics are often worse than the PKDs in the sense that there's also a component of ineffective erythropoiesis. So with a viral infection, it shuts down -- well, it causes more hemolysis but also shuts down the -- any residual erythropoiesis in these patients. So you only have -- these red cells surviving only 20 and 30 days, right? So -- and then suddenly, you have no production at all. There's nothing coming out of your marrow. And so you have these -- you experience these rapid drops. With mitapivat, you'll at least be able to extend the life of these red cells so that they hang around longer, to buttress that effect of reduction in production -- increase in production.

We should prespecify that as an exploratory endpoint in the Phase III studies, right, we can look at it in DRIVE PK, too. It will be an interesting series of analyses.

Yes, that's right.

Or in ACTIVATE, I mean.

In ENERGIZE, yes, in terms of number of on-demand transfusions. I think that will be a very worthwhile exploratory endpoint to look at.

I'm having fun. You have anymore, Steve?

Yes. Just 1 follow-up from Peter, and I think we could wrap up. With the various patient support models and outreach, Anemia ID, 23andMe, how do you -- do you have a better sense of the incidence of the number of PKD patients?

Yes. I think we're going to learn more about incidence and prevalence as we get -- they get past the approval and gain some more experience. I think what we've -- we're breaking ground every day on identifying -- increasingly identifying more and more patients. It will take some time before you actually hit your peak in terms of identifying or getting your best sense and generating the greatest confidence in what the actual incidence and prevalence of the disease is. I'll note that the -- we expect to have in the U.S. an ICD-10 code approved before the end of the year. And so that won't help to address the prevalence question very quickly, but it will -- over time, it will help us to get more accurate on the true incidence, at least in the U.S. The -- and we'll be able to take much of what we learn from there and our on-the-ground experience and shore up our sense of prevalence as well.

And just to supplement that, we used to accept people having hemolytic anemia without the reason and followed these patients for -- year after year. And we did it in somatic assays, which have many problems. And now with the gene panels, when a child is born with a low hemoglobin, we will eventually get a broad genetic testing, including PKD testing or PKLR testing. So I think we'll -- without any major effort, actually find a lot more patients now. And with the targeted therapy coming up, it will be much, much more interesting for us to identify these patients in any country.

And to follow-up on that, Andreas. I mean, I think traditionally, because both of these diseases had no treatment options available, clinicians sort of essentially have shelved these patients. I hate to use that word, but it's kind of true. Like, I'm sorry, there's nothing for us to do, just come see me once a year or not even. And then patients get disappointed and they never had any proper follow-up. And it's really sad because the amount of complications that they accumulate, especially those who come to me, I mean, I'm an adult hematologist and so are you, Andreas. So we see all sorts of disasters and train wrecks coming our way as our patients age. We have patients coming in at 40s, 50s that I'm still taking out their spleen, had to resort to that. And then we know that the risks of splenectomy increases with age, right, and in terms of the perioperative complications. It's not something that we love to do, but we have no choice because we have no treatment options. And I wish this has come earlier because otherwise, I wouldn't have needed to whack out some of these spleens.

Okay. Well, I think -- Steve, any others or are we going to wrap up?

Yes. I think we can wrap up, Chris.

Okay. I'll turn it over to Jackie in just a second. I just want to thank you both and all of the investigators. We're sitting here today talking about a positive pivotal data and the next wave -- data with thalassemia, for example, that informs the next wave of trials. And it seems like, oh, wow, it's working and everything. But none of this was preordained and the work that you all have done, of both my colleagues at Agios and the investigators two of which are here today, and the patients who've signed up for this. When you think about the context that Kevin just presented, it really is a tremendous amount of effort, and we're really grateful for that. So Jackie, let me turn it over to you. Thanks.

Yes. Hear, hear, Chris. Thanks very much, Kevin. Thanks very much, Andreas. I mean it's just terrific discussion. We're really excited about bringing this drug to patients. And I think it's great that we can start with a disease like PKD and then get that usage of the drug in the real world in that indication and take it into thalassemia patients and sickle cell patients eventually. So we're proud to being part of this, excited about it and grateful for all of you, investigators, all the patients and all the people at Agios who've made this happen and any of our other collaborators over time. So thank you to analysts and investors for being with us this morning. And I wish everybody a great continuation of EHA. There's a lot of presentations from a lot of companies, both oral, posters, e-pubs, everything else, and we've got a total of 14 of them. So get out there and see, hear, read them all. So thank you very much to everybody, and have a great rest of the day.

Bye-bye. Thank you.

Bye-bye.

Bye.