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

Welcome to our Agios investor breakout session at ASH 2024. My name is Chris Taylor, and it's great to see so many of you in the room. Thanks, everybody on the webcast, for joining us. One quick note is that the slides for the program today are on our website. They've been posted, and you can find them in the Investors section of the website. And before we get started, I'd like to remind everyone that some of the statements that we make on this session will include forward-looking statements. Actual events and results could differ materially from those expressed or implied in any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and other filings that we may make with the SEC. We have an exciting agenda and speakers for you today from Agios. You'll hear from Chief Executive Officer, Brian Goff; and Dr. Sarah Gheuens, our Chief Medical Officer and Head of R&D; and we are quite fortunate to be joined by Dr. Kevin Kuo, University of Toronto, who will reprise the Phase III ENERGIZE-T data overview presented in an oral presentation yesterday, and Dr. Julia Xu from University of Pittsburgh will present some slides from the tebapivat Phase I sickle cell data presented in a poster last night. And then after the presentations, we'll have time for Q&A in the room, and then Chief Commercial Officer Tsveta Milanova and Chief Financial Officer Cecilia Jones, who are also here today, will join for the Q&A. So thank you all very much for coming today. And with that introduction, I'll turn things over to Brian.

All right. Thanks, Chris, and good morning, everybody. Thanks a lot, everybody who has dialed in online and especially thanks to the folks who got up very early who are joining us in person here at ASH. Agios is the pioneering leader in pyruvate kinase activation. And I must say, it's a real privilege to be able to share our continued progress developing and delivering transformative medicines to elevate and extend the lives of patients who are living with rare diseases. This year at ASH, we had a tremendous showing featuring presentations from data from our own company as well as from collaborators. And as Chris noted, we have a lot to share, so I'm going to go ahead and get started. As you can see on -- let me advance these slides here. As you can see on this slide, and it's also reflective of what we featured in our November 5 press release, we were really pleased to have had 16 abstracts accepted for presentation or publication. And this really covers a wide array of data. It really highlights the potential of our PK activation franchise as novel treatments addressing very high unmet needs across a wide array of diseases. And what you can see here are 3 notable highlights, each of which will be featured in this morning's discussion. The first is the ENERGIZE-T data. So this was a pivotal Phase III study that looked at adult patients who are living with transfusion-dependent thalassemia. And as was noted, this was presented yesterday in an oral presentation, and we're really happy to have an encore presentation of that data again today. Secondly, in sickle cell disease, we featured the first data of tebapivat, which is formerly known as AG-946. This was a Phase I study that assessed safety, tolerability, PK/PD of patients with sickle cell disease. And third is we recently commenced a Phase IIb study looking at anemia in low-risk MDS patients, and we were pleased to have a poster that featured the design of this study. And so that -- we'll have that discussion as well today. So with that, I'm really pleased to have in the room with me Dr. Kevin Kuo, as Chris noted. And we're very fortunate to have Dr. Kuo here. He is one of the world's experts in the field of thalassemia. He comes from the University of Toronto Division of Hematology, and Dr. Kuo will give us really an encore of what was presented yesterday for the ENERGIZE-T data. I will just note, before he comes up, that this is the first time that we've had an oral disease-modifying therapy demonstrating data for adult patients in transfusion-dependent thalassemia, which we're very excited about. So with that, let's welcome Dr. Kuo. Thank you.

Good morning, everyone. Thank you for your very generous introduction, Brian. So now I'm going to present to you the ENERGIZE-T data. And on behalf of the -- [indiscernible] and then we'll switch over. On behalf of -- I don't think this is on either. Oh, it is. Okay. All right. On behalf of the coinvestigators and the co-authors, I'm pleased to present to you ENERGIZE-T, a global Phase III double-blind, randomized, placebo-controlled study of tebapivat in adults with transfusion-dependent alpha and beta thalassemia. So just to provide you with a little background, even though that the survival and the clinical outcomes of patients with transfusion-dependent thalassemia has improved over the past decades, as you can see from this Kaplan-Meier plot of 709 patients where you see an improvement in overall survival over the years, you can see here that the complication-free survival still lags behind. And more importantly, there is not much of a change between the third and the fourth most recent cohorts, indicating that these patients are still locked in an unsustainable ever-going cycle of transfusion and are in chelation. And most of these patients, unfortunately, succumb to the disease as a result of this unsustainability. And therefore, we have a huge unmet need here. In addition, I would like to remind everyone that there is currently no approved therapy for alpha thalassemia. As many of you know who have heard my talks in the past, that the imbalance between the alpha and beta globin results in the aggregation of the excess globins, leading to oxidative stress and ineffective erythropoiesis as well as hemolysis. This, in turn, leads to iron overload. Of course, ATP inside the red cell is very limited in terms of combating this oxidative stress. Mitapivat is an activator of pyruvate kinase, including the PKR, which is a red cell version of pyruvate kinase, as well as the M2 version, which is responsible for early erythropoiesis which acts on the glycolytic pathway to generate more ATP. And as a result of this increased amount of ATP, it is able to combat the oxidative stress inside the red cells, resulting in improved ineffective erythropoiesis hemolysis. And I'm going to now present to you the ENERGIZE-T data. And we also know from last year in the Phase III ENERGIZE study that has been shown to have an improvement in patients with non-transfusion-dependent alpha and beta thalassemia. So here's the study schema. You're going to see that patients are randomized -- adult patients with transfusion-dependent thalassemia are randomized in a 2:1 fashion between mitapivat and placebo for a 48-week period, followed by mitapivat at 100 milligrams BID for both groups in an open-label study up to 5 years. Here are the primary and secondary endpoints, and I'm going to dive into these endpoints in the next few slides in terms of what they mean. So let's start with the primary endpoint. The primary endpoint is defined as a transfusion reduction response of any 12 consecutive period for more than 50% reduction and having a 2 units reduction. So if you can do a little imaginary game with me, you can imagine that this patient, for example, was being transfused at 2 units every 3 weeks. And after starting on the study on day 1, you can imagine that this patient then had a reduction in transfusion to 2 units every 6 weeks. Now keeping in mind that it is up to the investigator on how to reduce the amount of transfusion. They can either reduce by reducing the number of units or they can lengthen the transfusion period or reducing the frequency. And so you can imagine that in this particular patient, if they had a reduction in this 12-week period, then they would have met the TRR, the primary endpoint. Now some patients, as you can imagine, can meet this primary endpoint multiple times because of this consistent reduction in transfusion. However, we only count that once. Now let's move on to the secondary endpoint, the TRR2, 3 and 4. Okay. So in TRR2, we're doing exactly the same thing as in TRR except that now we are lengthening the period that we are considering. Instead of every 12 weeks, be considering any 24-week period, and we're looking at a 50% reduction. Now in TRR3 and 4, instead of any consecutive period, now we're looking at a fixed 36-week period looking from week 13 to week 48. In TRR3, we're looking at a 33% reduction or higher. In TRR4, we're looking at a 50% reduction or higher. Furthermore, you can see here that in addition -- I'm just going back to the slide -- you can see here that the stringency in which we're testing is goes ever, ever higher as we move down in the secondary endpoints. More importantly, in the statistical testing strategy, you can also see that the -- this also requires the bar is also moved ever, ever higher as we move down on the key secondary endpoints. And now I'll be showing you some results. Of the 258 patients that are randomized in a 2:1 fashion, 171 was allocated to the mitapivat and 87 were allocated to placebo. However, in the safety analysis set, you can see here that there were 172 patients receiving mitapivat and 85 receiving placebo, and the reason was because 1 person was randomized to mitapivat but was not dosed, and another patient, because of a pharmacy error, received 1 to 2 doses of mitapivat. And you can see here in the analysis, hence, there's a slight difference in the full analysis set and the safety analysis set. You can see here that the demographics for both the mitapivat group and the placebo group are well balanced between the two. And particularly, I want to note that a good number of patients, majority of patients, require more than 12 units for over a 24-week transfusion period prior to enrollment. Mitapivat is demonstrated a statistically significant reduction in transfusion burden versus placebo in this primary endpoint. You can see here that 30% of patients in the mitapivat group met the primary endpoint versus 12.6%, with a very significant p-value there. And you can see here that in this subgroup analysis, it is consistent with the primary outcome. Next, we're going to move on to TRR2, TRR3 and TRR4, and as mentioned before, even with the increasing stringency of testing, that all 3 met the statistical bar here with a p-value of p=0.0003, p<.00001 -- lots and zeros -- and p=0.00056. And specifically, 13.5% of patients met TRR2 in the mitapivat group, 14.5% met the TRR3 in the mitapivat group and 7.6% in TRR4. More importantly, 17 patients in the mitapivat group achieved transfusion-free over an 8-week period. And more importantly, 3 of that 17 patients were transfusion free throughout the 48-week double-blind period. Now let us move on to safety. You can see here that the safety in the mitapivat versus placebo is pretty much balanced. You can see here, there is 90% of any TEAE in the mitapivat group versus 83%, and in terms of serious TEAE is 11% in mitapivat group versus 15%. And of that, that led to -- that treatment-related is 2.3% and 1.2%. And of that, those that led to study discontinuation of the study drug is 5.8% in the mitapivat group versus 1.2% in placebo. In terms of the types of TEAEs, you can see here that this is very consistent with all the previous trials that were run in both thalassemia as well as in the pyruvate kinase disease group, including headaches, upper respiratory tract infection, insomnia, diarrhea and fatigue. So in summary, the primary and all key secondary endpoints in this study were met and mitapivat led to a significant reduction in transfusion burden with a durability of response up to 36 weeks during this 48-week double-blind period. And as we have seen, the efficacy was not driven by any prespecified subgroups. There were a higher proportion of patients in the mitapivat group that has achieved transfusion independence compared to those in the placebo group, and 3 patients in the mitapivat group were transfusion free throughout the entire 48 double-blind period. Mitapivat was generally well tolerated, with a low treatment discontinuation rate, and the AEs were consistent with all the previous trials. So in summary, ENERGIZE-T, with the treatment mitapivat as a disease-modifying therapy, was effective and resulted in significant reduction in transfusion burden in a globally representative population of TDT, including both alpha and beta thalassemia. And with that, I would draw to a close, and I would like to invite Dr. Sarah Gheuens to come up to the podium.

Hello, everyone. So I will actually provide the totality of our thalassemia program and give you a clinical and regulatory update. So Kevin just walked us through the ENERGIZE-T results, so I won't spend too much time on that, but also drawing your attention to the ENERGIZE trial, which was part of our overall thalassemia program. So with the results that were presented yesterday, we have completed 2 global Phase III randomized controlled trials of PYRUKYND in thalassemia. And what is special about this program is that we really enrolled the full range of thalassemia patients, so ended up with a patient population in those 2 clinical trials that are really reflective of a general thalassemia patient population. The design -- the ENERGIZE clinical trial design, we had 194 patients enrolled there, 2:1, so very similar randomization in the ENERGIZE-T trial. But of course, that trial was focused on a non-regularly transfused patient population. So we were able to look at a primary endpoint of a mean hemoglobin increase of 1 gram per deciliter or more from baseline, which was supported by a lot of secondary endpoints. The 2 trials together were designed with an aim to deliver the first therapy for all thalassemia subtypes, and the trials are represented here in the circle. On the left, you see the ENERGIZE trial, which represents about 2/3 of the thalassemia patient population, so the non-transfusion dependent patient population. And we were able to announce the top line results of that trial at the beginning of this year and then presented the data at EHA. And then, of course, yesterday was the another highlight for the program because the top line data was presented first via press release, but then the full data set was presented yesterday for the transfusion-dependent program. So then we are -- I'm going to walk you through the overall benefit risk profile of the -- of PYRUKYND for thalassemia. So I'll start with the efficacy summary. So as I mentioned, the patient population reflective of the whole thalassemia patient population, which we're very pleased about. And then both trials achieved their primary endpoint. So ENERGIZE achieved primary endpoint of hemoglobin response, which was statistical significant with 42.3% of the patients meeting that endpoint who were treated with mitapivat versus 1.6% in placebo. And then ENERGIZE-T implemented that with the primary endpoint of transfusion reduction that Dr. Kuo just highlighted, again showing statistical significant transfusion reduction for those patients. Secondary endpoints, what we are very, very pleased with is that for ENERGIZE we were able to support that that hemoglobin improvement also led to people actually feeling better, which is very important in the context of hemolytic anemias. So we demonstrated a statistical significant improvement in FACIT-fatigue in those patients. And then what was also very nice to see was that we actually had a functional improvement as well, as measured via the 6-minute walk test. And then ENERGIZE-T, we just went through that data, but all of the other key secondary endpoints were statistical significant, which is also very special because the last transfusion reduction response that we measured, a 50% reduction over 36 weeks, is the longest interval ever demonstrated in blinded trial. Then the next slide, we're summarizing the safety here per trial. So ENERGIZE on the left, the adverse events were similar across mitapivat and placebo, the rate and the type of events. So ENERGIZE-T, Kevin just highlighted that data as well. So again, very similar results in the trials. We had 3.1% in ENERGIZE experiencing an adverse event leading to discontinuation, compared to 0 in the placebo arm. And then on ENERGIZE-T, it was 5.8% versus 1.2%. And then the TEAEs that led to discontinuation within the trial, each of those events was observed once. So there was no cluster of events in the ENERGIZE trial and no cluster of events in the ENERGIZE-T trial. Which then, of course, allows us now to put everything together, and we were able to demonstrate a favorable benefit/risk profile across those 2 studies. If we walk through the regulatory framework, we can make the statement that the program enrolled a patient population that was reflective of that overall thalassemia patient population. We're very proud of that because that is the first time that that is actually done. Then the other highlight, of course, is that the both studies achieved all primary and all key secondary endpoints, demonstrating benefit of mitapivat over placebo. On the safety profile, again, the treatment events that led to discontinuation were overall low in occurrence. And then when putting the totality of the data together, we saw 2 patients that had an AE of hepatocellular injury within the first 6 months of exposure that led to treatment discontinuation. And those liver tests improved when they stopped the drug. So based on the totality of the data, we are highlighting hepatocellular injury in our regulatory applications as a potential risk for mitapivat in patients with thalassemia, and we have proposed monthly monitoring of liver test for the first 6 months of treatment with mitapivat. And we also updated our clinical trials to incorporate similar monitoring. Putting all of that together, the favorable benefit/risk profile that we have observed in this program has allowed us to file an sNDA with the FDA. And then this is really a point of pride for the organization because we were able to, at the same time, which is unprecedented, submit to 3 other regulatory authorities for review, so the European Union, the Kingdom of Saudi Arabia and the United Arab Emirates. And then the anticipated approval decision and potential U.S. launch in 2025, and we will update more on upcoming milestones at the beginning of next year. And with that, I am very pleased to conclude this by saying we have a lot of firsts in this program. We had the first program to enroll alpha thalassemia -- Kevin highlighted that as well -- which is a patient population that has no therapy available to date. So the first program that is an oral treatment candidate. This is important in the context of the transfusion burden as well, because it really can -- has the potential to untether patients from the clinic. It is the first program to demonstrate quality of life improvements and reach statistical significance on something that we know is very important for a patient population, as when you speak to patients, they really highlight fatigue. And then it's the first program to demonstrate that 36 weeks durability of reduction on transfusion burden. So with that, of course, leaving thalassemia, we have a lot going on in sickle cell disease as well, and it's my pleasure to invite Julia Xu up to the podium here to walk you through the results of the Phase I trial for tebapivat.

Thank you so much for the introduction. I'm Julia Xu, I'm from the University of Pittsburgh. I will be delighted to walk you through the results of our Phase I study of tebapivat in sickle cell disease on behalf of my co-investigators. This is our title slide. This abstract was presented last night at the poster session. So we've already heard some background about the mechanism of action. I will just mention that we think of tebapivat, and pyruvate kinase activators in general, as really multiple therapeutic mechanisms in sickle cell disease. In sickle cell disease, there are multiple pathophysiological abnormalities that lead to the vaso-occlusion, hemolytic anemia, sickling and end organ damage. One of them is hemoglobin S polymerization, which causes the formability of the red cells to decrease, red cell sickling, hemolysis and vaso-occlusion. And then the other issue is that the red cells get damaged over time with the cycles of sickling-unsickling. The membrane gets damaged as well, they're stiff and they lose ATP as well. So we know that the documented levels of elevated 2,3-DPG, this is compensatory for the anemia in sickle cell disease, and also decreased levels of ATP available to red cells in sickle cell disease. Pyruvate kinase activators are able to target both of these abnormalities in sickle cell disease by increasing flux through the glycolytic pathway. It's able to decrease buildup of 2,3-DPG, which is a glycolytic intermediate. So that decreases the polymerization of hemoglobin S. 2,3-DPG keeps hemoglobin S in the state, the oxygenated state, that's more likely to polymerize. So it sort of shifts, pushes hemoglobin S away from polymerization, so has that anti-sickling effect. And then at the same time, with increased flux through the glycolytic pathway, of course, you get that increased pyruvate kinase activity and increased production of ATP, which is so beneficial for red cells in pretty much any inherited red cell disorder. So we're very excited about these mechanisms and also excited about the data that has come out of the studies of mitapivat in sickle cell disease. When I was at the NIH, we conducted the Phase I study of mitapivat in sickle cell disease and saw improvement in hemoglobin and a reduction in hemolysis. And we have a long-term treatment study of patients at the NIH as well in mitapivat, looking at things like tissue oxygenation. We saw some improvement in cerebral oxygenation as well, plenty of other endpoints like quality of life. And then, of course, very excited about the Phase II results of RISE UP and, hopefully soon, the Phase III results. So we are very excited on the progress that has been made in sickle cell disease. This compound, tebapivat, particularly caught my attention for a couple of reasons. One, it's daily medication compared to mitapivat, which is a twice-daily medication. And then the other difference is the pharmacodynamic effect which you will see as we move into the presentation. And so what we'll talk about today is the data in sickle cell disease. The previous data that was presented on tebapivat was in healthy volunteers. So the initial part of the Phase I study was a single ascending dose and multiple ascending dose study of tebapivat in healthy volunteers, and that was reported at ASH last year. And so this year we presented as a poster the third part of the study looking at a nonrandomized open-label study of safety, tolerability, PK and PD in patients with sickle cell disease. So here is the study design. This part I had 3 actually planned dose levels with interim city and PK/PD evaluations. The study design included adults aged 18 to 70 with hemoglobin SS or S-beta 0 thalassemia receiving either 2 milligrams or 5 milligrams of tebapivat for 28 days, followed by a 28-day observational safety follow-up period. The reason why there's only 2 dose levels is that we actually were able to collect enough safety, PK and PD data after the 2 initial dose cohorts. So we did not need to progress to the third dose cohort to be able to select a dose. And further details are available about the eligibility criteria from the QR code at the end. Here, our primary and secondary endpoints. So as I mentioned, there's a focus on the pharmacokinetics. But certainly, we also cared about safety and then hemoglobin response, what happened with 2,3-DPG and ATP, as well as markers of hemolysis and erythropoiesis. So out of 16 adults with sickle cell disease who received at least 1 dose of either 2 milligrams or 5 milligrams daily of world tebapivat, 14 patients completed the 28-day dosing period. 1 patient in the 2-milligram cohort discontinued -- self-discontinued tebapivat due to an AE which was a pain crisis, and then 1 patient in the 5-milligram cohort was discontinued due to a hemoglobin increase. There is a pre-diversified hemoglobin ceiling, and so because of that, the patient was taken off of the medication, but otherwise did well on the medication and was able to complete the study. And here, we're presenting the data from all 16 patients in the intention-to-treat analysis. Here are the baseline demographics and disease characteristics. So you can see the disease characteristics for the most part are well matched. Hemoglobin concentration is similar, 7.8 versus 8.1 grams in the 2- versus 5-milligram cohorts. The one demographic difference I'll point out is the median age, 28 years in the 2-milligram cohort versus 37.5 years in the 5-milligram cohort, but otherwise well balanced. Here are safety data. The important point to note would be that there were 2 patients in the 2-milligram cohort and 1 patient in the 5-milligram cohort who experienced an SAE of sickle cell anemia with crisis. These events occurred during the safety follow-up period after tebapivat was discontinued. It was interesting to note that during the 5-milligram dosing period, there were no crises reported by patients who otherwise regularly historically do have crises, and then also to note that the SAE reported in the milligram cohort was the only SAE of sickle cell anemia with crisis that was considered treatment-related by the investigator. That was mostly because of timing, that there were 2 patients who experience a vaso-occlusive crisis around the same time, not necessarily because the situation of that AE was particularly concerning to be drug-related. And then all of the pain crises occurred in the setting of known triggers for those patients. In terms of response, hemoglobin and markers of hemolysis, we will walk through figures which I think will be best to look at. This is a summary of what the data looked like overall. So I'll just point your attention to this. This figure shows the mean change in hemoglobin from baseline. And you can see the 2-milligram cohort in blue and 5-milligram cohort in red. And the first part of the figure here shows the treatment period up to 28 days. And this period is the safety observation period where patients are off drug. And you can see a nice hemoglobin response at 28 days, 1.2 grams per deciliter in the 2-milligram cohort and 1.9 grams per deciliter in the 5-milligram cohort. And also important to note that this hemoglobin response persisted past the dosing period. You see a similar trend in the markers of hemolysis. So this is total bilirubin. You can see both a reduction in total bilirubin in the 2- and the 5-milligram cohort, and specifically it's interesting to note that the 2-milligram cohort seems to have a larger reduction in total bilirubin here at 28 days. But I pointed out that there was a slight difference in the age of the cohorts. There was some amount of disease difference, and there was higher levels of hemolysis in that first cohort. So the decrease in total bilirubin is really just those patients having a higher level of hemolysis at baseline and therefore having a higher amount of reduction. And then we see a pretty impressive decrease in LDH. So in the 2-milligram cohort, there was a 207 units per liter decrease, and in the 5-milligram cohort 132 unit per deciliter decrease in LDH. And finally, we also see a similar decrease in reticulocyte percentage in both cohorts. And notice that all of the hemolysis parameters also show this decrease past the 28-day dosing period. In terms of pharmacokinetics, tebapivat exposure increased with higher dose of drug and the exposure levers are very similar to what we saw in healthy volunteers. Pharmacodynamically, it was very interesting to note that the effects that we saw on 2,3-DPG and ATP also endured up to 4 weeks past the dosing period. So you can see here -- so with 2,3-DDG, there's a nice reduction in both cohorts -- and then there's a slow return to baseline in the 2-milligram cohort, and then the 5-milligram cohort 2,3-DPG level does not return to baseline. And then with ATP, similarly, you see a nice steady increase in the ATP levels. Around 2 weeks it plateaus, and then it has a nice prolonged effect up out to 4 weeks after the last dose of treatment. So in conclusion, mitapivat was well tolerated in patients with sickle cell disease, receiving either the 2- or 5-milligram daily for 28 days. Increases in hemoglobin and trends towards improvements in hemolytic and neurothopoietic markers were observed, and there was a sustained effect after tebapivat was stopped. ATP levels were increased and DPG levels were decreased during the study, consistent with the proposed mechanism of action tebapivat, and a sustained pharmacodynamic effect was observed up to 4 weeks after the last dose. Tebapivat will be evaluated further in additional clinical studies, with a Phase II study coming up, and we believe that it is a potent pyruvate kinase activator with the potential to provide benefit in sickle cell disease. Now with that, I will hand it back to Dr. Gheueuns. Thank you.

Thank you. So as was just mentioned, we are adding the Phase II to our pipeline. So we are going to move forward with tebapivat in sickle cell disease, and we're very excited about that. But as you know, we also have a program ongoing in lower-risk MDS. So I want to focus on that a little bit more. We have a IIb open-label study in lower-risk MDS that we are currently enrolling. The Phase IIb primary endpoint we -- is a transfusion independence endpoint defined as transfusion-free for 8 or more consecutive weeks during the core period, and secondary endpoint being safety change in hemoglobin and then different ways of looking at transfusion independence PK and PD. This is enrolling adult patients with lower-risk MDS who are transfusion dependent. So that was a change that we've made based on the IIa clinical trial. And then the other change that we have made is the dose levels. The Phase IIa was a small exploration study in which we tested the 5-milligram dose. Based on the PK results obtained in that study, we realized that we actually needed to test higher doses for the MDS program because the PK was different than in healthy volunteers. And so that's where we now have 3 dose cohorts, 10 milligrams, 50 milligrams and 20 milligrams that will be tested for 24 weeks, and that is then followed by an extension period. So with that, I'm actually going to immediately hand it over to you.

All right. Thank you, Sarah, and thank you so much, Julia and Kevin, for those excellent presentations. Before we close and transition to Q&A, I just had a couple of closing thoughts, and it's a bit of a reflection on what a great year this has been for Agios in 2024. So you may remember that we started this year with a number of ambitious objectives, and I'm very pleased to highlight that you can see a variety of checkmarks. In fact, every single box has a checkmark. And all of these accomplishments were delivered on or ahead of schedule, which we are very, very proud of. And then, of course, today, as you've heard, we've added one more checkmark, which was our final objective for the year. And that's on the right-hand side, the filing of the sNDA for thalassemia, which we now have accomplished, but I do want to highlight that not only has the team achieved that, but also, as you heard simultaneously, in a Herculean feat, simultaneous filings in EU, in the Kingdom of Saudi Arabia, as well as in United Arab Emirates, all areas that are important for thalassemia. So we're really proud of this. It really shows the commitment of the team, not just to deliver on what we say we're going to do, but also deliver on behalf of patients and our shareholders. And then I'll just note that next month, of course, we will update our new objectives and our road map of accomplishments for 2025, which is not that far away. Moving to my last slide, which is just a highlight of the 4 pillars that will continue to drive our success going forward at Agios. First is the fact that, as you've seen from the data today, we are actively building a PK activation franchise with multibillion-dollar potential, which we're very proud of. Secondly, given the data that's now been featured and collected over the course of several years and really this year in particular, we have a lot of conviction in the differentiation of this very unique mechanism of action. Third is we're continuing to collect data now across our PK activation franchise which further puts us in a position of strength, and we're especially proud with the opportunity we now have to not just talk about data for mitapivat in later stages, but also the emerging data that we see now with tebapivat across both sickle cell disease and hopefully, over the course of the coming months, in lower-risk MDS. And lastly, our foot is on the gas to continue to grow our pipeline in a diversified fashion. And the main ambition here is to make sure that we do what we do best at Agios, which is address diseases that have very high unmet need on behalf of patients. I'll just highlight at the very bottom, too, we have the unique position of having a very strong balance sheet. And as of the third quarter, we reported $1.7 billion. The point of that capital is really threefold. One is to make sure that we're successful with our near-term potential launches, thalassemia potential in 2025, sickle cell disease in 2026; secondly, you've already heard that we have an emerging later-stage pipeline, and we will deploy that capital to advance that pipeline; and then third, of course, we're always looking to expand, and that can be done through organic options as well as externally discovered assets. So really proud of the achievements and, again, very, very proud of the team. So thank you so much. With that, I think this is a great time to transition to Q&A. And Chris Taylor has the microphone, so just wait one moment while Chris has a chance to pass that around the room.

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Okay. I'm not taking notes. I'll listen carefully.

[indiscernible]. Could you provide a little bit more detail on the severity [indiscernible] can you provide a little bit more detail on the severity [ of cases ] [indiscernible] the potential [indiscernible]?

Sure. Okay. So I'm going to try to remember all of the subparts of the questions, but if I forget to answer something, please just prompt me. In regards to what we have observed in the clinical trial, the severity, so as you saw in each trial, we had one adverse event, not serious adverse event, that led to discontinuation. And then the totality of the open-label data, there were 3 additional events in the open-label data set, of which 1 again was an AE, two were SAEs. When you look at what happened there, everything was within the first 6 months of exposure, and it's only 1 patient who didn't really have confounders, which was what made this for us a signal for a potential hepatocellular injury, which is very complex in this disease, and I'm sure Dr. Kuo will speak to that more, because thalassemia patients have a lot of comorbidities and have a lot of fluctuations. So it's truly the totality of the data that we needed to look at. In regards to severity, all of these patients had great outcomes because people are routinely watching for things like this in this context of this disease. So they are -- without us knowing that this could be a potential, we're able to act appropriately based on the routine monitoring that was already occurring. And so when patients discontinued the drug, they all had a great outcome. We feel based on -- while there is a lot of uncertainty, we do think it's the right thing to do to implement monitoring like this for the first 6 months in the context of thalassemia, and we do not -- we have not heard that that would be creating a hassle for physicians or for patients. But I will let you actually comment on that one.

Thank you, Sarah. So I think we need to keep in mind that the population in which mitapivat was deployed in this Phase III trial are heavily pretreated. First of all, thalassemia is a lifelong disease. And second of all, when I say heavily pretreated, these patients had never-ending cycles of transfusions and iron chelation. As we all know, iron chelation is extremely toxic. And iron itself is also extremely toxic in body to begin with. So many a times, we actually observe increase in ALT in these patients, or just an increase in liver enzymes in general, that often cannot be explained. And this is outside of the clinical trial context. And the reason why we know this is because every time a patient comes in for transfusion, we would do a set of blood work that is on par with standard of care, and this is the recommendation, including liver enzymes, the renal function as well as the hematologic parameters. And I think it's important to keep in mind that we need to weigh the risks [indiscernible] and weigh the risks and the benefits of this therapy and that the benefit here, in my opinion, at least, outstrips the potential risk of hepatocellular injury, given the rarity of the event, and also the fact that our patients are heavily monitored as a result of the fact that they are heavily pretreated to begin with, and they have a lot of comorbidities.

And then, Eric, I realize there's two more parts to your question that I forgot to answer. So we have not observed any cases in PKD or any other indications. So this is truly a thalassemia observation. And then in regards to the mechanism of action, the data is -- like we do not -- I mean, again, but not observed in PKD. It is a drug that gets metabolized in the liver. So is that part of it, who knows? But the thalassemia patient population, it's such a limited number of observation that you can't really identify risk factors, which is why we do think it is better to just monitor the patient population, per what Kevin just mentioned.

But if you really want my opinion, like we see liver enzyme abnormalities all the time in our patients. And then we have no idea how to explain it. Often, we just blame it on the chelators that they're on, because we know that chelators can do this as well. But again, who knows? We have to remember that when iron sits in the liver, right, for any measurable amount of time, excess iron, they create oxidative damage. And often these damages are cumulative. And with our technology currently, FibroScan and [ FerriScan ] and so forth, the ability for us to detect liver damages -- or even biopsies -- is quite limited. So we're dealing with injuries on a cellular level and a subcellular level.

[indiscernible].

All right. Great. So I'm going to try to recap all the facets of your question, Greg Renza, thanks a lot for that. So the question really pivots on tebapivat, and a multipronged approach here. How do we think about tebapivat in the broader portfolio? How do we think about it specifically in sickle cell disease and the potential ahead as well as the competitive landscape? So I'll start, and then perhaps Sarah and Tsveta from commercial can comment as well. We're really proud of the fact that, as I said, we're building a PK activation franchise. And we're intentionally not subtle about the potential we see as multibillion -- multibillion-dollar potential. The anchor point, of course, is mitapivat and we are delighted with the progress that we've made across all the hemolytic anemias that you've heard about over the course of the year and certainly this morning. That said, sickle cell as a starting point, because we talked about the first tebapivat Phase I data there, is incredibly high unmet need. And at Agios, we spend a lot of time in depth with the sickle cell community, which has been through a lot, particularly this year, and clearly need multiple therapeutic options. We believe strongly in the emerging data set that we've seen already, particularly with the RISE UP Phase II data that we featured last year. We're very excited about the potential that we look to see from the RISE UP Phase III portion later next year, but the ambition is continue to expand the breadth of the patient population that can benefit a PK activator. And so it's early days right now, of course, with the Phase I data that Dr. Xu talked about. We're encouraged to be able to take that next step to Phase II, but the work that remains to be done is gather more data, define an optimal target product profile that builds upon the foundation that we're establishing with mitapivat. And the final thing I'll just say is the ambition that we have -- there's a lot of rare disease experience at Agios, myself included. And every time we enter into a new disease state, our ambition is to be in it generationally. And that is really our approach with our PK activation franchise. Sarah, anything you want to add, or Tsveta?

Yes, I have nothing to add, really.

No. I think Brian covered it well. Obviously, when we look at it commercially, I want to start with the potential of pyruvate kinase in sickle cell disease, because we do have the potential to have the first innovative oral therapy that delivers on all the endpoints that are meaningful for patients, physicians and payers. And this is increasing hemoglobin level, reduction in VOC and potentially improvement in quality of life. Having said that, it's such a disease with so much unmet need. So one therapy will not solve the problem for all patients. Having the need for more therapies is definitely, definitely there. And having 2 potential therapies in a disease like that allows to -- co-positioning allows us to really build a franchise and potentially deliver value for more patients.

And maybe just one last quick one, too, Greg, because you used the word competitive. And we have maybe a different philosophy in the way we think about rare diseases, particularly in sickle cell disease, that we talk about the progress we're trying to make internally. This is a disease that requires multimodal options. And so we've said this many times, we really cheer for everybody. And that's always amplified when you spend very close times with patients and you hear the suffering and the unmet need. So it's going to be a long journey ahead, but we're very excited about it.

If I may just add from a clinical perspective as well, we will never complain about more therapies, coming from the perspective of not having had anything other than hydroxyurea. We were talking about this last night: when all you have is a hammer, it doesn't really matter what you're hammering. So we have treated sickle cell disease as one entity essentially, but we know that there is so much heterogeneity in the disease. And certainly biologically, by country, by genotype, but also personally, like the psychosocial component of disease, every individual is different and how they take the drug, how they respond to the drug. And I mean, if you think about personalized medicine, how wonderful it would be to have multiple options for pyruvate kinase activation for our patients. So I really don't think of this as a problem of competition.

Excellent. Dr. Xu. Thanks so much. I'll do a better job of triaging the questions around.

[indiscernible].

Okay. Let me set up the question and then we can go ahead and start. The first one from Mark is a question about the hepatocellular injury signal and the cases that we've seen and how do we tease apart that this is drug related versus, as Dr. Kuo talked about, all the background complications that exist and can we characterize the specific cases themselves. And the second one relates to extending this into sickle cell disease, what are the considerations if we were to have a similar situation. Maybe, Sarah, you want to start?

Yes. So it's in the hard in the context of a disease like this look for signals like this. But that's why we also call it potential and not call it identified, because there are things here that indeed are -- is this part of the disease? Is this part of drug? Is this how -- there's questions on this. The fact, though, is that when people discontinue the drug, they got better. And so in that context, it's just safer to make people aware of this potential so that they can be on the lookout for -- monitor their patients and take a very easy action, which is stop the drug. So this is an event that is monitorable, manageable and then actionable. And in that context, in the context of the totality of the data, I think it's the right thing to do for patients and physicians to highlight it. From a monitoring perspective, I think you spoke to it earlier, it is really already kind of part of care, which I think is also why it is physicians are so in tune with this in the context of this disease and not looking at this as an issue that is out of the norm. So from that perspective, we feel comfortable with this risk profile update and, as mentioned, really consider this a very favorable benefit/risk profile in the context of all of the efficacy data generated in a very underserved base population of which the vast majority of patients have no options. And so to that, it's really about that context needs to be taken into account. And that's why we look at this as a very favorable benefit/risk leading to all of those submissions. And in regards to sickle cell disease from a clinical development perspective, this is why we have to study each indication, because the drug needs to generate its benefit/risk profile in each indication. As I just mentioned, we have not observed this in PKD. We have now observed this in thalassemia, which is another indication. In sickle cell disease, we are running the blinded trial, and we need to just generate data and generate open-label extension data to see what happens.

I will just say a couple of things commercially, and I'll hand it over to you. And I will start with thalassemia first. We talked a lot about the transfusion-dependent patients and the fact that they are monitored all the time for liver because they also come transfusions. The reality is the nontransfusion-dependent patients are monitored when they come for their like scheduled visits. We are privileged to be surrounded by the community here during ASH and get some of the feedback there, both from patients and clinicians. It's a simple blood draw. So which can be done in a local lab. We haven't heard any concerns in terms of adding really a treatment burden or anything to the patients. And when you think about sickle cell disease and Dr. Zhou really characterized it well, if that is to happen in sickle cell disease, we have to remember this disease with super high unmet need, increased mortality if you have a product that can deliver on all the clinical relevant meaningful endpoints, we don't see that as an issue at all, but I would want you to...

I mean the fact that we've had so many years of experience with mitapivat in pyruvate kinase deficiency as well as in nontransfusion-dependent thalassemias, and also some data in sickle cell disease, to me -- and we have not observed this sort of signal in the other diseases -- to me, that speaks to the fact that it's, in my opinion, at least, is completely personal opinion that this is disease specific and is limited to TDT, again, because -- I mean there's -- I can throw out all these hypotheses to you. I mean they are all supported by the literature about -- especially about the effect of nontransferrin-bound iron and having high nontransferrin-bound iron in the circulation causing damages to the liver and to other organs as well. To me, I think that's what's happening. But again, better to be safe than sorry.

Yes. And we will be data-driven throughout our development. And so Dr. Xu, and then we'll transition to the next question.

I agree. I think we have not seen signals in sickle cell disease and certainly sickle cell patients can also be iron overloaded and we can see what seemed like somewhat random [ transaminitis ]. Because you can have sickle hepatopathy, it's not so well understood. But in general, we follow those patients with labs and they self-resolve, and any time we start a patient on disease-modifying therapy, we tend to follow them closely. Like if we're starting hydroxyurea, we check labs every month, and we always check liver function and kidney function. It's a multisystemic disease. And so this really does not add any additional burden. I think it makes sense to be careful.

Great. Thank you. And for the next question, we'll have Greg Harrison come to the microphone.

Greg Harrison, Scotiabank. Congrats on another very productive ASH meeting. So in ENERGIZE-T, we've seen this nice response across different subgroups. So is there any specific group that may see more or less use of mitapivat within that patient population and then as well as the broader thalassemia population, just given the varying standards of care?

So one of the mission of the thalassemia community is to bring the standard of care to par in all areas, regardless of income and regardless of the socioeconomic status. And to this, I feel that in the past 3 to 4 decades, we have made tremendous progress. Certainly, there is still some differences between the different regions of the world. But in my opinion, that the fact that iron chelation is now widely available, for example, right, in most parts of the world where thalassemia exists, to me tells me that a disease-modifying treatment like mitapivat should be widely deployed as well across the world and regardless of the socioeconomic status.

Tsveta, do you want to comment as well?

Yes. So -- and I think the question was related specifically to the ENERGIZE-T data, right? The transfusion-dependent. Well, our goal, and Sarah mentioned it, is to go for a broad label, where we'll have the opportunity to have a label potentially for thalassemia across all subtypes. When you think about the unmet need in the transfusion-dependent patient population, Dr. Kuo really characterized it well, any reduction in infusion burden is beneficial for patients. So we see the product having a broad application across this patient population. And then, of course, it's going to be the discussion between the patient and the clinician of how they define benefit and how they assess it over time.

Thanks. And for the next question, Andy Berens from Leerink.

Thanks, Chris, and congrats on all the progress. I just wanted to clarify -- ask a clarifying question about the hepatocellular injury, and then I had a question about the sickle cell presentation. You guys chose to characterize it as potential hepatocellular injury, which is different than we've seen some other companies talk about transit LFT elevations. I assume that Hy's Law can't be diagnosed in hemolytic setting, given the bilirubin. But what was it that caused you to call it hepatocellular injury. Were there any patients that did not reverse or ended up with a cirrhosis or end-stage liver disease. And then for the sickle cell trial, it looks to me that based on the baseline, I think it was 50% of patients had like 3 or 4 pain crises in the past 12 months, but we saw a fair amount in this short trial. Just wondering if you felt like the rates were actually higher than what patients were experiencing prior to going in the trial. It looked like on one of the slides you said that most of them happened with withdrawal, but it did seem like numerically, there were some that happened maybe during the dosing period. So just any color on that would be really appreciated.

Thanks, Andy. Sarah, do you want to start on the first part?

I'll start with the first part. So in regards to what to call -- it's indeed tough -- like Hy's Law in the context of hemolytic anemias where people have already abnormal values, enzymes that are being used to define Hy's Law is very tough. And on top of that, it means that it is for sure drug-related as well, so it's a constellation of lab abnormalities, plus for people who don't have abnormal labs at baseline and then the context of drugs. So it's a very complex problem in the context of hemolytic anemias where people start with abnormal lab values. And then therefore, you're more looking at patterns that you can recognize, et cetera. So that's where transaminitis is being looked at. And then people look at how direct bilirubin changes, indirect bilirubin changes, and try to make like a judgment call on that part in the totality of the data. What we see, though, is an ALT increase in these cases, and that -- like the enzymes all came down when mitapivat was stopped. So from an outcome perspective, we had great outcomes, which is what is wonderful, that people can take an action and discontinue drug. And in regards to -- because they all had improvement, no, we don't have people who have permanent issues or cirrhosis or something like that or -- yes. So no is the short answer there.

And then transition to the question -- the second part on sickle cell and the background profile of the patients, Dr. Xu.

Thank you, very good question. In terms of being able to compare the rate of VOCs, the 28-day treatment period is just such a short period. I don't think it makes sense to really think about whether or not there is a change in the frequency of VOCs. I think stochastically, even 1 or 2 events during that period can certainly change the numbers. But from the co-investigators' perspectives, there did not seem to be an increased frequency of VOCs among their patients. And so for that reason, none of the events were deemed treatment-related, except for one possible which I mentioned, it was really a timing situation where 2 patients happened to have a similar presentation around the same time, but both of them had additional triggers and were sort of unrelated. And most of the events did occur during the follow-up period, but not necessarily from withdrawal. We didn't see any evidence of withdrawal hemolysis, for instance. Despite the overinterpretation, but the thought could be that if they were receiving benefit during the treatment period, then maybe they're returning more to their disease phenotype after stopping treatment.

Did patients generally feel better while they were on the drug?

Some patients did, not all patients. And obviously, I can't speak for all of the PIs, but at least some of the patients at our site did report a subjective improvement.

So there are lots of questions, but we have time for one last question from Tess Romero from JPMorgan.

Okay. So please forgive me here, but I have to double click. You talked about 2 AEs and 1 SAE in the open label. What were these events, including the serious one? Were they in the same or different patients? And can you clarify which events occurred in what background, transfused or non-transfused? Getting a lot of investor questions here, so I think it's important just to put a finer point on this.

So okay, I'm going to try and repeat this in a way that it may be more understandable. So it's one adverse event that led to discontinuation in the ENERGIZE trial core period and one adverse event that led to discontinuation in the ENERGIZE-T core period. Then we have extension studies. In those extension studies, we had a total of 3 events. One was an adverse event, 2 were serious adverse events. All of these patients ended up discontinuing the drug and improved all of their liver enzymes with no bad outcomes basically. Out of the total of those 5, we had 1 patient in the open-label extension who did not have clear confounders that were reported in the context of this liver enzyme abnormalities. The exact preferred term is a little bit different for each case. As you saw, the AE that led to discontinuation, that person decided to report it as different lab values in ENERGIZE-T, the other one I think it was hypertransaminitis. I honestly forget because we lump them together based on the lab abnormalities as an event, and therefore we chose to, rather than list out each preferred term that an investigator gets to report, lump these events together under the term hepatocellular injury, which we believe is the best a way to reflect those different reported adverse events.

Same or different patients?

Different patients -- different patients -- in 5 different patients. So one in each blinded study during the core period, the rest is in open-label extension. I think we've spoken about this many times, but safety profiles, they continue to evolve as drugs are used, right, because efficacy is the blinded gold standard. This is the period in which you get to claim efficacy. Safety, however, you continue to expose people, you continue to gather data over time. And so this is where you always look at the totality of safety data versus just what happens within a blinded controlled trial. Obviously, you don't have the benefit anymore of placebo, but that's where medicine is an art, right, so you look at the totality of the data and try to make the best calls possible that you believe are reflective of your safety profile.

Okay. I think I'm going to wrap up here and just close by saying, first off, again, we are really proud of the totality of 2024 and all we've accomplished. I hope you got a really good sense of all of that this morning. More importantly, we're even more excited about what's to come in 2025. And as I noted, we'll share our objectives very shortly coming up next month for the year. But I want to take a moment to say again a special thanks to Drs. Kuo and Xu. Thank you so much for taking the time to give us an overview of the data. And thanks to all of you for listening in and for your continued support. So wishing you the best for the conclusion of ASH, holidays ahead, and we hope to speak with you soon. Thanks a lot.