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

All right. Good morning, everyone. Welcome to Agios EHA webcast. I will go ahead and share our slides and then kick it off to Jackie to get us started.

Thank you, Holly. Good morning, everybody. Hope everybody is doing well, and thanks for joining us at this EHA 2022 event. One of the things that we like to emphasize, well, we don't so much want to emphasize the forward-looking statements, so we need to do that. So here they are. And then subsequent to that, one of the things that I want to point out real quick is just the agenda, and then I've got a couple of introductory slides. So my remarks will be very brief, so we can get to the more interesting, more important parts of the event today. You'll hear from Sarah regarding an update on pyruvate kinase deficiency and the story that is playing out very nicely for us there. She will also talk about thalassemia and the burden of disease and where we are with the clinical program for mitapivat. And then we're very happy to have Eduard van Beers with us to talk about his results from the estimate study of mitapivat in sickle cell disease and then Dr. Van Beers will be available for the first 15 minutes of the Q&A so we want to get those sickle cell questions in during that first 15 minutes before he has to drop off and then the rest of us are available for the remainder of the Q&A. So one of the things that we'd like to emphasize at Agios are our connections to our patients, the health care providers to all of the parties that we work with to hopefully bring innovative drugs to patients -- you see some photos here and some of these [indiscernible], but one of the things that -- them to bring treatments forward for them, we consult with patients regarding our clinical trial protocols and how we run things. We get input from them as to what they need to help them manage their diseases better. And we think that this gives us better outcomes with all the programs that we run and we do that early in the process and continue to stay engaged with patients all the way through, even through approval in terms of how we support them with our patient support programs and continue to invest behind the diseases that we hope to bring treatments forward for. We have been active in the PK activation space for a long time. We're the pioneering leaders with this mechanism. We've been in the clinic with this mechanism over 8 years, and we're the only company that has data in this mechanism across 3 different disease areas and an approval now for pyruvate kinase deficiency and in pivotal programs for both thalassemia and sickle cell diseases, and you'll hear more about that today. We are -- have created a number of first, so that are shown on this slide. I'm not going to talk about all those that we've published heavily in these areas. And because we've been doing this for quite a long time, we think we understand this mechanism as well as anybody in what it can do to help patients with these serious hemolytic anemias. So with that, I think that I am going to summarize just a very few things about Agios in terms of our overall profile and where we are today, some genetic disease-focused company. We have, again, the strong connections, both internally and externally that we think allows us to have better execution on everything that we do. We have a strong cash position and a strong balance sheet that we're very happy about, especially at this moment with market volatility, and we are committed not to squandering what is a strength today. We want to make the most of that. We've been bringing our expertise in cellular metabolism to patients for the 14 years that we've been in existence and are looking forward to a very bright future continuing to leverage that science in hemolytic anemias and other genetically defined diseases. And as I already mentioned, we are the pioneers in PK activation, and we are in the middle of our first launch as a genetically defined disease-focused company with PKD in the U.S. and look forward to giving you ongoing updates about that. So with that, I think I'm going to turn things over to Sarah. Thank you.

Thank you, Jackie. So I am delighted to be able to talk about our PK activator clinical programs and also by the data that we presented at EHA over the past couple of days. Just a reminder of where we are, the orange being mitapivat. So as you know, we have been studying mitapivat in pyruvate kinase deficiency, alpha and beta thalassemia and sickle cell disease. We're very pleased with the FDA approval coming out of the ACTIVATE and ACTIVATE-T data, establishing positive benefit risk for adults living with PK deficiency, which allows us, of course, to have initiated now our pediatric program with ACTIVATE Kids and ACTIVATE KidsT 2 trials -- 2 pivotal trials that will allow us to establish benefit risk in children all the way up to age 18 with the goal to expand the label past adults. Then similarly, for alpha and beta thalassemia, we are very pleased with the progress of our pivotal program there with the 2 trials ENERGIZE and ENERGIZE-T, which encompass all genotypes for thalassemia and all of the transfusion burden in thalassemia, and we'll talk a little bit more about that. And then sickle cell disease with the RISE UP trial is in the Phase II portion right now, and we're excited about that one as well. That data, of course, is supported by data coming out of our investigator-sponsored trials, and I'm very happy that Dr. Van Beers is with us here today to talk about [indiscernible] sickle cell disease trial or estimate. We are also excited about the hereditary spherocytosis IST that is about to be initiated. And then of course, we're not going to spend time on that today. We're also very pleased with the progress made with AG-946 and are currently in the sickle cell disease component of the Phase I and are about to initiate our MDS program there as well. So -- of course, all of this -- with all of this, our clinical focus is to transform the course of hemolytic anemia by increasing red blood cell energy, health and longevity via PK activation. And that premise can work because what these diseases have in common PK deficiency, thalassemia and sickle cell disease is that those red blood cells have insufficient energy, have abnormal red blood cell shapes and are prone to increase oxygen radical injury. And that hemolytic anemia common in those diseases translates into chronic fatigue, challenges with school and work, social and emotional health challenges, iron overload that leads to a bunch of secondary organ damage and thus to potential very serious complications as well. And that is where we hope to make a difference with PK activation. So now focusing on what we actually presented at EHA for PK deficiency; first, to further underscore what I just highlighted about the comorbidities in PK deficiency. We had a poster on -- which was an analysis from the PEAK registry, which highlighted the different genotypes that can be found in PK deficiency. And what I wanted to highlight here is that it's truly a global registry. You can see representation from North America, Europe, Asia and the Middle East. And you see that the genotypes that we found across the patients participating here are very similar to what we saw as a distribution in our clinical trials with missense mutations being the most common followed by missense, non-missense and then non-missense mutations being the least common. But what is very important is that independent of those genotypes, we can go to the next slide, that you can see comorbidities and complications a wide range of dose across those different genotypes and that dose do require disease management. And you can see here presented in this graph, it's truly across different organ systems that you can see complications being present, cardiac, liver and the biliary system, jaundice being one of the presentations of the hemolysis, which we know we can improve with mitapivat. Endocrine organs, bone health, thromboembolic events and then all of that, of course, also ties into the presence of iron overload, which drives a lot of those secondary organ damages. But what is very important that is independent of the genotype, you see that many patients actually have at least 2 or more different complications. So there is a significant disease burden with PK in the context of PK deficiency. And that is, of course, not currently still part of the natural history of the disease, which we hope to impact over time with the treatment of mitapivat which brings me to the next slide because now I can highlight some of the efficacy data that we continue to show, which will be -- which is very meaningful in that context. So this slide represents data from our extension study. On the left, you see in the green -- light green, you can see the randomized controlled trial data. And then in the gray is the extension study data. And what you see here is that in ACTIVATE, as you know, we saw hemoglobin improvement. So the mitapivat patients had a hemoglobin improvement as represented by the blue line going up while the placebo patients remain stable. But what you saw is that once the placebo patients were allowed to switch over to mitapivat at the beginning of that gray zone, the gray line equally goes up in a similar pattern and then you can see that originally exposed mitapivat patients and then the placebo to mitapivat switchers, both start having the same hemoglobin response, which they maintain over a long period of time. Most importantly, there is also that we saw that not only does the hemoglobin go up, but we saw a normalization of hemoglobin levels, which we can see on the next slide. If you look at the overall mitapivat population, so 36% of all study patients and almost 84% of the hemoglobin endpoint responders achieved a normal hemoglobin level at least once while receiving PYRUKYND. This is quite significant because the inclusion criteria of the trial was having a hemoglobin of less than 10 -- equals or less than 10 grams per deciliter. And so again, here, you see consistency in the data. We saw patients in ACTIVATE that were originally exposed to mitapivat 14 out of 16. So 87.5% reached that normal hemoglobin level at least once versus 12 out of 15 in the placebo to mitapivat switcher. So very consistent pattern again. If we go on to the next slide. So in total, we have 26 patients who achieved normal hemoglobin at least once out of the hemoglobin responders and all those 26 patients are represented here with the duration projected over this graph as well. And what you can see is that the normal hemoglobin level is reached rather quickly within first 4 months of treatment with mitapivat, you can see that the patients actually reach that normal hemoglobin level. And many of them actually keep that going. So you can see throughout each time point represented that patients actually reach that normal hemoglobin level. And the time points at which they maintain that. And the people in yellow actually had a normal hemoglobin level consistently throughout their entire exposure to mitapivat. So that is definitely a very nice treatment effect from being on mitapivat and quite remarkable. Not only did we present the data on this hemoglobin endpoint and the maintenance of that. But we also were able to highlight new data around our PROs. As you know, we had 2 patient-reported outcomes that were developed within the trial and validated within the Phase III trial. One, the pyruvate kinase efficiency diary was focused on signs and symptoms and then the pyruvate kinase deficiency impact assessment was focused on disease impact. If you can go to the next slide. What we saw in our original analysis in the intent-to-treat analysis was that both PROs actually had an improvement when compared to placebo. So mitapivat treated patients as a group, had an improvement in comparison to placebo. So placebo being the gray line and the blue line being the mitapivat treated patients. But then when we focus specifically on the hemoglobin endpoint responders for the clinical trial definition, you saw even a greater improvement on those scales, and that's represented in the orange line. And you can see how that is also maintained over the period -- a long period of time. So if you can go to the next slide, that's the other PRO, you can see a similar pattern. So patients who had a primary endpoint of hemoglobin response achieved did show greater improvements in both PROs. So with that, key takeaways for PK deficiency. From the PEAK registry, we've seen that there is a wide range of serious comorbidities and complications across multiple organ systems across the genotypes of PKD. Treatment with mitapivat was associated with early and robust hemoglobin responses with 36% of all study patients and 84% of the hemoglobin endpoint responders achieving normal hemoglobin levels at least once, while receiving mitapivat. Then further examining our PROs, we saw that improvement in the quality of life or even greater and were clinically meaningful in mitapivat-treated patients who achieved primary endpoint of hemoglobin response. And then, of course, all of these data continue to highlight that mitapivat is an effective in a disease-modifying therapy for patients with PK deficiency irrespective of transfusion needs. So with that, we're going to move on to thalassemia. Similarly, we'll first talk a little bit about the burden of disease. So it's a significant opportunity. Thalassemia has -- it's a rare disease in the U.S. with 18,000 to 23,000 alpha and beta thalassemia patients across the U.S. in the 5 EU, with approximately a 50-50 split between the U.S. and the EU and approximately 1/3 of those are alpha thalassemia patients. But as you know, we've presented on that earlier as well, there is many patients across the globe, and there is a significant opportunity outside of the U.S. and the EU as well. The unmet medical need. There are no approved therapies for alpha thalassemia. There are very few options in that -- well, regularly transfused beta thalassemia and no options in nontransfusion-dependent thalassemia. And on top of that, it's very similar to PKD, nontransfusion-dependent and alpha thalassemia are actually now well understood. What we believe are critical success factors for our program is that we actually are focused on all genotypes. Our program is a program that for the first time, evaluate alpha thalassemia. We are evaluating nontransfusion-dependent and transfusion-dependent thalassemia at the same time, so -- and we believe that strengthens the program. There is a global approach to the clinical development program. So -- and we are building connections with thalassemia patients and physician communities. So the current classification of thalassemia syndromes. So on the top, you can see that there is a subdivision in the context of the amount of transfusions that patients need with nontransfusion-dependent thalassemia covering patients that occasionally need transfusions. For instance, when they have an infection or something like that or have a need for intermittent transfusions. And then transfusion-dependent thalassemia, they really need a regular administration of transfusions for life long. And on the bottom, you can see all of the different genotypes that are represented in each of these buckets. But you can see that across the board, both for thalassemia intermedia and thalassemia major, you can see alpha and beta thalassemia present. Common clinical complications. So these are complications that are often described on the left for transfusion-dependent thalassemia, on the right for nontransfusion-dependent thalassemia. As you can see, the list is quite long. And these are not exclusive. So while they are listed in the 2 areas, you can see these complications across the board in thalassemia. Needless to say that the list of these complications is long and bad, silent cerebral ischemia, pulmonary hypertension, right-sided heart failure, all horrible disease manifestations. And so there is huge disease burden across the spectrum here. Now the disease has changed over time. So before people who were born before 1955, when transfusions actually weren't used as part of the standard of care tended to not survive very long beyond age 12, the survival rate was very low, and you can see that reflected in that black line going down very fast. And then with the introductions of transfusions per each 10-year age cohort, you can actually see an improvement on that, but it's still definitely not what the normal general population looks like. You can still see that there is -- while there has definitely been an improvement, there is still a huge unmet need there and something that we can -- that we need to address. Now while transfusions are commonly being used there is still limited access across the globe. And so there's some optimal use. There's huge resource utilization. Some patients also may not adhere or don't want to be transfused, which brings by itself also complications. And then there is also not perfect efficacy and there are adverse events associated with that as well. So despite all of this, there is still significant advances of the transfusions. There is still a huge unmet need and there are continued challenges within. Now as mentioned earlier, the nontransfusion-dependent thalassemia is less well understood as well as alpha thalassemia. And it used to be that people thought that if you had transfusion-dependent thalassemia, you were per definition, more sick. Now more and more data is coming out that actually highlights that nontransfusion-dependent thalassemia patients have a huge range of complications and that they're actually very common and severe as well. And you can see here on this graph, a list on the bottom, you can see all of the medical complications that are described in the context of NTDT. And you see that these complications increase with age. So the other people become the more of those complications appear. And so this goes to extramedullary hematopoiesis continues to be ongoing leg ulcers, thrombosis, pulmonary hypertension, heart failure, cholelithiasis, abnormal liver functions, diabetes, hypothyroidism, osteoporosis and hypogonadism. So serious complications across the board. And then when you look at alpha thalassemia, similarly, you can see that these complications are also present there. So both of those diseases -- well, it's one disease, but both of these genotypes have severe complications. A lot of this is driven by iron overload. It's -- iron overload is commonly linked to the presence of transfusions, but there is an abnormal dysregulated iron metabolism independent of transfusions. And so that definitely contributes to those multiple morbidities with pulmonary hypertension, endocrinopathies and osteoporosis, proteinuria and end-stage renal disease, hepatic fibrosis, cirrhosis and hepatocellular carcinoma and then neurovascular events and cardiovascular events associated with that as well. Now that is, of course, where we also hope to make a difference. In our Phase II open-label trial of mitapivat in adults with alpha or beta nontransfusion-dependent thalassemia does support the advancement to our pivotal programs. And we have reported before, the results from our core period in which we had 80% of the patients meet the primary endpoint of hemoglobin response which was defined as an equal or more than 1 gram per deciliter increase in hemoglobin concentration from baseline and 1 or more assessments between week 4 or 12. But very importantly, we've also seen the improvements in markers of hemolysis and ineffective erythropoiesis which are a driver of a lot of those complications too. Consistent with our mechanism of action, we've seen a mean ATP percent increase from baseline and the drug was well tolerated and safety profile was consistent. And then, of course, now many patients have continued on in the extension period, and we continue to very similar data on the efficacy side with the maintenance of the hemoglobin response and a continued improvement on the hemolysis and ineffective erythropoiesis. And across those different genotypes enrolled into the trial and the safety profile remained consistent as well. And very importantly, bone mineral density that we've been following over time remains stable as well. And it's that data has actually allowed us to design our Phase III pivotal program which consists of those 2 trials, ENERGIZE and ENERGIZE-T. ENERGIZE being the trial that enrolls nontransfusion-dependent thalassemia patients and ENERGIZE-T being a trial that enrolls transfusion-dependent thalassemia patients. Both have a 2:1 randomization. ENERGIZE because of the nontransfusion-dependent population that allows us to actually measure the primary endpoint via hemoglobin increase, mean hemoglobin increase of 1 gram per deciliter from baseline over a 24-week core period, while the ENERGIZE-T trial looks for a 50% reduction in transfusion burden in any 12-week rolling period over 48 weeks. Both of those trials the patients then have an opportunity to roll over into an open-label extension in which we can continue to follow their efficacy and safety. The goal of this program, of course, is to support the entire thalassemia population independent of genotype and those 2 trials complement each other and will cover a range of transfusion needs and hemoglobin levels. So key takeaways for thalassemia. Thalassemia represents a significant opportunity to make a global impact, and it has the potential to address a range of thalassemia types and severity. Despite the significant advances via transfusion administration, continued challenges remain in the management of thalassemia. And the patients with non-transfusion-dependent thalassemia experienced a significant disease burden, comorbidities and complications that increase with age. There is not much data available on literature available in nontransfusion-dependent thalassemia and alpha thalassemia, in particular, but that is where we are actively working on a number of activities to fill those data gaps and improve the understanding of the burden of disease in alpha thalassemia as well. And then sickle cell disease, again, represents a significant opportunity here with 120,000 to 135,000 patients across U.S. and the 5 EU, but many more patients outside of those areas as well. Significant unmet need, no fully approved therapies that address both pain episodes and anemia, and there is a need for innovative therapies that are convenient and have an oral administration. Our clinical development program, we believe the design that we have with an innovative seamless Phase II/III operational trial design that was developed with the community inputs that was focused on reducing enrollment barriers. And on top of that addresses key aspects of disease that the community has highlighted to us is poised for success. We have a global approach to clinical development. And we, of course, also build connections with sickle cell disease patients and physician communities here. The 2 collaborator-led studies of mitapivat in sickle cell disease, they support also the advancement of program to the pivotal study RISE UP. And across those 2 investigator-sponsored trials, you've seen -- we've seen a positive impact on the anemia. So with the hemoglobin increase, again, consistency here with sickle cell disease. In the sickle cell disease trials, we've also seen an improvement on the hemolysis markers. ATP and 2,3-DPG consistent with the mechanism of action of mitapivat moved into the right direction as well. We have seen an improvement on the sickling markers as well, which is a good sign for the VOC readout. And then the safety parameters, safety events were also did not show anything new. So overall, these data are very supportive as well to continue into the RISE UP trial, which is on the next slide. As mentioned, this is a one protocol with a Phase II and a Phase III. In the Phase II, there's a 1:1:1 randomization to mitapivat 50 milligrams or 100 milligrams or placebo in which we will follow 69 patients for 12 weeks with the primary endpoint of the safety and mean hemoglobin increase defined as equal more than 1 gram per deciliter from baseline. When that trial in the Phase II completes, we will, of course, evaluate the data -- and then when all that looks good selected dose based on predefined criteria and then move into the Phase III component of the trial which is a 2:1 randomization of 198 patients to the mitapivat-selected Phase II dose and matched placebo, and we'll follow those patients for 52 weeks with 2 primary endpoints, one being focused on hemoglobin increase and the other one on annualized rate of sickle cell pain crisis and then evaluate the data again and continue with our regulatory path. And with that, I am very excited to -- well, introduce, everybody knows Dr. Van Beers. But he is the Associate Professor in the Department of Clinical Chemistry and Hematology and an Associate Investigator at the Van Creveldkliniek in Utrecht, the Netherlands, where he's also an attending physician, and Internist Hematologist -- Internal Medicine and Hematology. He -- after receiving his MD, he completed his PhD in the University of Amsterdam on sickle cell disease, pathophysiology and clinical complications. And then he completed fellowships in hematology at the academic center in Amsterdam and also served as a visiting fellow at Greg Kato lab in the hematology branch at the NIH in Maryland. And so currently, he is the coordinator of research and trials for the European Reference Network and EuroBloodNet. Dr. Van Beers, his interest, of course, are classical hematological conditions and specifically today, we'll be focused on sickle cell disease and the estimate trial. We've had the pleasure of having Dr. Van Beers as our investigator on many of our trials, as you can see below, and I'm very much looking forward to hearing from him today.

Thank you very much, Sarah, for your kind introduction and excellent explanation of the burden of disease in all the patients I care for every day. And I'm very pleased that we can share our results from the fixed dose extension period, which were also presented at EHA this year. You already have shown the highlights of the short dosage, but here we are going to look into long-term experience in these patients. And the short 8-week data cut is already published in the American Journal of Hematology in April. But here, we're looking at the fixed dose extension. If we look at the background of mitapivat, we have seen in the presentation from Sarah, the effects of intervening and adding ATP to red cells, first in a chronological example of a disease where energy is lacking. So that's pyruvate kinase deficiency, but also in other hemolytic anemias, such as thalassemia and sickle cell disease, where there is no defect in energy itself, but there are other defects, which make that red sickle has combat all kinds of mechanism where they are needing more energy. So more energy will help. We have seen this in thalassemia. But in sickle cell disease, there is a two-pronged approach by mitapivat because it not only adds ATP, but upstream, it will also drill down all the glucose intermediates, such as 2,3-DPG, which will make the red cell, more oxygen affinity, more prone to hold oxygen, and it means that the oxygen hemoglobin will be preferred against the deoxyhemoglobin, which for sickle cell, of course, is very good because it prevents polymerization of red cells. We have shown this in the short-term follow-up of the patient, which has been published and it's exactly the same as an independent group at the NIH has done with the same drug that we've had in the same patients. So I think that this proof of concept has been established now. So today, next slide, the objective is to report follow-up data on safety and efficacy of mitapivat treatment in subjects with SCD enrolled in the currently ongoing Phase II investigated initiated open-label study, the ESTIMATE study, which was conducted in my center by the Sickle Cell [ Alcon ] Research Collaborative Group in the Netherlands. Next slide. Here, again, you see the design of the study. So dose finding period has been reported. Patients were allowed to increase every 2 weeks by dosage and then were maintained on a fixed-dose extension period. And here, we give you the data cut from January 2022. Major eligibility criteria were subjects older than 16 years, which are considered elderly patients for regulatory standards in Europe, and we were a little bit generous with the genotypes because homozygous SS was allowed with also double compound S-beta 0 and S beta+ were allowed. We had 6 SS patients, and we recruit 1 0 and 1 beta-plus patient here. VOCs were limited to 1 to 10 or patients needed to have another SCD-related complication, a 1-year prior enrollment hemoglobin levels were restricted and patients were able to use hydroxyurea when it was on a stable dose 3 months prior to the first day of study drug. So nothing special here for eligibility, of course, adequate organ function, and no chronic transfusion was allowed 3 months before the study drug. Then we go to the baseline characteristics. So 9 patients received mitapivat, 8 patients were evaluate able because the first didn't reach the first checkpoint. I will come back to that later. Most were female, most use hydroxyurea and the genotypes already mentioned. So here is the safety data for ongoing study. Most have been shown already because most safety data we have seen was at the start of the study, initial headache, initial some ALT increase but no new safety events we're seeing beyond what has been described in the previous studies of mitapivat in PKD and thalassemia. We had one nontreatment-related severe adverse events of a urinary tract infection needing admission in the hospital, and this was after 2 days of 20-milligram mitapivat. So the lowest dose and she already had [indiscernible] at starting when asking back to this patient, this patient was lost to follow up, and we couldn't evaluate the effect -- immediate effect that in these patients. Median treatment duration of the other patients was 38 weeks range from 11 to 60 weeks on drug, and we -- they haven't seen any other safety severe events for grade 3 treatment-emergent adverse events for the reporting period. So if we look into the efficacy, I will show you Table 1 in a minute where we summarize the change in primary and secondary endpoints for the extension period. Hemoglobin levels significantly increased accompanied by a decrease in markers of hemolysis, retic count, total bilirubin and lactate dehydrogenase. Red cell sickling as quantified by the oxygen scan, which is a new method of oxygen gradient ektacytometry, where we look into one of the parameters, which is the point of sickling, the point where this -- the oxygen tension where the cells start to sickle is decreased and 2,3-DPG levels are also decreased. Hemoglobin affinity is increased as measured with Hemox Analyzer and the ratio maintains significantly improved. And now for the first time, we report also the mean annual VOC rate -- related hospital admission days in 2 years prior to starting study treatment compared during those fixed dose extension. So for the 2 years prior study, they were respectively 1.5 VOCs and 5.9 days admitted for SCD-related hospital admissions and it produced during the time on mitapivat to 0.5 for VOCs and only 1.6 for hospital days admitted. And this was weighted by follow-up duration of the cases. Here, the results for the hemolytic parameters and metabolic parameters, hemoglobin was significantly maintained significant increase, which over 1 milligram per deciliter increase over the board. Retic count still dramatically decreased. Total bilirubin still dramatically decreased. Lactate dehydrogenase, another hemolytic marker decreased. Point of sickling was still decreased, but didn't reach significant anymore, but has more to do with the variability of the measurement, but we think the end rates was still trends going down by 5 millimeters of mercury, which is over 10% change. p50, which is the oxygen affinity is still significantly decrease. 2,3-DPG still significantly increased. ATP, which is still a little bit increased, but not significantly and moreover, the ratio, which is still proved of long-term treatment. So next slide, we see this in graph bars where you can appreciate the individual results, and you see that most results are at the same direction in every patient. Let's have a look at hemoglobin here baseline from fixed dose extension. You see virtually all patients are going up. Absolute retic count is going down in every patient. Bilirubin is going down in every patient. Lactate dehydrogenase going down, but almost in every patient. Point of sickling almost going down in every patient. p50 the same. 2,3-DPG in every patient going down and also the ratio. Also for the ratio compared this to the healthy controls, which are presented in the gray bar, you see that which has been known from the 60s that patients with sickle cell disease have a worse ratio compared to healthy controls, which with mitapivat seems to cross the line and [indiscernible] ending up above healthy controls. So this drug clearly seems to be correcting the metabolic problem in these red cells. So I think for me, this extended fixed dose period shows that a lot of the effects we have seen in the short dose are maintained and still a very clinical relevant and significant. Treatment with mitapivat for up to 60 weeks in subjects with SCD showed no treatment-related TEAEs grade over 3 or more. Improvements in anemia, markers of hemolysis, hemoglobin oxygen affinity, 2,3-DPG and the ratio, we're still seeing and maintained. And although preliminary, the data was not published where we do see a significant reduction in VOC rate and almost a significant reduction in SCD-related hospital admission days, showing beneficial effects for patients. Now I'd like to add, it's not only significant in terms of statistical testing, but also clinical relevant. I think this brings us to the end of the update we have done at [indiscernible] from the ESTIMATE trial. Very happy to ask questions also about the short term follow-up with these patients or other insights in any of the trials from a physician's perspective.

Thank you, Van Beers. Everyone on the line, if you have a question, you can submit it through the Q&A function. You may need to click the 3 dots on the side if you can't see it. Dr. Van Beers has a hard stop at 9:00 a.m. Eastern. So we'll focus on the sickle cell questions first. Okay. They're coming in fast and furious. Okay. Dr. Van Beers, the first question is, isn't p50 in sickle cell disease patients normally above 30, why are baseline p50 value is lower in the study population?

So normally, they are slightly lower than in the healthy population. Data from us, but also other study groups show that this is very strong to 2,3-DPG. And again, this is again very closely related to point of sickling. And as you have known, this has been a goal for many therapeutics all over the board, which are investigating in sickle cell disease, which most of them we don't have and have seen. To me, the good thing here is that reducing the p50 goes by a very physiological manner, which is attacking 2,3-DPG and not by fixing hemoglobin itself in a certain state. So there's still a normal unloading red cells are still sensitive to pH shift and to temperature for instance. So if there is a severe hypoxia and pH drops in the patient, these cells can still respond on normal regulation of hemoglobin in contrast to other agents.

Great. And apologies, that question came from Mark Breidenbach at Opp Co. So the next question comes from Anupam Rama at JPMorgan. So Dr. Van Beers, how do you see the PKR class fitting into the current and emerging sickle cell treatment landscape, including gene therapy? And as a follow-up to that, based on what we know today, what do you see as potentially in-class differentiators for mitapivat versus Forma? And is there room for multiple PKR activators?

So I think that many patients with sickle cell disease are incompliance. So that's why it's very hard to do trials and patient management is rather difficult. So having in which is a very low level for patients to take is important. Patients are very skeptical of medical innovations, so I don't think that gene therapy is for most patients, they go there. So if you want to look -- dive into this further, you really have to talk to patients how they think about it. If you say to a patient, we have something which will cure you, and they wanted all they want. But if you tell them all the side effects, then it becomes a different story, especially seeing all the side effects, which have been in literature for certain compounds of gene therapy. Having said that, for me as a physician, I would love to have something which has a very long time of acting. So twice day or daily dosing is good, people can try it, but it would be better if there is something very long acting, but none of the Forma or the mitapivat as yet has it. So I'm very much looking forward into this new compound of Agios really to see if we can improve this. But still, having seen this in my patients, you have seen a very long follow-up if the patients feel the benefits, then it helps. So yes, I think that's my answer about this.

Great. A question from Greg Renza at RBC. And speaking to the challenges of sickle cell study enrollment and execution. How broadly applicable are the solutions across regions or studies that investigators can employ to address these challenges? What is the level of tolerance that we should have in terms of like screening metrics, dropouts, discontinuations?

Very good question because I don't know how role -- so how enrollment is against what we have expected. I think it's very important to do this clinical trial as clean as possible. And obviously, you really want patients who have some sickle cell events because I think from regulators, but also patients and also physicians are very keen to see whether this drug will deliver on these outcomes. So I believe it will do because I've seen it in my patients but I'm not the only one who needs conviction, but the patients needed, physicians need it and regulators need it. So I think there are enough groups who can enroll patients. I think there's a lot of centers have enough patients who can go on trial. So especially in Europe, I know some big centers who just spare patients for everything, which is ongoing because they know that the pipeline is big and their many trials are ongoing. Obviously, they want to try it on as many patients as possible. So I feel confident but what can I say about this because I'm not the CEO guy running the trial.

Maybe I should add a little bit to that point. It's indeed challenging in regions like the U.S., where there is many, many trials ongoing where there's also gene therapy opportunities, things like that. But that is where I think we've positioned RISE UP well with that operationally seamless design because it allows us to bring other countries on board faster. And so we are truly going everywhere on the globe where sickle cell disease is present, and we do hear from when we moves to what Dr. Van Beers was talking about that there is a lot of excitement about that as well. And then -- so it's a matter of being smart operationally, I think, is very important there. There is to Dr. Van Beers' point, like many patients who prefer an oral therapy in comparison to gene therapy, which is very permanent.

Absolutely.

Very -- if there is a side effect, it's there and oral therapy can be stopped when they no longer want to take it. Now that being said, what we've seen with mitapivat across the board on PK deficiency, thalassemia extension studies, the extension study or the follow-up period of time that Dr. Van Beers describing estimates for the patients is good. Patients once they feel something, they tend to want to continue to be part of the extension studies, and that's what we've seen across our hemolytic anemias.

If I can add to that, Sarah.

Yes.

I think that the RISE UP is pretty generous in terms of genotypes. So that really helps because some -- some studies are restricted for SS only, which I don't understand because as the 0 and severe as beta+ can have a severe disease SS. So -- and especially in Europe, that's a huge group of patients were not allowed to do some of the other trials and also SCD disease, especially in the Netherlands. For me, it's an additional opportunity to help some of our patients. So that's why open RISE UP as well next to the estimates that I already have.

Yes. Yes, indeed, good point.

So we have a few non-sickle cell questions, I'll go ahead and move to those. So does the recent withdrawal of luspatercept's sBLA in nontransfusion-dependent beta-thalassemia have any impact on development strategy or prioritization of ENERGIZE versus ENERGIZE-T?

Short answer is no. The program has been set up from the beginning, so to encompass all of the transfusion burden that patients experience across all of thalassemia, all genotypes. So there will be no change to that based on what happened with the luspatercept. We also strongly believe in the way our trials are designed and the -- what we are measuring to demonstrate what it would mean for patients clinically. And believe that, that has no impact to that as well. So we -- from our way we're running the program, we continue as is we've always had in mind to go after that population together and our regulatory strategy is based on that as well.

Yes, I just want to add something from a physician standpoint to this about luspatercept. I think what's very important is the mechanism of action of mitapivat. And what this does to physicians when they try to prescribe or think about safety, about the new drug. So if you look at the data of erythropoietic activity in iron metabolism and luspatercept, it does completely opposite thing than mitapivat does. So look at these data from [ John Porter ] presented it at last year, where they showed that if you add -- I think it was a BELIEF trial where they looked into markers erythropoiesis when using [indiscernible]. They go up so transferring a receptor goes up. EPO goes up and retics don't drop and you see then iron metabolism markers go over. So hepcidin drops even further, [indiscernible] increases and the general outcome for LIC and myocardial iron doesn't improve and might even worsen for myocardial iron. So then I can believe that this also does something with regulators, but I'm not sure about it, but it does something with clinicians. And if clinicians look at this data, you look in mita. You see a drop in EPO, which is for -- which is very telling there's better oxygen delivery. It's not a proof, but it feels good. It feels safe. There's no such oxygen drive, which make the kidneys go make more EPO. And this -- it goes the same way for every marker. Retics go down. So bone marrow gets more [indiscernible] marker of bone activity. It goes down. [indiscernible] goes up. So there's less iron uptake, and you see LIC going down. And this is -- we see at PKD. And these markers going the same way in thal and in sickle cell just retics go down, hemolysis goes down and hemoglobin goes up. So this, again, all in the right direction.

And we indeed saw across our clinical development program in all those indications, positive impact on iron metabolism, and we also saw it in the mice. I know it's not human but we saw it in thalassemia, we saw in hereditary spherocytosis. So there is a very consistent package there that we see across our indications and across how mitapivat works in all these hemolytic anemias.

And I think that also helps for patients and physicians is that Agios is doing trials in many forms of hemolytic anemia. So you get a lot of safety data early on. So when I needed to enroll patients in ESTIMATE study, I have to explain them that we're the first in the world to try this drug, patients with sickle cell disease. But I tell them they now decades of patient years of safety data from other hemolytic diseases, which essentially face the same problems as they have, except for [indiscernible].

Yes, indeed.

So it all helped to sell the message, and I like to sell a message because I think this is a good drug.

Another thalassemia question in the LTE. This is from Mark from Cowen. We noticed that the beta-thal patients saw 72 weeks of follow-up in the trial. Is the lack of 72-week follow-up in thalassemia just an artifact of the enrollment time lines or our alpha-thal patients still on the study?

No, they're still on the study. So it is an artifact of the enrollment time lines and reaching a certain time point. And alpha-thal patients were enrolled in the later part of the trial.

A question from Andy Berens at Leerink. In PKD, can you walk us through the different genotypes in terms of the data that you've seen from mitapivat? And if you have any data on the diagnosed prevalence of each genotype? And then finally, for Richa, wondering how many PKD patients are diagnosed as children and whether you are seeing pediatric usage thus far despite the label, not extending to the stage?

So in regards to the genotypes, the data that I just highlighted, the comorbidity presence across the different genotypes that we did enroll missense/missense/non-missense patients in ACTIVATE and ACTIVATE-T with the same type of distribution and we did do subgroup analysis on those patients as that was prespecified and did not see a difference in overall a difference in our responses. So meaning that all patients independent of the genotype had an opportunity to respond to mitapivat treatment across the board. And I think that is indeed reflected -- you can look at bars looking a little bit differently. But when you look at the overall prespecified analysis of that, there was no meaningful difference. And that effectively is reflected in our label with us being allowed to treat any PKD patients in the U.S. independent of the genotype.

Well, it would exclude the double [indiscernible] patients from the study, and we think that runs about 9% to 15% of the overall PKD prevalence. So there is reason to believe those patients could potentially respond, right, Sarah?

And yes, that is exactly -- that was based on the DRIVE PK data where we saw the non-missense/non-missense patients not reach that clinical trial threshold that we use to define a response. However, there were patients in that trial that were non-missense/non-missense and because there was some impact observed not reaching that threshold of the hemoglobin bar of 1.5 grams per deciliter, but still seeing an improvement on the hemolytic parameters. That data was used in our filing to highlight that some patients may still receive a benefit despite not reaching a certain hemoglobin threshold. And that's how we ended up with that broader label because there were indeed signs of improvement observed.

And I can talk a little bit about the pediatric patient population, but also how the drug is being used currently for the adult PK population. So just building on what Sarah said, we are not seeing physicians limiting the drug to a certain hemoglobin level, a certain transfusion status or certain genotype. It's being used as you would expect for the adult pyruvate kinase deficiency patients at per label, which was our expectation and it is how the market is currently playing out based on what we see from the early script data. To answer the pediatric question, a couple of things we have pointed out before 20% of the entire prevalent population where in the U.S. we believe is about 3,000 and admitted in Europe as well is about the same size is the pediatric population labeled. Sarah talked about in opening remarks, we are currently studying the benefit risk of the drug in the pediatric patient population. So that has not been established yet. So we are not seeing use of the drug in the pediatric population, we would not expect it. We don't have data there. We are working on getting that data. In terms of diagnosis, we do anticipate just based on conversations with physicians and what is happening from a market standpoint. The pediatric patients are likely -- you have centers like the pediatric hospitals a sector where these patients are and so they are tested. They will be -- we believe the diagnosis will be quicker in the pediatric population than it is at the adult. That's our current working assumption. However, no use right now in that population and to established benefit risk for our Phase III protocols.

Great. Thanks, Richa. Dr. Van Beers had to drop off, but if there are questions, again, please submit them to the Q&A section. I think I have 1 or 2 more. So will the long-term data for the Phase II thalassemia study be used for the filing along with the ENERGIZE trials?

We always use all data across all of the programs for any filings. So yes, safety that typically gets cited across the board. And it will not be -- you have your primary data package that is used to assess the efficacy, and that will be from the randomized controlled trial data. But for instance, long-term efficacy messages where we follow liver iron concentrations in the context of MRIs, things like that will obviously be part of the data package too.

In thalassemia, how will Agios position made a pivot against Reblozyl and other gene therapies?

Can you repeat that because somebody was at the door?

How will Agios position -- maybe Richa speak to it, Richa, I think you're needed.

I can start, Holly and then when Sarah comes back, she can add the clinical perspective. So I think there's a couple of components. So first of all, as Sarah discussed in the context of our clinical study, we are the only drug right now that we are seeking -- we are going to be seeking approval in alpha thalassemia as well as beta thalassemia. So we really don't have any treatment options available for that patient population. When we think about the transfusion-dependent beta thalassemia population where luspatercept has an approval, you're still wanting to have a convenient therapy. And then if you look at the total data we have and Dr. Van Beers alluded to this as well, in terms of the mechanism of action and some of the benefits that we are seeing. We're also collecting data in a non-transfusion dependent patient population, as Sarah can talk about in more detail or not just [indiscernible] improvement but also on how patients feel and function. So we feel that the combination of all of that having covered a broad spectrum of genotype, ensuring that we are collecting data, not just on drug fusion burden, but also hemoglobin improvement as well as how patients feel and function that knowing our experience from the ACTIVATE/ACTIVATE-T study is going to be a very compelling data package and competitively differentiated in that market as an oral convenient therapy, which we know patients want and physicians appreciate as well.

Great. Well, I'm not seeing any final questions. So Jackie, I can turn it over to you to close this out.

Great. So in closing, we're really excited about everything that we've got going on at Agios. We're excited about the launch of PKD in the U.S. and look forward to giving everybody an update on that with some metrics and some data for -- in our Q2 results call, which will be the first week of August, and we're very excited with our pivotal programs that are up and running in thalassemia pediatric PKD and sickle cell disease. We really like the way the total story around PYRUKYND, mitapivat is coming together across all of these hemolytic anemias as we continue to add incrementally to the data while we wait for these -- the bigger data readouts in sickle cell and thalassemia over time. So we're excited about where we are. We hope that all of you can get excited about where we are and where we're going as well, and we appreciate very much that you attended this session for our EHA Investor Event 2022. And thank you to all of the presenters and management team here and Holly.

Great. Thanks, everyone.

Take care.

Bye.