Good morning, and welcome to our Agios at ASH 2023 Investor Event. My name is Chris Taylor, Investor Relations for Agios. We're pleased to have so many of you with us, both in person and on the webcast. Before we get started, I'd like to remind everyone that some of the statements we make during this event will include forward-looking statements. Actual events and results could differ materially from those expressed and implied as a result of various risks, uncertainties, and other factors, including those set forth in our SEC filings. We have an exciting agenda for you this morning. Our CEO, Brian Goff, will provide opening remarks and then turn the microphone to Dr. Sarah Gheuens, our Chief Medical Officer and Head of R&D, who will provide highlights of Agios presentations at ASH this year. Dr. Ahmar Zaidi, Senior Medical Director for Agios in the area of sickle cell disease, will review the complete data set for the RISE UP phase II study presented on Saturday afternoon. Then Dr. Jeremie Estepp, Medical Director for Agios in thalassemia, will review the phase II study data of mitapivat in thalassemia as context for two anticipated phase III data readouts next year. Sarah and Brian will provide additional commentary, and we will have time for Q&A at the end. So with that, welcome. Turn the call to Brian. All right, thanks a lot, Chris, and good morning everybody. Thanks for joining us. So this is the second consecutive year where Agios has been very proud to feature more than 20 abstracts that have been either presented or published and we're very, very proud of that. I think it's a testament to the caliber of our team and our collaborators, as well as the quality of the data. So let me begin by sharing three key reasons why I believe Agios is exceptionally well positioned for significant growth. First is the fact that we have continued to deliver consistent and striking data across multiple hematologic diseases. These data sets have demonstrated that we have the potential to significantly transform patient function, quality of life, and ultimately, the potential to improve long-term outcomes. Secondly, over the next two years, we're expecting to deliver five phase III data sets, and included in those five data sets is the potential for two additional indications by 2026. Now, as we prepare for those indications, we're building upon a commercial platform and capabilities that we began with our PYRUKYND journey with the launch into the ultra-rare disease PKD, or pyruvate kinase deficiency. We now have more than 100 patients on therapy, and every day we continue to learn and build upon this launch, again, as we prepare for these indications. And third, we are well capitalized. We have, as of the third quarter of 2023, we have approximately $870 million on the balance sheet, and we expect that these funds will allow us to continue to completion our ongoing programs, as well as providing the opportunity for disciplined business development to expand our portfolio into 2026. Now, as we build our PK activation franchise, I must say we are very pleased to have not one, but two PK activators. And as I noted, the first, PYRUKYND, began its journey commercially with the launch of PKD in early 2022. All of the data sets that we're building upon since then, from PKD, are moving into larger patient populations with higher diagnosis rates and frankly higher burden of disease. And we're preparing for all of those by building upon our commercial capabilities. Additionally, as I noted, we have not one, but two PK activators, so we're very excited about the potential that we see with our other PK activator, AG-946. And there we're pursuing a phase I study in sickle cell disease. And as you can see on this slide, we also recently reported our phase II-A data in low-risk MDS, where we were able to demonstrate AG-946 achieving 40% transfusion independence in the low treatment burden cohort. Now, we've made tremendous progress and if we just reflect for a moment on this year, which is not even done yet, 2023, we're on track to deliver all of our 2023 goals that we put forward. And just to name a few, first of all, we completed enrollment, in fact, ahead of schedule of both of the ENERGIZE thalassemia trials, both ENERGIZE and ENERGIZE-T. A few months ago, we did top-line data readout of our phase II study of the phase II/III portion or phase II/III seamless study called RISE UP for sickle cell disease. In fact, two days ago, we were very proud to have that data featured at ASH, and you're going to hear more about that today. We also, as I noted, just recently reported out the top-line data for low-risk MDS for AG-946. Earlier in the year, we did a license agreement with Alnylam to bring in an asset for polycythemia vera, which is right in our sweet spot of classical hematology. Then lastly, as I noted, throughout the year, and certainly moving into a very important year next year, we've continued to make great progress on our commercial capabilities. Now, I'm really proud of the progress that we've made. The next 12-24 months will be truly transformational for Agios. As I noted, we are looking at five late-stage phase III readouts across four different—three different hematologic diseases. Two of the areas that are especially important are thalassemia and sickle cell disease. Specifically, this morning, you will hear more about those data sets from Sarah, from Ahmar, and from Jeremie. With that, what I'm going to do now is transition to Sarah Gheuens, our CMO and Head of R&D, and she'll share more about the data ahead. Sarah? Thanks, Brian. So as Brian mentioned, we're very, very excited about ASH. I know we're getting to the completion of it, so a lot has been presented at this point in time. But it does highlight the continuation of our pipeline and the diversification of our pipeline, still reflecting our core expertise. On the top, you can see everything in orange. That is the clinical trial development that is ongoing with PYRUKYND. Of course, for pyruvate kinase deficiency, we have reached approval in the U.S. and in the EU and in Great Britain, and are now fully focused on our pediatric pyruvate kinase deficiency program. And that is important because it's our first pediatric clinical trial development that we are doing, and we'll provide the first data set there that we also are going to leverage for pediatric development for the other two indications. ENERGIZE and ENERGIZE-T, that is our thalassemia program. Jeremie will speak more about our phase II data and how that feeds into the phase III. And then, of course, RISE UP, very exciting day on Saturday with the presentation, and you'll hear that again from Ahmar. The blue bars, so the dark blue is AG-946. That is our other novel PK activator that is in phase I in sickle cell disease. Healthy volunteer results were presented earlier last year. And then the myelodysplastic syndrome, phase II-A, we had just announced the top-line results for that and are very excited to move that program forward to phase II-B. And then we have a program, as Brian mentioned, there is an IND that we are going to submit by the end of this year for phenylketonuria, and then the in-licensed assets from Alnylam. So focusing on PK activation, it truly has the potential to correct red blood cell metabolism across multiple diseases. It's a complex pathway in which PK activation is really the last step in that pathway that generates more energy for the red blood cells. This is the process by which red blood cells are dependent on generating their energy. And so by boosting that, we provide them more energy, which is important for all of those different diseases. There are different components along that pathway that are important for other some of the other indications that we are studying. So 2,3-DPG is very important in the context of sickle cell disease, that is disturbed in sickle cell disease, and we know that by reducing that, we can have anti-sickling effects. And then MDS is another one that is different. It's not a hemolytic anemia, but more an anemia of ineffective erythropoiesis. And it has been described that PK activity is reduced in this disease, and that there is a disturbed PK/ HK ratio in MDS as well, that we know we can correct. That brings me to this slide. These are the four buckets that we have really focused on for this ASH, specifically. You'll see the three indications, but then also patient advocacy as an area of focus. And we are extremely proud with the educational session on PK activation that is independently organized by ASH. So this is a session that gets selected via ASH. They choose speakers, they set this up, but it highlights that the importance of PK activation is being recognized and that they are now educating the community on this mechanism of action independently. As Brian mentioned, we had a lot of abstracts, so we did not place them all here, but we are focusing on a few. for sickle cell disease, beyond the phase II data set, we have continued support for the development there, both by more preclinical work, but also with the NIH data set, which continues to highlight the long-term efficacy and safety in adults with sickle cell disease. So that's data that has been presented up to three years, which we're very excited about and really complements the phase II data set. For thalassemia, we have because we are really now focused on providing readout for phase III, we also are now focusing on continuing to highlight the burden of disease. There's work that has been selected here for presentation on burden of disease, both in alpha thalassemia and non-regularly transfused patients population, highlighting that with every, you know, 1 g/dL hemoglobin decrease, there are more comorbidities, further supporting there is truly a need for therapy there. We low-risk MDS. A lot of the work presented here is more mechanistic at this point in time. Of course, as Brian mentioned, we're very excited about the top-line results that we were able to press release, specifically because we have the 40% transfusion independence, which we know transfusion independence is something that is really driving quality of life for MDS patients, but also because of hemoglobin response, in which we had one patient who had a 1.5+ hemoglobin response in the trial and one patient who had a 1+ hemoglobin response in the trial. PKD, we didn't put this on the slide, but still the data is definitely worth looking at as well because it continues to support a maintenance of effect in the data set. But it also continues to highlight that while a clinical trial bar may be put at 1.5 g/dL, we have a group of patients that did not quite meet that bar in the clinical trial, but were continued to be followed in the extension studies, had an improvement early on hemolytic parameters and have now reached that threshold of 1.5 g/dL in the extension. And then last but not least, I think the efforts that our patient advocacy group has put forward as a collaboration across the different hemolytic anemias is unique, but truly supports our theme at the company of being fueled by connections. And, you know, the lessons learned from the patient community that we incorporate in our clinical trials, plus the engagement we have with the community, truly helps us in delivering on our goals as well. With that, I will hand it over to Ahmar to talk about the very exciting sickle cell disease Phase II data set. Thanks, Sarah and Brian. I'm thrilled to be here to talk about the RISE UP phase II data. Once again, my name is Ahmar Zaidi, and I'm presenting the RISE UP data on behalf of the RISE UP investigators. So sickle cell disease is characterized by the presence of sickle hemoglobin, which is caused by a mutation in the beta globin gene. Sickle red blood cells are deficient in form and function. This results in red blood cells that sickle and are prone to break down. This results in a shortened lifespan for those red blood cells and often causes impedance of blood flow to tissues that results not only in vaso-occlusive crises, but recurrent microvascular damage and chronic hemolytic anemia that amplifies the morbidity and mortality that these patients face. This is a global disease and affects approximately 8 million individuals worldwide. The life expectancy of these individuals, despite best care, is three decades less than others. Patients report low quality of life. They report tremendous fatigue and pain. In addition to that, it's well known that individuals have more morbidity and more mortality in proportion with the anemia that they face. The RISE UP phase II, phase II/III study is a double-blind, randomized, placebo-controlled trial that evaluates the efficacy and safety of mitapivat in patients with sickle cell disease. The phase II portion of RISE UP was a dose-finding study built to evaluate two doses of mitapivat, 50 mg and 100 mg, versus placebo to select the dose of mitapivat for assessment in the phase III portion. Shown here are some of the key inclusion and exclusion criteria. The study aimed to include individuals who were 16 years of age and older, with a confirmed diagnosis of sickle cell disease, with at least two sickle cell pain crises, but no more than 10 in the prior 12 months, and hemoglobins between 5.5 and 10.5. Individuals were absolutely allowed to be on hydroxyurea as long as that dose was stable. The key exclusion criteria are shown here, but just to name a few, we were excluding individuals who were receiving regular red blood cell transfusion therapy or had recent hospitalizations for sickle cell pain crises, either in the duration shortly before informed consent or during the screening period. And of course, we were not allowing for inclusion of individuals who were on therapies outside of hydroxyurea. The primary and secondary endpoints are shown here. For primary endpoints, along with safety, we were monitoring hemoglobin response, which was defined as a one g/dL increase in the average hemoglobin concentration from week 10 through 12 when compared to baseline. The pre-specified secondary endpoints are also shown here, which were also looked at as an average change from baseline from week 10 through 12, and this included hemoglobin levels, it included markers of hemolysis, markers of erythropoiesis, and the PROMIS Fatigue score. In addition to this, one of the pre-specified secondary endpoints of interest was the annualized rate of sickle cell pain crises. The statistical analysis was performed according to the pre-specified, you know, statistical methods in the protocol. Looking at the study and its enrollment, 120 patients were initially assessed for eligibility. After exclusion of 41 of those patients, 79 patients underwent randomization. Those 79 patients broke down into 26, who received 50 mg twice daily, 26, who received 100 mg twice daily, and 27, who received placebo. Importantly, 73 out of the 79 randomized patients elected to go on into the open-label extension period. Shown here are the demographics and baseline characteristics of the individuals who were enrolled in the RISE UP phase II study. Importantly, we can see that there's no major differences across not only demographics, but also baseline characteristics. We see a mean age of around 30 years old, a slight advantage to females. We see a mean hemoglobin between 8.5 and 9. We also see that this population was appropriately hemolytic and anemic, with baseline pain crises of around three and hydroxyurea use of around 70%. This represents a population that is very representative of the intended population we wanted to study. So mitapivat, of course, met its phase II primary endpoint, demonstrating a higher hemoglobin response rate when compared to placebo. We see here three panels: 50 mg, 100 mg, and placebo. In the 50 mg arm, we note that there was a 46% response rate. In the 100 mg arm, we note there was a 50% response rate, and in the placebo arm, we see there was a 3.7% response rate. It's important to note that when looking at the 100 mg arm of evaluable patients between week 10 and 12, every patient in that group had some incremental increase in their hemoglobin. Looking at the magnitude of improvement in hemoglobin levels across both doses when compared to placebo, we note that the average change from baseline in the hemoglobin level through week 10 through 12 was around 1.1 g/dL, compared to 0.05 g/dL in the placebo arm. Looking at this response in a little bit more detail, we see that this response was not only early, as early as two weeks, but also durable over the duration of the double-blind period for both dose levels. Reduction in sickle cell pain crises were observed at both dose levels when compared with placebo. In the placebo arm, we see an annualized rate of sickle cell pain crises of 1.71. In the 100 mg arm, we see a rate reduction of 70% and an annualized sickle cell pain crises annualized rate of 0.5. In the 50 mg arm, we see a rate reduction of 51.6% or an annualized rate of 0.83. Improvements in markers of hemolysis were observed at both dose levels when compared to placebo. Shown here are two important markers of hemolysis, an indirect bilirubin on the left and LDH on the right. You can see here, very similar to the pattern that we observed in hemoglobin, there's an early response in reduction of hemolysis, and that response is sustained over the double-blind period. There's also a slightly higher magnitude of effect in the 100 mg arm, seen in both of these hemolytic parameters. Further looking at markers of erythropoiesis, namely erythropoietin and reticulocyte count, we see that, there's a reduction, actually a trend towards reduction in erythropoietin in both dosing arms when compared to placebo, and we see in general, across the double-blind period, a reduction in reticulocyte count over the double-blind period. Once again, that effect is seen early and is sustained over the duration of the double-blind period. Improvement in PROMIS fatigue scores was also observed but was observed only in the 50 mg arm when compared with placebo. The summary of TEAEs is shown here. Importantly, the distribution of TEAEs across all three groups appears fairly well-balanced, and very importantly, there were no serious TEAEs across any of the cohort. There were no TEAEs that led to discontinuation of study drug, that led to dose reduction, that led to dose interruption, or led to death. Building on the expansive experience we have in other hemolytic anemia indications, the sickle cell study continues to show that mitapivat is generally safe and well-tolerated. You can see the distribution of the most common TEAEs in this table here, with nothing standing out as particularly different. So in conclusion, the phase II 12-week randomized, placebo-controlled, double-blind period of RISE UP, treatment with mitapivat demonstrated statistically significant and clinically meaningful improvements in hemoglobin response at both dose levels that were tested. A reduction in annualized rate of sickle cell pain crises was observed in both treatment arms when compared with placebo. Further, improvements in markers of hemolysis and erythropoiesis were also observed in both treatment arms when compared with placebo. It's important to note that the magnitude of improvements were generally larger in the 100 mg twice-daily arm. Once again, mitapivat has an observed safety profile that remains consistent with previously reported data of mitapivat in sickle cell disease, as well as in other hemolytic anemias. In conclusion, mitapivat, through its dual mechanism of action, increasing ATP and reducing 2,3-DPG, may provide clinical benefit to patients with sickle cell disease. These current phase II data support the continued development in the phase III portion of the RISE UP trial, evaluating a 100 mg twice-daily dose. Going forward, we can see that in the phase III study, patient enrollment and dosing are underway. The key inclusion and exclusion criteria remain the same in effort to study a similar population. We aim to randomize 198 patients in a 2-to-1 sequence. The double-blind period this time around will be 52 weeks instead of 12. We continue to offer a 216-week open label extension period to all patients that go through the double-blind period. With that, I think I'm going to turn it over to my colleague, Dr. Estepp. Good morning, everyone. It's truly a wonderful position to be standing here with you today because for me, it highlights the excitement and optimism that we have with where the program for thalassemia is. Next year is going to be a huge year for us, and we want to reflect it a little bit about what we have done to get us here. This morning, I'm going to be reviewing the phase II data of mitapivat and thalassemia that was previously presented last year here at ASH. As a reminder, thalassemia is a group of genetic disorders that impact both alpha and beta globin generation, and that those mutations result in an imbalance of globin production. The excess globin chains that are then a part of thalassemia precipitate and are toxic to erythrocytes and erythroid progenitors, and directly lead to ineffective erythropoiesis and hemolysis. One of the underlying challenges with thalassemia is because of this globin imbalance, the thalassemia erythrocytes don't have sufficient ATP to be able to support the endogenous mechanisms that are required to clear the toxic hemoglobin precipitates. Although patients with non-transfusion dependent thalassemia don't require regular transfusions for their survival, they do have chronic anemia and serious complications that we'll talk about on further slides. Treatment options, especially for that population, are very limited. Mitapivat is an exciting and investigational first-in-class oral small molecule allosteric activator of pyruvate kinase, which is a key enzyme that Sarah highlighted that we believe has significant potential for a therapeutic option for thalassemia. The pathophysiology of thalassemia is highlighted on the left of this slide. So it all goes back, whether it's alpha or beta thalassemia, to this imbalanced globin ratio that is generated. The excess globin chains that are in erythroblasts or in peripheral erythrocytes, precipitate and aggregate. Intracellularly, these lead to direct oxidative damage, membrane instability, and other challenges for the red blood cell. Whether or not it happens in the peripheral erythrocytes or whether in the bone marrow, really impacts whether it manifests as hemolysis or ineffective erythropoiesis, but both of those contribute to the overall microcytic anemia that's observed in the disease. The ineffective erythropoiesis, which is a key component of thalassemia, further has downstream implications for iron metabolism and results in a dysregulation of iron metabolism and iron overload, both in non-transfusion dependent and in transfusion dependent patients. Mitapivat is promising because by enhancing glycolysis and increasing ATP generation, it really supports the normal endogenous mechanisms that can be used to improve the overall globin balance, reduce oxidative damage, and that we think can have significant improvements in both hemolysis, ineffective erythropoiesis, and the anemia that is observed. And by doing so, and by having positive impacts on ineffective erythropoiesis, there's downstream positive impacts potentially for iron metabolism and overall iron overload. Now, it should come as no shock to anyone that because we're talking about a fundamental problem with the erythrocyte and the bone marrow compartment, because those red blood cells go to all of the organ systems, thalassemia patients have complications that are vast and affect essentially every end organ system. And on the left, you see just a highlight of some of the complications that you can observe in patients with thalassemia. It's by no means an exhaustive list, just meant to highlight the morbidity of the disease. Because they have such significant manifestations, these patients also have a reduced quality of life, and unfortunately, similar to sickle cell disease, they have premature mortality. The therapeutic landscape for thalassemia across both transfusion-dependent and non-transfusion-dependent has been sparse historically. The cornerstone is transfusions, either given scheduled or intermittently, but this paradigm seems to be changing as we learn more about the disease, with people really advocating that we should be targeting higher hemoglobin levels because those with a more severe anemia have been shown to have many more complications and earlier mortality. Additionally, recent approval of luspatercept has given more tools in the toolkit for providers, but the approvals for transfusion-dependent thalassemia and non-transfusion-dependent are highlighted here. A key concept for us is that we are also evaluating mitapivat for alpha thalassemia, and to date, there's no approved therapies for alpha thalassemia. The phase II study for mitapivat in thalassemia patients is highlighted here. There was a 24-week core period that evaluated 50 mg BID, and then 100 mg BID, and then there was a 10-year extension period. The data that I'm going to show you today is both the core period and then the data that was presented from the long-term extension period. The summary of the results from this phase II are on the slide here. The primary endpoint of hemoglobin response was met in 80% of the patients that were enrolled. That was also seen with improvement in the markers of hemolysis and erythropoietic activity. The mitapivat was generally well tolerated at both the 50 mg and the 100 mg dosing, and the most common AEs were initial insomnia, dizziness, and headache. The results from the long-term extension period, which again, have previously been presented, we see a durable response of hemoglobin, with an average increase of 1.7 g/dL at week 72, and we'll show that data in a second, and we see concomitant improvements in markers of hemolysis, and erythropoiesis. And again, during the long-term extension period, we continue to see that mitapivat is well tolerated, with a safety profile that's very consistent with our experience across PKD and other hemolytic anemias. Here are the patient demographics and baseline characteristics for this 20-person cohort. So about 75% were female. The race is reflective of where enrollment occurred and that of the thalassemia condition. And the genotypes for this cohort, it was 25% alpha thalassemia and 75% beta thalassemia. The baseline biomarkers of the disease are presented on the right, with a mean hemoglobin baseline of around 8.5 g/dL, and then markers of ineffective erythropoiesis and hemolysis that are very consistent with the disease. Here is the data for the hemoglobin response, both in the core period on the left side of the graph, and the key takeaway from this is that during the long-term extension period out to 72 weeks, we see a very durable response to, to hemoglobin improvement. These are the markers of erythropoietic activity are selected from the cohort, and these also remain stable or improved over time out to week 72. Specifically, here, we're looking at the changes in erythropoietin on the left and erythropoietin on the right. Also, we're seeing marked improvement in markers of hemolysis through week 72, which are also durable and stable, with indirect bilirubin being shown on the left, and then a representation of the reticulocyte count or the very immature red blood cells compared to that of the total erythrocyte compartment. We also see trends towards improvement in iron homeostasis, which remained either stable or improved in this cohort through week 72, with here showing hepcidin changes over time, soluble transferrin receptors, and then the changes in the liver iron concentration in this non-transfused cohort. In conclusion, the phase II data, along with long-term improvements in hemoglobin concentrations, we do see improvement in markers of erythropoietic activity and hemolysis through week 72 in both patients with alpha and beta thalassemia non-transfusion dependent. The markers of iron homeostasis remain stable or improved through week 72, and the new data in this cohort suggests that mitapivat's mechanism of action may ameliorate multiple aspects of the complex disease underlying both alpha and beta non-transfusion dependent thalassemia. Sarah is going to tell us and talk a little bit about our ongoing phase III studies, which we've completed enrollment for, and we're very excited about 2024. Come on, Sarah. Thanks. Okay. So Jeremie walked you through the phase II data. I think we're indeed very excited about next year, about our ENERGIZE program, in thalassemia. And why? Well, thalassemia is, there are different types of thalassemia, alpha and beta thalassemia, which are subdivided by their transfusion burden, and our program really aims to address all of these subtypes. There is only one approved therapy in the U.S. for transfusion-dependent beta thalassemia. All other subgroups have no therapeutic options available, and as Jeremie highlighted in the beginning, there is a very big burden of disease across all of these subtypes. What we are hoping to deliver for everybody living with thalassemia is a drug that is safe to use oral, but of course, that has great efficacy by improving hemoglobin and ineffective erythropoiesis with downstream positive effects and then reduce the transfusion burden. The trials, we have two trials that are aiming to deliver this. One is ENERGIZE, is focused on the non-regularly transfused patient population. It enrolls both-- it enrolled both alpha and beta thalassemia patients, with a primary endpoint of hemoglobin response that we're looking for over 24 weeks of observation. And then ENERGIZE-T is a regularly transfused population that is enrolled. Again, alpha and beta thalassemia patients are allowed to participate. It's a longer trial, 48 weeks, in which we are looking for transfusion reduction response. The two trials together, therefore, with the two primary endpoints, are supportive of each other in highlighting an improvement in hemolytic anemia. Now, we are measuring many different things across these different programs, and this slide highlights how these two trials are really complementing each other and how they can deliver a meaningful data package across the board that can support clinical benefit. So on the first component, the anemia, the endpoints really will support that, but there is different secondary endpoints allowing us to speak more on how we improve anemia. It can be supported by patient-reported outcomes or quality of life improvements that actually on the ENERGIZE trial, we are truly aiming to highlight how an improvement in hemoglobin makes people feel better via the FACIT-Fatigue, and we have additional patient outcome measurements and exit interviews as well. Because hemolysis and ineffective erythropoiesis, as Jeremie highlighted, are really driving organ damage, we are, of course, also focused on highlighting that hemolysis is improved and ineffective erythropoiesis is improved. And then, also monitoring iron metabolism, which we know can take a while, but we're already looking at the data from these pivotals in combination. Safety, the type, the severity relationship, of course, will be monitored across the program and deliver the risk profile so we can speak to benefit risk. With that, I will hand it over to Brian. All right. Thank you very much, Sarah. And I just want to say I really appreciate hearing from Sarah, Ahmar, and Jeremie. These are true experts in the field, and this is on top of all the other exciting activity that we have at ASH. So we believe that based on our industry-leading PK activation franchise, hopefully, it's clear that we have the potential to transform a number of important hematologic diseases, and that spans across PKD, thalassemia, sickle cell disease, and low-risk MDS. And we also believe that this positions us very well for significant growth ahead. That's based on the fact that we have five phase III data readouts coming over the next two years, and of course, the consistency of the data that we've seen thus far. So the next event to come, in terms of data readouts, will be the ENERGIZE non-transfusion-dependent thalassemia phase III trial, and that's coming in the first half of next year, and we very much look forward to that. So with that, I just want to close by thanking all of all of you for your attention, all of our Agios employees who continue to just work as hard as they can to deliver on the potential we have ahead. Of course, the physicians, caregivers, patients, and perhaps most importantly, the participants in our clinical studies. So thank you very much. We're now going to open the floor for questions. I'll just ask that if you have a question, please just give a moment to let Chris Taylor give you the microphone. Hey, Greg Harrison, Bank of America. Thanks for taking the question and for all the updates. What would you say is the importance of showing benefit in sickle cell beyond hemoglobin improvement as far as patient adoption down the road? You've seen some signs of VOC benefit so far that are encouraging. Do you need to show clear benefit, in your view, on VOCs in phase III to have a competitive product? Okay, Ahmar. Thanks, Greg. Oh, is this on? Can you guys hear me? Yeah. Awesome. That's a great question. Thank you for that. I think that it's clear that there's two mechanisms by which sickle cell patients face, you know, bad outcomes. It's clear that there's devastation from anemia, and it's very important to address not only the anemia, but the hemolysis that causes that anemia. In addition to that, though, your question is great around sickle cell pain crises. Of course, we know that this is a driver of healthcare utilization. It's also a driver of mortality. I think showing benefit independently in anemia and sickle cell pain crises is a very valuable thing for patients. So, we're really excited to hopefully replicate the data we see in phase II as we go into phase III over this long study period. But I do think that both aspects of the disease are critically important to patients as far as adoption goes. Divya from TD Cowen. Congrats on all the data at ASH. So I have two questions. One, could you provide some color on why in the phase II for the sickle cell data, the 50 mg cohort had a pretty strong improvement in fatigue scores, but the same didn't translate into the 100 mg cohort? And then second, I guess this is more for maybe Sarah. Could you remind us on the powering assumptions for the phase ii-phase III trial, both on in terms of VOCs and the hemoglobin benefit? Thanks. Sure. Thanks, Divya. I'll take the first question there with the PRO data. You know, PROs and sickle cell disease, of course, you know, we want to show quality of life benefit. It's very difficult sometimes, though, to do that in a 12-week study. We're really looking forward to being able to tell that story a little bit more clearly over a longer period of time. Sarah. And then for the second part, the prior assumptions we had made, we actually leveraged a lot of data that was available across different programs, plus our small data sets at that point in time in sickle cell disease to make assumptions. And so we did make an assumption that we or we were, we are targeting to reduce sickle cell pain crisis from 3 to 2, and that led to the sample size that we have, you know, in the phase III. That was before the phase II was actually run. So we did verify our assumptions at the now, and we are not changing anything at this point in time. Hi, this is support for Greg, Greg Renza from RBC. On the RISE UP data, I'm just curious if you look at the correlation between hemoglobin improvement and sickle cell pain crisis or other efficacy parameter, if there's any correlation there? And second question on the AG-946 program. I know that the primary completions for the phase I is happening in 2024. What's the gating factor whether you are going to continue developing in phase II/III in sickle cell disease for that program? Thank you. Thanks for the questions. So for the first part, we have done the intent to treat analysis as is. So these are the data points that we had set primary, secondary endpoints. We, of course, have done subgroup analyses around the primary endpoint, but it is a phase II. So we do not further try to correlate different outcomes to each other 'cause the sample sizes are then too small. For the second component, for AG-946, yes, we're excited that we have another PK activator that can provide us a lot of optionality. We are looking at the phase I as a way to study sickle cell disease and hemolytic anemia as a whole. Obviously, we will be very data-driven. It depends on what the ultimate benefit-to-risk profile looks like coming out of that trial, what we do next. You want to add to? No, I agree, and, and we'll continue to be very disciplined on the way we started this, question discussion is that for patients, it's—there's a number of factors that are important. It's hemoglobin, obviously, as Ahmar noted, fatigue, which is one of the elements that we hear from patients very often. As bad as vaso-occlusive crises are, fatigue is one of the elements that, where patients just cannot accommodate, or, or, essentially mitigate so that they can function appropriately in life. So we're looking at the totality of all those dimensions. Now, of course, in the phase I pursuit for AG-946, hemoglobin will be the element that we'll look at first, but it's the totality of data, and we'll get our decision-making accordingly. [Amit Vizieri] on Salveen Richter's team at Goldman Sachs. Just three questions from us. So we also saw data from GBT601 in the same session. Just wondering if you could provide some context on how PYRUKYND from the phase II data is differentiated from the data that was presented there, specifically on safety as well as hemoglobin improvements. And then just in the 100 mg arm in the sickle cell trial, I guess what was the reason why the physician wanted to discontinue that one patient? And then just on the thalassemia trials, just wondering if the number of patients that you have enrolled in alpha thalassemia is enough to get approval in that setting. Sure. Thank you for those questions. I'll take the sickle cell ones and then pass it to you. You know, it's an exciting time in sickle cell disease. It's really neat to be on the cusp of potential options for patients that haven't had new therapies in quite some time. I think it's important to note that, you know, the mechanism of action between GBT601 and PYRUKYND are very independent. Though they both increase hemoglobin, they do so in very different ways. You know, mitapivat works by harnessing the preexisting physiology of the red blood cell, activating pyruvate kinase to generate more ATP and decrease 2,3-DPG. I think it's exciting to see, you know, increases in hemoglobin, and, I think that, you know, we, we stay, like I said, we stay very, consistent with what we know about our safety data, and, and we're quite pleased with our safety profile at this point in time. And I think that's, that's all I want to say about that right now. You know, we're going to watch this over the 52-week phase III study, and, and we have this huge open-label extension period, which allows us to continue to monitor for safety, effects and, efficacy results. To the second question, which was around the, the physician reason of withdrawal, that, that was more, logistical in the physician's ability to have the patient follow up appropriately, to study related assessments. The patient had some life changes that was making it quite difficult for them to follow through and end up in clinic when necessary. The one thing that I would like to add to the first part of the question is that we are very pleased with the data set that we have 'cause it's the first placebo-controlled phase II clinical trial data set that truly allows to follow patients and compare them in a dose level to a placebo group, which I think is critically important, both from an efficacy perspective on the hemoglobin, the sickle cell pain crisis, and the safety. Did you want to do the alpha thal or you want to? No, no. Go for it. Yeah. So thank you very much for the question about the alpha thalassemia. We are very optimistic that given our mechanism of action, that we will have significant improvements in both beta and alpha thalassemia. The trials were constructed in a way that at the end of the day, that we would have sufficient safety and efficacy data to support a broad label strategy, and I think we're very comfortable that we have successfully achieved those goals. Hey, Ken Shields on from Leerink Partners. I'm on for Andy Berens. So you've talked in the past about mitapivat being a foundational therapy, potentially in sickle cell disease, and that could potentially be used in combination with existing therapies instead of potentially competing with them. And you've mentioned some color on DDI work or maybe preclinical work. Are there any additive toxicities, and how can you think about that opportunity for combination use? Thanks. So right now, the therapy that is allowed in our clinical trial is hydroxyurea, and we stratify on hydroxyurea because that is truly, that is a standard of care therapy in sickle cell disease in many parts of the world, and specifically in the U.S. About 70% of patients actually use hydroxyurea, which is actually also reflected in our phase II data set. You know, the sickle cell disease population enrolled looks like the general sickle cell disease population. At the time that we designed the trials, we did not want to allow for other sickle cell disease therapies that were available. One, because this was a global trial, and not all of those therapies were available globally. And then, two, we really wanted to establish the benefit-risk profile of mitapivat by itself. In the meantime, I think that was, you know, a smart decision, in the context of what occurred with, crizanlizumab now in the EU. So it allows us truly to assess mitapivat by itself. It's true that people are thinking about combination therapies. That is very common in any bad disease where people need many more options. It's very common that physicians start thinking about how, if they don't see enough response with one drug, would it work if they add another one? I think this is gonna be a physician-driven, effort. We are not planning to do a combination study right now, as we are truly focused on delivering our phase III. And maybe I, I love that you asked the question the way you did. Maybe I'll push it a little bit further to say that, yes, we think there's the potential for mitapivat to be foundational therapy in sickle cell disease, but that also expands to thalassemia. And we certainly have already demonstrated, not only foundational, but first ever in PKD for the more than 60 years that PKD has been known as a disease. And so the beauty of this is, PK activation is not necessarily a competing mechanism with other potential therapeutic options. And so maybe that's the way it plays out, that as patients need multiple options, there could be combination therapy, but foundational is really where we're focused in our development. Yeah, Eric Schmidt, Cantor Fitzgerald. Just a question on the dual mechanism for mitapivat in sickle cell. It sounds like you're insinuating that because of the dual mechanism, we, we may not just see more red blood cells, but we might see healthier red blood cells as well. And how would you expect that to evidence itself? And if it does evidence itself, maybe in, say, higher VOC reductions per milligram of hemoglobin, are you seeing just that? It's a great question and thank you. Truly, I mean, I completely, I'm aligned with you. I do think that specifically in sickle cell disease, this dual mechanism of action is in fact a superpower, right? We have this intracellular red blood cell increase, which we know biochemically certainly can influence rheology, the way red blood cells interact with endothelium, the way red blood cells hydrate themselves, the way they carry out their homeostatic function. That's all very important, particularly in the microenvironment of vaso-occlusion. The further effect of the 2,3-DPG reduction changes the way oxygen and hemoglobin interface, and we know that that's critically important in sickling kinetics, which drives polymer formation, which drives that crescent moon shape that causes destruction and contribution to vaso-occlusion. So I firmly believe that, you know, helping both form and function of red blood cell can manifest by, of course, reducing hemolysis, which generates that poison, which is heme, free heme, but also aid with sort of this microvascular occlusion that occurs. Great. I think that concludes questions. I'll turn it back to Brian. Well, thank you so much. I know, I know it's. For those of you who are at ASH, I know this is a very busy period for you, as it is for us. It's an exciting period, and we certainly appreciate your interest and continued support. And maybe I'll—we're not quite done with 2023, but I'll take the opportunity to wish for all of you a wonderful holiday and certainly a great start to 2024. So stay tuned, and thanks a lot.