Agios Pharmaceuticals, Inc.

Good morning and welcome to AGO's third quarter 2024 conference call. At this time, all participants are in listen-only mode. There will be a question and answer session at the end. Please be advised that today's call is being recorded at AGO's request. I would now like to turn the call over to Chris Taylor, Vice President, Investor Relations and Corporate Communications for AGO's.

Thank you, Operator. Good morning, everyone, and welcome to AGO's conference call and webcast. to discuss our third quarter 2024 financial results and recent business highlights. You can access the slides for today's call by going to the investor section of our website, agios.com. On today's call, I'm joined by our Chief Executive Officer, Brian Goff, Dr. Sarah Hewins, Chief Medical Officer and Head of R&D, Sveta Milanova, Chief Commercial Officer, and Cecilia Jones, Chief Financial Officer. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those we set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. With that, please turn the call over to Brian.

Thanks, Chris. Good morning, everyone, and thank you for joining us. Our mission at Agios is to develop and deliver transformative medicines that elevate and extend the lives of patients living with rare diseases. We are especially focused on rare diseases that result in the dysfunction and destruction of red blood cells, including pyruvate kinase deficiency, or PKD, thalassemia, sickle cell disease, and low-risk myelodysplastic syndrome, or MDS. As red blood cells comprise over 80% of all cells in the human body, optimizing red cell health represents an important path to improved individual health. Our lead product, Midipivet, a pyruvate kinase activator, has a novel mechanism of action that improves red blood cell metabolism and increases the amount of energy, or ATP, available to support red blood cell health. We are proud to have delivered positive data in Phase III programs in PKD and thalassemia, and we are excited about the prospects of Minipivet for sickle cell disease. Complementing those data readouts and the continued progress across our current pipeline, I am delighted to confirm today that Agios has received $1.1 billion in milestone payments following FDA approval in August of voracidinib, which originated at Agios. These payments include a $905 million payment from Royalty Pharma in connection with the voracidinib royalty purchase agreement Agios announced in May 2024, and a $200 million payment from Servier in connection with Agios' divestiture of its oncology business in 2021. Given the positive phase 3 data readouts of midipivette in thalassemia accomplished this year and the recently announced achievement of full enrollment of the phase 3 rise-up sickle cell disease study, we aim to deploy this strong cash base to prepare for the potential launches of midipivette in thalassemia in 2025 and in sickle cell disease in 2026. Beyond this significant infusion of capital, we also made important progress across our advancing clinical pipeline. First, we announced top-line data from the Phase III Activate Kids T study of midipivet in children with PK deficiency who were regularly transfused, our first pediatric study of midipivet. And second, we achieved two milestones in our clinical development program for lower-risk MDS. We announced that the FDA granted orphan drug designation to our potent PK activator, Tebapivet, formerly known as AG946, for the treatment of myelodysplastic syndromes, or MDS. And we have initiated enrollment and begun patient dosing in the Phase 2B study of Tebapivet in lower-risk MDS, an area with profound unmet need and significant market growth. Importantly, as we round out a very productive and successful 2024, we are on track to achieve our key remaining milestone for this year, submission of an SNDA for mid to pivot in thalassemia by the end of the year, seeking a broad label that includes adults living with all subtypes of thalassemia. Sarah will provide a detailed update on our progress and upcoming milestones across R&D in just a few minutes. Leveraging the positive data observed in the ENERGYZE and ENERGYZE-T Phase III studies of midipivet, our expanding commercial organization is actively preparing for a potential U.S. launch of midipivet in thalassemia in 2025. Sveta will provide greater detail on the market opportunity in thalassemia and the team's robust preparation, as well as an update on our current launch in PKD in just a bit. Finally, as you'll hear from Cecilia, we ended the third quarter with a very strong cash position with approximately $1.7 billion in cash and investments on the balance sheet, which includes the $1.1 billion in milestone payments we received following FDA approval of voracitinib. And before handing off to Sarah, I want to emphasize how incredibly proud we are for all that's been achieved thus far in 2024. how intensely focused we remain on finishing the year strongly, and our enthusiasm for continued progress in 2025 and beyond. With that, I'll now turn the call over to Sarah.

Thanks, Brian. Just recently, we were able to attend two significant meetings where we continued engaging with the community. At both the Academy for Sickle Cell and Thalassemia Conference and the SCDAA Annual Convention, we were reminded once again about the difficult journey for sickle cell patients, and it reinforces our conviction for what we are aiming to bring to patients. Turning to sickle cell disease, we are saddened by the recent events impacting this community and continue to be steadfast in our commitment to deliver a novel oral therapy that potentially improves anemia, VOCs, and how patients feel and function, particularly with respect to fatigue. Given the positive data we generated in the Phase II portion of the RISE-UP study, as well as the positive data we have generated in other hemolytic anemias that share a common pathophysiology, we are excited about the potential for Metapiva to become a convenient first-in-class and best-in-class treatment option that improves red blood cell health for patients living with sickle cell disease. As announced last week, we are very pleased that we met our goal of completing enrollment in the Phase III Rise-Up Study by the end of the year, just over a year after we began recruiting this cohort. As a reminder, the Phase III study has a planned sample size of 198 subjects, randomized two-to-one to metapivate versus placebo across approximately 112 sites globally. There are two primary endpoints. Hemoglobin response defined as an increase of at least 1 gram per deciliter in average hemoglobin concentrations over weeks 24 to 52 compared with baseline, and annualized rate of sickle cell pain crises. Driven by a differentiated mechanism of action, we believe that Metopivac has the potential to address the high unmet need in this disease by improving anemia, reducing sickle cell pain crises, and making patients feel better. We look forward to reporting top-line data from the Phase III next year. For thalassemia, we aim to deliver the first therapy approved for all thalassemia subtypes. Based on the positive data generated in both the Phase III energized study of metapivate in adults with non-transfusion-dependent alpha or beta thalassemia and the Phase III energized T study of metapivate in adults with transfusion-dependent alpha or beta thalassemia, We believe METAPIVAT has the potential to become a foundational and convenient oral treatment option for all subtypes of thalassemia, including all genotypes and all levels of transfusion burden. We are working diligently to progress the filing and continue to expect to file an SMDA by the end of this year, seeking a label that includes adults living with all subtypes of thalassemia. In pediatric PK deficiency, we were pleased to announce top-line data from the Phase III Activate Kids T study of metapivate in children with PK deficiency who are regularly transfused. We are proud of this trial because, first, this is the first Phase III study to report data in this population, and importantly, it's the first completed pediatric study of metapivate for algeol. While the pre-specified statistical criterion for the primary endpoint was not met, we believe these results were clinically meaningful, given the percentage of patients that achieved a transfusion reduction response, including those who had a transfusion-free response with no red blood cell transfusions, and those who achieved a normal hemoglobin response, defined as hemoglobin concentrations within normal limits at least once in eight weeks or more after a transfusion. And second, safety results from METAPIVAT were consistent with the safety profile for METAPIVAT previously observed in adults with TK deficiency who are regularly transfused. With enrollment completed in the Phase III ACTIVATE KIDS trial, we look forward to an anticipated data readout next year. In parallel with the progress we continue to make across the METAPIVAT development program, this quarter we also made important advancements in our DEPAPIVAT program. First, we initiated the Phase II study of tebapivate in lower-risk MDS. This open-label study will enroll a total of 60 individuals with transfusion-dependent lower-risk MDS across three dose levels, 10 mg, 50 mg, and 20 mg, each of which is greater than the 5 mg dose that was evaluated in the previous Phase IIa study. Each dose-level cohort will be open for enrollment sequentially without pauses between the cohorts. meaning that we will first enroll 20 patients in the 10 milligram dose cohort, and once those slots are filled, we will begin enrolling 20 patients in the 15 milligram dose cohort, and then we will do the same for the third cohort of 20 patients at the 20 milligram dose. There is a 24-week core period for each cohort, followed by a 156-week extension period. The primary endpoint of this study will be transfusion independence, defined as remaining transfusion-free for at least eight consecutive weeks during the core period. Secondary endpoints will include safety, changing hemoglobin, and additional measures of anemia. Similar to thalassemia, with this program, we aim to deliver the first oral therapy that addresses anemia due to ineffective erythropoiesis in lower-risk MDS patients. which affects approximately 75,000 to 80,000 patients in the U.S. and EU5, and accounts for approximately 70% of all MDS cases. Also this quarter, we were delighted to receive FDA Orphan Drug Designation for Tevapivax for the treatment of MDS. This underscores the importance of bringing new oral treatment options to patients suffering from this rare disease, and we expect to provide additional milestone timelines once enrollment is further along. Looking forward, we are excited to be attending the upcoming annual meeting of the American Society of Hematology, ASH, and look forward to the publication of accepted abstracts on November 5th. With that, I will now turn the call over to Sveta. Thanks, Sarah.

As we prepare for a potential launch in thalassemia, we are reminded of the significant unmet need in this disease, and also the value pyrokin may bring to thalassemia patients across all subtypes. We continue to validate this through the powerful patient connections we experience at conferences like ASCAP and in local community meetings at selected patient centers. Thalassemia is much more prevalent than PK deficiency, with approximately 6,000 adults diagnosed in the US, approximately 4,000 of whom are non-transfusion dependent. The diagnosis rate in thalassemia is high, with many patients diagnosed before adulthood. Given the availability of claims data and ICD-10 codes, these patients are known to the healthcare system, which provides important clarity for our launch preparation. Treatment options are limited, especially for patients with non-transfusion-dependent disease, with most patients relying on supportive therapy. All forms of thalassemia bring high rates of serious morbidities, reduced quality of life, and a heightened risk of premature death. The burden of disease is high, and the associated cost of care is significant. Galvanized by the positive data from the ENERGIZE and ENERGIZE-T studies, our commercial organization is actively preparing to address this high unmet need with a potential US launch of pyrokine in thalassemia next year. We're especially enthusiastic about the potential for pyrokine to become the first therapy approved for all thalassemia subtypes. Our team continues to make progress across four areas of launch preparation. First, we continue to conduct extensive market research and claims-based analysis to further refine our market insights and inform our launch targeting and execution. Based on the work we've done, we estimate that PyroKind's initial launch focus will address approximately 65% of the adult thalassemia patient population. We expect patients who already have regular contact with the healthcare system due to symptoms of their disease to be considered for therapy first. These patient segments include transfusion-dependent patients as well as non-transfusion-dependent patients who are already experiencing complications or are living with debilitating fatigue. Our team is actively engaged in the field, deepening our insights across the different patient segments and the diverse multicultural aspects of thalassemia. Our ongoing disease state education campaign has been focused on three areas. First, we are highlighting the pathophysiology of the disease, including ineffective erythropoiesis and hemolysis. Second, we believe it's important for patients and physicians to understand the long-term complications and burden of disease across all thalassemia subtypes, particularly for patients with non-transfusion-dependent disease who suffer from the misconception that they are at less risk. And third, as we continue to engage with both patients and physicians, we highlight the importance of frequent disease monitoring and management so treatment plans can be tailored to the individual patient's needs. To bring all of this together, we are pleased to share another example of the powerful Rethink Thalassemia campaign which we have rolled out in the recent months. The striking image and headline invite closer inspection of the words depicting the hidden risks of thalassemia. The feedback from this campaign has been very positive from both patients and physicians. They highlight how relevant and valuable they find the disease education content, not only when it comes to understanding the disease pathophysiology and complications, but also to connect that to the importance of ongoing monitoring and management. Our third area of focus in launch preparation is the discipline expansion of our commercial and medical teams to right-size the organization for a successful launch in this larger but still rare market. We're steadily building the team and adding additional capabilities as we approach a potential launch. with a keen focus on being as capital efficient as possible. And fourth, our market access team is already engaging with payers on disease state education. I'm proud of the broad access our team has achieved for pyrokines in PK deficiency, and we are aiming for the same strong outcome in thalassemia. Outside the US, the Gulf Cooperation Council, or GCC region, is home to approximately 70,000 patients with thalassemia, and some of the leading treatment centers in the region were part of our clinical trials. As we announced last quarter, we're pleased to have entered into a distribution agreement with New Bridge Pharmaceuticals to prepare for a potential commercialization of pyrokines in the GCC region. Complementing this partnership, we are delighted to have secured breakthrough medicine designation for pyruvatein thalassemia granted by the Saudi FDA or SFDA. We're actively collaborating with New Bridge to develop an optimal regulatory and commercial strategy for the GCC region. As a reminder, the access part in individual GCC countries usually begins with a price set at the regulatory level, followed by access negotiations with health authorities, local institutions, and the private sector. We look forward to navigating each of these elements in collaboration with NewBridge. Next, let me provide a brief update on the current launch of pyrokines in PK deficiency. In the third quarter of 2024, we generated $9 million in net pyrokines revenue compared to $8.6 million in the second quarter of 2024. In the U.S., A total of 211 patients have completed a prescription enrollment form, including 10 in the third quarter of 2024, a 5% increase versus the prior quarter. This has translated into 127 net patients on therapy. We believe the capabilities we continue to strengthen through the current launch will provide a firm foundation from which to maximize potential future U.S. launches of pyrokine in thalassemia in 2025 and in sickle cell disease in 2026. In closing, we are inspired and energized by the potential to bring a new therapy to these underserved patient populations around the world. With that, I will turn the call over to Cecilia.

Thanks, Farah. Our third quarter 2024 financial results can be found in the press release we issued this morning, and more detail will be included in our 10Q, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Third quarter 2024 net Pyroclin revenue was $9 million, an increase of 22% compared to the third quarter of 2023. Consistent with other rare disease launches, growth to net has been and is expected to be in the 10 to 20% range on an annual basis. Going forward, aligned with a strategic shift towards preparing for the potential launch in thalassemia, for PKD revenues, we expect to see muted growth and quarter over quarter variability in line with what we have seen in recent quarters. Cost of sales for the quarter was $0.8 million. R&D expenses were $72.5 million for the third quarter, a decrease of $9.4 million compared to the third quarter of 2023. This decrease was primarily driven by the $17.5 million upfront payment associated with the license agreement with Anilam, which was recorded in the prior year. SG&A expenses were $38.5 million for the third quarter, an increase of $12.7 million compared to the prior year quarter. This was primarily driven by an increase in commercial-related activities as we prepare for the potential approval of pyrokine and thalassemia in 2025. Importantly, this quarter we received a total of $1.1 billion in milestone payments following the FDA approval of voracitinib. These payments include a $905 million payment from Royalty Pharma in connection with the voracitinib royalty purchase agreement I just announced in May 2024. as well as a $200 million payment from Servier in connection with Agile's divestiture of its oncology business in 2021, both of which were recorded under other income in the P&L. As a reminder, Agile will retain a 3% royalty on annual U.S. net sales of voracitinib greater than $1 billion. Including these milestone payments, We ended the quarter with cash, cash equivalents, and marketable securities of approximately $1.7 billion. We expect that this balance, together with anticipated product revenue and interest income, will provide the financial independence to prepare for potential pyrotechnic launches in thalassemia and sickle cell disease, advance existing programs, and opportunistically expand our pipeline through both internally and externally discovered assets. We remain focused on creating shareholder value, including by proactively managing our cost base and deploying a disciplined cash allocation approach as we prepare to support potential future launches of Parakind. As we move toward additional potential value creating milestones in the near term, I am confident that our balance sheet will continue to enable us to execute from a position of strength. I will now turn the call back over to Brian.

Thanks, Cecilia. Before we open the line for questions, I want to conclude with a few words. 2024 has been marked by exceptional progress at Agios. We continue to deliver on our key priorities and have a very strong financial position, allowing us to maintain this great momentum in the final months of the year and beyond. In addition to its approved indication in PKD, midiPIVAT represents a significant opportunity to meaningfully elevate the standard of care for patients with thalassemia and sickle cell disease. We consistently hear firsthand from these communities that there is an immediate critical need for new regimens to treat these diseases. With this, we believe midiPIVAT is poised to become a first and best in class treatment option for multiple indications, translating into a franchise with multibillion-dollar potential. In addition to MediPivot, we continue to drive our other promising clinical programs forward, focusing on areas where there is a high patient need and providing us with additional opportunities to create significant long-term value and impact for all stakeholders. We look forward to the future as we strive to change the trajectory of these rare diseases. With that, I'd like to open the call for questions. Operator, please open the line.

Thank you. And at this time, we will conduct a question and answer session. As a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please send by while we compile the Q&A roster. One moment for our first question. Our first question will come from Greg Harrison from Scotiabank. Your line is open.

Hey, good morning. Thanks for taking the question and great to see all the progress. Two for me. First, how are you thinking about capital allocation and appetite for business development now that foresight has been largely monetized? Maybe there's a particular area you guys find attractive or complimentary. And then on sickle cell, maybe you can speak to expectations for the phase three portion of the trial, and if you can comment on powering with respect to VOCs.

Sure. And Greg, welcome back. Great to hear you again. Great to be here. Two parts. Well, Cecilia can handle the capital allocation question, and then Sarah can take over for rise-up phase three expectations.

Great. Thanks, Greg. So in terms of capital allocation, we're, of course, very proud of the strong balance sheet we have now. And in terms of how we think about that, our priorities, of course, will be the potential launches for Thal and then hopefully Sickle Cell, continuing to advance our pipeline, which you'll hear a little bit more about MDS today as well, and then expanding that pipeline both internally and or externally. We're pretty disciplined, and the amount of cash we have in the balance sheet doesn't change that. We look at things, you know, with our same criteria we have in the past in terms of being rare, transformative, have a clear regulatory path, and obviously create value for a shareholder. So that hasn't changed. We continue to look at that. And different areas, we've said, are agnostic in terms of modality, and we keep looking at how we want to expand that.

And then I'll turn it over to Sarah, but I do want to just lead in by saying how proud I am of Sarah and the team for this incredible, consistent, executional excellence. We were really pleased with the fact that even before today's call, we were able to announce complete enrollment of the Phase 3 study for Rise Up. And if you're keeping track, it's been about 12 months. And I think that says a lot about the profile, the trust the community has in us. And again, very importantly, the executional excellence from the team. So with that, Sarah, how about that as a setup?

Wow. Thank you, Brian. Thanks for the question. So, yes, we are very proud of the Rise Up team. We indeed accomplished complete enrollment, which was one of our milestones for this year. So we're very excited about that and are now looking forward to finish the trial, to get it to the end soon. So the expectations for phase three, so it's a one-year duration. We have two primary endpoints, as you know. One is hemoglobin response. The other one is sickle cell pain crisis reduction. And that is, of course, with the goal to try to deliver a drug that can hit on the totality of sickle cell disease, meaning both hemolytic anemia and vaso-occlusion improvements. Both endpoints are powered to have 90% or slightly more. to be able to detect that difference. So we're very excited about this and are looking forward to the end of the trial.

Great. Thanks so much.

Sure. One moment for our next question. Our next question will come from the line of Danielle Brill from Raymond James. Your line is open.

Hey, guys. This is Alex for Danielle. Thanks for taking our question. Another one on Rise Up. Can you talk a little bit about your primary endpoints in the Rise Up study? Do you think you need to hit on both endpoints or will success on just one support a regulatory filing? For example, is it possible that hitting on hemoglobin response and another secondary clinical endpoint like fatigue could support a regulatory filing? Thanks so much.

So thanks for the question. So yes, we have two primary endpoints, one being hemoglobin, as I just mentioned, and then the other one focused on VOCs. We did choose the two primary endpoints because they can provide relevant information for the totality of the disease. So in a situation in which we would not be able to hit on one endpoint but only would hit on the other endpoint, we still have an opportunity to transfer alpha to secondary endpoint testing. which would allow us to further look for clinical benefits. One of those endpoints is indeed fatigue. We always try to deliver with our drug across the different hemolytic anemias that we have studied, the hemoglobin plus story, meaning that we improve hemolytic anemia, but then also try to hit on feel and function. And as you know, we've been able to deliver to that on PKD and thalassemia, highlighting an improvement in fatigue. Our thalassemia data also highlighted that there was an improvement in the six-minute walk test. And so, our RISE-UP study is set up in a similar way to provide, you know, multiple ways that we can speak to clinical benefit for sickle cell disease patients. In regards to what is needed for regulatory approval, that is the regulators who look at the clinical trial data at the end of the package, of course, when we submit, we always We believe that there is a benefit-risk profile that supports approval, but it's ultimately the regulators that do the review and decide on approval.

I would like to add, and this is, again, echoing not just the point of executional excellence, but also the scientific expertise from the team, that everything that Sarah just went through was actually outlined in a poster in 2021. In other words, we didn't change the design. From day one, it's been set up this way. Yeah. And I think that's important, particularly in the context of the recent evolution in sickle cell disease with other therapeutic options. And we're very proud of the fact that from day one, we had a design that was intended to be a so-called hemoglobin plus design.

Thank you. One moment for our next question. Our next question will come from the line of Greg Renza from RBC Capital Markets. Your line is open.

Great. Good morning, Brian and team. Congrats on the progress, and thanks for taking my question. Brian, you've commented on just the trust that you've earned with respect to the community on the execution and the value that you're providing in the development program for Pivot with Sickle Cell. I'm just curious if you can comment on that general feedback, the potential for mistrust from the community just given the Oxbride withdrawal and the happenings that you alluded to there. what is AGIES doing to at least track that, detect that, and sort of incorporate that into your go forward with the trial and also how you are touching patients? And just secondarily, have you had any communications or plan to with regulatory just on the potential risks that have been sort of highlighted about running trials in the Africa site? Thanks so much and congrats.

Yeah, thanks a lot, Greg. It's an important question that you ask because The sickle cell disease community, I think, not surprisingly to anybody, has been through a lot. It's always been limited treatment options that have been available. And the community at large has certainly gone through a journey of drugs available and then not available in certain regions. And it's a real challenge. And an example of what we do is Sarah and I and others from the team just attended the annual Sickle Cell Disease Association of America meeting in Atlanta. And it was a chance for us to listen, most importantly, and hear what's on their mind, what their concerns are, how they think about treatment options in the future. And again, just to echo what I'm very proud of is we have always looked to maintain high touch with the community. And an example of that goes all the way back to when we designed the Rise Up trial, we very deliberately involved members of the sickle cell warrior community. And the input that we got was not just in the trial design, inclusion, exclusion criteria, but very importantly, how to appropriately recruit for the trial. And now you've seen the results of that. It recruited beautifully. And then hopefully when we get to the point of commercialization, we're leaning on that community to guide us in that regard as well. So I think the main message about trust is, you know, we try to be very visible, we listen, we listen without bias, and we make sure that the community sees their fingerprint on what we do based on the input that they've provided.

Yes, and then to add to that in regards to going forward with the trial, so we continue to, you know, it's a phase three trial, so obviously we do monitoring of data as we go along. We do all of our standard procedures to make sure that we continue to execute well on this trial, and we'll continue to watch carefully as this trial evolves. And in regards to potential risk for sickle cell disease, specifically with running clinical trials, You know, it's a tough, devastating disease in which patients are suffering from a ton of comorbidities, and it's a deadly disease. So there's always challenges when you run a trial like this, but it speaks to the unmet need in this patient population. So while these trials are challenging and difficult, there's such unmet need in this patient population that we really hope to be able to deliver

drug that can be meaningful for the patient community and treat the fatality of the disease just maybe one more point on this to drive it home is Sarah and I also had a call with with members of the sickle cell disease warrior community actually part of the advocacy group that I just talked about and on that call there were seven members of the community and among that three of them are were in crisis or recently had a crisis. And we walked away with a sobering reminder about just how serious this disease is and how desperate the community is for new therapeutic options. And it should be plural form. We always cheer for progress from everybody because this is a disease that needs multiple options.

Thanks so much, Ken.

You're welcome. One moment for our next question. Our next question comes from Eric Schmidt from Cantor Fitzgerald. Your line is open.

Thanks for all the updates and for taking my question. Just sticking with this topic of the unfortunate withdrawal of Voxbrita about a month or so ago, what have you learned scientifically or what kind of thoughts do you have scientifically with regard to the mechanism of that drug and how it relates or doesn't relate to the PVAD and how it sort of

um maybe influences your chances of success in the ongoing study thank you um so thanks for the question um well as you know bryta has a very different mechanism of action and we feel you know i should start like we really feel sad about what happened and to brian's earlier point it's it's a sad circumstance right because this patient community really has barely any options. So we're sad to see this. It is a very different mechanism of action. The clinical trials were set up differently as well. So I think that we don't know what happens beyond what has been publicly declared. But then focusing on our trial, our drug works very differently and has that multimodal approach to potentially treating sickle cell disease. So we do reduce 2,3-DPG and increase ATP, and we think both of these components can interplay and be important to avoid sickling and to improve hemolysis and thereby the anemia component. So very different mechanism of action than Oxbrisa, which then also, of course, translates into the clinical data that we have seen so far with a Phase II clinical trial data set that was very robust. a placebo-controlled trial, and that mechanism of action has translated into us demonstrating an improvement on hemoglobin and then also observing that positive trend for hemolysis and VOC reduction. So we are excited to continue to progress the drug forward in this history.

Thank you. One moment for our next question. Our next question will come from Chris Raymond from Piper Sandler. Your line is open.

Thanks for taking the question and congrats to you guys. Maybe just another question with regard to the Exbrita situation. I know you talked about engaging the sickle cell community, but this is a question that's come up with investors a lot, and I'm not sure if there's a real good answer here, but do you have a sense as to how the regulatory perspective has changed on this situation? There's some debate that perhaps this made it raise the bar, and then another debate that perhaps it's actually lowered the bar in terms of another therapy on the market. Just any sense there for how regulators might be reacting to this?

Thanks for that question, because I think Brian actually touched upon it. With the poster that we presented today, in 2021, which was a trial design or phase three. From the get-go, we had a very different clinical development approach plus a regulatory approach than the pathway that OXBRITA followed. So OXBRITA had an accelerated approval by demonstrating hemoglobin improvement at the time of submission and then had to follow on studies to further demonstrate clinical benefits. Our goal from when we first designed this trial is to deliver a treatment that at the end of the clinical trial can speak to clinical meaningful benefit, meaning hemoglobin plus and sickle cell pain crises reduction. So based on what happened, we have not changed our approach to our clinical design or our approach to the regulators. As I mentioned earlier, for any data package you submit, it's always a collaboration with the regulators after they review the first package, and then they'll ask us more questions, and ultimately they get to decide on the ultimate benefit risk.

Thank you. One moment for our next question. Our next question comes from the line of Tessa Romero from JPMorgan. Your line is open.

Good morning, Brian and team. Thanks so much for taking our question. So switching gears a little bit to thalassemia, you outlined this morning several patient groups in your slide deck that are part of your initial launch focus for pyrokine. Are you able to provide a little bit more specific quantitative detail around how the epidemiology breaks out in terms of patient numbers in each of these three key target populations you mentioned? And how often are these patients generally seeing their healthcare provider across these three key groups? Thanks so much.

Thanks, Tessa. I'm just going to start by saying that you're making Sveta smile because, you know, we love the questions on sickle cell disease. We're very excited about the potential, with a potential launch scenario in 2026. But even closer is thalassemia, where we've consistently message that we're looking forward to this potential launch in 2025. So I'm going to let Sveta take over on your questions.

Absolutely. Thanks, Seth, for the question. We are very excited with the potential of having an approval for thalassemia next year and actively preparing for launch. When we think about thalassemia, truly it's an indication, it's a beautiful rare disease indication when it comes to commercialization for three main reasons. The first thing is that we know that there are 6,000 adults diagnosed with thalassemia in the U.S., and I'm going to underline diagnosed here because these patients are known and engaged to the healthcare system, and we know that that's the case because there are ICD-10 codes available, which allows us to effectively and efficiently deploy our resources when it comes to launch preparation. We talked a lot about sickle cell disease and the high-end meds need there, but that's also very, very true for thalassemia as well. The unmet need is known, and we continue to engage both with patients and physicians in our pre-launch efforts to continue to educate on the burden of disease. When it comes to which patients will be considered for our initial launch focus, first, as you mentioned, we believe that about 65% of the 6,000 patients will be our focus for initial launch. And these patients are three groups of patients. These are patients that are very actively engaged with the healthcare system. The first one is the transfusion-dependent patients who are going frequently for their transfusions and have an engagement with their hematologist. That depends on their transfusion frequency, but more or less you can say that they are seeing and engaged with the healthcare system probably on a monthly basis. The second group of patients are the non-transfusion-dependent patients who have already developed comorbidities. They require frequent monitoring and management. It depends on the specific patient population and the frequency there, but we know both from claims data and our initial count profiling that these patients are relatively regularly seen, and they will be considered for management and further monitoring as well. And the third part of the patient population, which comprises the 65%, are the non-transfusion-dependent patients who are experiencing debilitating fatigue. It's impacting their daily life, and they will be seeking for a potential treatment option as well. We haven't provided specific details on this patient population, but as the launch progresses, we'll be providing additional information as well.

And I'll just add, too, I mean, Sveta, with all of her rare disease launch experience, is the first to remind us that launch sometimes is a sort of odd term because it's not a point in time. It's a continuum. So even on this guidance with the sequencing, if we could say it that way, of segments, will continue. And Sveta is constantly working on keeping the team ahead of segment one, segment two, et cetera. And we expect to be – you know, progressing for the long term in thalassemia and then again, hopefully in sickle cell disease as well.

Okay, great. Thanks so much for taking our question.

You're welcome. Thank you. One moment for our next question. Our next question will come from Divya Rao from TD Catlin. Your line is open.

Good morning, team. This is Divya on for Mark. Thanks for taking our question. One, to stay on thalassemia, would you be able to discuss how you're thinking about timing and design of the pediatric trials now that we have at least initial data or the top line data from the kids trial in PKD. And then our second question is, the initial data with Tebapivet and MDS, it obviously showed a little bit of signal, but it was relatively modest for the five-meg dose. Could you talk about what you think the bar for success is for the Phase IIb now that you're looking at, you know, dose levels that are higher than the initial dose tested? Thank you.

Thanks, Divya. So for thalassemia, the pediatric trials, yes, so indeed we are very, very proud of the first PKD pediatric trial in which we were able to demonstrate that some children experienced transfusion independence. So we're very pleased to see that because that's definitely clinically meaningful. For the timing and the design of the trial, so we also now have the benefit-risk profile in the thalassemia adult patient population, so you can expect a similar approach from us as what we have taken for PKV. We have not gone into further detail on the timing of when we would initiate, so that more to come at a later time point. In regards to MDS, yes, we did meet our pre-specified for the Phase IIa in which we observed 40% of transfusion-independent in the patient population we had enrolled. And to your point, we did learn there that the PK in MDS patients was different than what we had observed in healthy volunteers. So that, of course, led to changes for our Phase IIb. And as you see, we now have moved forward with the phase 2b testing higher doses, three higher doses, to be able to hopefully strengthen the observations that we had observed and are focused on transfusion independence in that trial and eight-week or more transfusion independence based on clinical advisory feedback that we received. So are excited to progress that trial and more to come.

And we are... We're very excited about the potential in MDS. I know folks pay attention to others who are in this market, and we took note this morning of the continued progress that we see with Revlazol. And it's a rapidly growing market. There is very high unbent need. It's similar in a way to sickle cell disease in that multiple therapeutic options will be the answer. And we're very proud of the fact that we have a very differentiated mechanism So this is an important step for us to be able to start the Phase 2B.

Thank you. One moment for our next question. Our next question will come from the line of Alex Ranahan from Bank of America. Your line is open.

Hey, guys. Thanks for taking our questions. Two from me. First, on the thalassemia launch prep, given it is a continuum, as Brian said, I wonder if you have a sense as to how quickly payer access come online? And would you say payers are fairly aware of Medipivac's clinical profile and its unmet need, or maybe some more work to do there? And then on the upcoming full readout for Energize T, should we expect any additional efficacy data from the readout beyond what was shown in the top line? I guess, where would you direct people's attention in the next update? And it seems like Ash is probably the next most likely venue, right? Thank you. Thank you.

Thanks, Alec. And so Sveta can start with the question on the payers and the thalassemia launch, and then Sarah can take over with energized tea.

Absolutely. Thanks, Alec. It's a very good and relevant question. So from a payer perspective, probably as you've seen from the slides and what we communicate today, the market access is a core pillar in our launch preparation. Our market access team is already engaging with payers on disease state education. When you look at thalassemia and you put a pair lens on it, it's a rare disease. There is a relatively low awareness of the disease, so we are definitely educating on the disease. But on the positive side of it is that it's a rare disease, and we don't expect that to be high on the payer radar for management as well. So the team is preparing for launch. I must say we've had an excellent outcome in our access efforts from PK deficiency. We have a very strong team, and we continue to see the same success and progress moving forward with the Leukemia.

Great. And then, Sarah, for Energize-T?

Yes, for Energize-T. So, in our press release, you know that we've declared our primary endpoint plus one of the secondary endpoints. So, you can expect from us typical to how we do all of our Phase III readouts and intend to treat analysis with the details around key secondary endpoints as well in the safety overview. Indeed, we're hoping to be able to present at an upcoming medical meeting. ASH is currently not available yet. So, you know, abstracts will be released on November 5th. So, we are eagerly waiting for that as well.

Thank you. One moment for our next question. Our next question will come from the line of Salvein Richter from Goldman Sachs. Your line is open.

Hi, this is Lydia on for solving. Thanks so much for taking our question and congrats on all the progress. I'm just two quick ones from us. So, on sickle cell now that enrollment is complete are able to provide any details on the number of baseline. And then just on can you just discuss when you plan to share data from the face to be and just remind us what will be included with this update. Thank you so much.

So, for sickle cell disease, we do not present baseline characteristics. We typically tend to present everything when we release the top-line results. So, nothing to come before we provide the full data readout. And then, in regards to TEP-APIVAT and the MDS Phase IIb, we have obviously now met our corporate milestone for this year. So, we are looking forward to provide more detail and timing on the rest of the trial next year.

Thank you. One moment for our next question. Our next question will come from the line of Andrew Behrens from Leerink Partners. Your line is open.

Thanks. Two for me. On 946, I think you dose some patients in the phase 2A trial higher than the 5 milligrams. If that's correct, will we see those data presented somewhere? And can you remind me of how much headroom you think you have on dosing before you might hit a DLT? And then I think this was touched on a bit, but we've heard that there was a problem with sepsis and malaria in the African trial sites, and some investors think that this was related to problems in conduct at those sites. I think your trial is at some of those sites, and can you give us some color on what's being done to ensure that a similar problem doesn't occur? Thanks.

Thanks, Andy. I'm going to let Sarah go, but I did want to first say you asked in terms of 946, and we're practicing on our end to say Tebapivac. We're very proud of the the new INN that we have for our second more potent PK activator. And Sarah, you want to start with the 2A?

So the phase 2A tested the 5 milligram dose, and so we did not test higher doses in that 2A. So right now, the higher doses that are being tested is in the 2B portion of the trial, which is 10, 15, and 20 milligrams. In regards to when I expect to hit the DLT, I don't know, because we haven't gathered the data yet. So the data will accrue over time, and then we'll see if we observe anything that makes us not want to further explore a certain dose. So more to come on that. In regards to what you asked for metapivus and sepsis and malaria observed in the OXBRITA trials. Malaria is endemic in certain regions of the world. We have part of our trials are indeed conducted in Africa as well, but we have a very good geographical distribution across the board within RiseUp, so we are excited about that. The observations that have happened on Oxbrisa are not observations that have happened on hydroxyurea, for instance, that have been observed in Africa.

so i think our data will accrue over time and and we'll we'll observe when we have the the final trial date okay thank you thank you and this concludes our q a i'll now turn it over to brian for any final remarks all right thanks a lot victor and thank you very much everyone for participating in today's call it is clear this is a very exciting time in agios we We truly believe that we're poised to deliver transformative new therapies for patients and to create significant long-term value for shareholders. So thanks again, and we look forward to speaking with you again soon.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone have a great day.