Agios Pharmaceuticals, Inc. Aktie

Good morning, and welcome to Agios Pharmaceuticals Second Quarter 2026 Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Agios' request.

I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals Second Quarter 2026 Financial Results and Business Highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com.

Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

On the call with me today from Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions.

With that, I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining us. Before we review our second quarter results, I'd like to take a step back and highlight the strong position from which Agios is executing as we continue advancing toward our goal of building a multibillion-dollar rare disease business.

We are executing against multiple drivers of value creation, including the launch of AQVESME in thalassemia, the potential expansion of Mitapivat into sickle cell disease and a pipeline that continues to grow through both internal innovation and disciplined business development.

During the quarter, we further strengthened our portfolio with the addition of cevidoplenib, a next-generation, highly selective oral SYK inhibitor that expands our rare hematology franchise into immune thrombocytopenia or ITP. We also advanced AG-236 into an operationally seamless Phase II/III program in Polycythemia Vera, adding another potential growth driver within hematology. Beyond hematology, AG-181 continues to progress, and we expect Phase Ib proof of mechanism data in phenylketonuria patients in the second half of the year.

We also continue to apply a disciplined approach to portfolio management, making focused investment decisions and directing resources toward opportunities with the greatest potential to create value for patients and shareholders.

As you'll hear throughout today's call, our progress this quarter reflects the strength of that strategy, combining commercial execution, pipeline advancement, disciplined capital allocation and strategic business development to position Agios for sustainable long-term growth.

Turning to our second quarter highlights on the next slide. We delivered a quarter marked by strong commercial performance, meaningful pipeline progress and continued portfolio discipline. First, we delivered sustained commercial momentum with $44.7 million in total net revenue, including $40.9 million in the U.S. and 442 cumulative AQVESME prescriptions for REMS-certified physicians.

Second, we further diversified our pipeline through the in-licensing of cevidoplenib, a next-generation, highly selective oral SYK inhibitor for ITP, progressing towards Phase III and strengthening our rare hematology pipeline. Third, we advanced Mitapivat toward a potential new indication in sickle cell disease. During the quarter, we received FDA acceptance of our sNDA with priority review and were assigned a PDUFA goal date of November 1, bringing us one step closer to delivering a first-in-class medicine in an area of significant unmet need.

And finally, we ended the quarter with approximately $1 billion in cash, cash equivalents and marketable securities, providing financial flexibility to support both commercial growth and pipeline progression. Overall, we entered the second half of 2026 with strong commercial delivery, a more diversified pipeline, an important near-term regulatory catalyst and the capital position to execute on our strategy.

With that, please advance to the next slide, and I'll turn the call over to Cecilia to discuss financials.

Thank you, Brian. Next slide, please. Turning to our second quarter financial results. Total Mitapivat net revenue was $44.7 million, including $40.9 million in the U.S. and $3.8 million outside the U.S. Cost of sales for the quarter was $3 million and research and development expense was $100.8 million compared to $91.9 million in the second quarter of 2025, primarily due to an increase in-process research and development $15 million, driven by a $25 million up-front payment associated with the agreement with Oscotec.

Selling, general and administrative expense was $51.5 million compared to $45.9 million in the prior year period, reflecting an increase in commercial-related activities as we executed launch of AQVESME in thalassemia. Net loss for the second quarter of 2026 was $100.7 million compared to a net loss of $112 million for the second quarter of 2025.

We ended the quarter with approximately $1 billion in cash, cash equivalents and marketable securities, which we believe provides financial flexibility to support commercial execution, advancement of our pipeline and continued investment in opportunities to create long-term value.

Turning to our outlook for 2026. We continue to expect approximately $45 million to $50 million from PK deficiency revenues in the U.S. Full year operating expenses are expected to remain approximately flat versus 2025, excluding the $25 million upfront payment associated with the cevidoplenib in-licensing transaction recognized in the second quarter and include investments to prepare for a potential sickle cell disease launch aligned with our November 1 PDUFA date.

Our priorities for the remainder of the year remains clear: driving the AQVESME launch, preparing for potential sickle cell disease approval, advancing our pipeline and maintaining financial discipline.

Please advance to the next slide, and I'll turn it over to Tsveta to cover commercial highlights AQVESME U.S. thalassemia launch progress.

Thanks, Cecilia. Next slide, please. With 6 months of launch experience now behind us, we are encouraged by the underlying drivers of performance. What we have seen so far continues to reinforce our confidence in the long-term AQVESME opportunity in thalassemia. Importantly, the strong execution across our commercial and patient-focused organization further strengthen our confidence in future launch opportunities.

In the U.S. performance reflected continued growth in thalassemia demand and solid commercial execution. Net revenue in the quarter reflected approximately $5 million of one-time benefits related to stocking in thalassemia, along with modest gross to net favorability. We continue to expect gross to net within our previously guided 10% to 20% range with quarter-to-quarter variability.

Outside the U.S., we delivered $3.8 million in net sales, reflecting anticipated demand for thalassemia in Europe following approval and continued consistent early demand for thalassemia in the GCC. As we've been seeing consistently across rare disease launches, the shape of new patient starts naturally moderates as adoption broadens beyond the earliest wave of highly motivated patients and prescribers. We continue to expect quarter-to-quarter revenue variability, reflecting order timing, inventory movement and gross to net dynamics.

Next slide, please. I'm very pleased with the continued U.S. launch performance of AQVESME. During the second quarter, we generated an additional 200 prescriptions from REMS-certified physicians, bringing cumulative prescriptions to 442 as of June 30.

As a reminder, this metric captures unique prescriptions for patients with completed start forms from REMS-certified physicians and serves as an early indicator of underlying demand. Importantly, the underlying launch dynamics remain healthy. While demand continues to come from highly motivated patients, we saw a growing proportion of non-transfusion-dependent patients in the second quarter, a profile consistent with the therapy moving beyond the earliest, most motivated cohort of transfusion-dependent patients.

We continue to see strong conversion from prescription to treatment initiation. Time to start is naturally trending towards our anticipated 10- to 12-week range as adoption broadens across the NTDT population where treatment decisions often involve more deliberate clinical discussions and patients may have less frequent interactions with the health care system.

Access continues to strengthen, and we now have approximately 75% of thalassemia lives covered under payer policies. Additionally, physician REMS certification continues to progress in step with prescribing activity, and it's not a barrier to patient access.

As the launch matures, prescriptions with completed start forms become a less informative measure of performance, whereas revenue increasingly reflects both new patient starts and persistence on therapy. For that reason, in anticipation of a potential FDA approval for Mitapivat in sickle cell disease, we plan to discontinue reporting prescriptions from REMS-certified physicians after the third quarter and transition to revenue as our primary measure of commercial performance. Upon a potential sickle cell disease approval, we will assess the most meaningful metrics to communicate the progress and outlook of the broader Mitapivat franchise.

Next slide, please. I wanted to take a few moments to highlight thalassemia launch considerations in the second half of this year. The first half reflected a distinct initial phase of the launch. The first quarter benefited from a strong prelaunch anticipation and momentum built in the period leading to approval following the more than 3-month PDUFA delay.

Second quarter demand continues to reflect adoption from highly motivated patients and prescribers with time to treatment initiation beginning to approach our anticipated 10- to 12-week average at launch maturity. Looking ahead, we expect the shape of the launch to naturally evolve. Adoption is expanding into a broader non-transfusion-dependent population where patients are typically seen less frequently and treatment decisions may take more time.

As the patient mix continues to shift towards non-transfusion-dependent patients, we expect time to treatment initiation to move well within the 10- to 12-week range we consistently discussed. We are also mindful that the first cohort of patients who initiated therapy in the earliest months of launch is approaching 6 months of treatment, a natural point at which physicians assess clinical response. This is an important part of the treatment journey, and it is the period during which we will begin to build a broader real-world understanding of how physicians and patients evaluate response and integrate Mitapivat into long-term care.

Taken together, these dynamics reinforce that AQVESME is delivering a healthy launch that is successfully progressing beyond the initial wave of adoption and into a broader expansion phase. As we move through the second half of the first launch year, our focus remains on expanding reach across the thalassemia community, expanding adoption in the non-transfusion-dependent segment while continuing to add new prescribers. We remain highly confident in the long-term opportunity for AQVESME and in our ability to build a durable growing thalassemia franchise over time.

Please move to the next slide. We are actively preparing for a potential sickle cell disease launch in the U.S. and are encouraged by both the commercial opportunity and the unmet need we see in this community. Our initial launch focus is on approximately 25,000 patients who are actively treated or in need of therapy today. We believe that population alone represents a meaningful opportunity for Mitapivat with potential to expand beyond the initial segments over time.

Importantly, we are leveraging the capabilities, relationships and insights we have developed through the thalassemia launch while continuing to invest in market access, education and community engagement activities ahead of the PDUFA goal date. Pending FDA approval, we believe these efforts position us well to support a successful launch and to deliver Mitapivat to patients in need of innovative treatment options.

Please move to the next slide. And with that, I will hand the call over to Sarah to cover key R&D highlights from the quarter.

Thank you, Tsveta. Turning to our pipeline on the next slide. Following recent portfolio prioritization decisions, we remain focused on advancing a diversified rare hematology portfolio with opportunities across multiple stages of development. Mitapivat continues to anchor the portfolio with approved indications in pyruvate kinase deficiency and thalassemia and a potential accelerated approval in sickle cell disease later this year.

During the first half of this year, we achieved an important milestone with thalassemia approvals in Europe and the UAE, completing regulatory approvals across all 4 priority launch geographies following prior approvals in the U.S. and KSA. Since first quarter results, we filed and received acceptance in the U.S. for the Mitapivat sNDA in sickle cell disease with priority review and a PDUFA goal date of November 1.

We remain committed to bringing Mitapivat to patients with sickle cell disease and recently dosed the first patient in REIGNITE our Phase III confirmatory trial, an important milestone in advancing the program. We also strengthened the pipeline during the quarter through the in-licensing of cevidoplenib, a next-generation SYK inhibitor that expands our reach within rare hematology and adds a compelling opportunity in immune thrombocytopenia.

Beyond Mitapivat and cevidoplenib, we continue to invest in future growth drivers, including AG-236 in polycythemia vera and AG-181 in Phenylketonuria. Taken together, we believe the pipeline reflects a focused allocation of capital and resources towards programs where we see the greatest potential to create long-term value for patients and shareholders.

Please move to the next slide. As we discussed when we announced the in-licensing of cevidoplenib, our interest in the program is grounded in its potential to address some of the limitations that have historically constrained the SYK inhibitor class. Cevidoplenib was designed to optimize both selectivity and pharmacokinetics, supporting sustained target inhibition while maintaining a tolerability profile suitable for chronic use. The clinical data generated to date are encouraging and support this design rationale, demonstrating dose-dependent activity, no dose-limiting toxicities through Phase II and evidence of durable platelet responses.

Taken together, these data support the rationale for advancing cevidoplenib as a next-generation highly selective SYK inhibitor. We're looking forward to engaging with the FDA in the coming months to align on progression to Phase III.

Next slide, please. At EHA in June, we were pleased to share a broad body of data across both thalassemia and sickle cell disease that continues to strengthen our confidence in Mitapivat. Across the portfolio, we have 10 abstracts accepted, including the RISE UP Phase III study, which was selected for the EHA oral plenary session.

In sickle cell disease, RISE UP demonstrated hemoglobin responses consistent with the mechanism of PK activation with hemoglobin responders experiencing clinically meaningful improvement in sickle cell pain crisis related endpoints and fatigue. At EHA, we presented new data showing clinically meaningful reductions in transfusion burden and red blood cell unit transfused across the total trial population, exceeding historical experience with hydroxyurea.

Importantly, outcomes from the subgroup of patients with at least one transfusion in the 52 weeks prior to enrollment directly informed the treatment effect and powering assumptions for the ongoing REIGNITE confirmatory trial supporting accelerated approval. We also presented additional patient-reported outcomes data showing clinically meaningful improvement in how hemoglobin responders feel and function, including reductions in physical pain.

In addition, 56-week follow-up data from the SATISFY Phase II investigator-sponsored trial in related membranopathies showed robust hemoglobin response rate and mean hemoglobin improvement as well as suggesting decreased iron burden. In non-transfusion-dependent thalassemia, we shared open-label extension data showing that 60% of patients continuing on Mitapivat met criteria for hemoglobin response and 60% of patients who switched on to Mitapivat in the open-label extension achieved hemoglobin response.

Additionally, subgroup analyses indicate high hemoglobin response rates for non-transfusion-dependent patients with high baseline hemoglobin levels, indicating that less severely anemic NTD patients achieved improvement in hemoglobin levels and fatigue. These data were received very favorably by the thalassemia community and reinforced the value of Mitapivat in non-transfusion-dependent patients, which comprise the majority of the diagnosed adult patients in the U.S.

Taken together, these data reinforce the consistency of Mitapivat's profile across indications and further strengthen our confidence in the long-term potential of Mitapivat in hemolytic anemia. While we continue to advance and expand the Mitapivat opportunity, we're also focused on building the next generation of potential growth drivers within rare hematology. AG-236 is an important example of that strategy.

Next slide, please. Following encouraging Phase I data, we're advancing AG-236 into an operationally seamless Phase II/III development program in polycythemia vera. What continues to differentiate AG-236 is its potential profile with an evolving treatment landscape. The molecule demonstrated hepcidin induction through day 57 and favorable effects on iron parameters in extended follow-up, supporting the potential for an every 6-month dosing regimen without titration.

The Phase II portion of the study is designed to identify the optimal therapeutic window across multiple dose levels while enabling efficient progression into the registrational portion of the program. More broadly, the seamless Phase II/III strategy reflects our commitment to disciplined execution while advancing development as efficiently as possible with Phase II initiations planned for the second half of 2026. We believe AG-236 has the potential to further diversify our rare hematology leadership and contribute to our long-term growth beyond Mitapivat.

With that, please move to the next slide, and I will hand the call back to Brian for closing remarks.

Thank you, Sarah. Next slide, please. As we look across the business, we continue to make meaningful progress against the strategic priorities we established for 2026. We're building commercial momentum with AQVESME in thalassemia, reaching 442 cumulative prescriptions as of June 30. We're advancing Mitapivat toward a potential approval in sickle cell disease, which represents an important opportunity to expand our PK activation franchise and a potential next growth driver for the company.

We're also advancing AG-236, our siRNA TMPRSS6 inhibitor for polycythemia vera into an operationally seamless Phase II/III program expected to begin in the second half of this year. And during the quarter, we further diversified our portfolio through the addition of cevidoplenib, a next-generation, highly selective SYK inhibitor in ITP progressing toward Phase III.

Importantly, our progress this year reflects both execution and discipline. We're investing behind the opportunities where we believe Agios can have the greatest impact for patients and create the strongest long-term value for shareholders.

Next slide. Taken together, we entered the second half of the year with a growing commercial foundation, a meaningful near-term regulatory catalyst and an increasingly diversified pipeline and the financial strength to execute on our strategy.

Next slide, please. Today, Agios is anchored by a growing commercial business and supported by a pipeline spanning multiple development stages and disease areas. Across the portfolio, we are pursuing opportunities where differentiated biology, meaningful patient unmet need and disciplined execution can support durable long-term growth. Collectively, these opportunities represent rare disease markets estimated at more than $10 billion in 2030.

Before we open the call for questions, I'd like to thank the entire Agios team for their unwavering commitment to patients and their continued dedication to executing on our strategy. Their passion, resilience and focus have been instrumental in the progress we've made this year.

And with that, thank you all for joining us today. Operator, we're ready to begin the question-and-answer session.

[Operator Instructions] Our first question comes from the line of Alec Stranahan with Bank of America.

Congrats on the really strong quarter here. Two questions from me. First, on time -- on treatment in the commercial setting, do you think the ENERGIZE studies are a good barometer here? Just trying to think about how the dynamic of patients potentially coming off therapy could play into second half sales?

And then, when you look at the time on treatment, did this change at all between 1Q to 2Q? Did it move closer or further away from that 10- to 12-week average range that you're setting out? And I guess, are you starting to see any repeat prescriptions under the REMS program at this point?

Thanks, Alec. So 2-parter. So Tsveta, you can take the first one. Actually, you'll take both of these, on the time on treatment and ENERGIZE as an analog. And then the second one, I think, Alec, you're asking about not time on treatment, but time to treatment from the demand to initiation. So Tsveta, do you want to take that?

Absolutely. We are very pleased with the strong initial start of the AQVESME launch, Alec. And as we mentioned, we had in total 442 prescriptions from REMS-certified physicians for the first 2 quarters of the launch.

As we look ahead, in the first couple of quarters, we benefited from faster-than-anticipated time to treatment initiation. So it was faster than the 10 to 12 weeks, given that we have prescriptions coming from highly motivated patients and physicians. Keeping that in mind, we will start kind of the natural -- to reach the natural point of the 6 months at which physicians and patients are going to evaluate benefit for the product and continuation rate, but that's going to be more in the second half of the year, and we will monitor that closely.

Currently, what we see from the market is a very kind of strong feedback and a positive feedback from the community. So we expect continuation rates to be in line with the ENERGIZE study. And we'll continue to monitor that, but the product performance is very strong in the market.

When it comes to time-to-treatment initiation, we start seeing that as we penetrate into the NTDT settings to move closer and closer to what we initially expected, the 10- to 12-week range. And as we move into the second half of the year, we will continue to monitor that, but we expect to be well within the 10 to 12 weeks given the strong penetration in the NTDT setting.

And your third question was around repeat prescriptions for the REMS. When we look at that, of course, we have patients who have been on therapy for multiple months. So we do start seeing the repeat prescriptions and patients and physicians are going through the ramp process very, very smoothly.

Our next question comes from the line of Andrew Berens with Leerink.

Congrats on the strong execution. I guess I just want to expand a little bit on the persistence rate since it's so important going forward. Is there anything that you can tell us about maybe the expanded access program at all, what the experience will be like for these patients in the real world?

And then the other thing that's obviously very important is going to be a sickle cell label, whether it's on AQVESME or PYRUKYND. What factors will go into that? And is there anything you can tell us in these early days ahead of the November 1 PDUFA that give us confidence that you won't have a REMS or have to potentially reduce the pricing for AQVESME in thalassemia?

Thanks, Andy. And I will just say again, and thanks for the comments about the strong quarter. I am really pleased and proud with the continued execution from Tsveta and the team. I think on the persistency, Andy, maybe we'll start with Sarah just reflecting on the clinical trial, the open-label extensions and what we saw because it still is early days for us to quantify persistence, but we always look at the trials and OLEs as a proxy.

Yes. Thanks, Brian. And I think, Andy, here, we can really look at the open-label data that we presented at EHA recently as well. So, as you know, we have very high continuation rates for people who finish the clinical trials and then go into the open-label extension. And now we have the benefit of being able to have followed them for a period of time post randomized controlled trial.

What you see there is a good maintenance of response. So patients do continue on the drug. And you see that maintenance of hemoglobin and maintenance of antihemolytic response and people feeling good. Another point there, what was exciting to see at the EHA data was that people with higher hemoglobin also had good response to the treatment, which is important, of course, as we continue to expand the patients we capture in the launch for the non-transfusion-dependent patients. And so yes, so I think the clinical trial data is actually the best way to look at that question right now.

Yes. And I just want to add that we -- I've been spending a lot of time with clinicians in the field, had the opportunity to hear their feedback on the EHA data. And as we enter into the second half of the year and we start experiencing kind of the real-world evaluation of persistency, I'm very confident that we will see the repetition of what we see in the clinical trials in terms of continuation rate for 6 months.

And then in regard to...

I was just going to ask, can you give us a number, a percentage that you saw in the open-label extension study of patients who stayed on?

So for ENERGIZE, we had like an over 90% continuation from the clinical trial. In regards -- yes, and then, of course, it always -- as time continues, clinical trials are a burned, so it drops a little bit, but it's very, very good persistence, both for PKD, for thalassemia, for sickle cell disease in the clinical trial. What was interesting there is also the response rate with longer exposure, which is important for thalassemia from -- in the early 40%, we had some non-responders convert into responders. So we got to a 60% response rate there. So the clinical trial data is very good.

And we know, obviously, that's an important metric for us going forward. And -- but we're still early days. We're -- this is our second full quarter of launch, which in a way, matches the period of time for the ENERGIZE trial. So we'll continue to monitor and, of course, implement appropriate patient services support to help patients continue on therapy.

And Andy, maybe you can just repeat the second part of your question.

Yes. Just -- I mean, obviously, I don't think anyone expects sickle cell pricing to be as resilient as thalassemia or PKD. So it really depends on whether you get a sickle cell added to AQVESME or PYRUKYND. What do you think is going to drive that decision? And any insights now that we're several months away from the PDUFA about which brand sickle cell may be added to if approved?

Yes. So the PDUFA is indeed November 1 priority review. So we're very excited about that. We have not further discussed which brand name is going to be used. But as you know, the clinical trial data looks very good. We did not have the hepatocellular injury observed in the sickle cell disease patients. So therefore, it may not warrant the REMS. Either way, our teams are ready to execute the launch with or without the REMS, so more to come.

Absolutely. And as always, we'll provide more specifics at the time of launch once we have the label, we'll price the product for that indication and across the portfolio to maximize the opportunity based on the clinical data and of course, the market environment at the time.

I must say we are in a very strong position given that it's our third indication. There is a very high unmet need in sickle cell disease. And we do have a very strong market access team. I'm very proud of the progress they made in thalassemia with the payer policies, and we'll continue to learn and build from here.

Congrats again on the strong quarter. It looks like it's going to continue.

Our next question comes from the line of Gregory Renza with Truist Securities.

This is [ Supath ] on for Greg. Congrats -- let me add the congrats to the team too on an excellent quarter. So my question is 2 parts as well, if I may. So as we enter the second half of 2026 and we move beyond the initial wave of highly motivated transfusion-dependent patients, how should we think about the run rate of new patient starts, particularly in the broader non-transfusion-dependent population? And the second part is, where are you at in terms of growth? I know it's favorable this quarter. Where you are within the range of 10% to 20% expected target, now you're at 75% of covered lives. Thanks and congrats again.

So, Tsveta, maybe you can start with -- and I think you said it the right way as we extend further into the broader reach in the NTD population. Tsveta, do you want to take that, and then we'll do gross to net separately?

Absolutely. I'm very pleased with the progress so far. We are really seeing a very healthy start of the launch, both from penetration into the community setting where the majority of prescribers are as well as the penetration in the NTD setting, which is the bigger commercial opportunity. As we mentioned, in the second quarter, we added 200 prescriptions from REMS-certified physicians.

As we move into the second half of the year, prescription growth and revenue growth are not going to be directly correlated on a perfect basis given that we're moving into the more mature phase of the launch. And revenues really also depend on time to treatment initiation, REMS onboarding and persistency as we've discussed.

Moving ahead, as we move into the NTDT setting, we expect the time to treatment initiation to move well into the 10 to 12 weeks, given the fact that these patients have less frequent visits to the health care professionals and they'll need to go through the insurance verification as well as the REMS process as well. But we are really, really encouraged by the rate of patient adoption, the progress that we are making, the way the patients are converting and staying on therapy at this part of the launch and most importantly, the really positive feedback from what I'm hearing from the clinicians on the product profile in the real world.

Great. And then, [ Supath ], I think the second part of your question was around the 10% to 20% guidance that we've given on gross to net. Cecilia, do you want to comment here?

Yes. So we expect that to continue to be in that range of 10% to 20% as we've guided before. There's always some quarter-over-quarter variability. But on aggregate, that's the range we still expect to see.

Our next question comes from the line of Marc Frahm with TD Cowen.

Thanks for completing the kind of pushes and pulls on turning a TRx into actual revenue. And of course, there will be some drop-off of patients on kind of the back end starting in the second half. But do you view that kind of 200 patients at the top of the funnel as now kind of a sustainable rate? Or does that still reflect a little bit of that bolus that you kind of talked about for Q1 of the backlog of REMS certifications and kind of the highly, highly motivated patients?

Yes. Maybe I'll start, and I'm going to turn it over to Tsveta. I think, Marc, a good way to think about a comment we've made several times in terms of engaged patients, engaged clinicians is that's a gradient. And we know that we're still on the front end of that gradient. As we -- and Tsveta just commented on it, too, as we move further into the NTD population, by definition, these patients tend to have less frequency of clinical interactions. And so that's essentially the dynamic that we're up against. Tsveta, what would you add?

Yes. No, absolutely. And as I also mentioned in my prepared remarks, looking into entering a new phase of the launch in the second quarter, we expect prescription growth and revenue growth not to correlate directly in every single quarter due to the time of treatment initiation, the patient conversion rate, persistency and kind of inter-quarter ordering variability. That's why we will actually move away from this initial indicator of demand after the third quarter, which is prescriptions to something that we believe is more reflective of the underlying health of the business, which is going to be revenue.

When you think about how the first half is going to transition into the next phase of the launch, which is the second half, in the first half, in Q1 and partially in Q2, we really benefited from the early adopters, highly motivated patients and physicians, the delay in the PDUFA, which created the anticipation of the launch in the -- for the launch and patients and physicians were ready to start as quickly as possible.

As we move into the second part of the launch, what I'm looking for is really the underlying dynamics of the launch, which allow us to further penetrate into the community setting, a very strong adoption into the NTDT setting across alpha and beta thalassemia patients and moving into that more steady state of 10 to 12 weeks treatment initiation. So we are very encouraged of the way the launch is going and the way the team is executing.

Okay. That's all helpful. And then maybe just on the other end of the funnel, on the discontinuation rate. Do you view these initial kind of very highly motivated patients and clinicians that are using -- that we're starting therapy in Q1 and early Q2. Are those patients do you think more likely to stay on drug because of that motivation? Or are they perhaps the very hard-to-treat patients and maybe they'll have a somewhat higher discontinuation rate than kind of the long-term number might end up being?

As we progress into the next phase of the launch, we'll provide more color on to what we see in the real world. My suggestion for now and what we're hearing from the clinicians is that the core period in the clinical trials is a very good proxy for continuation, and we'll continue to learn more.

I'm very pleased with the payer policies that have been issued. They really allow a lot of flexibility for patients and physicians to make informed treatment choices on continuation. The policies are really managing -- for managing patients to clinical trial criteria or better. So let's use for now the clinical trial as a proxy.

Our next question comes from the line of Samantha Semenkow with Citi.

Let me add my congrats on the strong quarter. I'm wondering if you could just speak a little bit more to the dynamics of the clinical evaluation after 6 months of treatment that you were speaking on in your prepared remarks. What are your physicians viewing as acceptable clinical bar for continuing treatment? And is this 6-month clinical mark, is that pretty strict? Or is there some flexibility where it could vary when a physician would be looking to assess the clinical progress for a patient? And I have a follow-up.

Thanks. And this is another good one for Tsveta and also where we have important learnings from our experience already with PKD now over many years in terms of evaluation.

Absolutely. So there is a variability of how patients and physicians define benefit, and I'm going to use the word benefit because it quite often goes beyond what is defined as the primary endpoint in the clinical trials. Of course, for transfusion-dependent patients, both patients and physicians will look at transfusion reductions, both in terms of ability to expand the time between transfusions as well as reducing the amount of transfused blood and both of these aspects are important.

What we hear from physicians, and I had the opportunity to meet both with patients and physicians recently at the Cooley's Anemia Foundation meeting is they really do that on a patient-by-patient basis. A majority of them mentioned the 6 months, both driven by the fact that our clinical trials were within that time frame, but it's also a natural opportunity for them to evaluate initial benefit and they'll make decisions based on that.

Transfusion reduction in the TDT patients will be important. They are not necessarily going to stick to what was defined as a 50% reduction in the clinical study. It's going to be on an individual patient basis and if they want to continue on therapy as well and how they feel between the transfusions is also important. On the NTDT setting, they're going to look on improvement in hemoglobin. The 1 gram per deciliter is not like a hard yes or no.

They'll also look at the improvement in hemolytic parameters and very importantly, in the NTDT setting is how patients feel. The reduction in fatigue is a key driver both for patients and physicians to continue on therapy irrespective of the actual level of hemoglobin improvement. So we are very encouraged from what we hear from our customers and look forward to learning more in the second half of the year.

Great. And then just a second question about the evolution of the prescriber base. Are you seeing physicians write scripts for multiple patients that they manage? I'm wondering if there's any sort of, I guess, dynamic that you could share that you've seen over the first 2 quarters of launch.

Absolutely. When I look at our prescriber base, the most important thing for me is to look for breadth of prescribing because thalassemia, majority of the patients are managed in the community, and we don't have that much breadth across the therapy area. And I see a very, very strong breadth of prescribing across the country from different clinicians.

So I'm very pleased with the healthy start of the launch. We do have a small number of key opinion leaders who have written for more than one patient, and we continue to see prescriptions coming from these prescribers. And we expect that to continue. They do have a stable patient base, but really our opportunity is to continue to penetrate the community setting.

Our next question comes from the line of Eric Schmidt with Cantor.

Congrats on all the progress as well. And unfortunately, another question for Tsveta. Seems like she's on the hot seat today. So I just want to be clear about what's in the 442 cumulative prescriptions that you're reporting. Historically, I think you said those are for individual patients mapped to individual start forms and wouldn't include refills or anything like that. Is that still the case?

Absolutely. They are unique patient prescriptions. In a way that's kind of equivalent of a start form and it's written by a REMS-certified physician.

And I assume, Tsveta, you have some insight into how many refills have also been written thus far?

So yes, the refill rate continues as patients reach their second and third month of therapy. So the refills are continuing according to plan. So depending on the patients that have started and are progressing to the REMS, the refills are coming in. We are not providing a specific kind of refill dynamics and total patients on therapy. And as I said, moving forward, we will move away from start forms and really start focusing on revenue more because it takes into account all these dynamics that you're asking about, Eric; new patient starts, time to treatment, initiations, refills and continuations.

Okay. You anticipated all my questions. I've just got one left, which is conversion of patients from start forms to therapy. Do you have a sense of whether there have been many or any patients who have dropped out of the queue as they await therapy?

We have a very positive payer policies and we have market access kind of hurdles for now at the beginning of the launch, but I'm very pleased with that. Our fill rate, which is basically prescriptions to patients starting on therapy is very high and it's very much in line with other rare diseases. So nothing unanticipated there. So I'm very pleased with that very high conversion rate.

Yes. And Eric, I'll just add that this is again where our PKD experience, smaller scale, but the experience really comes into play because it's usually a time element, not necessarily a loss element in the translation from a start form to a patient starting on therapy. And again, we know with these NTD patients as we move deeper into that penetration, it could take longer, which is why the translational aspect of going from a start form to revenue gets harder and harder from your perspective.

Our next question comes from the line of Emily Bodnar with H.C. Wainwright.

Congrats also on the positive quarter. I'll ask on Europe sales for thalassemia. Were any of the 2Q revenues driven by Europe specifically? And how do you kind of think about ex U.S. revenue growth for the remainder of the year? And then maybe secondly, with the sickle cell disease PDUFA coming in November, are you expecting to launch by year-end? And should we be expecting any kind of initial revenues for the fourth quarter?

Thanks, Emily. Cecilia can comment on the European question, and then we can come back to the question about sickle cell.

Yes. So, Emily, the ex-U.S. revenue, so for this quarter is a combination of the consistent continued demand in GCC as we have like early access there as well as anticipated demand for thalassemia in Europe following the approval in May. I'd say the vast majority of our revenues are still expected to come from the U.S. for the upcoming quarters as we're still kind of ramping up the other regions, early access for both. So -- but we don't expect either one to be material contributors. And then the other question on sickle, again, given the PDUFA date being November, it wouldn't be a material contribution to our full year revenues for 2026.

And I will just add, Emily, we're enthusiastic about the opportunity of a priority review in November 1 PDUFA for sickle cell. And none of you will know this, but we're actually at a pretty important sickle cell KOL and community physician meeting. So the reason I bring that up is I'm really proud of the work that Tsveta and the team are doing to get ready for that launch, and we're certainly looking to amortize as much as we can from the progress we're making in thalassemia towards that launch as well.

[Operator Instructions] Our next question comes from the line of Salveen Richter with Goldman Sachs.

This is Lydia on for Salveen. Congrats on the progress. Could you just speak broadly to the current breakout between transfusion and non-transfusion-dependent patients and when you anticipate the non-transfusion population to make up a majority of patients on treatment? And then as a quick follow-up, once you reach that 10- to 12-week range, do you expect that to sort of be the run rate going forward?

Tsveta?

Absolutely. What we're seeing now is a growing proportion of the NTDT segment as we've always said and as anticipated. In the first quarter and partly in the second quarter, a significant proportion of the patients were the TDT patients, given they have more frequent interactions with the health care system and are in generally the more engaged patient population.

We've seen a significant growth of the NTD patients in the second quarter. We expect that to continue. And if you look at our breakdown of the -- our initial launch focus, we have about 4,000 patients that we are initially targeting and about 60% of them are the NTDT patients. So we'll continue to penetrate that segment. And we expect the 10- to 12-week average time to treatment initiations to stabilize and remain constant over time.

Our next question comes from the line of Tess Romero with JPMorgan.

So as a matter of quick housekeeping, can you just remind us what is the right way to think about the LOE for Mitapivat? And then second, to double-click here, what is the right way to think about how cumulative scripts for AQVESME should evolve from end of 2Q to end of 3Q? And then when might you be in a position to guide to revenues if script count will no longer be reported after 3Q?

Okay. Thanks, Tess. First one will be quick. Mitapivat, you could think of LOE as 2035 of composition of matter plus extensions. And there are additional potential for patent extensions beyond that. The second one, which, of course, for where we go from 2Q to 3Q will be directional. We're not giving specific guidance, but qualitatively, Tsveta, I think this will be similar to earlier comments you've made about further penetration.

Absolutely. As we look into the second half of the year, we're looking forward to continue to penetrate the NTDT segment. And as we know, these patients have less frequent visits to the health care providers. And with that in mind, we also anticipate time to treatment initiations to move into the 10- to 12-week range, which will be a key dynamic of the quarter.

As well we are reaching this important 6-month point of treatment benefit evaluation, and that's one of the main reasons we will start transitioning beyond Q3 into actually providing revenues rather than continued prescriptions. Very importantly, we have an important date, November 1, with the addition of the sickle cell disease launch. And once we have, hopefully, that launch, we'll provide more information of how we can characterize the evolution of the Mitapivat franchise across indications, but we will do that at the time of launch.

And Cecilia, Tess snuck in a third question about guidance and when, so do you want to comment on that one?

Yes, yes. So, Tess, as mentioned, also with sickle cell coming on board upon potential approval in November, we look into the appropriate time to provide guidance for the franchise going forward.

And our final question comes from the line of Luca Issi with RBC Capital Markets.

This is Shelby on for Luca. Maybe on the commercial preparation for a potential launch in sickle cell. I believe this has a higher Medicaid mix versus thalassemia and PKD. So one, is that correct? And two, how are you thinking about gross to net dynamics and net revenue per patient in sickle cell relative to your other existing commercial products? And also, does de novo competitive dynamic factor into your pricing approach at all? Any color there. Much appreciated.

Absolutely. We will provide definitely more specifics on pricing at the time of approval. And that's going to be driven by the label and the competitive environment at the time, and we'll continue to observe that moving forward. Of course, the sickle cell disease population has a higher Medicaid proportion and that by definition has a mandatory rebate of 23%, which will drive the gross to net to a higher level compared to PKD and thalassemia. But I can tell you, we are super excited about the PDUFA date and the team is ready for launch.

Ladies and gentlemen, at this time, I would like to turn the call back over to Brian Goff for closing remarks.

All right. Thanks, everyone, for your questions and for joining us today. Tsveta was in the hot seat today, which we quite enjoy. So thanks a lot for that. To close, we're really pleased with the progress we made in the second quarter. That includes delivering on continued AQVESME launch momentum, advancing Mitapivat toward a potential sickle cell disease approval, as we just discussed, strengthening our pipeline with cevidoplenib and AG-236 and maintaining the financial flexibility to execute.

So ultimately, we enter the second half of the year focused, disciplined and confident in our ability to build long-term value for both patients and shareholders. So thanks a lot, and we look forward to speaking with you all soon.

Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Agios Pharmaceuticals European Hematology Association 2026 Investor Webcast and Conference Call.

[Operator Instructions] Please be advised that today's call is being recorded. I would now like to hand it over to our first speaker, Morgan Sanford, Head of Investor Relations at Agios. Please go ahead.

Thank you, operator. Good morning and good afternoon, everyone, and thank you for joining us. We're pleased to host today's webcast in conjunction with the 2026 EHA Congress, where we are presenting a broad set of data across our portfolio. You can access the slides for today's presentation on the Investors section of our website.

Please note that we will be making forward-looking statements during this presentation. Actual results may differ materially due to risks and uncertainties described in our SEC filings.

Joining me today are Brian Goff, Chief Executive Officer; Dr. Sarah Gheuens, Chief Medical Officer and Head of R&D; and Tsveta Milanova, Chief Commercial Officer. We will also be joined for Q&A by our participating key opinion leaders: Dr. Alan Anderson, Associate Professor of Pediatrics at the University of South Carolina School of Medicine Greenville and Director of the Comprehensive Lifespan Sickle Cell Disease Program at Prisma Health; and Dr. Kenneth Ataga, Plough Foundation Endowed Chair in Sickle Cell Disease and Director of the Center for Sickle Cell Disease at the University of Tennessee Health Science Center.

With that, I'll turn the call over to Brian.

Thanks, Morgan, and good morning and good afternoon to everyone. We appreciate you being here and are excited to share new data presented this weekend at the 2026 EHA Congress here in Stockholm, strengthening the profile of mitapivat across thalassemia and sickle cell disease.

I'd like to start by highlighting the evolution and strength of our rare disease business at Agios and why this is a pivotal moment for the company. We're transitioning from a single asset story to a multi-asset, multi-indication platform with multiple independent drivers of value now coming into focus. At the same time, our execution and clinical data are meaningfully derisking the PK activation platform in hemolytic anemias, which include 2 PK activators, mitapivat and our next-generation asset, tebapivat.

We've demonstrated that we can translate biology into clinical benefit. And importantly, we're building strength and momentum in our commercial capabilities to launch and grow these medicines in a repeatable way. Looking ahead, we have multiple near- and midterm catalysts over the next 12 to 24 months. From our continued scaling of the U.S. commercial launch of AQVESME in thalassemia to potential advancement into larger rare hematology populations, including sickle cell disease; polycythemia vera, also known as PV; and immune thrombocytopenia, referred to as ITP. Taken together, this is not just about any one program, it's about a broad and increasingly diversified pipeline targeting multiple large underserved rare hematology communities.

Guided by these principles, we are executing a strategy that extends our leadership in hemolytic anemias with selective expansion into adjacent rare hematology opportunities where we see clear pathways to innovate and lead. This slide captures where and how we are driving targeted disruption across rare diseases. We are highly selective, focusing on underserved rare disease communities where the biology is well understood, the disease burden is significant and current treatment options remain limited. In thalassemia and sickle cell disease, we are building from a foundation of PK activation where we've demonstrated the ability to translate mechanism into durable, clinically meaningful outcomes.

At the same time, we are intentionally diversifying our portfolio with assets supported by unique mechanisms and best-in-class potential, including next-generation SYK inhibition in ITP and siRNA TMPRSS6 inhibition targeting polycythemia vera. These are areas where we believe we can deliver differentiated profiles with the potential for improved tolerability and durability of treatment effect.

And beyond hematology, we're applying the same mechanism-driven approach in phenylketonuria, or PKU, where we see the potential to bring a disruptive new therapeutic option to patients. Across each of these opportunities, the strategy is consistent: focus on biology, execute with discipline and target areas where we have potential to transform the standard of care. This is not broad diversification, it is selective, grounded in science and designed to create value across multiple independent clinical programs.

Within that framework, AG-236 represents a clear expansion into an adjacent rare hematology disease, PV. Following completion of the Phase I healthy volunteer study, we've made the decision to advance the program into late-stage development for this indication. The data demonstrate clear dose-dependent hepcidin induction along with strong and sustained pharmacodynamic activity and a favorable tolerability profile. Importantly, these results in healthy volunteers support the potential for up to every 6-month dosing with consistent exposure in patients, a meaningful advantage in a chronic disease setting. In an evolving landscape, we believe AG-236 is well positioned to advance chronic treatment for PV patients with a profile defined by extended dosing without titration, strong tolerability and durable activity. These are important elements to redefine the treatment of PV. We look forward to discussing our development plans following end of Phase I interactions with the FDA. And given the evolving treatment landscape, we are prioritizing speed and disciplined execution as we approach late-stage development for this clinical program.

With that, I'm pleased to turn the call to Sarah to review our data presented at the 2026 EHA Congress this weekend. Sarah?

At this year's EHA Congress, Agios is presenting a broad and comprehensive data set for mitapivat across multiple hemolytic anemias, including 10 accepted abstracts and an oral plenary presentation of the RISE UP Phase III trial in sickle cell disease. Across these presentations and publications, our goal is clear to demonstrate consistent, durable and clinically meaningful impact across multiple rare diseases.

Starting with thalassemia, we shared long-term data from the open-label extension period of the ENERGIZE Phase III trial in adult patients with nontransfusion-dependent alpha or beta thalassemia. These data show sustained and clinically meaningful hemoglobin improvements over time. In patients that continued on mitapivat into the open-label extension period from the double-blind period, the mean duration of hemoglobin response more than doubled from 17.9 weeks to data cutoff at 43.6 weeks with responses still ongoing at the time of data cutoff.

Notably, patients who switched from placebo to mitapivat in the open-label extension period achieved hemoglobin improvements consistent with those seen during the double-blind period, reinforcing reproducibility of effect. Additionally, data from the open-label extension trial showed a robust proportion of hemoglobin responders. Nearly 60% of patients that continued on mitapivat into the open-label extension period demonstrated hemoglobin response defined as at least 1 gram per deciliter improvement from baseline in average hemoglobin over any 2 consecutive visits in the open-label extension period. This represents an increase from the 42.3% response rate observed during the double-blind period of the trial, suggesting that response rates may improve with longer exposure.

Additionally, approximately 1/3 of prior nonresponders in the double-blind period achieved hemoglobin response in the open-label extension period. Furthermore, we observed a nearly 50% response rate amongst placebo patients switching to mitapivat in the open-label extension period. Across the open-label extension data, the mean change from baseline in hemoglobin was 1.3 grams per deciliter. Importantly, there were no new safety events that changed our understanding of the safety profile of mitapivat in thalassemia.

Another interesting data set presented this weekend is a post-hoc subgroup analysis also from the ENERGIZE Phase III trial. It focuses on patients with higher baseline hemoglobin levels defined as at least 9.5 grams per deciliter at baseline, a group where treatment effect is typically more challenging to demonstrate. Despite this, mitapivat shows clear biologic and clinical activity. 38.9% of patients achieved a 1 gram per deciliter or more hemoglobin increase. This was accompanied by a clinically meaningful improvement in fatigue with a 5.1 point change in FACIT-Fatigue scores based on least squares mean change from baseline from week 12 to week 24. These data support a consistent treatment effect across baseline hemoglobin levels and reinforce the potential for mitapivat to provide benefit across a broader non-transfusion-dependent thalassemia population.

I'll also briefly highlight data from the SATISFY Phase II trial. This is a collaborator-led study that helps contextualize the biologic effects of mitapivat across rare hemolytic anemias, including hereditary spherocytosis, hereditary xerocytosis and congenital dyserythropoietic anemia type 2. At 56 weeks, we saw sustained activity across multiple domains. Hemoglobin improvements are maintained over time with nearly half of patients achieving response, defined as an improvement of at least 1 gram per deciliter during the fixed dose period 2.

We saw rapid and sustained reductions in hemolysis markers, including reticulocytes and bilirubin. And importantly, these upstream effects translate into reductions in iron burden, an important marker of downstream complications in hemolytic anemias. Together, these data reinforce a direct effect on the underlying pathophysiology of hemolysis with evidence that improvements extend to downstream disease consequences. This consistent biologic profile provides important context as we now turn to the RISE UP Phase III data set of mitapivat in sickle cell disease, where these effects are evaluated in a large randomized setting.

The RISE UP Phase III trial is a global randomized placebo-controlled study evaluating mitapivat in patients aged 16 years or older with sickle cell disease. The study enrolled 207 patients above targets of 198 patients and randomized them 2:1 to mitapivat or placebo over a 52-week double-blind period. The dual primary endpoints were hemoglobin response and the analyzed rate of reduction in sickle cell pain crisis. Key secondary endpoints included measures of hemolysis and fatigue. Here, we see the primary efficacy results from RISE UP, reinforcing mitapivat's role as a strong antihemolytic agent.

Mitapivat demonstrated a 40.6% hemoglobin response versus 2.9% on placebo with responses maintained through week 52. Among responders, the mean increase in hemoglobin was 1.6 grams per deciliter, reflecting a clinically meaningful improvement. We saw rapid and durable improvements in both hemoglobin and indirect bilirubin with clear separation from placebo and sustained effect over time. This consistency across multiple endpoints reinforces mitapivat's antihemolytic mechanism of action with aligned improvements across key biologic markers. While we did not achieve statistical significance on the trial's other primary endpoint, the annualized rate of sickle cell pain crisis or the key secondary endpoint of change from baseline in PROMIS Fatigu, we observed directional responses favoring mitapivat over placebo across key measures of hemolysis and other sickle cell pain crisis-related endpoints.

Importantly, hemoglobin response translated into clinically meaningful benefit across key disease outcomes in sickle cell disease. Compared to nonresponders, hemoglobin responders experienced reductions in sickle cell-related events, including a 26% reduction in analyzed rate of pain crisis, 34% fewer hospitalizations, 53% reduction in the analyzed rate of ER visits for sickle cell pain crisis and a 37% reduction in the analyzed rate of hospitalization dates for sickle cell pain crisis.

In addition, we see a clinically meaningful improvement in fatigue based on the PROMIS Fatigue measurement scale. These data reinforce that for patients who demonstrate a hemoglobin response of mitapivat, there is potential for downstream clinical benefits, including sickle cell pain crisis measures and fatigue. In a new post-hoc analysis presented for the first time here at the 2026 EHA Congress, hemoglobin responders showed improvements across a number of other patient-reported outcomes.

All of these measures, including pain, sleep and physical function favored hemoglobin responders compared to nonresponders. The safety profile for mitapivat was favorable overall with adverse events broadly balanced between the mitapivat and placebo arms, lower rates of serious and Grade 3 or higher adverse events versus placebo and no treatment-related deaths. Importantly, we also see a clinically meaningful reduction in transfusion requirements. Mitapivat reduced the proportion of patients requiring transfusions by 41% and the number of units transfused by 56% relative to placebo in the total patient population investigated in the RISE UP Phase III trial.

These are highly relevant endpoints in sickle cell disease, reflecting real-world disease burden. When benchmarked against historical data with hydroxyurea, which showed approximately 30% reduction in transfused patients and 37% reduction in units transfused, the magnitude of effect observed with mitapivat is notably greater across both measures. Importantly, these data inform the design of the REIGNITE Phase III confirmatory trial under the U.S. accelerated approval pathway, which has a primary endpoint defined as transfusion-free from week 4 through week 52.

On the next slide, you can see the design of the REIGNITE Phase III trial intended to confirm clinical benefit of mitapivat in sickle cell disease. The REIGNITE trial is a 52-week global double-blind, randomized study evaluating transfusion independence along with additional measures of transfusion burden, hemoglobin response and hemolysis. We are also enrolling patients aged 12 and older, supporting the potential to expand the label beyond the 16 and up population studied in RISE UP.

The REIGNITE trial was informed by the transfusion benefit data generated from the RISE UP Phase III trial, including powering for the primary endpoint as well as effect side. Additionally, we leveraged insights from the RISE UP trial to inform other assumptions for the confirmatory trial, including dropout rates and baseline characteristics. We intend to enrich for patients with clinically meaningful disease burden requiring at least 1 packed red blood cell transfusion in the prior 12 months, baseline hemoglobin of 5.5 to 10.5 grams per deciliter and additional evidence of hemolysis to support a measurable treatment effect. What's most important in the RISE UP data set is the consistency we're seeing between biology and clinical outcomes.

Mitapivat delivers a reproducible antihemolytic effect across the overall patient population, which aligns with its mechanism. And in patients who achieve hemoglobin responses, those improvements translate into meaningful clinical benefit, including on sickle cell pain crisis measures, fatigue and other patient-reported outcomes. Importantly, the RISE UP analysis now show that this effect also drives a clinically meaningful reduction in transfusion burden, which we view as a key indicator of impact on disease severity for sickle cell patients. All of this is supported by a large and maturing safety database, now exceeding 1,300-patient years across 3 hemolytic anemias, an important consideration in a chronic disease like sickle cell disease.

Taken together, we strongly believe mitapivat represents a differentiated antihemolytic approach with the potential for meaningful clinical impact in this underserved patient population in desperate need for innovative therapies. What this slide highlights is the repeatability of the PK activation mechanism across multiple hemolytic diseases. In PK deficiency, we've already established that activating PK can drive meaningful and durable improvements in hemoglobin and transfusion burden with long-term safety now well characterized in both adult and pediatric populations.

We then see that, that same biology translates into thalassemia, where mitapivat delivers consistent improvements across both transfusion-dependent and nontransfusion-dependent populations, including patient-reported outcomes, which is an important proof point. And in sickle cell disease, we're again seeing a consistent antihemolytic signal with hemoglobin improvements translating into clinically meaningful outcome in responders, supported by a favorable safety profile. Therefore, across 3 distinct rare diseases, the data consistently shows that targeting red blood cell metabolism can drive both biologic and clinical benefit. We view our PK activation portfolio, which also includes tebapivat, our next-generation PK activator being explored in sickle cell disease, as a validated and scalable franchise, not a single asset story.

Now I'm pleased to introduce Ahmar Zaidi, our Senior Medical Director for Sickle Cell Disease and an accomplished pediatric hematologist in his own rights, who will moderate the fireside chat with Dr. Kenneth Ataga and Dr. Alan Anderson.

Hello, everyone. I'm Dr. Ahmar Zaidi, Senior Medical Director in Clinical Development at Agios Pharmaceuticals, where I lead the development of mitapivat in sickle cell disease.

Before joining Agios, I spent nearly a decade caring for people living with this catastrophic illness. And that clinical experience continues to shape how I think about the field. Today, I'm pleased to be joined by Dr. Kenneth Ataga and Dr. Alan Anderson, 2 leaders in the sickle cell disease care and research fields. Together, we're going to discuss the current burden of sickle cell disease, mitapivat and the RISE UP clinical program and the future of pyruvate kinase activation. Dr. Ataga and Dr. Anderson, welcome. I want to dive right in and talk a little bit about the state of sickle cell disease as it exists today. You both collectively spent decades caring for patients with this illness, how would you characterize the burden of this particular disease in patients today?

I'm lucky to have the perspective of seeing patients across the age continuum. And what I recognize coming from a pediatric background is that we were seemingly doing good work with one disease modifier with hydroxyurea and patients who were seeing the improvements in terms of reduction in stroke and pain events, decrease in acute chest syndrome and some of those things. But what I now recognize wearing an adult hat is that the adults who are still significantly struggling, not only struggling to find locations for treatment, but also struggling to limit the organ damaging effects of the disease over the lifespan and that single modification therapy is just not enough.

And so I think the major deficit that I see across the spectrum is that our adults are still living 30 years less in terms of their life expectancy than age-matched counterparts without sickle cell disease. They lack options for disease modification, and they have this cumulative toxicity of the disease that we see coming over time without great options so far for us to be able to impact that and prevent it.

Does that resonate with you, Dr. Ataga?

Yes, definitely. So one thing I would add to what Alan has said is the fact that sickle cell disease is very heterogeneous, right? So within patients and between patients, they can have varying severities of disease at certain times, at different times. And we also know that as patients get older, they have this cumulative progressive organ damage. So I remember a few years ago, there was some controversy locally because someone had said something to the effect that, we'll take good care of children and then they come to the adult side and die, which was missing. Typically, it means that adult providers did not do a very good job, right? I don't think that's what that provider meant by that statement. But it just kind of shows the fact -- illustrates the fact that as patients get older, they have this cumulative and progressive organ dysfunction, which increases the risk of dying. And so it just tells us that we need to do more work to try and improve the care that provide patients with sickle cell disease, prevent complication from developing, help them to lead better quality lives and survive for much longer as well.

That's really important clinical framing. Thank you for those perspectives. I'd like to dive a little bit into the pathophysiology around the disease and kind of get a sense from the both of you around the importance of addressing chronic anemia and hemolysis in the overall management of sickle cell disease as you think about patients holistically. Let's go ahead and start with you, Dr. Anderson.

So I think what I talk to my patients about every visit is that the crux of the issue in sickle cell disease is the fact that, that red cell changes shape, dies too quickly. And ultimately, the downstream effects of that are release of all these inflammatory cytokines. We know that, that chronic inflammation is leading to damage within the organs. And it's a continuum. It's a latency period until which that individual is going to develop significant enough damage in that organ to cause organ failure. And everybody is moving along that pathway in some degree.

And so what I wanted to really draw my patient towards is that, that damaged red cell that's dying too quickly is leading to all the downstream complications. In that is that fast turnover of the cells that's leading to the chronic anemia. And so what we're trying to do now is have our patients recognize that anemia is at the crux of the issues that they have with fatigue, with inability to tolerate activities that they want to, whether that's sporting activities, school performance, whether that's work-related things and trying to use the right questions to ask a patient about what it is they want to see improve. And I think historically, our patients, what I've noticed is that they will not know how to necessarily say that I want to see this improve, they're so used to having the fatigue, having this inability to do the things that they want to do. And so asking the right questions to really tease out what is it you want to see improve and how can we showcase that this is related to the chronic hemolysis and anemia that you've experienced. And I think it's when we connect those things that you really start to see patients desiring to see improvement in their hemoglobin to see reduction in hemolysis and the downstream effects.

Thanks for that, Dr. Anderson. Dr. Ataga, this is something you've published about. I'd love to hear your perspective.

Yes. So I think it's important to understand that much of the problems we see in patients with sickle cell disease are driven by vaso-occlusion, right, as well as hemolysis, so it's not just one. So there's significant overlap in terms of how [indiscernible] sickle cell disease. And so it's not that one problem is caused purely by hemolysis and one is caused purely by vaso-occlusion, but this thing actually interrupts. But lots of studies also show significant relationship between hemolysis, hemolytic anemia and a variety of complications in sickle cell disease. So we know that anemia is bad. I mean it doesn't matter whether you have sickle cell disease or not, right?

What we know it's particularly bad in patients who have sickle cell disease. So like Alan said earlier, so there's lots of studies that show associations between anemia and lots of problems. So increased mortality in these patients and organ dysfunction. So increased risk of stroke, for example, abnormal TCD velocities, patients who might have pulmonary hypertension, kidney disease and so on and so forth. So it drives a lots of things, fatigue and all of that. So I think what we haven't really shown in a prospective manner is the fact that if we're able to fix this problem, that we can actually mitigate or prevent this problem from developing, right?

Intuitively, it would seem like that, but we need to kind of prove that, right? And I think we are getting there now with the new therapies that we have coming on board that if we are able to do that, we could actually prevent many of these problems. I think where we have shown that somewhat is the case of patients who have abnormal TCD velocities, so Alan treats patients who have -- treats children who [indiscernible], I'm an adult hematologist, so I don't really treat. I don't get TCD velocities myself. But in those patients, we know that transfusion therapy does help to decrease the risk of abnormal TCDs. And there's also data for the use of hydroxyurea as well, which might work at least in part from increasing hemoglobin levels in these patients as well. So I think now that we are having therapies come on board that seem to have more robust effects on hemolytic anemia, right? We might see even greater benefits in decreasing or perhaps preventing some of these complications. So we need to do these studies going forward and see if what we think happens if it's actually correct.

I'd love to shift the lens of this conversation just a little bit towards clinical trials. The FDA has recently discussed the inherent challenges that sometimes are associated with the vaso-occlusive crisis endpoint. When you think about vaso-occlusive crisis as a clinical trial endpoint, how do you sort of think about that when compared to other measures of clinical benefit? I'd love to start with you, Dr. Ataga, on this question.

All right. So that's a good question. And that's a discussion we have a lot as sickle cell doctors, right? So I think -- so for one, most of the big studies in sickle cell disease have focused on vaso-occlusion, painful crisis as the primary endpoint, right? And that's not particularly surprising because this is the most common reason for which we see patients, right? And so that's -- most of these studies are focused on this endpoint. And many of these studies have not been successful trying to address this endpoint as well.

And many people have speculated or suggested that maybe we should stop looking at painful crisis as an endpoint because many of these studies have not been positive. But I don't think we can ignore it. I think what we need to do is we try and see if we can better define this problem in patients with sickle cell disease. It's a very difficult problem to define because it's subjected in terms of pain, right? And we don't have any biomarkers that can tell us that someone is having pain or not, right? So it's not like there's some test you can do that tells you patient is having pain or the pain has resolved, right? I think there's a variety of ways the definition can be improved because it's problematic, right? So when we look at the current definition of painful crisis, it's confounded by a variety of factors.

So for one, if I look at patients getting opioid analgesics, the patterns of use of opioid analgesics different depending on where you live in the world, right? If you live in Memphis, Tennessee, where I live, compared to a patient who lives in Mali or in Côte d'Ivoire or in Nigeria or in Ghana or even in Europe, in the U.K., for example.

I agree 100% with what Ken was talking about and just in terms of there being inherent differences in how we manage pain here in the United States, let's say, versus in -- on the continent of Africa, where I have seen in -- working in multiple places that it is much less common to have access to high potency narcotic pain medications versus here in the United States, where for a long time, it was validated to say we needed to check a pain scale and everyone every time they touch the health system, and we sort of conditioned individuals to have as much -- as close to 0 pain as possible. We have worked long and hard to find the right balance in sickle cell disease and blocking pain when we can, but also understanding that pain can be driven by things outside of just sickling and the mental health of patients goes into that. All of these things can be center-specific, geographic specific, et cetera, and can ultimately have an impact on that -- the VOC incidences that is seen in that specific trial.

These are wonderful clinical perspectives. Thank you so much for offering them. I'd love to move our conversation forward to talk a little bit about the RISE UP clinical program and mitapivat specifically. Why don't we start by just talking about our primary takeaways from the RISE UP Phase III results? I'd love to hear from both of you, Dr. Ataga, why don't we start with you first?

So I think this was a very important study that showed, for one, in a large group of patients across the world pretty much global study. I looked at patients in the U.S., in Europe, in sub-Saharan Africa, that treatment with mitapivat, which is this pyruvate kinase activator, increases the likelihood of patients having what's called a hemoglobin response. In a large number of patients, so little about 40% of patients had this hemoglobin response, in which the hemoglobin went up by at least 1 gram when you compare them from baseline between 24 and 52 weeks compared to patients who got placebo. So the study did not show any significant differences between patients who got the active medicine and placebo with regards to annual rate of pain episodes. But in those patients who had a hemoglobin response, there did seem to be a meaningful decrease in the frequency of pain in these patients.

So I would say that I was extremely excited to see just how robust the hemoglobin response was and how the hemoglobin response in the RISE UP trial also correlated with reduction in hemolysis. So LDH percent reticulocyte count measures that we know go along with -- also bilirubin, they go along with the hemolysis that our patients are experiencing. Not only was the hemoglobin response very robust, but also happening very quickly. And our patients want to see that. They want to see that if they start something that they're seeing the benefit of that in the trial results seeing that happening in the first 2 weeks of treatment with that first CVC time point.

The other thing that we want to see in a trial like this is the durability of hemoglobin response. So seeing that hemoglobin rise greater than 1 gram per deciliter and then maintaining over that in the trial results showing between week 24 and week 50 durability of that hemoglobin response. So all those things are very exciting, I think as well the tolerability that was seen in the results. So side effect profile was very mild and mostly self-limited in terms of the side effects that we're seeing.

I think also just seeing that there is historical data on the use of mitapivat in PK deficiency and thalassemia and that, that same efficacy and safety profile has been seen before, that's going to be important to our patients because they've sort of been burned with results in the past where they felt that things were safe or certain results of the trials and then to find out later that there were concerns. And so I think that patients are wanting to see that the results have held up over time and in this case, in different disease populations. And so I think that we're going to see that's beneficial.

The transfusion -- decrease in transfusion burden, I think, is extremely important, especially as we look at some of our adult patients that have developed iron overload and alloimmunization and other things where we need to try to reduce the need for transfusions. And then we'll see about pain over time. I'm also reassured by the responder analysis that showed a meaningful decrease in pain in those who are responding. And my hope is that we'll see that play out with this type of a therapy in the future as well.

So just to follow on to that. When you think of the RISE UP data, Dr. Ataga, what patients do you believe are most likely to benefit from mitapivat? How do you -- how are you thinking about where mitapivat sort of places itself in the clinical context?

Yes. So that's a good question. So from the RISE UP study, everyone seem to benefit, right? So when looked at the subgroups, whether it was based on age, whether it was based on genotype, based on hemoglobin levels, patients seem to -- all patients seem to have adequate benefits to the intervention. Having said that, there were eligibility criteria to take part in the study and so patients had to have hemoglobin levels of between 5.5 and 10.5, right? And so the question is, if you have someone who has a hemoglobin of 11 or 12, is that someone you consider putting on a drug like mitapivat?

So it's not very clear, right? We don't have data to support that. So we as sickle cell doctors always get worried when the hemoglobin level goes too high. We are worried about hyperviscosity and things like that. So we don't have data for that. But at least within patients who've studied and who fit the SCD criteria for the RISE UP study, it seems like this drug would be beneficial for just about anyone in terms of hemoglobin response. And at least amongst those who have hemoglobin responses, there seems to be some meaningful decrease in painful episodes and fatigue. And so the question is, if we have the next-generation pyruvate kinase agonist, might that do even better, right? So not just with regards to hemoglobin response, but with regards to its effect on pain and so on and so forth. So I think there are some good lessons we can take from this, but it doesn't answer all the questions just yet. Still needs some more work.

Yes. I think we're moving into an era of combined therapy and that the way I'm sort of setting that groundwork for my patients is to just draw them into the fact that despite single-agent modification therapy that we've had now for over 30 years, we're still seeing this progression towards end organ failure. There have been massive benefits in the short run, but we realize that the disease modification has not been good enough to give us the outcomes that we want to see. And so that's why I'm excited about these results from the RISE UP study is because I can see the data showing benefits now with improvements in hemoglobin, decrease in hemolysis, the fatigue scores that we're seeing, decrease in transfusion burden that we've already talked about that is clinically meaningful.

And then the hope is that we can take the lessons we've learned from the disease and we can expect -- but we'll still have to watch, but we can expect that we could see improvements in organ function related to the results that we see now. So we have to monitor over time. We're watching for those benefits. But we have those patients right now that have hyperhemolysis that are -- that fit within that phenotype that despite hydroxyurea use, they maintain low hemoglobins. They don't have high frequency of pain, many times. They're not in the hospital all the time, but we know they develop those downstream complications, significant pulmonary hypertension, early death related to respiratory and cardiac causes.

And so we have reason to believe that from data that we're seeing come out of RISE UP, reduction in hemolysis, improvement in anemia could lead to very beneficial changes in our patients in the long term in terms of their organ function as well. So again, I'm excited about the idea of options, something that we can add. We know the data from the RISE UP trial showed that the mitapivat was safe when taken with hydroxyurea, and that's crucial. And in fact, over 70% of the patients were on hydroxyurea at the time they were on mitapivat. And so I think that that's crucial. It can be used single agent or combined with hydroxyurea. So that's going to be critical to our patients moving forward as well.

Dr. Anderson, after a period of a lot of stagnation in sickle cell disease, we're really living in a time where there's been just an explosion of advancements, whether it be PK activator, mitapivat, etavopivat, tebapivat now coming or really any other mechanism, I'm curious how you think about this sort of upgraded toolbox that you're going to have as a clinician in your lifespan clinic? Where sort of your mind -- what are you looking for in this toolbox? How do you sort of approach the future of sickle cell disease when it comes to improving care?

That's a great question. I think that patients are hungry for options. For far too long, they've had one daily disease-modifying therapy with hydroxyurea, which has had a huge effects in terms of improvement in outcomes, but they have still been dealing with the chronic complications of the disease that they've been very excited about potential new options. And so I think that we're starting to see several different mechanisms of action that are very exciting. PK activation, as we've been talking about, is extremely exciting.

I'm loving to see these first results coming out of Phase III trials in terms of PK activation. We're excited about the future of fetal hemoglobin induction and where we may see additional agents that could improve fetal hemoglobin even on top of hydroxyurea. We've also seen some frustration within the community regarding agents. We've had the removal of voxelotor from the market that there were patients that were seeing benefit, they were frustrated. There were others that just didn't understand what was happening and had to do a very quick crash course in the way trials run and the understanding of that. And so that was difficult for the patient population.

And so I think that what we will be seeing over the coming years is that patients are very hungry for options. They want to see individualized care. They want to be able to try things just like you can in diabetes and in heart disease and other chronic illnesses where they see options, and they have not had that in the past. And so I, as a clinician, seeing the patients every day, I want to see options. So I'm excited about what we're seeing come out of RISE UP. I'm also very excited to see data that is going to be coming out over the coming year that may give us a glimpse into what the future landscape is.

Just as sickle cell disease is not a homogeneous disease, there are various -- variant genotypes. Within those genotypes, there's different other genetic factors that can change the phenotype for that individual. And so we're going to see that patients need different options. They're going to go on one for a while, and they may say that one didn't work as well for me, let me try this mechanism of action now. And so we are going to be able to listen to the patient to be able to have a discussion with them at the bedside where we can offer new potential therapies and work with them on an equal playing field to be able to figure out what works best for them. So I'm excited about options. I think that's always the best case scenario for the patient.

Thank you, Dr. Anderson and Dr. Ataga, for joining us today for this discussion. I'll now hand the call over to Tsveta to highlight how the new mitapivat data presented at the 2026 EHA Congress reinforce our commercial positioning in thalassemia and sickle cell disease.

Thank you, Ahmar, and thank you, Dr. Anderson and Dr. Ataga, for sharing your perspectives on mitapivat and the sickle cell disease landscape.

Our commercial organization is focused on 2 priorities this year: continuing to execute and scale the U.S. commercial launch of AQVESME in thalassemia and preparing for a potential future launch of mitapivat in sickle cell disease. The data presented at the 2026 EHA Congress positions us well against both.

Let me start with thalassemia. AQVESME is off to a strong start in thalassemia with 242 prescriptions written as of March 31 by REMS-certified physicians. Early demand has been supported by efficient REMS onboarding and shorter-than-expected time to treatment even as we continue to plan for an average 10- to 12-week initiation time line. From here, our focus is on broadening prescriber reach across community and academic settings and expanding adoption in nontransfusion-dependent patients who represent roughly 2/3 of diagnosed adults.

As Sarah highlighted, we are presenting 2 important analyses from the ENERGIZE trial here at EHA, focused on the non-transfusion-dependent population. The data reinforce the commercial opportunity in 2 key ways. First, durability. In the open-label extension, the mean duration of hemoglobin response more than doubled with continued treatment, supporting sustained disease control and long-term patient persistence on therapy.

Second, breadth. Responses observed in patients with higher baseline hemoglobin levels supports the opportunity to treat earlier in the disease course, expanding the addressable population across a broader range of disease severity. Taken together, these data strengthen our confidence in the durability and broad applicability of AQVESME and in our ability to expand adoption over time as we continue to build and communicate its value within the medical community. I'm proud of the team's execution and encouraged by what these results could mean for patients living with nontransfusion-dependent thalassemia.

As you saw earlier, the RISE UP Phase III data highlight mitapivat's strong antihemolytic profile, directly addressing hemolysis, a core driver of both disease burden and mortality in sickle cell disease. We believe this profile underpins a compelling opportunity with a clear right to win on behalf of patients. From a market perspective, there are approximately 75,000 diagnosed patients aged 16 and older in the U.S. with roughly 25,000 actively treated or in need of therapy. We also believe the treated population can expand over time as new market entrants drive greater disease education, awareness and engagement.

Our initial launch is focused on the patients with hemolytic profile, a defined patient segment with a nonprescriber base, which we have begun to map and prioritize. We see that as a focused entry point with opportunity to expand over time. Our confidence in our ability to achieve commercial success comes down to 3 factors: First, experience. Mitapivat has the potential to be the first PK activator in sickle cell disease and could represent our third hemolytic anemia indication following PK deficiency and thalassemia.

Many of these prescribers are already familiar with the molecule and mitapivat is supported by more than 1,300-patient years of data, providing the kind of clinical foundation that supports confidence in this setting.

Second, clinical differentiation. Beyond any single study, mitapivat is backed by a substantial body of evidence across 3 hemolytic anemia, supporting a proven clinical profile and consistent hemoglobin benefit.

Third, our commercial foundation. The rare disease infrastructure and patient support capabilities we have built in thalassemia and PK deficiency position us well and gives us a platform we can scale appropriately to support sickle cell patients as we move forward. Taken together, we believe mitapivat brings the right combination of targetable opportunity, clinical depth and commercial readiness to support a successful entry in sickle cell disease and to build from that initial launch focused over time.

With that, I will hand the call back to Brian for his closing remarks.

Ultimately, execution is what brings our strategy to life. Over the past year, we have activated the thalassemia market with a high-quality U.S. commercial launch, delivered key clinical and regulatory milestones with speed and precision, maintained disciplined operating expenses while investing for growth and we've expanded our pipeline with strategic precision, most recently with the addition of cevidoplenib. This consistent execution underpins our confidence in the company's path forward.

We remain laser-focused on delivering against our 2026 strategic priorities. Of key importance is continuing to drive a strong U.S. commercial launch of AQVESME in thalassemia. We'll share updates on launch progress with our second quarter results, and I am extremely pleased with the team's execution as we sit here today. I'm also encouraged by the positive reception we've seen from the thalassemia community. We're advancing mitapivat in sickle cell disease and look forward to hearing from the FDA shortly on acceptance of our mitapivat sNDA and we look forward to the Phase II sickle cell top line data for tebapivat in the coming months.

Next, we'll continue to advance our maturing pipeline. Today, we announced the progression of AG-236 in PV to late-stage development following a successful Phase I trial in healthy volunteers. Additionally, we'll have Phase I proof of mechanism data for AG-181 in PKU patients before the end of the year. And finally, we were pleased to recently announce the addition of cevidoplenib, a next-generation SYK inhibitor for the treatment of ITP. Here, we see a potential $1 billion nonrisk-adjusted peak year U.S. sales opportunity and look forward to updating you as we progress towards Phase III initiation. What you're seeing here is the evolution of Agios into a multi-mechanism, multi-asset company with strength and breadth of rare disease capabilities. We built a leading position in PK activation with broad clinical validation across hemolytic anemias and a deep dataset supporting durability and safety.

At the same time, we are intentionally diversifying our approach, bringing forward complementary programs, including SYK inhibition and ITP and additional genetic and metabolic targets beyond hematology. Each of these programs fit within a focused and disciplined strategy, targeting well-characterized biology and meaningful areas of unmet need. As we look ahead, we're not just advancing individual assets, we're building into a sustainable leadership position in rare hematology with the capability to extend that leadership into other rare diseases over time. Today, our pipeline represents the potential to bring forward transformative medicines in markets totaling over $10 billion in 2030.

Thank you for joining us. And with that, we're pleased to open the call for Q&A, where we'll be joined by Dr. Anderson and Dr. Ataga. Operator, please open the line.

[Operator Instructions] And I show our first question comes from the line of Andrew Berens from Leerink.

Congrats Brian and team on the progress on the plenary session of the meeting. I guess a question on the label. And do you think the potential label could be for the accelerated approval would reflect the RISE UP trial population or is there a chance it could reflect the confirmatory trial population? Just trying to get a sense for how we should consider the addressable population. And then maybe similarly, you have 2 different brands now for mitapivat, what's going to go into the decision about which one you would use for sickle cell?

Yes. Thanks, Andy. I'll have Sarah start with the label. So I think it's a good opportunity to explain the role of RISE UP in the label and then the importance of the confirmatory study as well. So Sarah, do you want to start there?

Sure. Thank you. Thanks, Andy, for the question. So as it relates to the label, so the RISE UP data is the package which we filed. So in the clinical trial section, you will always see the RISE UP clinical trial being reflected in that label. The confirmatory trial for us is a way to further confirm benefits that we now have observed in the RISE UP trial. And then at the time of -- when that data package would be available for review, then -- when we submit that part, then that clinical trial population would be added to that section of the label as well. So first label, RISE UP trial, then as the label evolves, next trial gets added.

No, that's great. And then the second part relates to the 2 different brand names and how we think about that.

Yes. So for the brand names, so we have PYRUKYND and AQVESME, as you know. So these 2 brand names basically give us optionality. It will be a matter of review ultimately where -- which brand name ultimately gets chosen. But for us, we feel very ready and prepared in either scenario, and we know that our -- we now know based on the data that for us team has generated with the thalassemia launch that the team would be ready to launch [indiscernible] That being said, I'm going to repeat that the safety profile of the drug is favorable. So we see an option to launch visible.

And I show our next question comes from the line of Eric Schmidt from Cantor.

Well, thanks for taking my call and appreciate all the information this morning -- this morning, New York time at least. Maybe one on AG-236 and the decision to take that forward into later-stage studies. I'm not sure who's best to answer this. But can you talk a little bit about what you think is the unmet need in PV? And then of course, this isn't the only TMPRSS6 targeted therapy, there were a bunch of other modalities in development. Can you speak to how you think this is going to be differentiated from others, including I think, some that are more advanced?

Yes. Thanks, Eric. I'm glad you asked about AG-236. We're excited about the opportunity. I think this is yet another disease polycythemia vera that is really in need of being disrupted on behalf of patients. And it's exciting that there are different modalities being pursued. In our case, we're quite excited about the TMPRSS6 inhibition pathway. Maybe, Sarah, you could talk a little bit about what the overall target is as we look ahead towards more advanced development.

Yes. And so we're very excited about our AG-236 assets. Based on the healthy volunteer data that we now have, we really see the potential for best-in-class in polycythemia vera and are looking forward to move it forward into patients living with this disease. We believe that based on the data that we now have that there is really an opportunity to extend the dosing frequency up to 6 months of -- in between doses and that, that would allow for a very durable and maintained hematocrit control, so we really see that as a major advantage to this, yes.

And Eric, I'll just say, in this case, too, I draw a bit on my own experience in hemophilia. And we saw similar dynamics as different modalities evolved in hemophilia where you went from significant frequency of dosing, which is difficult for patients chronically, to then longer intervals of therapy that really maintains that durability that patients look for. So again, this is -- it's a pretty important step that we see to now have the healthy volunteer data, which looks compelling and the opportunity to move forward.

And I show our next question comes from the line of Samantha Semenkow from Citi.

I have 2, one for the physicians on the call and one for management. For the physicians, in the fireside chat portion, which is very helpful, you mentioned how important reduction in transfusion burden is. I'm wondering if you could just contextualize that a little bit further and talk about the magnitude we're seeing out of the RISE UP data and how impactful that is in your views?

And then for management, I'm not sure if you've done this analysis, but was there any correlation in the patients that achieved a transfusion burden reduction with also seeing a reduction in pain crisis, fatigue or hemoglobin improvements?

Thanks, Sam. So let's take the opportunity to have both of our KOLs comment on your first question about the reduction in transfusion burden and the magnitude of that reduction that we saw in RISE UP and the meaningfulness of that. And then -- and we'll start with Dr. Ataga, and then go to Dr. Anderson and then Sarah can comment on your question about the correlation. So Dr. Ataga, do you want to start on that?

Yes. So thank you for the question. So with regards to transfusion, so that's something that happens relatively frequently in patients who have sickle cell disease. And patients can get transfused when they have acute complications, for example, when they have acute pain episodes or what you call acute chest syndrome or when they have strokes or they could get transfused chronically, which means that they have repeated episodes of transfusion perhaps every month going forward. The problem with transfusion is that when patients get transfused a lot, it can be associated with a variety of risks.

So there is the risk of infectious complications, which is not very common in the U.S., but it's not 0, right? So patients can have a variety of infections. HIV infection is a possible risk, hepatitis infection is a risk. But then more commonly is the fact that patients can have problems like, what you call, iron overload because when you give red blood cells, red blood cells have hemoglobin in them that has iron. And over time, that can accumulate and accumulating iron levels can cause organ dysfunction as well. And so that becomes an additional burden for patients with sickle cell disease.

And then another problem that we see with repeated transfusions in patients with sickle cell disease is that they can have this problem called red blood cell alloimmunization. So that means that these patients actually have antibodies that makes it more difficult for them to get subsequent blood transfusions. And so the benefit of mitapivat in patients who have hemoglobin responses that we see in post-hoc analysis now shows that we can reduce this transfusion requirement and potentially reduce these complications, including iron overload, risk of alloimmunization and things like that. So that's very exciting to see.

Yes. Great. And Dr. Anderson, anything you'd like to add?

Yes. I'll just say I agree with everything that Ken said. I think our patients, what I've seen as a lifespan physician is I see that transfusion burden starting in pediatrics, the iron buildup starting at that point and then just rising over time. So this clinically meaningful decrease in transfusions that was seen in the trial and the responders, I think is significant to the patient population, and we can't lose sight of the fact that every reduction in a transfusion time point for an individual affected by the disease means potentially 2 visits that they don't have to come to a center. So there's a visit -- our patients typically require their blood to be typed specifically for them on average about 48 to 72 hours prior to their transfusion because of the need to get very specific units so they don't develop alloimmunization over time.

And so oftentimes, patients will come in for labs 48, 72 hours before and then they come back to the clinic for transfusion. And so I think that the transitions have a significant impact on quality of life for patients and that's on top of all the other risks associated with transfusion with iron, alloimmunization, infection and other things like that. So I think it's very exciting data showing reduction in transfusion in patients where it's been very difficult to reduce transfusion burden historically.

Well, thank you very much. I must say it's great having both of you on the call, so we can hear the questions and get a real-world response from both of you. So Sarah, then there was the second question from Sam about, is there any correlation between transfusions, and I think she'd asked about the pain, for example?

Yes. So Sam, this was an overall population analysis that we've done looking at the transfusion burden in mitapivat versus transfusion burden in placebo to go in line with the improvement in hemolytic anemia that we saw in the overall patient population. And I do want to stress what the 2 physicians actually just highlighted the importance of reducing transfusions just because of the risk and the impact to the patient population. And we hear that sentiment when we now present the REIGNITE trial, the Phase III confirmatory trial, to physicians to participate with their center that there's a lot of enthusiasm for that trial because of all of the reasons that were just highlighted by Dr. Anderson and Dr. Ataga.

And I show our next question comes from the line of Gregory Renza from Truist Securities.

It's Anish on for Greg. Just a couple from us. On the RISE UP data, the hemoglobin response was clearly rapid, separating from placebo by week 2 and holding through week 52, as you remarked on. I'm wondering how you're thinking about leveraging that rapid onset clinically, does it lend itself to a trial of therapy or treat-to-target approach where you can identify nonresponders early?

And then on the theme of responders, just if you could help frame any leading indicators from baseline characteristics you've seen that would help predict whether or not a patient is likely to be a responder and thus fit into the important responder findings you've discussed today?

Thanks, Anish. That's -- both of those are good ones for Sarah to answer.

Well, yes, indeed, you could see in the dataset that the hemoglobin responses were observed rapidly. As Dr. Andemariam had highlighted that week 2 is the first measurement we take within the trial, and that's where you start seeing the separation of the lines. That being said, I hope people also have an opportunity to look at the thalassemia data in which we see that, yes, we have a lot of great response early on, but some people continue to evolve their response along the way.

And now in the thalassemia data, actually, the response rate went up to 60% with prolonged exposure. So this is why it's important to continue to follow patients in the extension study to understand how -- up to how long one can expect hemoglobin response to arrive. And in regards to the baseline disease characteristics that were -- is there anything that can predict who is going to respond? Again, as Dr. Andemariam highlighted in the presentation, we really looked at -- like prespecified a lot of factors to look at to try to determine who would respond versus who would not respond and there is nothing that actually pops out that proactively can predict who is going to have a response.

And that is, again, very consistent with what we've observed in the thalassemia and in the PKD patient population. And therefore, we do anticipate that this is more going to be around patients try the drug, there will be an assessment of over a couple of weeks to months of is this actually working for the patient, yes or no, and then decisions can be made by the physicians and the patients together on what is the best course of action.

And we've heard that consistently since November, actually, when we did the top line release of the RISE UP data, and we heard a lot of, both thought leaders as well as community physicians comment on the fact that the safety and tolerability is really reinforces this try-first dynamic, which is a really important opportunity. So thank you, Sarah.

And I show our next question in the queue comes from the line of Emily Bodnar from H.C. Wainwright.

Congrats on the progress as well. Maybe one on the transfusion burden data. Can you kind of help us understand the differences between the total RBC units transfused, which didn't look too different from placebo compared to the average RBC units transfused, which was clearly more significant?

And then for a second question, given the confirmatory trial is lowering the age to 12 from 18, can you maybe discuss how much you would expect that to increase the addressable patient population versus RISE UP and maybe just like unmet need in adolescents versus adults?

Okay. So thanks, Emily. Sarah, do you want to comment first on the transfusion aspect of the clonal -- I think the question is about clonal RBCs?

Emily, so when you look at the data of the RISE UP patients, we actually see positive effects for -- however, we look at the red blood cell units transfused, both meaning the frequency plus the red blood cell units. So the totality of the data shows that it is very consistent pointing towards favoring mitapivat. The other thing here is for RISE UP, when you're saying the overall red blood cell units transfused, this is not a heavily transfused patient population, right? There was -- this is not a chronically transfused patient population for stroke prevention or something like that. Just as it occurred clinically, and that's where we did see these great results. And as I mentioned also in the remarks, these results were stronger than hydroxyurea results. And so we feel very confident about where we are going with this confirmatory trial.

And then, Sarah, comment on the confirmatory trial age reduction actually to 12 and older, and the importance of that opportunity to the overall population and commercial opportunities.

Absolutely. So Emily, we provided some information on the population as it currently stays. As a reminder, our label, the initial label, potential label will be based on the RISE UP data, which is ages 16 and older. And in the U.S., there are about 75,000 patients with sickle cell disease that reflect that patient population. We have further refined that looking deeply into the claims data and identified about 25,000 patients who are either being treated or have been previously treated and are in active care for sickle cell disease, which gives us an initial kind of clarity of where we should focus our launch preparation and efforts.

We're super excited about the opportunity through the confirmatory study to actually study the product and provide data in the younger age groups of 12 and older. And then that data kind of gets added to the label over time, I think it's going to position us very well to move into that broader patient population and bridge the gap towards the 100,000 patients that are living with sickle cell disease in the U.S.

Great. Thanks, Emily.

And I show our next question comes from the line of Salveen Richter from Goldman Sachs.

This is Lydia on for Salveen. Congrats on the updates. Maybe just another for the 2 physicians on the call. Could you just speak to what percentage of your sickle cell patients receive transfusions regularly? Looks like it was around 25% of patients in the RISE UP study. So is this more or less reflective of the overall population?

Thanks, Lydia. So let's send it to our thought leaders on the line. This time, I'll reverse the order. Dr. Anderson, do you want to start with the percentage of your patients that received transfusions, just reinforcing the point that Sarah made, this is to match the confirmatory trial. It's really about episodic transfusions.

Correct. Yes. So I would say in my population, it's about 10%, maybe little less than 10% that are receiving transfusions with therapy, meaning that they're on a recurring basis of transfusion scheduled because of a certain indication. The majority of those are historical individuals who've had either stroke or have had an abnormal transcranial Doppler ultrasound showing increased stroke risk, and so they're in recurring transitions for that.

I think what this data speaks more to would be those patients that are receiving transfusions because of some acute complications or because of symptomatic anemia potentially leading to some of the early signs of organ toxicity that we see in our adult patients like renal insufficiency. And so we have a much larger group that are receiving enough transfusion scattered throughout each year that they are developing significant iron overload. And on the adult patient side, we see diminishing returns from hydroxyurea, where patients that had been doing great with higher hemoglobins, those hemoglobins are starting to decline and they are needing more frequent episodic transfusions due to symptoms.

And in certain patients that are also needing erythropoietin add-back in combination with hydroxyurea in order to try to reduce transfusion burden. And so I think there's a significant portion of patients that are falling into that category where we would like to see the frequency of transfusions reduced and therefore, the excitement around the data coming out of RISE UP.

And Dr. Ataga -- before we just move on, we'll have Dr. Ataga comment as well.

Yes. So thank you. So I do agree with Alan. And just to add to that. So I would say that when we transfuse patients, so there are 2 ways we transfuse patients. So patients can get transfused episodically. And many times, it's because they have acute complications. They come into the hospital because they are sick for a variety of reasons. It could be that they're having an acute pain episode or some other complication like what we call acute chest syndrome.

So hemoglobin level goes down and they get transfused either for symptoms or for treatment of their disease complication. All patients can have what's called chronic transfusions. And typically, this refers to patients who get blood transfusions approximately every 4 weeks-or-so, 3 to 4 weeks. And many times, it's something that's ongoing. And so for patients who get chronic transfusions, commonly for reasons like stroke prevention or because they've had an actual stroke in the past, so it's for secondary prevention of stroke or other reasons. I would say that the numbers in my patient population is similar to what Alan talked about between 5% to 10% of patients get transfused chronically.

But amongst patients who get transfused episodically, that's much higher. So I don't have the actual numbers in front of me, but I would say it's much higher, so 30%, 40% or even 50% or even higher than that. So patients that get transfused once a year or maybe less than that. And so having data for a drug that decreases transfusion requirement in patients with sickle cell disease is obviously very exciting to be able to help to reduce complications linked to transfusions in these patients.

Very helpful. Sarah?

Yes. Thank you for both those perspectives. And I think for us, like from a clinical trial perspective, we're really just looking at the transfusions as an endpoint to further confirm and measure clinical benefit for the improvements we now have seen in the RISE UP trial for the antihemolytic effect that we've seen the improvement of hemolytic anemia overall, so we are excited to embark on the REIGNITE trial.

And I show our next question in the queue comes from the line of Tess Romero from JPMorgan.

I think one of the KOLs touched on this earlier, but in the context of what you know today, around mitapivat's potential in sickle cell disease, what do you think you need to see for tebapivat to move this program forward? Is there a threshold on hemoglobin response that would trigger you to say this could materially improve the profile that you're seeing with mitapivat and I want to move this into Phase III?

Thanks, Tess. So maybe we'll start with Dr. Ataga, and I'll just phrase the question: it's generally what's on your wish list for continued progress? Of course, to remind everybody, we have tebapivat, our next-gen PK activator and we're looking forward to the Phase II sickle cell data in the second half of this year. But Dr. Ataga, perhaps you could start by just commenting on what else you'd like to see?

Yes. So thanks for the question. So I would say that the data for mitapivat are actually quite exciting. But obviously, we can always do better, right? And so I would say that with tebapivat, a couple of things. So for one, that drug seems to be administered once a day. And so if you have a drug that's taking once a day compared to a drug that's taking 2 times a day, most people would prefer that. The likelihood of missing doses is less. So I think that's an advantage to that.

And then if the results of the available data are confirmed that tebapivat has this impact on having a higher hemoglobin response, so that may also be a good thing. So not only might that be a higher hemoglobin response so patients have higher responses in terms of hemoglobin, but that might also translate into decreased complications such as painful episodes, decreased -- improvements in fatigue scores in patients with sickle cell disease. So that hemoglobin response may also translate into improved clinical benefit for patients with sickle cell disease.

So we'll have to see what the data show. But I think potentially, if it does what we hope it does, tebapivat might be more convenient in terms of administration to patients and then might have even better hemoglobin responses and decrease in complications such as pain and improvement in fatigue.

Okay. Thanks. And Dr. Anderson. And then what I'll do is have Sarah comment on, of course, what we're looking for in terms of continued development. But Dr. Anderson, maybe you could comment as well?

Sure. Yes. I think that what we'd be looking at would be the further improvement in hemoglobin. What we're seeing come out of gene therapy results is as you near normalization of hemoglobin and you have the decrease in all of these hemolysis parameters, you see that many of the complication symptoms that are occurring in patients start to go away. And so I think that the further increase in hemoglobin, I'd like to see even further normalization of hemolysis markers as well, bilirubin, retic, LDH and then seeing the downstream effects of that. So hopefully, reduction in VOCs that's clinically significant across the patient population, I think, would be also very critical to see in the future as well.

Yes. Thank you, both. And I think you guys summarized it perfectly because now we know, of course, from the RISE UP trial that hemoglobin response, once we have hemoglobin response, it drives a lot of the other benefits that we can observe in the sickle cell disease patient population. So that's indeed what we're hoping for that tebapivat can deliver more hemoglobin responders or higher hemoglobin response because we do now understand based on the RISE UP data that, that is really important to drive all of the additional benefits. So well just now, as you know, we've announced that we are anticipating data for tebapivat in the second half of this year, so more to come.

Thanks, Tess.

Thank you. And I show our last question in the queue comes from the line of Luca Issi, RBC.

Maybe a quick one. Maybe, Sarah, you obviously filed mitapivat for sickle cell disease almost exactly a month ago to this day, I think, on May 12. So 60-day clock is obviously ticking. Have you had any informal interactions with the FDA since you filed? And maybe bigger picture, how confident are you that the filing will be accepted? And do you expect standard or priority review? So that's one.

And then maybe second, Tsveta, on the commercial side, how are you thinking about a scenario where you get approved on an accelerated approval basis based on RISE UP, but your competitor maybe reached the market with a full approval, obviously based on reduction in crisis. Do you think that docs and payers will favor your competitor or do you think that everybody would kind of look at these 2 molecules as broadly similar given the same mechanism of action? Any thoughts there, much appreciated.

Thanks, Luca. So Sarah can start just with 1 clarification, we're talking about mitapivat. And then Sarah can comment on the unmet need that exists and how we think about the commercial opportunity.

Yes. Thanks for the question. And yes, so it's our mitapivat sNDA filing that we indeed announced about a month ago. And we, of course, continue to engage with the agency along the way because we have actively filed at this point. And that's really it. So I'll maybe hand it over to you for the second question.

Absolutely. And I think we've heard it from the call today, and it's very consistent with what I hear interacting with physicians like now here at the moment as well, sickle cell disease is a disease with a high unmet need and very, very limited treatment options. So the opportunity to have multiple products on the market is a huge advantage across the board. We don't know much about the data, but what we know, especially now and the broader perspective of the RISE UP data has been presented, we know that it really resonates with the treating physicians.

From the perspective that the hemoglobin improvement can lead to downstream benefit for patients, both in terms of quality of life as well as reduction in pain crisis, and we'll wait to see how the data continues to evolve, but these things that the reduction of hemolysis can be potentially linked in the future to reduction in the cumulative organ damage, which is observed in these patients as well. So we feel extremely good about our profile and opportunity for us to commercialize.

And don't forget, this is our third potential indication in the hemolytic anemia. We have very strong consistent and cumulative profile and a lot of safety accumulated not through the clinical studies -- so not only through the clinical studies, but also in the market as well. So we are getting ready for a potential launch.

Thank you. That concludes our Q&A session. I would now like to turn the conference back to Brian Goff, Agios' Chief Executive Officer for closing remarks.

Thank you, Dylan, and thanks again to everyone who joined us today at the 2026 European Hematology Association Congress. We really appreciate your engagement and interest at Agios. And again, I want to say a special thank you to Dr. Anderson and Dr. Ataga, for sharing their perspectives and their expertise on sickle cell disease and the potential role that mitapivat can have for patients.

The data presented at EHA reinforce the consistency and durability of mitapivat's antihemolytic profile across both thalassemia as well as sickle cell disease. More broadly, these data highlights an important inflection point for Agios, as we enter the next phase of our evolution, expanding mitapivat across multiple indications while building a broader multi-asset rare disease company with multiple mechanisms, programs and opportunities to create value. So we leave EHA confident in our path forward, executing the AQVESME launch, advancing mitapivat's sNDA in sickle cell disease and continuing to build a differentiated pipeline with discipline, focus and clear value drivers ahead.

Thanks again, and we look forward to updating you on our progress along the way.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.

Good morning, and welcome to Agios Pharmaceuticals Business Update Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios.

Thank you, Michelle. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals Global License for Cevidoplenib, a next-generation SYK inhibitor for the treatment of Immune Thrombocytopenia, or ITP. You can access the slides for today's call by going to the Investors section of our website, agios.com.

Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements due to risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

On the call with me today from Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development.

Joining us for the Q&A session are also Tsveta Milanova, Chief Commercial Officer; and Krishnan Viswanadhan, Chief Strategy and Operations Officer. Following prepared remarks, we will open the call for questions. With that, I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining us. Please move to the next slide. We are pleased to announce that we have entered into a global license agreement with Oscotec, a clinical stage drug discovery and development company headquartered in South Korea for Cevidoplenib, an oral next-generation SYK inhibitor for the treatment of Immune Thrombocytopenia, or ITP.

This agreement represents a natural extension of our long-term strategy, which is centered on building sustainable leadership in rare hematology, starting with our established foundation in hemolytic anemias with Mitapivat and Tebapivat.

From there, we're executing a disciplined expansion into adjacent diseases where we can leverage our proven capabilities, focusing on indications with well-understood biology, chronic management and shared specialist physicians.

Next slide, please. Importantly, we're not starting from scratch. We've built and scaled a differentiated rare hematology capability with Mitapivat, demonstrating clinical proof of activity in PK deficiency, executing a strong early AQVESME U.S. commercial launch in thalassemia and advancing toward potential U.S. accelerated approval in sickle cell disease with additional Phase III data to come at the European Hematology Association Congress later this month. Together, these capabilities spanning development, regulatory execution and commercialization position us to efficiently develop and deliver Cevidoplenib, a next-generation SYK inhibitor in ITP.

Next slide, please. Sarah will provide more details shortly, but at a high level, this transaction represents a disciplined move into a clinically validated mechanism where we believe Cevidoplenib can meaningfully improve on first-generation SYK inhibitors.

And importantly, where Phase II has already demonstrated activity on endpoints aligned with ITP registrational trials. In the U.S. alone, approximately 90,000 adult patients are diagnosed with ITP and roughly 24,000 adults have failed a prior therapy, creating a significant unmet need.

SYK inhibition is a clinically and commercially validated mechanism. However, there are meaningful tolerability limitations with first-generation SYK inhibitors that limit durability of treatment effects. Here, we see potential for Cevidoplenib as a next-generation SYK inhibitor to transform the treatment landscape.

ITP is a clear adjacency to our existing portfolio, one that capitalizes on our existing expertise in rare hematology. Similar to thalassemia, ITP patients are mostly treated by community hematologist, oncologists and also similar to thalassemia, this is a chronic rare disease management model requiring effective, impactful patient support and community engagement.

We view this as derisked across several dimensions. First, the SYK mechanism is clinically validated. Second, the ITP treatment paradigm is well established. And third, Cevidoplenib has already demonstrated activity on endpoints aligned with ITP registrational trials. Above all else, this in-licensing opportunity is disciplined capital allocation with a $25 million upfront payment and milestones gated to key value inflection points and up to $1 billion in nonrisk-adjusted peak year sales potential in the U.S.

With that, I'll hand the call to Sarah to discuss the ITP landscape at a high level as well as the unique attributes of Cevidoplenib. Sarah?

Thank you, Brian. Next slide, please. ITP is an autoimmune disorder characterized by antibody-driven platelet destruction, leading to increased bleeding risk. Diagnosis is often made by exclusion, typically at platelet counts below 100,000 with patients experiencing chronic symptoms such as bruising, bleeding and fatigue.

Despite the availability of multiple treatment classes, ITP remains a disease where durable disease control is difficult to achieve. Of the approximately 200,000 diagnosed patients globally, including 90,000 adults in the U.S., many continue to cycle through therapies without sustained platelet responses.

In practice, the limitation is not lack of options, but the inability of current therapies to consistently deliver durable, well-tolerated responses. On the next slide, you can see the current ITP treatment landscape. First-line therapy remains corticosteroids, which provide rapid platelet increases through broad immunosuppression, but are often not durable and carry meaningful toxicity.

In the second-line setting, Thrombopoietin Receptor agonists are widely used. While effective at increasing platelet production, these therapies do not address the underlying disease biology, contributing to high rates of relapse. More recently, targeted therapies, including BTK inhibitors and first-generation SYK inhibitors have demonstrated activity.

However, durability and tolerability have remained inconsistent. As a result, despite multiple lines of therapy, patients often continue to cycle through treatments without achieving sustained control. SYK inhibition directly targets a central driver of disease biology in ITP. Autoantibody-coated platelets are recognized by Fc receptors on macrophages, activating a SYK-mediated signaling cascade that drives platelet destruction. By inhibiting SYK, this pathway is interrupted upstream, preventing immune-mediated clearance of platelets.

Importantly, because SYK sits at the convergence of these immune pathways, targeting it offers a mechanistically focused approach to address the underlying disease rather than simply increasing platelet production.

Next slide, please. While SYK inhibition has established proof of mechanism, first-generation agents have been limited by tolerability and inconsistent coverage restricting sustained responses. Cevidoplenib is a next-generation SYK inhibitor designed with improved selectivity and a PKa profile that enables consistent exposure and sustained target inhibition, key drivers of durable response in a chronic disease setting.

Clinically, we see clear dose-dependent activity supporting target engagement alongside a favorable safety profile in Phase II without evident dose-limiting toxicities. Taken together, Cevidoplenib is a differentiated SYK inhibitor with the potential to deliver more consistent durable responses in ITP.

Please move to the next slide. Cevidoplenib was evaluated in a global randomized controlled Phase II trial. The primary endpoint was a composite that assessed platelet response greater than or equal to 30,000 per microliter and a doubling of platelet count relative to baseline, an average of 2 previous counts based on the last 2 platelet counts at the time of evaluation.

Importantly, this was a novel endpoint that is not aligned with primary endpoints typically used in ITP registrational trials. In a disease characterized by significant day-to-day platelet variability, an endpoint based on a response at any single visit can introduce variability and may not fully capture the durability of platelets response over time.

When evaluated using endpoints aligned with clinical practice and regulatory precedents, specifically platelet counts equal or more than 30,000 per microliter, we observed a clear separation versus placebo, consistent with biologic activity for this mechanism. And importantly, when durability is considered, defined by repeated responses across visits, the data demonstrates sustained platelet control, particularly at the 400-milligram dose.

Taken together, these results establish a clear signal of clinical activity and support advancement into Phase III with a program designed around durability-based endpoints aligned with regulatory precedents. We plan to initiate Phase III in the first half of 2028 following completion of additional CMC work. With that, I'll hand the call to Cecilia to review the financials.

Thank you, Sarah. Next slide, please. The Cevidoplenib licensing deal is structured to be capital efficient with a modest upfront and the majority of consideration tied to key development and regulatory inflection points. Specifically, the deal includes a $25 million upfront payment and up to $140 million in development and regulatory milestones. While our initial focus is ITP, the structure also provides optionality to expand into additional indications.

On the back end, Oscotec is eligible for tiered royalties and milestones upon successful commercialization. There are 2 points to highlight. First, capital is deployed over time with balance of payments aligned to value-creating milestones. Second, excluding the $25 million upfront payment, we still expect full year 2026 operating expenses to be approximately flat versus 2025.

With that, I will hand the call back to Brian for closing remarks.

Thanks, Cecilia. Next slide, please. This transaction brings together 3 key elements: a clinically validated mechanism, a differentiated next-generation asset and Phase II data demonstrating activity on registrational relevant endpoints. Just as importantly, we've structured the deal with clear capital discipline, enabling us to expand into ITP while remaining fully focused on delivering our 2026 priorities.

Next slide, please. With the addition of Cevidoplenib, we are further strengthening our position in rare hematology, broadening our mechanistic portfolio, adding a next-generation SYK inhibitor and expanding into a high-value adjacent indication where our capabilities directly translate.

Looking ahead, we are focused on advancing Cevidoplenib toward potential Phase III initiation in the first half of 2028, following completion of additional CMC work. We see this as a compelling combination of validated biology, differentiated molecular design and efficacy aligned with registrational expectations, supporting a credible path forward. With that, we appreciate your continued interest in Agios, and I'd now like to open the call for questions. Michelle, please open the line.

[Operator Instructions] Our first question comes from Marc Frahm with TD Cowen.

On the transaction. Maybe one for Sarah. Just I think in the ITP space, we've seen historically a handful of kind of earlier stage smaller data sets look quite attractive and then in different cases, sometimes meaningfully decline but still be positive in Phase III and others get so bad that they ultimately don't get replicated at all in Phase III.

Just what gives you kind of confidence that this data is more reliable than some of those prior cases in ITP? And then maybe just on a process thing on getting to the Phase III in the first half of '28.

Can you maybe walk through what exactly needs to happen? Is that just tech transfer work? Or is there also kind of some longer-term tox studies and things like that, that also need to be completed before you can move into Phase III?

Yes. Thanks, Marc. I'm going to start just by again reiterating we're really excited to have this opportunity. It's a really nice fit strategically with our rare hematology leadership, has diversifying elements, larger market potential, et cetera.

I have the benefit this morning of having Krishnan with us, who has worked really hard on identifying this asset and with the diligence that comes with it. So I think this is a 2-parter. One is differentiation points versus incumbents, which we talked about a little bit in the prepared comments. And the second is the CMC further development.

Yes. So if you look at the ITP market today, what we see is really there is no dominant oral therapy that exists that provides a well-tolerated profile and a durable response. And that's what Cevidoplenib is intended to deliver on.

With respect to your question around what additional activities need to occur, it's really the rate-limiting step is CMC scale up from a process development perspective. It's typical of any oral molecule that's advancing into Phase III registrational trials. That's what we see.

And then as part of diligence, we've done a deep dive in terms of the total data sets that enable us to give confidence around the potential for advancing into Phase III. And I'll turn it over to Sarah around the Phase III components.

Yes. Thanks, Marc. And so I think the question around the confidence of -- based on other SYK inhibitors going into Phase III. So to Krishnan's point, like I think here, the data across several secondary endpoints have been very consistent, including all of the endpoints that are aligned to primary endpoints and registrational endpoints into Phase III.

So that gives us confidence, the consistency across the data there. And then in addition, the safety profile generated in a global Phase II trial was very favorable, meaning that many patients were being able to be assessed, which also gives us confidence into Phase III.

Our next question comes from Gregory Renza with Truist Securities.

It's Anish on for Greg. Congrats on the deal. Just a couple of quick ones from us. First, just on asset differentiation. How does Cevidoplenib's improved, kinase selectivity translate to the consistent exposure mentioned today, that mean for patient tolerability and chronic use?

And second, on commercial synergies, you mentioned a strong overlap with your existing prescriber base. Can you quantify how much of the Mitapivat hematologist base currently treats ITP? How does this asset leverage your current commercial footprint?

Yes. Thanks for the question. So on the first part, the potency of this SYK inhibitor, it's a very potent SYK inhibitor. And at the same time, it is actually very targeted selective inhibition. So some of the kinases that are implicated in some of the side effect profiles are really not being touched by our SYK inhibitors. So that gives us confidence and that paired with the Phase II data observed gives us confidence on that favorable safety profile. And in regards to the overlap in the commercial space, I'll hand it over to Sarah.

Absolutely. We do see this asset with 2 potential commercial synergies, as we mentioned in the remarks. The first one is it is exactly the same community hematology, oncologist treater base. We haven't provided the direct numbers on the actual treater overlap, but it is significant when you look at the community setting and the thalassemia and sickle cell disease. Very importantly, it is the same commercialization model and capabilities, which we have built for thalassemia and we'll continue to expand through sickle cell disease. On 2 dimensions.

The first one is kind of the data-driven targeted deployment, utilizing a lot of claims data and analytics for us to be very efficient in the way we approach our customers. And the second one is the community engagement and the comprehensive patient services capabilities, which are critical for successful execution of a launch like that, both when it comes to patient starts, but also patients continuing on therapy.

In the short term, there will be a very minimal commercial investment given we are starting the study in the first half of 2028. And as we progress the thalassemia and the potential sickle cell disease launch in the future, we will look for further synergies when it comes to the ITP indication launch for [Cevidoplenib].

Our next question comes from Samantha Semenkow with Citi.

Congrats on the in-licensing. I just wanted to ask a bit about the durability response that you've been talking about. What degree of durability are you looking to see? And what gives you confidence that you can achieve that from the Phase II data specifically? And I guess, will you test this as well in Phase III so we can actually see that effect?

Yes. Thanks for the question. So the Phase II data generated in this global trial, there were several endpoints that were specifically looking at a platelet improvement in at least 4 out of 6 visits, which is speaking to durability in the response. And that percentage was higher than what has been generated so far on other -- with other SYK inhibitors and BTK inhibitors. So that gives us confidence to take this forward. And that is, of course, also one of the endpoints that we know is important to continue to study in Phase III. And then the safety, again, like the fact that people have really tolerated this drug very well is important as well as we take this forward into Phase III.

Okay. That's very helpful. And then I had a follow-up. There's one slide where you talk about chronic use with a combinable profile. I'm wondering if you could elaborate a bit on what you mean there. Do you see potential for combination regimens here? And if so, what mechanisms would you see as potential combination partners?

Yes. Maybe I'll have Krishnan weigh in on that one as well because we spent a lot of time studying the ITP market.

Yes. As you think about the evolution of the ITP market, one of the advances we're seeing is combination therapy. So an agent that's very well tolerated is important to have as a combination partner as agents are moving earlier lines. And so we think Cevidoplenib has the potential to really maximize value, both in the context of the second-line population plus as monotherapy with the potential of combination.

Our next question comes from Salveen Richter with Goldman Sachs.

This is Lydia on for Salveen. Could you just speak to any FDA feedback that you've gotten on the Phase II data package, particularly around the lack of [indiscernible] on the primary endpoint?

Lydia, this is Sarah. So in regards to the FDA engagements, we are now going to work on to our Phase III and take the CMC work into account as well. So those will happen in the context of normal development.

Our next question comes from Eric Schmidt with Cantor Fitzgerald.

This is [indiscernible] on for Eric. A few more on the CMC aspect here. Could you share a little bit more on the cost of that CMC scale up and what you're expecting for the probability of staying on schedule for 2 years and how that impacts the cash runway?

Yes. Thanks, [indiscernible]. I think it was a little hard to hear, but I think you were asking about CMC and the cost of CMC. Yes, go ahead.

I'll take the first part. So for -- as we mentioned, for 2026, we are not changing our guidance. Our OpEx does remain approximately flat to 2025. We are looking to absorb the expenses for the next couple of years into our operating expense base as well. So this doesn't change our continued path to profitability.

And I'll comment on the work that's necessary for the CMC efforts. Really, if you think about where the asset is today, the assets have completed Phase II. So the manufacturing has been completed for Phase II. What we're really doing now is scaling up the manufacturing process and optimizing that process to get ready for Phase III to meet an ideal commercial profile.

So really, that's the work that's necessary now. And that's what we intend to do between now to initiate a Phase III trial in the first half of 2028.

Our next question comes from Tess Romero with JPMorgan.

Double-clicking here, how much will this development program in ITP cost Agios? And what is the right way to think about time lines for completing pivotal and a potential approval here?

Maybe Cecilia can start. It's probably a little bit too early, Tess, to comment on the time lines, but we can at least reiterate some of the comments around OpEx.

Yes. So the structure and the time line for this allows us to continue to focus on our 2026 priorities, which we've established earlier this year. The initial spend, as we mentioned, is going to be focused on CMC. And then obviously, starting in 2028, we'll see the Phase III expenses there as well. So we continue to evaluate our cost structure, as we mentioned, if you take out the onetime upfront payment milestone of $25 million, we are keeping the guidance for this year, and we'll continue to evaluate our cost structure as we go through the different catalysts that we have for the rest of the pipeline as well.

And Tess, taking a step back, too, what's really exciting about this is it does set us up without doing time lines today, this sets us up for the next wave of launches to start. And certainly, nearer term, we're quite excited about the opportunity that we have with AQVESME in thalassemia. That launch, as you know, is well underway, has started very nicely.

We're also, of course, looking forward to our opportunity in sickle cell disease with mitapivat. So it's -- the cadence of launches is something that we're very mindful of as well.

Our next question comes from Emily Bodnar with H.C. Wainwright & Company.

This is Joey on for Emily. Congratulations on the deal. Just 2 from us. On safety, just wanted to touch on -- there's transient liver enzyme elevations and GI events seem the most common for -- in terms of AEs. How frequent were those elevations in Phase II? And any patients discontinued due to toxicity, trying to compare it with fostamatinib.

And then on modeling, just wondering the $25 million payment to Oscotec, is that second quarter you're anticipating or later given the first half '28 time line?

All right. So we start with -- Sarah, do you want to start on the safety questions, and then we can bridge to OpEx.

Yes. So the drug was very well tolerated in the Phase II with very limited GI events which are the most commonly observed or one of the most commonly observed AEs on the BTK inhibitors and on the SYK inhibitors. And so nausea and diarrhea is very limited in the patient population. As it relates to ALT increase and AST increase observed in the Phase II, also much less actually compared to others.

And then very importantly, as it relates to safety, there have been cases of hypertension described on other drugs because like as I highlighted before, the selectivity on different kinases is not as specific on certain SYK inhibitor and BTK inhibitors versus Cevidoplenib is actually very specific.

So we -- like the hypertension and the neutropenia that has been observed in these other compounds was also much, much less on this one. So the safety profile overall has been very good. And therefore, we're excited about that aspect. We are excited about the efficacy, of course, but we're also excited about the safety profile and tolerability profile observed today.

And in terms of the upfront payment, similar to how we booked the Alnylam deal back, it's going to be recognized as an R&D expense, and you can model it in Q2.

And our final question comes from Luca Issi with RBC.

Maybe, Brian, congrats on the deal. It seems like a kind of great strategic fit here for Agios. Also, I know this is maybe a little bit of kind of beyond the scope of this call, but this is the first public call since the discontinuation of Tebapivat for MDS.

I wonder if you could comment on what happened there and whether there's any kind of read-through to sickle cell disease? And maybe related to it, if you can kind of remind us the doses that you have tested in MDS versus the doses that you're planning to test in sickle cell disease. Again, any context there, much appreciated.

Yes. And Luca, I'll let Sarah speak in just a second. I'll just say, first emphatic comment, no read-through to sickle cell disease. These are 2 very different diseases. And -- we disclosed last week that we have made the decision to not proceed with development of Tebapivat for MDS for low-risk MDS, but we are very much looking forward to the readout of sickle cell disease, the doses.

Yes. No. And indeed, as Brian mentioned, so we discontinued the program because the efficacy that we observed in this broad patient population, the signal was not strong enough to warrant us to move forward. And as you know, we've had made changes from Phase IIa to IIb, and we went into a more challenging patient population with IIb and indeed also tested higher doses.

These higher doses, they did lead to good ATP increases across the range of the different doses tested there. So we know we really had the full target engagement as it relates to ATP. And very importantly, the safety profile was very good. So from an efficacy perspective, we do not see a read-through to sickle cell disease just because it was a non-hemolytic anemia, a different concept than the other hemolytic anemias that we've tested with PK activation. And that's why we have highlighted that as a high-risk program and the safety profile was very good. And so that is important.

I'm showing no further questions. I'd like to turn the call back over to Brian Goff for closing remarks.

All right. Thanks, Michelle. Thanks, everyone, for joining. In closing, this transaction reflects a clear and disciplined step forward, building on our established foundation to expand into a high-value adjacent indication where our capabilities directly translate. We remain focused on execution with a strong path ahead across our core programs and important data readouts in the near term.

I would like to thank the entire Agios team for their continued dedication and execution, which has enabled us to reach this point and continue to advance our leadership in rare hematology. We look forward to updating you on our progress in the months ahead, including sharing new Mitapivat data in thalassemia and sickle cell disease at the 2026 EHA Congress later this month in Stockholm, highlighted by an oral plenary presentation featuring our Phase III RISE UP trial in sickle cell disease. So thank you very much for your continued support, and we will speak soon.

Thank you for your participation. You may now disconnect. Everyone, have a great day.

All right. Great. Good morning, everyone, and welcome to day 1 of the 2026 Bank of America Healthcare Conference. My name is Alec Stranahan. I cover SMID Biotech here at BofA. And I'm the analyst covering Agios, and I'm pleased to be joined today by Brian Goff, Chief Executive Officer; Sarah Gheuens, Chief Medical Officer and Head of R&D; and Tsveta Milanova, Chief Commercial Officer. Thanks for being here, guys.

Thank you very much.

Yes. We're looking forward to a great 30-minute fireside. But maybe just to start off, Brian, if you want to tee up the conversation with recent updates. You've had a couple of press releases out this morning.

We did, which we're quite proud of. Yes, happy to. And thanks again, Alec, for hosting us yet again. And everybody, thanks for tuning in to learn more about the exciting year and future that we have underway at Agios.

2026 has been a lot of action already in a very good way. We started this year with our launch of AQVESME, mitapivat, for thalassemia. And we just reported our first quarter results, really the first quarter of that launch, which we're quite proud of, great momentum, really good healthy start. Launches, of course, are a long journey. But as a starting point, we're very pleased with how that's begun. And Tsveta is here to share more about that launch as well.

Secondly, as you just mentioned, Alec, we had a press release this morning where we disclosed that we have now filed our sNDA for mitapivat for sickle cell disease. We're pursuing the accelerated pathway, and we disclosed this morning, high level, the construct of the confirmatory study that is affiliated with that accelerated pathway. And I'll just say that for this morning's discussion, we're happy to talk about both of those 2 aspects. We won't go into more detail than what we put in the press release because we have coming in next month at the European Hematology Association meeting, actually a plenary session for RISE UP data for sickle cell disease. And there, we plan to give the totality of the data as well as more details on the confirmatory study.

We also have, as we're building out our pyruvate kinase activation franchise, we have another meaningfully more potent next-generation PK activator known as tebapivat. And tebapivat, we're pursuing in Phase II studies in 2 other areas. One is low-risk MDS. And actually, this quarter, we're looking forward to the readout for -- top line readout for low-risk MDS. We always describe that as a higher risk, very high reward potential program. And then secondly, also in sickle cell disease in the second half of this year, we have a Phase II study with tebapivat. We're looking forward to that data readout.

We have a couple of other earlier-stage Phase I programs. One is AG-236 for polycythemia vera, right in our sweet spot of rare hematology. And we have AG-181, which is a very novel mechanism for phenylketonuria, also Phase I study in PKU patients, and we're looking forward in the second half of this year to proof of mechanism data.

So the last thing I'll say is we are very focused on capital allocation discipline, OpEx discipline. We've guided to keeping our OpEx approximately flat to 2025. And I must say, given this range of high-quality value-creating opportunities, it is a challenge, but we're very committed to that. So exciting year, a lot to talk about, and I'll turn it back to you for questions.

Great. Yes. Obviously, a lot going on at Agios right now. And you mentioned a couple of key updates. You've got your newly launched product in thalassemia, AQVESME; an sNDA filing expected, I guess, now in 2Q or in 3Q for sickle cell; and tebapivat Phase II readout is coming this year, I guess. If you had to sort of direct the conversation, where do you see the biggest re-rating catalysts across these 3 milestones?

Interesting question. So you're indirectly asking me to pick a favorite catalyst, which I will not do because I think it's really exciting right now at Agios. And fundamentally, our mission is to deliver on all fronts. One way you could think about it is investors often look at 2 different things simultaneously. One is -- one lens would be short-term value creation, of course. And there, we have a lot to talk about with AQVESME as well as the pathway for mitapivat in sickle cell disease. And the other is investors are looking at how can you continue to advance and grow your PK activation franchise. And there, again, with the benefit of tebapivat and some really exciting near-term Phase II readouts, that's a really nice setup for the potential ahead.

I think from our perspective, as I said, all 3 are important, whether it's commercial execution, which Tsveta and the team are doing a really terrific job or regulatory progress. And there, Sarah and her team, as we just disclosed this morning, are really advancing things nicely. And then, of course, just continuing to move the pipeline along and diversify.

Great. You had a pretty meaningful update this morning, the alignment on the confirmatory endpoint of transfusion dependence in sickle cell. It sounds like the sNDA is over the finish line. So that's the ticking clock, 60 days, puts you in 3Q for an acceptance and a PDUFA date with an accelerated time line would put you maybe beginning of 2Q. Is that kind of the right way to be thinking about the path forward?

So we have -- I think you're right on all fronts about now we can check the box of sNDA filed confirmatory study clearly aligned. We feel very strongly that this represents clinical benefit as aligned with the FDA and certainly the community. But maybe I'll have Sarah talk a little bit about where we go from here and next steps.

Well, yes. So we are very excited about the update that we were able to give this morning. So the submission of the sNDA, which means that we indeed have alignment on the confirmatory trial in which we are further looking to demonstrate clinical benefit. As you know, we've observed very strong clinical benefit in the hemoglobin responders, which allows us to go on this path. And we've announced the details of the trial as well this morning in which we -- as you may have noticed, is 159 patients. So it's a relatively small sample size.

We try to optimize trial execution and feasibility as well as taking trial costs into account and are very pleased that we were able to get to alignment with the FDA, which allowed us to make that announcement this morning. Further data, we will be presenting at EHA that underpins the clinical trial. So more to come at EHA. Plenary there is, of course, a very big thing for us. So we're very excited about that.

And as it relates to the milestones, you've mentioned, indeed, it's now 60 days that the FDA -- that clock is basically ticking, which brings us to Q3 in which we'll get more insight in the PDUFA date at that point as well.

Great. I guess maybe double-clicking on the transfusion dependence. I think this was the question that folks had. And also the study population, you're now going from 12 years old and up, whereas RISE UP, I think, was 18, right?

16.

16. So I guess when you think about the powering assumptions within the study, how did you come to 159? It's a very specific number. And what would you expect on that transfusion burden dependence endpoint, especially as you move to earlier patients?

Yes. So it's indeed transfusion independence that we're looking for between week 4 and week 52. We are enriching the trial population to an episodically transfused patient population to be able to demonstrate that benefit, and it is completely informed by the RISE UP data that we have. So that data, as I mentioned, will be presented at EHA. Again, it's really about the sample size we need to be able to demonstrate clinical benefit driven by the data and then, of course, the feasibility on execution.

Okay. And I guess on that transfusion burden dependence, is there any signals that you've provided, either the top line of RISE UP or earlier data that you point investors to, to sort of understanding the potential benefit there? Or is it more of an additional burden of proof at EHA that will be supporting that data?

No. So it's -- the data was prospectively and systematically collected in RISE UP. So it's that data. We had episodically transfused patients in RISE UP. So that's the data that we base this on. This is completely informed by RISE UP data set. So all of that detail, though, we will highlight at the plenary. So come to the plenary.

Okay. And I guess on the perceived benefit from physicians that you've spoken to, obviously, you've got the hemoglobin benefit. I think that's pretty concrete from the data that you've shared. When you talk to physicians, what's important for their patients in terms of a meaningful benefit to disease? I know sickle cell pain crises has been sort of held in the industry, but it hasn't really proved out to be a great clinical endpoint. So how does transfusion burden dependence kind of reflect the patient need?

Yes. So it's like hemolytic anemia. So people do need on occasion transfusions for a variety of different reasons as we've seen in our clinical trial, just like other hemolytic anemias in which case people may not need regular transfusions, but they still need transfusions. So we have demonstrated a benefit in these other indications on transfusion burden. And in the RISE UP trial, again, we have clinically meaningful data there as well.

For sickle cell disease specifically, it is a problem. They really are trying to avoid transfusions because each transfusion can lead to alloimmunization and it's becoming then harder to transfuse people as well. So something that can lead to avoidance of transfusions altogether is always welcomed in sickle cell disease and hemolytic anemia.

And maybe, Tsveta can just add here, too, because, again, just to reinforce the confirmatory study, of course, and the transfusion endpoint is what is aligned as clinically beneficial, but really for the accelerated pathway, right? The bigger picture, I think, Tsveta could talk about for the hemolytic anemia profile.

Absolutely. The potential label based on the accelerated approval will be really based on the RISE UP data we've presented. And we had an opportunity to interact with the clinical community at ASH and follow-up ASH after we presented kind of the data as a press release about their feedback on the profile. So what we are hearing is like basically 3 things. The first one, they are very excited about the hemoglobin responder data because it very much aligns with how they treat and manage their patients. They will look for hemoglobin response, hemolytic parameters response and seeing that if they see an improvement from that aspect, the patients could potentially have a longer-term benefit in terms of quality of life, fatigue as well as VOCs is very beneficial.

The second thing that gives them confidence is the consistency of the data they see in sickle cell disease across the 3 hemolytic anemias that we have studied the product in PK deficiency, thalassemia and now sickle cell disease. And that also translates to the third point, which is the in-market experience with the product, both through the launches that we've had in PK deficiency and thalassemia and the years of patient exposure in the market and across the clinical development of mitapivat. And all of these 3 elements are very important for that community from a clinical perspective, but also from a patient perspective who will be looking for that experience as well.

And I'll just -- I'll add to that, that one, we get a lot of questions from investors about our profile, etavopivat and so on. And safety should not be underestimated. And the fact that as Tsveta notes, we now have years of safety establishment with mitapivat, very robust data set in sickle cell disease specifically. And the fact that we've got synchronization of the thalassemia AQVESME launch underway at the same time, where there is overlap of clinicians who treat thalassemia patients as well as sickle cell disease, that's a pretty important attribute that we have as well.

Right. And obviously, in RISE UP, if you go one level deeper on the hemoglobin responders, you actually do start to see a benefit on the pain as well.

Across the cohorts. Yes.

You mentioned etavopivat from Novo. We saw their Phase III data recently. I guess did these -- there was kind of a temporal overlap with the conversations you were having with the FDA. I wonder if that readout fed into any of the discussions you were having around your...

Well, the short answer is no. So that data did not influence our regulatory path. As we highlighted, we are on that accelerated approval path. In regards to the data that was announced, it's very limited, right? The data that was announced. So we really need to wait and see and get more data to be able to put interpretation around the numbers that were given.

In short, I think for us, it's -- what was put out there confirms that PK activation is a good thing for sickle cell disease. And so that, of course, is where we are excited because with PK activation, we have mitapivat that is now really far ahead. And I think the safety exposure on that product is really very important. And then we also, of course, have tebapivat, which is the next-generation PK activator that we're studying. And for which we are having a data readout for sickle cell disease second half of this year.

Yes. I guess just a follow-up to that, Sarah. In a world where there's multiple oral PK activators, whether it's mitapivat and tebapivat or mitapivat, etavopivat, I guess, what do you ultimately think drives prescribing here? Is it on the efficacy differentiation? If so, what is the efficacy endpoint that you differentiate on? Is it safety, like Brian mentioned? Is it on kind of timing to market? How do you think about that?

It's a little bit of everything, I would say. I think it's really a little bit of everything. The efficacy part, of course, it's hard to comment on that because we don't know everything yet on the other PK activators, right? So -- but experience in market is really important and then the safety exposure that is something that mitapivat is uniquely positioned with right now because we have so much across a different range of diseases, very important in the context of this disease as well.

Yes. This is -- I mean this one for sure is multifaceted. You have the product, as we talked about, clinical efficacy data, safety, experience in the marketplace. Then, of course, you have access dynamics that we have a lot of experience of how to navigate through that in rare diseases. And then, of course, I think sickle cell disease needs to be held to a kind of different standard because of the long legacy of setbacks this community has had. Trust and connection with the community really makes a big difference. And we've invested and I think invested in that and have established great credibility with the community broadly.

Okay. That's great. I guess last question on sickle, and then I want to talk about the AQVESME launch. Just around the sNDA, which label that will fall under? Is it PYRUKYND or AQVESME? Obviously, the REMS doesn't seem to be a huge hurdle for thal. It sounds like it's not a big burden either in sickle. But how do you sort of think about which bucket to drop sickle in?

Yes. So as you know, we have optionality, right? We have PYRUKYND without REMS and AQVESME with the REMS. I think one thing, if I may say, like I think Tsveta's team now has shown that they can really flawlessly execute on a launch in a rare disease with the REMS. So that's one. And then the second piece, of course, is, as we've stated before, that in RISE UP, the data is really favorable on the safety front. So this may not warrant the REMS. So more to come.

Okay. Okay. Is there a consideration around pricing within that, too? Because I think each drug has a different price point.

As Sarah mentioned, commercially, we'll be ready to execute irrespective of the scenario. And really, once we have the label, we will assess the pricing opportunities there. And of course, we'll monitor the competitive environment. But irrespective of the brand name, I think we'll be very well positioned to maximize the opportunity.

Okay. Great. And maybe we can shift to thalassemia. So you went from 44 prescriptions in January to 242 by the end of 1Q, which is a pretty strong sequential build. I guess what are sort of the internal metrics you're watching most closely to judge whether the launch is on track?

Absolutely. As Brian mentioned, we are very pleased with the initial reception of the thalassemia community when it comes to AQVESME. When I look at the first quarter, we generated 242 prescriptions from REMS-certified physicians. I wouldn't consider kind of the buildup from 44 to 244 (sic) [ 242 ] as a sequential growth because the demand was actually generated consistently across the quarter. The unique dynamic that we had is that the REMS was not operational until end of January. So some of the demand that was generated in January got pulled through later, but we still had a very, very strong quarter, reflective of the 242 prescriptions.

Looking ahead, the 2 elements that we were really focused on is increasing the breadth of prescribing because thalassemia is managed in the community. And as we think about sustainability of the launch over time, that's a very important element for us. We saw a very strong geographic representation from across the country in the first quarter, and we'll continue with these efforts. And the second element is the efficiency of moving patients through the REMS program because that is really important as we initiate therapy and patients continue on that dimension as well. And that will really allow us to further penetrate the NTDT patient segment, which is 2/3 of the opportunity for us.

Yes. Great.

And can I just add one thing, Alec, too, is that your very first question, if you had asked me maybe 3 months ago, which of the catalysts are the least appreciated by the investors? I think AQVESME fits right up there. And what's so exciting about where we are now is this team really knows what they're doing in rare diseases. And we knew that thalassemia would be a particularly hard launch to analog, so to speak. And we knew it was a show-me story. And here we are, as Tsveta said, great start. Of course, launches are a long journey. So we're already looking ahead several continued segments of penetration down the road, but the team is really executing well. And again, given all the things that we have in front of us, the timing is perfect because the next show-me story will be upon potential approval in sickle cell disease, okay, let's see how you can do, and this is a really nice backdrop.

Okay. And I guess, how should we think about scripts trending in 2Q and beyond? 44 to 242 is a big jump, but you expect that early in the launch. I guess, how should we be modeling scripts? And then you also have the 10- to 12-week lag as well. So how should people be thinking about the scripts ramp and also the conversion into sales?

Yes. As I said, for me, I think it's important to look at the first quarter as a totality of the 242 rather than the kind of acceleration from 44 to 242 because that's really a representation of demand across the full quarter.

Moving forward, the things that I said are very important for us. We will continue with breadth of prescribing when it comes to the clinicians and the penetration into the NTDT segment, which is going to be driven by continuous education, but also the fact that AQVESME has been on the market and that experience in the market is going to increase as well.

And the third element, we mentioned the 10 to 12 weeks from prescription to treatment initiation. In the initial quarter, that was actually a little bit shorter, and that's not completely unexpected because you get the most engaged and eager both patients and physicians to prescribe. Over time, we expect that to move closer to the 10 to 12 weeks. And that's primarily driven by the fact that we'll be penetrating the NTDT segment with patients who have less frequent physician visits, and they might take a little bit longer to kind of complete all the steps of the REMS.

When you think about actually time from prescription to treatment initiation, another important aspect is the insurance dynamic. That's completely independent of REMS, that's standard for any specialty program. And as the team is advancing in terms of getting payer policies in place and going through the REMS process, we'll be looking to shorten the time as much as possible as well.

Okay. And maybe just one further point on the transfusion dependent and non-transfusion dependent. You mentioned that the NTD patients are roughly 2/3 of the addressable population here. I guess what are sort of the specific levers that drive that inflection towards the larger NTD segment? I know most of the patients in early prescribing were transfusion dependent.

Absolutely. And the team already has done a great job in starting to penetrate that segment. In the first quarter, we had both transfusion-dependent patients as well as very engaged non-transfusion-dependent patients. And we see prescriptions coming also from the alpha and beta segment of the population, which is fantastic.

Looking ahead, we'll continue to do 2 things, which we have been already doing, and one of them is education, education on the burden of disease in the NTDT segment, which was a very strong focus for us ahead of the launch and continues to be. And the second one is really ensuring that there is a good understanding of the in-market experience with AQVESME, especially in the NTDT segment.

The TD segment is very well connected through the patient associations, and there is a lot of patient-to-patient interaction, and we'll look for ways to ensure that the NTDT segment also start hearing about that in-market experience. And as the clinicians get more comfortable with the product, we see that as an important step to move to penetrate that space as well.

I would add one really fascinating dynamic about thalassemia is it's a little bit of a global launch within the U.S. in a way because you have the Mediterranean population as a key part in the United States, Arabic. And then in the case of alpha thalassemia, it's often the Asian population. And one key feature that Tsveta and the team have put in place is multilingual, multicultural patient support. We have people who speak Arabic, Mandarin. Tsveta shared a recent example of even a thalassemia patient who needed American sign language, and we were ready. And those kinds of little vignettes of patient experience have incredible word-of-mouth effect as well. And so that will be really important as we penetrate further into the non-transfusion-dependent population.

So white glove service.

Very much so in a way that really matters.

Yes, yes, yes. And I know you've got a positive CHMP opinion in hand and also EC approvals may be imminent or expected shortly, I guess. How should investors frame the ex-U.S. revenue contribution? Is that maybe a second half? Or is that more of a 2027 sort of across Europe and the Gulf?

So we have a very capital-efficient deployment strategy when we think about commercial geographic expansion ex-U.S. First and foremost, the U.S. continues to be our biggest commercial opportunity, and we just talked about the successful start of the AQVESME launch, and we plan to continue on that one. Ex-U.S., there are 2 regions of importance. First is the Gulf region, GCC, that's driven by the prevalence of that region and the first approval for thalassemia is within the Kingdom of Saudi Arabia. What's important for that region is that there is a high prevalence of thalassemia. A small proportion of patients are actually managed in the institutions, but what is going to drive the actual penetration in the market and ultimately revenue is the market access process that is in there.

And initially, what happens in these regions is that you have named patient sales and prescriptions until the product gets the national procurement and kind of national adoption and penetration based on the tender dynamics in those countries. So for the first couple of years, we would expect kind of low penetration and slow ramp of the revenues.

In Europe, after we have the approval formally, we've been working with our partner, Avanzanite to prioritize markets with high prevalence of thalassemia as well as pricing and reimbursement system, which will support the value proposition of AQVESME, and we'll be executing on these selective launches across the region. Again, the European health care systems actually have a lag between European approval and actual in-country reimbursement of about 12 to 18 months. So I see the ex-U.S. opportunities really ramping up, not in the first couple of years of launch, but further down the line. That's why we continue to be focused on the U.S. and executing there.

Okay. That makes sense. And maybe one last question. I want to circle back on the EHA presence that you guys have. I think 10 presentations accounted in your press release. I imagine most folks will be focused on the RISE UP plenary. But maybe thinking more broadly, I think there was also some data for thal, some data on kind of benefits of long-term treatment. So maybe you could just unpack sort of the abstracts that we saw.

Yes, exactly. So we're very proud of our presence at EHA, which again confirms that PK activation is a good thing for hemolytic anemias across the board. The plenary -- the RISE UP plenary, of course, is like the crown jewel. It's going to be exciting to be able to present the totality of the data there and show the clinical benefit that we have demonstrated.

And then in regards to thalassemia, we continue to demonstrate long-term benefit. We were also able to include data on the placebo switchers who went into the open-label extension on drug and have shown even a better hemoglobin response rate in that group. So very excited about that data across the board.

And can I take the opportunity to drop in a plug? So we have, in addition to the very exciting RISE UP plenary in Stockholm, Sweden at EHA, we also will have on that Saturday, an investor event as well. And again, as we said upfront, we'll be really excited to unpack even more about RISE UP, talk more about the confirmatory study and of course, the rest of our exciting pipeline to come.

Okay. Great. Well, we'll stay tuned for that in June. And I think with that, we're out of time. So Sarah, Tsveta, Brian, thank you so much for the great conversation. Thanks, everyone, for attending.

Thanks a lot, Alec. Thank you, everyone.

Thank you.

Good day, and thank you for standing by. Welcome to the First Quarter 2026 Agios Financial Results and Business Highlights. [Operator Instructions] Please be advised that today's call is being recorded. I would now like to hand it over to our first speaker, Morgan Sanford, Head of Investor Relations at Agios. Please go ahead.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals First Quarter 2026 Financial Results and Business Highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

On the call with me today from Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions. With that, I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining us. Next slide, please. At the start of the year, we outlined our 2026 strategic priorities, which are designed to drive both near-term execution and long-term value creation. We are off to a strong start entering another catalyst-rich year with clear momentum across these priorities. Turning to first quarter highlights on the next slide. We delivered $20.7 million in net revenues, representing 138% growth year-over-year. The first quarter marks the U.S. commercial launch of AQVESME in thalassemia with the REMS fully operational as of the end of January. And already, we have shown strong initial demand. We continue to expect 2026 operating expenses to be approximately flat versus 2025, and we ended the quarter with a strong balance sheet, including over $1 billion in cash, cash equivalents and marketable securities. Importantly, we've advanced two priorities that are key to our growth inflection.

First, the U.S. commercial launch of AQVESME in thalassemia is off to a strong start with 242 prescriptions written as of March 31st by REMS-certified physicians, building significantly on the 44 prescriptions we reported as of the end of January. This early progress reflects solid execution as the launch continues to broaden. Tsveta will provide additional details shortly, but the early momentum highlights the strong work and rare disease capabilities of the Agios commercial team.

Second, following our pre-sNDA meeting with the FDA in the first quarter, we now plan to submit an sNDA for mitapivat in sickle cell disease in the second quarter under the U.S. accelerated approval pathway, marking an important step toward expanding our PK activation franchise into a significantly larger indication. I also want to underscore the caliber of our team whose ability to respond rapidly and rigorously to FDA feedback reflects the deep regulatory and scientific expertise we've built at Agios.

Next slide, please. Stepping back, our strategy is to build a sustainable rare disease company, anchored by a foundation in rare hematology. In the near term, our focus is on executing the AQVESME U.S. commercial launch in thalassemia and advancing the mitapivat sNDA filing in sickle cell disease. In parallel, we are preparing for important mid-term catalysts, including Phase II top line data for tebapivat, our next-generation more potent PK activator in both lower-risk MDS and sickle cell disease this year.

And over the longer term, we continue to advance our early-stage clinical programs and selectively evaluate expansion into other rare hematology diseases rather to support our sustained growth. With that, please advance to the next slide, and I'll turn the call over to Cecilia to discuss financials. Cecilia?

Thank you, Brian. The next slide summarizes our first quarter financial results. As we have previously shared, we will report mitapivat net revenues with U.S. and ex-U.S. components. In the first quarter, we delivered $20.7 million in worldwide mitapivat net revenues with $18.8 million from sales generated in the U.S., driven by the recent launch of AQVESME in thalassemia. Outside of the U.S., we reported $1.9 million in sales, reflecting expected quarterly fluctuations. We reported $81 million in R&D expense in the first quarter, an increase of roughly $8 million from prior year due to workforce-related expenses supporting pipeline advancement efforts as well as increased mitapivat process development expenses.

We also reported $48 million in SG&A spend, up approximately $7 million from the prior year due to an increase in activities to support the U.S. commercial launch of AQVESME in thalassemia as well as an increase in stock compensation expense. We ended the quarter with over $1 billion in cash, cash equivalents and marketable securities, positioning us well to remain disciplined as we invest to maximize portfolio value and build a pipeline for long-term growth. Turning to our approach to capital allocation on the next slide, our priorities remain clear.

First, we will continue to maximize the U.S. commercial launch of AQVESME in thalassemia. Second, we are managing operating expenses in a way that is aligned with our long-term value creation. Based on our current plans and accounting for the mitapivat confirmatory clinical trial in sickle cell disease, we anticipate 2026 operating expenses to be approximately flat compared to 2025. Finally, we will continue to diversify our pipeline, leveraging both internal capabilities and external innovation as we continue to execute our 2026 priorities with a disciplined approach to long-term growth. Please advance to the next slide, and I'll turn it over to Tsveta to cover commercial highlights and early AQVESME's use thalassemia launch dynamics.

Thank you, Cecilia. Next slide, please. Our commercial performance in the first quarter reflects exceptional execution as we transitioned the focus of our field force from PK deficiency to thalassemia. In the U.S., net revenues were $18.8 million, driven by strong early AQVESME launch demand. Outside the U.S., we reported $1.9 million in net revenue, driven mainly by thalassemia utilization in the GCC. This is in line with our expectations given early market access dynamics ahead of securing government procurement. As in prior quarters, we expect to see continued variability quarter-to-quarter, driven by ordering patterns, inventory dynamics and gross to net.

Please move to the next slide. I'm very encouraged by what we are seeing from the AQVESME U.S. launch so far, and I want to start by acknowledging the tremendous work of our commercial, medical and patient support teams. Launch execution in rare diseases is complex and the early progress we are seeing reflects both strong preparation and the depth of rare disease commercialization expertise we have built at Agios, supported by close coordination across the organization. 242 prescriptions were written in the first quarter by REMS-certified physicians, serving as an important early indicator of strong demand, keeping in mind the REMS became operational in late January.

Here are a few points that are worth highlighting to help frame how we're thinking about these early signals. As we exited the first quarter, early adoption was concentrated among highly engaged patients, including transfusion-dependent and motivated non-transfusion-dependent patients. This is consistent with expected early launch dynamics. In the first quarter, time from prescription to initiation was shorter than expected. This was due to early engagement by patients with stronger motivation to initiate treatment, physician readiness to prescribe as well as effective REMS coordination.

However, we continue to expect average initiation time lines of approximately 10 to 12 weeks in the coming quarters as we advance deeper into patient segments with less frequent clinical engagement. We are encouraged by the geographic breadth of early prescriber adoption, which has been driven by community-based hematologist oncologists. What we're seeing so far gives us confidence in our launch readiness and the quality of demand in the early days of launch. That being said, we do not view early prescription volumes as translating into a steady run rate at this early stage of launch, particularly as demand moves more towards non-transfusion-dependent patients and adoption progresses beyond the most motivated, highly engaged patients.

The next slide captures both, the strong early reception of AQVESME and how we're building towards sustainable growth. Feedback from the field has been very encouraging. Physicians and patients recognize AQVESME's meaningful clinical profile. REMS onboarding is running smoothly, and our patient support services are helping patients initiate therapy. As we look ahead, our focus is on three things: first, expanding prescriber engagement across both academic and community settings; second, broadening adoption into non-transfusion-dependent patients who represent most adult diagnoses; and third, advancing payer access to support timely treatment initiation.

Taken together, we are encouraged with how AQVESME is being received in the early days of launch, and we are focused on executing against the key levers that will drive durable adoption over time. I'm very proud of the team's execution to date. The performance in the first quarter reinforces the team's launch readiness and deep understanding of this market. We believe this strong foundation positions us to deliver on both the launch of AQVESME in the U.S. as well as potential future launches as we look to expand our rare disease portfolio. Please move to the next slide. And with that, I will hand the call over to Sarah to cover key R&D highlights from the quarter.

Thank you, Tsveta. Next slide, please. We continue to advance a robust pipeline anchored by our PK activation franchise and complemented by differentiated early-stage clinical programs. In the first quarter, we announced plans to initiate two pediatric mitapivat trials in thalassemia, ENERGIZE-KidsT in transfusion-dependent patients and ENERGIZE-Kids in non-transfusion-dependent patients. We look forward to the potential to expand access to this transformative medicine into pediatric populations. Finally, we are looking ahead to upcoming second quarter readouts, including Phase IIb top line data for tebapivat, our next-generation PK activator in low-risk MDS.

This study evaluates 10-, 15- and 20-milligram dose levels across a broad patient population with eight consecutive weeks of transfusion independence as the primary endpoint. While this represents a higher risk opportunity, we see meaningful potential for an oral therapy in this setting. Please move to the next slide. In the first quarter, we completed a pre-sNDA meeting with the FDA and aligned on a path towards U.S. accelerated approval for mitapivat in sickle cell disease. Since that meeting, we've had a series of informal and formal engagements to gain official alignment on the confirmatory clinical trial required under this pathway. We are pleased with the progression of these discussions and now expect we will file an sNDA in the second quarter. We look forward to sharing additional data from the RISE UP Phase III trial at an upcoming medical congress, including analyses that informed our selection of the confirmatory clinical trial's primary endpoint.

Taking a step back, as we consider development of the confirmatory trial design, we emphasized operational feasibility, including enrollment time lines and time to completion while looking to maximize probability of success and the potential to further enhance the mitapivat label should U.S. full approval be granted upon results of confirmatory trial. Next slide, please. In parallel, we are advancing tebapivat, our next-generation PK activator in Phase II studies across low-risk MDS and sickle cell disease.

Tebapivat was intentionally designed to go beyond first-generation PK activators. It is structurally differentiated with potent dual activation of PKR and PKM2 and PK and PD properties that support once-daily dosing without the need for a taper. Importantly, the early clinical data reflect these design features. In sickle cell disease, tebapivat demonstrated a long half-life of approximately 87 to 93 hours, dose-dependent reductions in 2,3-DPG and increases in ATP and pharmacodynamic effects that remain durable for up to four weeks after the last dose.

We also observed a mean hemoglobin increase of 1.9 grams per deciliter at the 5-milligram once daily dose. Beyond red blood cell metabolism, tebapivat shows broader biological activity driven by PKM2 activation. In preclinical models, this translated into antifibrotic effects, including reduced glomerular injury and myofibroblast signaling, supporting the potential for disease-relevant activity beyond mature red blood cells. In low-risk MDS, we observed early clinical signals, including transfusion independence in the low transfusion burden cohort.

However, we observed 60% lower drug exposure relative to healthy volunteers, which prompted investigation at higher doses. The ongoing Phase IIb study, which is evaluating higher doses in a broader lower-risk MDS population will test the hypothesis that deeper PKR and PKM2 activation may extend biological activity into erythroid maturation in the bone marrow. In sickle cell disease, our Phase II study is designed to rapidly assess hemoglobin response and key markers of hemolysis to confirm whether this deeper biology translates into broader clinical benefit.

We look forward to reporting top line Phase IIb data in low-risk MDS in the first half of this year, followed by top line Phase II data in sickle cell disease in the second half of 2026. With that, please move to the next slide, and I will hand the call back to Brian for closing remarks.

Thank you, Sarah. Next slide, please. As you've heard today, 2026 is shaping up to be a growth inflection and catalyst-rich year for Agios, with meaningful progress across our commercial business and our pipeline. In the first half of the year, we advanced the regulatory path for mitapivat in sickle cell disease, and we expect Phase IIb top line data for tebapivat in lower-risk MDS, along with Phase I healthy volunteer top line data for AG-236. In the second half of the year, we anticipate Phase II top line data for tebapivat in sickle cell disease as well as Phase Ib proof of mechanism data for AG-181 in phenylketonuria.

And throughout the year, we remain focused on executing the U.S. commercial launch of AQVESME in thalassemia with the goal of building a strong and sustainable commercial foundation. Next slide, please. Stepping back, we believe Agios is differentiated by the combination of a growing commercial base and a pipeline increasingly weighted towards later-stage high-value opportunities. As shown here, our current pipeline represents greater than $10 billion in potential market opportunity in 2030.

Most importantly, everything you've heard today is grounded in our commitment to the patients we serve, patients living with serious and often underserved rare diseases who are still waiting for better treatment options. I also want to recognize and thank our employees. Their focus, expertise and dedication are what make this progress possible from advancing critical clinical and regulatory milestones to executing a complex commercial launch with care and discipline.

With that, we appreciate your continued interest in Agios. And I'd now like to open the call for questions. Operator, please open the line.

[Operator Instructions] Our first question comes from the line of Samantha Semenkow from Citi.

Congratulations on the early launch progress for AQVESME. And just sticking with that theme, first question then is just a little bit about the demand of AQVESME you're seeing thus far in the second quarter. I'm wondering if there is a bit of a bolus component in the first quarter from those highly motivated patients. But as you look into the second quarter prescription performance, are you seeing a similar cadence in those prescriptions coming in as well as an increase in REMS-certified health care professionals? And I have a follow-up.

Sure. Thanks, Sam. I'm going to let Tsveta comment. And of course, we're going to stick to the first quarter dynamics, but there's obviously good momentum that we were proud to report today. So Tsveta, you want to take over?

Absolutely. So as I said, we are very excited with the early launch and the progress we've made. We said we had 242 prescriptions from REMS-certified physicians as of March 31st. The early uptake is really driven by the highly engaged and motivated patients, which included both the transfusion-dependent patients and the motivated non-transfusion-dependent patients. I wouldn't take Q1 to be the run rate for upcoming quarters. But what I can tell you is that we still expect very strong demand and uptake as the team continues to execute very strongly and the reception from both patients and physicians on the AQVESME profile has been very, very positive.

And Sam, you had a follow-up?

I did. Yes. That was helpful. A couple of follow-ups on tebapivat. Just first on the timing of the MDS data. I'm wondering if there's any additional clarity you could share there on when that data will come this quarter? And then just secondly, on sickle cell disease, I'm wondering how you're thinking about the market opportunity for mitapivat given some recent competitor's data? And then just how do you think about developing mitapivat? And obviously, you're moving towards accelerated approval filing, but you have tebapivat in the second half, that could have potential best-in-class efficacy based on those early data signals you walked through in the prepared remarks. Just how are you thinking about that market developing as we go forward?

So we'll go in sequence. Sarah can comment on tebapivat for MDS and basically, given the timing that we're expecting.

Exactly. So Sam, the timing that we've highlighted is the first half of this year. And so that is what we're sticking to. And then for sickle cell disease, the timing is the second half of the year and the teams are making great progress towards those deliverables.

And then I'll turn it back to Tsveta to comment on -- we're clearly, Sam, in a position of strength, having mitapivat and all the progress that we talked about this morning for our accelerated pathway for sickle cell disease and then the benefit of having tebapivat, the next-generation more potent PK activator that we're looking for to Phase II data. But Tsveta, perhaps you can talk about the overall franchise goal that we have.

Yes, absolutely. We see a very significant commercial opportunity in sickle cell disease, including both mitapivat and tebapivat. When we think about mitapivat, we see sickle cell disease as a disease that can support multiple treatment options, and we will be looking to maximize the commercial opportunity, assuming that we have a label. And that's driven by the fact that we've seen a very strong response and positive response from the KOL community on the strength of our hemoglobin responder data. They are communicating about the need of antihemolytic agent, especially an agent that can -- with hemoglobin responders can demonstrate a potential benefit in other meaningful endpoints such as quality of life and potential reduction in pain crisis.

So we haven't seen the HIBISCUS data yet to be able to comment more on but we're starting from a position of strength when you think that this is our third indication in the market. There is a strong familiarity of that community with the product. We have over 1000-patient years of data and a strong market experience, and we will see that as a good anchor for our franchise building. When it comes for tebapivat, of course, we'll need to see the Phase II data. We'll need to see how the competitive environment moves forward, but we'll be looking to have a best-in-class positioning with that product, and we'll provide more information as we get the data.

Our next question will come from the line of Alec Stranahan from Bank of America.

Congrats on all the early launch progress this quarter. Two questions from me, one on sickle cell and one on the launch in thal. I guess, first on thal, in patients transitioning from the clinical study to commercial drug, is covering costs of therapy part of ensuring continuity of treatment? Just trying to think through how many of the 242 scripts for patients moving from the clinical trial and how they might translate to revenue this quarter and going forward?

And then on the sNDA for sickle, curious when you expect to get feedback from the regulator on the proposed design of the confirmatory study and whether that's an update you'll share or if the next we'll hear on the program is just that the sNDA has been submitted.

Yes. And I think Sarah can -- we'll take them in sequence, starting with thalassemia and maybe just comment on the open-label extension and the studies.

Exactly. So Alec, so patients are in open-label extensions on the thal clinical program. So those are still ongoing and of course, help us to continue to highlight the maintenance of effect in this patient population. And in addition, the proportion of U.S. patients in those studies is small because it's a big global study.

In regards to sickle cell disease, we are very pleased with the progression of the engagements we've had and the pace of the engagements we've had with the FDA, which, of course, allows us to further fine-tune the time line for submission. So we've updated to say that we would file in Q2. More details on the clinical trial, we will highlight before it goes on clinicaltrials.gov. And then, of course, we've stated that we will also present data at or around EHA and that data did inform us in this trial.

I do want to take a step back here and just highlight that, as I stated in my prepared remarks that the trial, of course, is also designed in such a way that we prioritize operational feasibility and probability of success here. And so that is going to be our focus with this.

Okay. Maybe I could just follow up just on the continuity of treatment piece. I guess of the 242 scripts, I guess, how many of those were booked as revenues in the quarter? And I guess, how do you see that evolving sort of as payer access comes online over the coming quarters?

Cecilia, do you want to comment on the metrics?

Yes. So as we stated, we split U.S. and ex-U.S. revenues. So it's probably U.S. revenues, the way to think about it is we guided PKD to be about $45 million to $50 million for a year, and the quarter has been in line with that with the rest coming in from thalassemia. There is a lag on the prescriptions to when patients get on therapy, and that's what Tsveta was saying. We've seen it be a little faster than what we thought, but we think it's going to eventually be in that 10- to 12-week range.

Our next question comes from the line of Emily Bodnar from H.C. Wainwright.

First one, with your conversations with the FDA about the sNDA for sickle cell disease, are you also expecting a REMS for sickle cell disease? Or is that only for thalassemia? And then a follow-up question. With the Phase II sickle cell data for tebapivat expected later this year, can you maybe give us some expectations about what you'd like to see relative to Phase II data from mitapivat and etavopivat to kind of get confident in that best-in-class profile?

So Sarah, we'll start with continued encouraging interactions with the FDA and the question on REMS.

Yes, of course. And as you know, we now have optionality because we have PYRUKYND and AQVESME. Both of these are options, each having different pros and cons. Either way, our teams would be able to execute on any of those options. And as it relates to the Phase II data, it's a dose-finding study. So of course, we're looking for a dose in Phase II to bring forward, but we're also looking for depth and breadth of hemoglobin response.

Our next question comes from the line of Eric Schmidt from Cantor.

Congrats on a terrific launch. Maybe on this 242 prescription number in the first quarter, that's obviously an enormous number. I think, Tsveta, you told us back in February that through January 31, you had 44 prescriptions. So it looks like there's been a pretty meaningful acceleration in February and March. Maybe you could just confirm whether my math there is correct. And maybe square the circle relative to the comments you made about not extrapolating forward the current run rate because if anything, it seems like you're on an accelerating path.

Yes, we are very excited about the progress, Eric. And the 242 prescriptions from REMS-certified physicians of January 31st reflect the totality of the first quarter. As a reminder, we started actually actively promoting the drug as we got label. So the demand was generated throughout the whole quarter. The REMS became operational at the end of January, but the demand was generated throughout January as well. So I'll look at the quarter as a totality. And that's what I mentioned, I wouldn't take these two numbers and kind of extrapolate from there in the future quarters and wouldn't take that run rate. But we are still expecting to see a strong demand moving forward as the team is executing and the patients and physicians are very positive on the profile and looking to engage further.

And Eric, maybe I'll just take this opportunity to reinforce adding to your comments that what's so special about the AQVESME launch is we have 3 key ingredients. First is AQVESME addresses a significant unmet need with thalassemia. Secondly, the community, i.e., physicians as well as patients are already reflecting enthusiasm for the profile. And as you just said, third, Tsveta and the Agios team are very well prepared, and they know how to execute, and we're very proud of their early progress.

Terrific progress indeed. Do we have a sense of what percent of the initial REMS-prescribing patients are likely to convert or what the conversion ratio is?

So in the initial quarter, as I mentioned, we really kind of captured some of the most motivated and engaged patients and our conversion from prescription to treatment initiation was actually faster than expected. As the quarters progress over time, we still expect the initiations to be 10 to 12 weeks always. We'll try to shorten it. But the primary driver for that is that we'll be moving into patient segments that have less frequent interactions with the health care system as we go deeper into the NTDT segment as we've spoken in the past.

Maybe asking in a different way, have you lost any of the 242 patients that you now no longer think are likely to convert?

So far, I think we could characterize, Eric, that the REMS has been well embraced by both the physician community as well as, as Tsveta says, the motivated patients. And we feel very confident with the high conversion, I'll call it, of those early patients that have started on or were prescribed AQVESME and then converted on to therapy.

Yes. Sorry, Eric, maybe I didn't get exactly your question, but the REMS is not a hurdle to treatment initiation at all. What we see in terms of a conversion rate and it's very typical for rare disease launches. So we're not out of the extraordinary because of the REMS.

Our next question comes from the line of Marc Frahm from TD Cowen.

Congrats on the progress with AQVESME. Maybe just following up on some of the answers to Eric's questions. It sounds like at least some of these -- the extra kind of 200 prescriptions that you're kind of talking about now versus the end of January, I guess, maybe were even written before January. Is that right? They just weren't by a REMS-certified physician and kind of what's changed is the REMS certification status. Is that the right way to kind of square the commentary? And then some of this kind of caution around that trajectory of TRx maybe slowing or the fill time pushing out a little bit. Have you actually seen that yet? Or you're just cautious that, that may happen as we move into future quarters?

So thanks, Marc. Maybe what will help here is so that I can just like take a step back to the launch timing and what occurred in the first quarter because there was an initiation of demand and then there was the operationalization of the REMS. Do you just want to talk through that and then reflect on the source of the 242 prescriptions.

Yes, absolutely. So the 242 prescriptions are reflective of all of the work that we've done in excellent launch preparation. We had a lot of clarity of where likely the prescriptions are going to come first, and we initiated these interactions and promotional activities as soon as we got the label. So they're a reflection of the work that we've done for the whole quarter.

In the first month, we didn't have the REMS operational, and the team still did an excellent job to get prescriptions from REMS-certified physicians in that phase of the launch. And we continued on that journey once the REMS was operational. Obviously, more physicians who are waiting for that operational date to start prescribing, they did start prescribing. We are very pleased with what we are seeing right now because the prescriptions are coming from a very healthy geographic breadth.

They are coming from the community prescribers, where the majority of the patients are managed right now. And we see this kind of highly motivated and engaged patients starting therapy, which is fantastic for us because we know that the thalassemia community is actually very well connected and that early launch experience with the patients will actually support the kind of the positive feedback and the profile of the product as well.

So what I can tell you is that moving forward, I wouldn't take the two data points in Q1 and extrapolate from there, but I'm very confident that we'll have a strong uptake and penetration moving forward as we continue to the launch, typical with non-life-threatening rare disease conditions.

And Marc, on the second part of your question about the 10 to 12 weeks that Tsveta had commented on in her prepared comments, we have been encouraged that these motivated patients have translated to therapy faster than that in some cases. But again, this is relative to the motivation of both the physician and the patient. And the reason to guide on average, that's an expectation going forward is as we penetrate further into the non-transfusion-dependent patient population, we expect there will be perhaps a mitigating factor on the enthusiasm aspect, and it might take a little bit longer for those patients to convert to therapy.

Okay. I completely understand that, but maybe just to push on it a little bit, presumably also as you get further into the launch, you also have a dynamic of more payers kind of having regular processes and things that tends to kind of shorten the time lines within a given payer, but I guess, it sounds like you expect it to be more than counteracted by that kind of difference in enthusiasm from the patient itself.

Yes. We'll definitely -- the team is doing an excellent job right now, and we haven't had any payer hurdles so far. Of course, we'll continue to look for ways to shorten the time from prescriptions to treatment initiation. We'll look to advance. It takes about six months on average to get the payer policies in place. But as of now, similar to patients and physicians, payers have been very receptive of the profile and market access has not been a hurdle.

And our next question comes from the line of Salveen Richter from Goldman Sachs.

This is Lydia on for Salveen. Congrats on the launch updates here. Maybe just another question on the launch. Could you maybe just speak to the treating physicians and treatment settings that you're seeing here? And are you still seeing a majority of prescriptions coming from the community hem-oncs? And is the team starting to engage with physicians beyond those who were targeted ahead of the launch?

Yes, absolutely. So we see a very healthy start of the launch when we think from a prescriber base. We've seen prescriptions coming both from the academic and community setting, but the majority of the prescriptions are coming from the community setting, which is exactly as we expected it. And that's driven by the fact that patients with thalassemia are actually managed mainly in the community setting. We see prescriptions coming from across the country, which is fantastic. And as we move forward, the patients will continue to increase the breadth of prescribing. And of course, we'll focus on that as well, but the majority of the business is going to continue to grow breadth.

And our next question comes from the line of Tessa Romero from JPMorgan.

I just wanted to double-click back here to one of the initial questions on the call here. Ultimately, what do you see as the implications of Novo's recent results to next steps at Agios? And how does this change your view of what you need to see to drive tebapivat forward in sickle cell disease as well?

Maybe Sarah can start with our focus on mitapivat and then we can comment on tebapivat as well.

Sure. So we haven't seen the full HIBISCUS results yet. So as Tsveta highlighted, I mean, we see a clear commercial opportunity in sickle cell disease with mitapivat. And as she highlighted as well, there are multiple players given the prevalence and the disastrous nature of this disease. And of course, we'll look to maximize commercial opportunity with mitapivat. That is possible with our data sets in RISE UP. We have, again, a very strong antihemolytic profile in our data set. The strength of the hemoglobin responder data is definitely there because as we've highlighted, we have seen impact on VOCs, but sickle cell disease is more than VOCs. We've seen impact on hospitalizations, fatigue, quality of life. So there is really a lot of excitement for our drug in the community, both by patients and physicians.

And of course, we are also -- as we highlighted in our prepared remarks, very pleased with the progression of the engagements we've had with the FDA so that we're now able to update our expected filing into Q2. So we are very pleased with where we are.

Okay. Great. And Sarah, if I can just follow up quickly on that point. Is there anything that you would like to better understand in the fuller HIBISCUS data set when we do see it?

Well, yes, obviously, like the data is very limited right now that we have to our availability. So anything as it relates to standard study metrics, I would love to see.

And our last question comes from the line of Greg Renza with Truist.

This is [indiscernible] on for Greg. Congrats to the launch, Tsveta. One question on AQVESME. So with the momentum continuing to build, you have 242 prescriptions in the first quarter. Are you starting to see any early signals of patient persistence, patients staying on therapy, given that this is a chronic setting? And any differences in the patterns between transfusion-dependent versus non-transfusion dependent? And I have a follow-up.

Absolutely. As we said, we are very early in the launch, and there is a time lag between a prescription and treatment initiation and then the patients need to go from a month of therapy to start seeing what the continuation rate. But we've seen PYRUKYND in PK deficiency performing extremely well in the real world. We expect to see the same strong performance in thalassemia as well. Sometimes we talk about the REMS as kind of paperwork and work, but actually, it helps with the frequent interactions between patients and physicians and actually can support continuation of therapy as well. So we'll wait and see. That's one very important factor we'll continue to monitor.

Got it. And a second question on mitapivat in sickle cell disease. So assuming accelerated approval, how do you think about the opportunity for early uptake based on hemoglobin as a surrogate endpoint and potentially on the label while additional outcomes data are being generated in the confirmatory study and especially in light of etavopivat hitting the VOC endpoint?

Yes. This is a little bit reflective of what Sarah had commented on as well that sickle cell disease has very high unmet need. And as Sarah said, it's a multi-dimensional disease. There are many things to address clinically within sickle cell disease. And we stand proud and tall with the RISE UP data that we've seen, particularly as well the responder analysis. And Tsveta and her team are, of course, already preparing commercially for that potential opportunity ahead with the accelerated approval pathway.

And just if I may add, the data from RISE UP that we've highlighted to physicians and patient communities has been very well received.

And if I may, could you maybe expand a little bit on the confirmatory study? What are you thinking in terms of the confirmatory endpoint? And how might that compare to the potential VOC data that we might see in HIBISCUS just when it comes to treatment selection?

Yes. So thanks. So the endpoint, as highlighted, is informed by the RISE UP data set in which we've collected data systematically prospectively. So we've had also great engagements with the FDA, and that has progressed very nicely. So again, we are now able to speak to our intent to file in the second quarter. We've also highlighted before that we will be presenting data at or around EHA around all of the data, so including the data that informs this confirmatory trial and that we will also share more ahead of our posting on clinicaltrials.gov.

The last thing I wanted to stress, and this is really important, this is a confirmatory trial. So we really have prioritized the operational feasibility as well with probability of success to be able to deliver meaningful data that then, of course, would allow us at that time to hopefully be able to put that data into label at the time of full approval when the results allow. So we are very excited about where we currently are. We have really great confidence in our data and the path that we are on.

And this concludes the question-and-answer session. I would now like to turn it back over to Brian Goff for any closing remarks.

Well, thanks a lot, Victor. Thanks, everyone, for joining. The first quarter clearly reflected solid execution across our strategic priorities from the early progress with the U.S. commercial launch of AQVESME in thalassemia, as we've discussed, to continued advancement toward mitapivat sNDA filing in sickle cell disease and to maintaining a disciplined financial approach with multiple meaningful catalysts ahead this year, we believe Agios is well positioned as we move through 2026, and we look forward to continuing to update you on our progress, including at our planned investor event during the 2026 EHA Congress. So thank you very much, everyone.

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

Good morning, and welcome to Agios Pharmaceuticals Fourth Quarter and Full Year 2025 Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Agios' request.

I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Please go ahead.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals Fourth Quarter and Full Year 2025 Financial Results and Business Highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com.

Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

On the call with me today from Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions.

With that, I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining us on today's call.

Next slide, please. Just last month, we outlined our 2026 strategic priorities, which are focused on delivering long-term shareholder value. First, we're focused on executing a high-impact launch of AQVESME for the treatment of thalassemia in the U.S.

Second, we see meaningful opportunity to expand our PK activation franchise into additional high-value indications, including sickle cell disease and lower-risk myelodysplastic syndrome with key catalysts this year for both opportunities.

Third, through the advancement of our early-stage pipeline with AG-236 and AG-181, we have the potential to unlock future value in hematologic and other rare diseases.

And finally, we remain committed to long-term sustainability, supported by disciplined capital allocation and continued operational efficiency.

Building on those priorities, the next slide maps key pipeline catalysts in 2026 across multiple high-value indication opportunities. The AQVESME launch in thalassemia is underway in the U.S., and we look forward to the potential to expand our PK activation franchise into sickle cell disease and lower-risk MDS. These milestones and continued progress in our early-stage pipeline position the portfolio for growth and long-term value creation.

Next slide, please. We exited 2025 with solid momentum across the business, commercial execution, pipeline progress and continued focus on financial discipline, which together provide a strong foundation to deliver on our 2026 strategic priorities.

Starting with commercial performance, PYRUKYND delivered $20 million in net revenue in the fourth quarter, bringing full year 2025 revenue to $54 million, reflecting robust year-on-year growth. In the fourth quarter, we reported top line data from the RISE UP Phase III trial and we will meet with the FDA this quarter as anticipated for our pre-sNDA meeting to determine the regulatory path forward. Importantly, just before the end of the year, we received FDA approval for AQVESME and the U.S. thalassemia launch is underway.

Finally, we recently completed enrollment in the Phase II sickle cell disease trial of Tebapivat with top line results expected in the second half of this year. Importantly, we continue to operate from a position of strength, ending the year with approximately $1.2 billion in cash, providing flexibility to maximize the AQVESME thalassemia U.S. launch, pursue the path forward for mitapivat in sickle cell disease and continue to advance our pipeline programs.

Please move to the next slide, and I'll turn the call over to Cecilia to provide additional details on our 2025 fourth quarter and full year performance as well as our 2026 outlook.

Thank you, Brian. Next slide, please. Our fourth quarter and full year 2025 financial results can be found in the press release issued earlier this morning and additional details can be found in our 10-K, which will be filed later today.

Fourth quarter worldwide PYRUKYND revenue was $20 million, an increase of 86% compared to the fourth quarter of 2024 and a sequential increase of 55% compared to $13 million in the third quarter of 2025. In the U.S., fourth quarter revenues of $16 million were driven by continued commercial focus in PK deficiency ahead of FDA approval for AQVESME, an additional ordering week in the fourth quarter and favorable gross to net adjustment.

In 2026, we expect U.S. PK deficiency revenues to be in the range of $45 million to $50. Outside of the U.S., revenue of $4 million in the fourth quarter primarily reflects inventory stocking ahead of demand, driven by PK deficiency patients in Europe, transitioning from our Global Managed Access Program where PYRUKYND was provided free of charge to commercial supply. We anticipate a sequential decline in ex U.S. revenues into the first quarter of 2026.

Cost of sales for the fourth quarter was $1.9 million. R&D expenses were $88.1 million, an increase of $5.3 million compared to the fourth quarter of 2024, associated with the advancement of our earlier-stage pipeline program. SG&A expenses were $51.6 million in the fourth quarter and roughly flat year-on-year. We ended the fourth quarter with cash, cash equivalents and marketable securities of approximately $1.2 billion.

As a reminder, in future quarters, we will report mitapivat revenue as a whole, breaking out U.S. and ex U.S. performance.

Next slide, please. We remain committed to financial discipline as we work toward our goal of becoming a sustainable rare disease company. We anticipate operating expenses in 2026 to be roughly flat with 2025. This guidance assumes investments to maximize launch of AQVESME in thalassemia in the U.S.; gated investment for sickle cell disease; and operating model refinement.

Importantly, we see a clear path to profitability through our existing commercial presence in thalassemia and PK deficiency.

Please advance to the next slide, and I will turn the call over to Tsveta to share commercial highlights for the quarter.

Thank you, Cecilia. Next slide, please. As Cecilia noted, in the fourth quarter, PYRUKYND delivered $16 million in net revenue in the U.S., up 50% year-over-year, driven by continued demand in PK deficiency and additional ordering week in the quarter and certain gross to net adjustments.

Fourth quarter ex-U.S. revenue was roughly $4 million, which primarily reflects supply ahead of demand pull-through as PK deficiency patients in Europe transitioned on to commercial supply. We expect the ordering to moderate in coming quarters.

As expected, we continue to see quarterly variability driven by ordering patterns, inventory dynamics and gross to net adjustments. Fourth quarter performance underscores the strength of our commercial model and the foundation we are building for future growth, starting with the recent U.S. approval of AQVESME for the treatment of anemia in adults with alpha- and beta- thalassemia, regardless of transfusion burden.

Please move to the next slide. I am pleased to share that as planned, the final implementation of AQVESME REMS was completed in late January to align with the approved FDA label, and we have already begun dispensing products. As of January 30, we have seen 44 prescriptions written by REMS-certified physicians in the U.S., which reflects strong early recognition of AQVESME clinical value and excellent execution by our field teams.

What is especially encouraging is the healthy breadth of early prescribers at this stage of the launch. We see strong geographic distribution and as expected, predominance of community physicians as early prescribers.

We are also seeing in the early days of launch, emergence of the patient profile we anticipated, largely transfusion-dependent patients, along with a group of highly engaged non-transfusion-dependent patients. These early signals speak not only to our launch readiness, but importantly, to our deep understanding of this patient community and their unmet need.

Please move to the next slide. We are very encouraged by the early market response to AQVESME. Physicians consistently view its profile as addressing meaningful gaps in the current treatment landscape for thalassemia. Importantly, this aligns with what we heard ahead of FDA approval. We are not seeing the REMS as a barrier to prescribing with early experience suggesting the certification process has been straightforward.

We are also seeing strong engagement with our patient support program. Initial experience indicates that patients do not view the REMS as burdensome given the potential for meaningful clinical benefits, including reduction in transfusion burden and improvement in fatigue. Taken together, this early feedback reinforces both the significant unmet need in thalassemia and the value proposition of AQVESME. It also reflects the strength of our prelaunch planning.

On the next slide, I will take a few moments to discuss how we anticipate this demand will convert into treatment initiation and ultimately revenues in the first few quarters of launch. There are 3 key steps in the AQVESME REMS certification process. One of those steps, pharmacy education and certification is already completed as we use a single specialty pharmacy to discuss prescriptions and coordinate on delivery.

Additionally, physicians are required to be educated and certified on the AQVESME REMS. In parallel, once a prescription has been written, patients need to receive insurance authorization and complete a baseline liver test prior to initiating treatment. Our comprehensive patient support service, myAgios has a strong track record assisting patients with the insurance authorization process for PK deficiency, which we expect to continue with thalassemia.

Once these 3 components are completed, the pharmacy is authorized to dispense the prescription. Patients will then complete monthly liver tests for the first 6 months and as clinically indicated thereafter. Initially, we expect the time from prescription to treatment initiation to be on average 10 to 12 weeks. As physicians are onboarded and access expands, we see opportunity to shorten this time line as launch progresses.

Turning to the next slide. The thalassemia opportunity presents a major potential growth inflection for Agios. To date, we have received approval of mitapivat for thalassemia in 2 regions: marketed as AQVESME in the U.S. and PYRUKYND in Saudi Arabia. Our capital-efficient global commercial model enables us to focus our investment on the U.S., which presents the most significant revenue opportunity.

Outside of the U.S., we have executed commercialization and distribution agreement with Avanzanite Bioscience in Europe and NewBridge Pharmaceuticals in the GCC. Given access dynamics, we currently distribute PYRUKYND in Saudi Arabia on a patient-by-patient basis with potential to expand access following national procurement agreements.

In Europe and UAE, regulatory reviews remain underway. We anticipate a potential EC decision in the coming months following the positive CHMP opinion received in October 2025. Across these regions, we see real potential to expand access and deliver meaningful growth as we scale the launch globally.

Please move to the next slide. And with that, I will hand the call over to Sarah to cover key R&D highlights from the quarter.

Thank you, Tsveta. Next slide, please. Since we reported third quarter results, we have continued to make progress advancing our robust rare disease pipeline. We received the FDA approval of AQVESME for alpha- and beta- thalassemia regardless of transfusion burden on December 23 of last year. And as you heard from Tsveta, the U.S. launch is underway with strong reception from physicians.

Following the RISE UP Phase III top line data of mitapivat in sickle cell disease, we will have our pre-sNDA meeting this quarter to inform the regulatory path forward. We continue to advance our more potent PK activator Tebapivat, in 2 Phase II trials and anticipate results in lower-risk MDS in the first half of this year and in sickle cell disease in the second half.

We continue to advance our early-stage pipeline to important decision points this year and are on track to initiate a Phase Ib proof of mechanism trial of AG-181, our phenylalanine hydroxylase stabilizer in PKU patients in the coming months and report top line data from the Phase I healthy volunteer study of AG-236, our siRNA targeting TMPRSS6 for Polycythemia Vera in the first half.

Please move to the next slide. Turning to Tebapivat. We look forward to understanding more about the potential role of this more potent PK activator in low-risk MDS and sickle cell disease this year. We remain on track in low-risk MDS, where top line data from the Phase IIb trial are expected in the first half of this year. This study will provide important insights into dose optimization as well as the potential role of Tebapivat in different patient subgroups, including low and high transfusion burden patients as well as potential applications in later lines of treatment.

In sickle cell disease, enrollment in the Phase II trial is now complete, an important milestone that reflects the growing enthusiasm for PK activation following the RISE UP Phase III results of mitapivat in this debilitating and deadly disease. This 12-week double-blind trial is designed to further explore Tebapivat's potential to deliver meaningful improvements in hemoglobin as well as broader markers of hemolysis.

In turn, we see potential for higher hemoglobin response, building on the strength of the data established with mitapivat.

Together, these programs underscore the potential for Tebapivat to expand our leadership in hematology and address multiple high-value populations where unmet need remains significant. We have an exciting year ahead of us, and we look forward to updating you on our pipeline progress throughout the year.

With that, please move to the next slide, and I will hand the call back to Brian for closing remarks.

Thank you, Sarah. Next slide. In closing, we have another pivotal catalyst-rich year ahead of us. In line with our 2026 strategic priorities, we're focused on executing a high-value AQVESME U.S. launch in thalassemia.

In sickle cell disease, we're preparing for our pre-sNDA meeting for mitapivat this quarter, an important step towards defining our regulatory path. We also expect Phase II top line data for Tebapivat in sickle cell disease later this year, which will give us deeper insight into the potential of higher potency PK activation in this population.

In lower-risk MDS, Phase IIb top line data for Tebapivat remain on track for the first half of 2026. It will be a key readout as we assess its ability to drive transfusion independence and broader improvements in anemia.

We also anticipate Phase I top line data for AG-236 in polycythemia vera and Phase Ib proof of mechanism data for AG-181 in PKU, 2 important early-stage programs that expand our reach across hematologic and other rare diseases.

Please move to the next slide. As we look beyond 2026, our opportunity set continues to expand. The combined global market potential across our current pipeline indications exceeds $10 billion, reflecting both the breadth of unmet need and potential to deliver transformative medicines to patients. Beginning in 2026, we're focused on delivering a high-impact U.S. launch of AQVESME in thalassemia, which we believe has the potential to establish a strong foundation for our leadership more broadly in rare hematology.

Our combination of near-term catalysts, disciplined investment and a maturing pipeline creates a clear pathway to deliver long-term value. Agios is well positioned for the next chapter of growth while advancing the next wave of innovation across our rare disease portfolio.

Before we move into Q&A, I'd like to acknowledge the dedication of our employees whose unwavering focus and commitment continue to make a meaningful difference for patients with rare diseases.

With that, I'd like to open the call for questions. Operator, please open the line.

And our first question comes from Gregory Renza with Truist.

Congrats on the quarter and of course, another eventful year. Maybe 2 questions from us on AQVESME and then on sickle cell.

First, just on the AQVESME launch, we appreciate all the color you're sharing early in getting patients engaged and prescriptions written. Just on that translation perhaps on the prescription updates that we are seeing, how do you see that not only translating to treatment initiation, but also to revenue recognition? Maybe not asking for guidance on early quarters, but any color you can provide on the first quarter and even subsequent early days of the launch with respect to how it pulls through to revenue? And then I have a follow-up.

Yes. Thanks, Greg. Very happy to talk about the launch. And before Tsveta gets going here, I just want to say I'm really proud of the way the team has executed. It's early days. But Tsveta is excited to finally have a chance to begin talking about the AQVESME launch.

Absolutely. Definitely excited. And Greg, as I mentioned in my prepared remarks, we are really encouraged by the early demand that we are seeing with AQVESME. As you mentioned, we reported that we had 44 prescriptions from REMS-certified physicians up to January 30, which is the first 5 weeks of the launch, and that is fantastic to see.

With regards to your questions, what we expect is to see in the initial quarters, prescriptions and demand to grow ahead of revenues. And the main reason for that is that it takes about 10 to 12 weeks for us to convert prescriptions to treatment initiations and ultimately revenues. So we anticipate in Q1, the majority of the prescriptions to turn into treatment initiation. And as the year progresses, we'll expect to see revenues and demand to start tracking more closely.

We get a lot of questions about potential analogs. So when I think about another product, which also has a liver REMS the Filspari. So that's a good analog for you to look at of how the actual revenue trajectory throughout the first year of the launch actually evolved. It's a very different disease, of course, but from a shape of the curve of the revenue, I think it's a good one to look at.

Great. That's very helpful. And maybe just moving on to sickle cell and Tebapivat. And of course, not to overlook the MDS readout in the first half. But with enrollment complete in the Phase II in sickle cell and Sarah, the color that you've provided, maybe if I may, just ask a bit about how you're pegging expectations for what you want to see to get excited about the Phase II data in sickle cell coming later this year. You've spoken about the potency and the higher hemoglobin response potential. But any color that would help to get you excited and how that kind of fits into the larger portfolio relative to mitapivat and the larger sickle cell space even.

Thanks, Greg.

So yes, thanks for the question, Greg. So the Phase II Tebapivat trial that we've just indeed announced full enrollment is a dose-finding trial. So we are looking indeed to explore the doses. We are looking at the hemoglobin response.

It is a stand-alone Phase II trial. So our VOCs are included as safety assessment, which is different than how the Phase II/III seamless operational design was for RISE UP. But obviously, we're now in a position that we can leverage data across PK activation franchise basically, and we're able to use the RISE UP data to also model what we anticipate a hemoglobin response can lead to for clinical benefit.

So we're very excited about the trial. We think actually the fact that we can announce the enrollment completion also reflects the excitement of the community. The RISE UP data announcement really led to faster enrollment in the Tebapivat Phase II trial. So we are very excited about that.

Our next question comes from Samantha Semenkow with Citi.

Congratulations on all the commercial progress. Just one follow-up on AQVESME. I'm wondering if you could speak to a bit of the cadence of scripts that have come in since approval. And particularly, are you seeing an increase in the scripts written since January 30 after the REMS has become fully operational?

And then just a second question. I'm wondering if you could speak to the potential outcomes from the planned sNDA meeting with FDA on the sickle cell disease. What are the outcomes that could come out of that meeting?

Thanks, Sam. So we're going to stick with the 44 that we have so far for AQVESME, but I think Tsveta could continue to provide color on the early days of the launch. And so I'll have Tsveta start on that, and then Sarah can speak to the pre-sNDA meeting.

Absolutely, Sam. And a reminder, we started basically engaging and educating physicians and generating demand as soon as the product was approved. So within the first 5 weeks of the launch, we've been educating physicians on the value proposition of AQVESME and the REMS itself. So we are very encouraged with what we see in terms of demand in the early stages of the launch.

A lot of the things that are happening, and I'm really, really pleased with the execution of the team are happening as we expected. So we are seeing prescriptions coming from the transfusion-dependent patients and the very engaged symptomatic nontransfusion-dependent patients who have frequent interactions with the health care system, which is fantastic. And we see a very healthy dynamics of the launch in terms of the physicians prescribing. We see prescriptions coming from across the country. And a lot of them are in the community setting where the majority of the patients are treated, and I'm really pleased with the progress that the team is making.

Great. And then, Sarah, the pre-sNDA meeting and Sam's question about the potential outcomes.

Yes. Thanks, Sam. So we've guided to the pre-sNDA meeting in the first quarter of this year. The goal for that meeting is, of course, to gain insights in the regulatory pathways that we can use for mitapivat. As stated, we are, of course, going in with a data package that we can -- that we would like to present for full approval based on the data that was generated in RISE UP with the strong anti-hemolytic profile that is now confirming again the anti-hemolytic profile of mitapivat now in a third hemolytic anemia. With additional strong clinical benefit observed in those hemoglobin responders. And once we have that meeting, like we are planning to give an update when we have the meeting minutes to you guys.

And our next question comes from Alec Stranahan with Bank of America.

Great to see the continued progress for both the commercial and the clinical stage portfolios. Two questions from us. I guess, first, what is sort of the main bottleneck informing that 10- to 12-week prescription to treatment initiation? Is it getting the patient in for their baseline liver test or maybe something else? And how do you anticipate this shortening over the course of this year?

And then second, for Tebapivat in MDS, what does good look like on transfusion independence in this lower-risk population? And I guess, given what you learned from the Phase IIa, do you expect you could see activity at the 10 mg dose based on sort of the emerging PK data? Or is this maybe more likely at the 15 and 20 mg doses?

Thanks, Alec. So we're going to follow the same sequence here. Tsveta gets to talk about the AQVESME launch. And then Sarah, thankfully, we have a robust pipeline so she can discuss the MDS trial with Tebapivat.

Absolutely. So the 10 to 12 weeks is driven by 2 things. The first aspect is the insurance authorization, which is very standard for any specialty rare disease drug that's not unique to AQVESME. And most of the patients would need to go through prior authorization, which can take an average a month. And for some patients, it happens faster. For some patients, it takes longer. But that's one of the main drivers.

The second aspect is the requirement for a liver test ahead of the treatment initiation. So when we combine both of these factors, we anticipate the conversion from prescription to treatment initiation to be on average, 10 to 12 weeks. As I said, we'll see kind of patients pulling on either end of that time frame. And over time, we will, of course, look to shorten the time from prescription to treatment initiation on both fronts.

We have an excellent market access team that will be engaging with payers. So as some of the payers actually put the product on formulary, that can be an opportunity for us to move faster through some of the prior authorizations and supporting patients as well as we'll be learning throughout the launch and identify areas to support patients to have an efficiency in their liver testing initially as well.

Great. And Sarah, for Tebapivat in MDS, just some of the -- what are we expecting and then the different dosing?

Yes. Thanks, Alec. And so to your point, we indeed are testing higher doses than the dose that we tested in the Phase IIa. So we have a 10-milligram, a 15-milligram and a 20-milligram dose. So indeed, we are looking to explore the doses here in this Phase II to see which dose would be best.

And then in addition, we are -- because it's a heterogeneous patient population, this trial will also allow us to further define patient population. So we have low and high transfusion burden plus additional lines of therapy that have been used. So it will really give us a lot of insights on where this drug can play a role.

Obviously, it's an oral therapy, which, of course, can be very meaningful for a patient population like this because if patients will have treatment response, it allows them to be really untethered of the clinic.

Yes, it's going to be -- it's an exciting year for Tebapivat in 2026. We have 2 catalysts, as we noted. We have the MDS Phase IIb trial in the first half of the year. And then as we've already discussed, for sickle cell disease, the second half of this year, we look forward to that Phase II result.

Congrats on the continued progress, guys.

Thank you.

And our next question will come from Marc Frahm from with TD Cowen.

Maybe to start on AQVESME with the REMS-certified physicians. Just can you maybe talk about kind of where that is from a quantitative perspective within these first few months? And kind of what do you think that trajectory looks like in terms of number and breadth of certified physicians over the next quarter or 2 as that part of the ramp really happens? And then I'll have a follow-up on the pipeline.

Okay, Tsveta, can start.

Yes. When it comes to the REMS in this initial stage of the launch, I'm really pleased with what we are seeing and things are happening exactly as we anticipated. Physicians don't see the REMS as barrier to prescribing and the patients that we've engaged with, they basically -- they don't see it as burdensome given the strong value proposition of AQVESME and their willingness to consider and initiate therapy.

So what is happening with the REMS? Initially, a lot of the bigger academic centers and KOLs are getting certified. And when it comes to the community physicians, actual certification happens almost simultaneously with the first prescription. And we will see, in a way, the certification and REMS progressing simultaneously over time. But as I said, REMS hasn't been a reason or a reason for not to prescribe. It's the opposite. When physicians have patients that they want to initiate, they are more than willing to start to complete the REMS, which can actually take one visit, is a very quick process.

Okay. That's helpful. And then maybe just following up on Sarah's comments about the pre-sNDA meeting in that the package is really aimed for supporting full approval. I think at other times, you've also mentioned possibilities of an outcome of accelerated approval. Is that still something you think is a reasonable outcome? Or are you more confident in a full approval than maybe you have been as you've gotten a little deeper into the data and conversations? And then assuming Accelerate is on the table, what's your latest thoughts on kind of what a confirmatory trial might look like under that scenario?

Yes. So thanks, Marc. So for us, the data package really -- the benefit risk profile generated in RISE confirms a strong anti-hemolytic profile, as I mentioned. And we really see those clinically meaningful changes in the hemoglobin responders. So our view is that benefit risk here is seen in this trial and it's a supplemental NDA.

Now as you also know, at ASH recently, the FDA highlighted that hemoglobin can be a surrogate endpoint for sickle cell disease. So either one of those pathways for us allows us to discuss the data and have that meaningful conversation with the agency under any of those circumstances, then there is always the normal filing procedures that one would have to go through. But we're very, very excited about the data as it stands.

Then in regards to your question on confirmatory trials, obviously, we have several options that we can discuss in which some of these options have endpoints that have been used before. Some of them are novel endpoints as well. So we are ready to discuss as needed.

And our next question will come from Eric Schmidt with Cantor.

Sorry for any background noise. But Cecilia mentioned a direct path or clear path to profitability. I was hoping you could give a little bit more detail on thinking around the breakeven point of revenue needed to hit that and maybe time lines to profitability. And then were there any sales at all in the GCC countries in Q4?

So we have -- thanks, Eric. We gave the guidance on profitability with PKD and thalassemia regardless of the path forward for sickle cell that was our base case there. We haven't given specific timing of when that will happen. We believe thalassemia is a meaningful opportunity. We're excited about the initial stages of the launch. We also have, as you mentioned, ex-U.S. being part of that opportunity as well. And then part of that profitability path also requires us to proactively manage our OpEx as we navigate the multiple catalysts on the pipeline. We talked about teba, but we also have other earlier programs. So we haven't given specific timing on that. Second question...

And GCC.

And then for GCC, what we've seen that the ex-U.S. revenue we saw in Q4 is mostly driven by Europe, and that is in anticipation of demand. So that's why we guided to an expected decrease Q4 to Q1. GCC, as a reminder, today, is on a equivalent of our named patient like case by case. So you'll see some consistency quarter-over-quarter until we get to the point where we have more broad access negotiated over the next 12 to 18 months or so.

Yes. And Eric, I'll just add. We're pleased with the partner we have in place in GCC with NewBridge. Tsveta and I spent some time in Saudi Arabia late last year and really got a kind of a street-level sense about how the team is doing, the enthusiasm from clinicians as well as even at the Minister of Health level. And that's going to take some time to build traction. But I think in the early days, we feel quite good about the opportunity.

And our next question comes from Emily Bodnar with H.C. Wainwright.

Congrats on all the progress. I guess for the first one, can you give some color on the type of physicians who are initially prescribing AQVESME and whether they're mainly physicians who've used PYRUKYND in the past? Or are you getting physicians who are more new to drug?

And then on sickle cell disease, assuming you achieve alignment with the FDA, are you expecting potential approval in 2026? And can you maybe discuss some of the launch preps that you're planning to do this year ahead of approval?

Thanks, Emily. Tsveta, do you want to start with AQVESME and the types of physicians in the early days?

Absolutely. As I said, a lot of the early launch dynamics are playing as expected. The team did a fantastic job ahead of the launch. Profiling and prioritizing accounts. So the initial prescriptions are actually coming from the physicians we anticipated to see prescribing. As I mentioned, Emily, they are primarily the community [ among ] where a majority of the patients are, and these are physicians we've engaged with previously.

We don't see that much overlap between PK deficiency and thalassemia, and that's because PK deficiency is an ultra-rare disease. So there are very few physicians who actually have experience with PYRUKYND through PK deficiency. And as I said, I'm very pleased with the start of the launch. It is a very healthy breadth of prescribing that we see across the country, different physicians are engaged and really trying the product in the patients that they think will benefit the most initially.

Great. And then Sarah, for sickle cell disease and potential timing.

Yes. So Emily, we haven't guided to potential approval dates yet. We are now -- the first guidance we have given in this process is our pre-sNDA meeting anticipated Q1. And then in regards to the launch prep, I will ask Cecilia to comment.

Yes. So as a reminder, we didn't -- sort of very similar to how we did in thalassemia, we didn't win for sickle cell until we saw the data. And that's what we refer to when we talk about the gated sickle cell investments. We will look into that time line and understand the path to start building investment there accordingly.

And our next question will come from Salveen Richter with Goldman Sachs.

This is Lydia on for Salveen. Congrats on the updates. Is there any additional color you can provide on the split between the nontransfusion and transfusion-dependent patients amongst these 44 scripts that have been written? And then given scripts will be the key metric to watch, do you anticipate third-party services like IQVIA to accurately capture these scripts?

Tsveta?

Yes. So the initial prescriptions, as I said, very much as we anticipated come from a combination of transfusion-dependent patients. Obviously, a large proportion is transfusion-dependent patients and a very engaged symptomatic nontransfusion-dependent patients who are in active interaction with the health care system.

So when you think about kind of the evolution over time, as anticipated, I think we'll see initially more transfusion-dependent patients, but the scale-up of the launch will come from the nontransfusion-dependent patients later on.

When you think about IQVIA, we have a single specialty pharmacy that distributes the product. So IQVIA will not be the right source for you to look at. It's just the information, it will not be available. And this is the reason that we're looking to provide you initially with prescriptions, revenue as well as we gave you the guidance on PK deficiency, so you can see where the growth of thalassemia will be coming throughout the year.

And our next question will come from Tess Romero with JPMorgan.

So first one is just on AQVESME. Just can you just quickly touch on initial payer dynamics over the first couple of quarters here and remind us of payer mix? Just want to make sure that we're thinking about potential free drug the right way.

And then second question, a bit of a housekeeping question here. If you are indeed approved in sickle cell disease, how does your SG&A line change? Just trying to think through what you might need to successfully launch a drug in sickle cell from an expense perspective?

Okay. Thanks, Tess. And Tsveta can start on the payer aspects and maybe we could also just remind our gross to net assumptions, too. I don't think we...

Yes. Absolutely. So Tess, I'll start here. So the payer mix in thalassemia is quite similar to PK deficiency with majority of the patients being under the commercial payer bucket. Very similar to PK deficiency in any other drug. Initially, the actual market access and payer authorization it will happen through medical exceptions because payers would take time about 6 months, 6 to 9 months to actually start putting the product on formulary.

We have a very experienced market access team that is very familiar of how to navigate the medical exceptions process. And so far, in this early stages of the launch, I must say, as expected, we haven't seen any payer hurdles at all. I think the value proposition of AQVESME speaks to itself and the team is doing a great job in terms of those interactions.

Brian asked kind of to comment on the gross to net assumptions. Given that we don't expect that to be a managed category, very similar payer mix to PK deficiency, our gross to net assumptions for thalassemia similar to PK deficiency 10% to 20%.

And then on the SG&A question, Tess, as we think about it. So as I mentioned, we're going to gate and manage our spend based on the regulatory discussions and the timing. But if you want to think about it is we have an infrastructure that we have built for PKD and thalassemia that we would obviously leverage, but the scale of sickle is much bigger. So we will have to scale up those functions than we did, but we have a really nice foundation to build from.

And our last question, it will come from Luca Issi with RBC Capital Markets.

This is Shelby on for Luca. Could you remind us what's the rationale for dosing higher in lower-risk MDS versus the Phase II for sickle cell disease? And then maybe one more. Now that we have the label and REMS program for thalassemia, do you expect any read-through to sickle cell? And has it changed any internal expectations on the commercial opportunity there? Any color is much appreciated.

Yes. I think -- so we could start with MDS and the rationale for the -- all 3 of the doses being higher than what we tested in the IIa, and then we'll talk a little bit about REMS and sickle.

Yes. So for the rationale of higher doses, so we originally had a Phase IIa with the 5-milligram dose based on modeling from the healthy volunteer trial, but we learned in that trial that MDS patients metabolize it faster the drug. And so we pushed the dose higher in the Phase IIb to do further dose exploration versus sickle cell disease patients who are exactly the same as healthy volunteers. So that is why we have those dose differences between those 2 indications.

And then -- and Sarah, you can start on the sickle cell -- the question about REMS and read through and Tsveta can certainly comment on how we see it commercially.

Yes. So as you know, in the sickle cell disease program, we did not have the same observations as we had in thalassemia. So it's much more like the pyruvate kinase deficiency program where we do not have a REMS, as you know, versus thalassemia where we do have a REMS. So all of this actually does give us optionality. So our going-in position based on the data observed is that, that would not be needed, and we would propose something more like the pyruvate kinase deficiency path. Now a read-through, if it would turn out to be a REMS, I'll hand that one over to Tsveta.

Absolutely. Obviously, sickle cell disease is a devastating disease with high morbidity and mortality, no treatment options. So we see a meaningful commercial opportunity, assuming we have a label in the U.S. and the team will be ready to execute on it. We got ready and executing successfully on the ramp for thalassemia. It gives us a very solid foundation to continue to execute if we were to have something similar in sickle cell disease as well.

Yes. And I'll just take a moment to say, so Tsveta's team has continued to navigate through PKD as a launch, which is ultrarare and certainly not the easiest of launches that began back in 2022. And now we have AQVESME and off to a really good start in the first month of January. So I feel very confident the team in any scenario will be very well prepared. So I think that's our last question.

Yes.

Okay. Then I will go ahead and close it down. First, I just want to thank everyone for joining us this morning. It's an exciting time for Agios. As you heard throughout the call, we're entering 2026 with quite strong momentum and really pleased that we're already seeing strong initial progress with the AQVESME launch in the U.S.

We have meaningful clinical and regulatory catalysts ahead, as we've talked about, and we'll continue to operate with financial discipline. These near-term drivers, combined with our advancing pipeline, position Agios to deliver sustained growth and long-term value, and we very much appreciate your continued engagement and look forward to updating you on our progress throughout the year. Thanks a lot.

Thank you. This does conclude today's conference call. Thank you for participating, and you may now disconnect.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tess Romero, and I'm one of the senior biotech analysts here at JPMorgan.

Our next presenting company is Agios, and presenting on behalf of the company, we have CEO, Brian Goff. Brian, over to you.

All right. Thank you, Tess, and good morning, everybody. It is great to be back at JPMorgan, and I'm really excited to share our outlook for 2026 and why we're so excited about the path forward for Agios.

Before I get started, I'll just remind everybody that I will be making forward-looking statements, so I'd encourage you to take the time to read through the details of this slide. This is a pivotal moment for Agios. We're at a major growth inflection point. And it really comes down to 3 key components that I'll talk about this morning. The first is that our PK activator, pyruvate kinase activator franchise is proving itself to advance as the standard of care across a range of hemolytic anemias. And it also serves as the foundation for our leadership in rare hematology at Agios.

Secondly, we continue to advance our early and mid-stage pipeline, and this gives us the potential to unlock further value ahead. And third, especially based on the very recent approval that we've achieved for thalassemia, which I'm excited to talk about, we now see a clear path to profitability with our existing commercial portfolio. So the takeaway here is we are not just preparing for the short term. We're building a really exciting growth future at Agios ahead.

Now our pipeline is such that Agios has a long legacy of discovering, developing and delivering very differentiated medicines that ultimately achieve approval. And the foundation of this, as I noted, is our pyruvate kinase activation franchise, this is really anchored on mitapivat, which is already approved for pyruvate kinase deficiency as well as now at the end of last year, thalassemia, we continue to pursue sickle cell disease.

We also have another exciting asset in our PK activation franchise, tebapivat, where we're also pursuing sickle cell disease as well as low-risk MDS. Earlier in the pipeline, we have 2 other assets, AG-181 that's built on our cellular metabolism expertise. We're pursuing this for the treatment of phenylketonuria, and AG-236, which is a TMPRSS6 inhibitor that we're pursuing for polycythemia vera.

Now our pipeline is advancing beyond ultrarare diseases, which is really the current anchor point we have in pyruvate kinase deficiency. And if you look at each of the subsequent indications that we're pursuing in our pipeline in totality, these represent market potential by 2030 in excess of $10 billion. PYRUKYND, as I mentioned, is already approved as of 2022. Thalassemia now is our next approval. This is under the brand name AQVESME, which we achieved at the end of last year. And this alone, on a worldwide basis, represents in excess of $1 billion in market potential. We are very well prepared for this launch.

On the bottom of the slide, you see 3 key components: First, we have already deployed our highly experienced rare disease expert field force. Secondly, we have the myAgios patient support program. This has been in place since the beginning of our parkin PKD launch and is really geared to help patients onboard to therapy and stay on therapy for the long term.

And lastly, we've been very thoughtful about how to expand globally to capture the ex-U.S. opportunity. And we've had a very thoughtful selection process with full service distributors in both Europe as well as in the Gulf region. That has allowed us to be very capital efficient and focus our investments in the U.S., which is clearly our most significant market, which brings me to our strategic priorities for 2026. There are 4, and the first -- and I'm going to go through each of these in discussion this morning. The first is this exciting high-potential high-impact launch of AQVESME for thalassemia.

Secondly, expanding our PK activation franchise into these other areas like sickle cell disease and low-risk MDS which just those 2 alone represent worldwide market potential in excess of $7 billion. Third, unlocking future value, as I noted, with hematology as well as expanding beyond with our earlier-stage assets. And then lastly, as always, focused on continued financial discipline to ensure long-term sustainability and growth for Agios.

So I want to begin with a deeper discussion on our execution for this high-impact thalassemia launch. And the point I'd like to make here is, first of all, it was at the very end of last year on December 23, that we received FDA approval for AQVESME for thalassemia. This is in so many ways, a historic approval for the thalassemia community that has waited for this for decades. It also is, of course, a significant point of pride for Agios as we continue to solidify our leadership in rare hematology.

I will note that this is a separate brand from PYRUKYND. And the advantage of that is this allows us to isolate the REMS with thalassemia and provide regulatory clarity that in the case of PKD with PYRUKYND, there is not a REMS.

Now this launch or this approval, I should say, establishes a series of very significant first in thalassemia. The first one is we have a very broad label. This is the first ever approval in thalassemia for both key genotypes, alpha and beta thalassemia regardless of transfusion burden. Secondly, this is the first oral medicine approved. And with our twice daily dosing, this is, as you can imagine, significantly less burdensome for patients then frequency of transfusions or subcutaneous once-weekly therapy, which is currently approved only for beta thalassemia.

Third, this is a disease-modifying therapy for nontransfusion-dependent patients. And the highlight of that is from a quality of life measure, we were really pleased to have this significant improvement in fatigue as demonstrated in the ENERGIZE trial. And lastly, in the transfusion-dependent focused trial, ENERGIZED-T, what we demonstrated was that the transfusion reductions that those patients had was durable and lasted for up to 36 weeks. So we're really proud of this profile. It puts us in a great position to make AQVESME the standard of care in thalassemia.

A little bit more on the launch dynamics there are approximately 4,000 adult patients in the United States that we would deem addressable at launch. The total patient population of adults is about 6,000 patients. Now we know this because there have been well-established ICD-10 and ICD-9 codes for many, many years in thalassemia. So this has been validated from a claims database standpoint as well as from in-depth account profiling. Supporting this effort is our sales force of approximately 40 people. They are highly trained, fully deployed and already generating demand. In fact, I'll just make a side note, we were really pleased that even before the close of 2025, we already generated our first prescription for AQVESME for thalassemia.

In the middle, you can see the price point is a step-up from our pricing for PKD. It's $425,000 per patient per year in the U.S. And we really feel strongly this is reflective of the compelling value that we've demonstrated across both clinical studies for thalassemia.

Now as I noted, supporting the patient journey, onboarding access and continuing on therapy is our very well-established myAgios program. So we're really excited about this launch. We are set up to deliver. And again, this is already underway and a really exciting part of the 2026 story.

Next place I want to go is expanding our PK activation franchise into both sickle cell disease as well as lower-risk MDS. And before I do that, just a quick tutorial on what is PK activation. We're going to start with the red blood cell, which is the center point of the activity here, a normal lifespan for a red blood cell is about 120 days. But in the case of hemolytic anemias with both PKD and thalassemia, it's significantly shortened, as you can see, about 20 to 30 days.

And in sickle cell disease, it's even worse than that. So moving to the right, how does PK activation work? It's really focused on the glycolytic pathway, which is the sole source of energy for the red blood cell. And at the very last step with pyruvate kinase activation essentially does 2 things. One is it increases ATP or energy for the red blood cell. And secondly, simultaneously decreases 2,3-DPG and which ultimately increases oxygen affinity for hemoglobin.

The benefit of both of these activities is that the blood cell becomes healthier, better energized and last longer. And we know this is true because we have now completed 6 well-controlled trials across 3 different hemolytic anemias and have had remarkably consistent results. In the case of PKD, as I noted, we already have PYRUKYND approval for PKD as of early 2022. That was supported by 2 studies: thalassemia, I'm going to continue to brag about the fact that we now have approval as of the end of last year.

And now the next place that we're very excited about moving into is sickle cell disease. And that's as a consequence of the data that we just read out towards the end of last year. So I'm going to start with a quick overview of sickle cell disease. And the reality here is the unmet need is glaring. It is profound and frankly, very sad for this community. In the U.S., there are approximately 100,000 adults and pediatric patients that have sickle cell disease.

And the reality is all they have available in large part is hydroxyurea, which was introduced more than 25 years ago. It's basically a repurposed chemotherapy drug. So this community has been waiting and has had moments of hope which have then been taken away, and so we really have a lot of conviction in doing all that we can to advance our PK activation opportunity into sickle cell disease.

And on that journey, in November of last year, we reported the results from our RISE UP Phase III study. The highlight here is, on the left side, you can see that we demonstrated a very strong anti hemolytic profile. There were nearly 41% of the patients that had the prespecified response of hemoglobin improvement. We also saw other markers of hemolysis improved. And if you take those responders in the middle column, you can see that they had further benefits of reduction in sickle cell pain crises as well as improvement in fatigue.

The last point I'll make is that we're really pleased with the safety profile, namely, we did not see any of the cases of hepatocellular injury that match the pattern that we observed in thalassemia. And remarkably, and I think this is a really good proxy for how patients think about the profile more than 99% of the patients that were eligible to continue into the open-label extension trial elected to do so. So the next step for us, as we've already communicated is we will be sharing this data with the FDA in a pre-sNDA meeting this quarter.

Now we have another PK activator tebapivat rounding out this franchise. This is a more potent PK activator, a few key features. One is that both important ISO enzymes PKR and PKM2 are bound longer and stronger with tebapivat than even mitapivat. Secondly, because of the enhanced metabolic activity of this product, or this asset, there are lower drug-drug interaction risks. And third is that given the longer half-life that we see the potential for once-daily dosing.

So as I mentioned, we're pursuing different diseases, sickle cell disease and low-risk MDS, and I'm going to start with sickle cell disease. What we have seen here is established proof of concept in our Phase I study that demonstrated essentially that we have enhanced hemoglobin response. That's really what we're going after to again, widen the addressable opportunity in the sickle cell disease community. And importantly, this is well tolerated. And as we've advanced into the Phase II study, we're measuring 3 different doses, 2.5 milligrams, 5 milligrams, 7.5 milligrams daily. And we're really excited about reading out that data in the second half of this year.

Moving to MDS. What's encouraging here is that from our Phase IIa study, that we read out in late 2023, we saw a 40% response in the low transfusion burden patients with achieving transfusion independence. One thing I will really note here is that in the Phase IIa study, what we observed is that the 5-milligram dose tested, the exposure levels of tebapivat were significantly lower in the MDS patients than we had modeled. So in the Phase IIb study, which is now fully enrolled, we have significantly increased the doses of multiple of 10, 15 and 20 milligrams daily. And we're really pleased to be able to report out those results in the first half of this year.

This one, I would say, because this is a bit different from a traditional hemolytic anemia but still carries forward the ineffective erythropoiesis components. We deem as higher risk, but obviously very high reward given the size of this market and the significant unmet need for these patients. So that brings me to our earlier-stage products in our pipeline. And I want to start here with our opportunity to expand within rare hematology focusing on polycythemia vera, this patient population is very significant. There are about 100,000 patients in the U.S. They're really limited to cytoreductive therapies hydroxyurea and really burdensome and I must say, very dated phlebotomy approaches.

So our goal with our TMPRSS6 inhibitor is lower hematocrit and maintain that as a durable, sustainable result for these patients to get them out of these very frequent therapeutic interactions that they have to undergo. So we're going after 6-month dosing. And the mechanism here again is an anti-TMPRSS6 inhibitor. This is -- or TMPRSS6 inhibitor, I should say. This was in license from Alnylam and is built on their very well-established GalNAc platform. So we are looking forward to Phase I healthy volunteer for AG-236 in the first half of this year.

Moving to AG-181. This is for phenylketonuria. So this is -- we're now moving beyond hematology into an area that builds on our expertise in cellular metabolism. The reality for these patients is that they're subjected to incredibly restrictive diets. And frankly, only a fraction of these patients are currently treated with pharmacologic agents. The mechanism that we are pursuing with AG-181 is very novel. This is a chaperone approach where AG-181 binds to phenylalanine hydroxylase in a way, it's similar to the action of pyruvate kinase activation.

And this is the key translational step converting phenylalanine into tyrosine. So we are very much looking forward to getting these results of starting, I should say, our first patient dosed in the Ib trial and establishing proof of mechanism for this activity in the second half of this year. What we're going after on the patient's behalf is faster onset, durable response and ideally removing some of that dietary restriction that the patients are subjected to.

So that brings me to the last of our key priorities here, which is all about financial discipline, a continued commitment from our organization. And a couple of points I want to highlight is that our financial discipline is really geared towards achieving long-term sustainability for Agios as a leading rare disease company. What that brings us to is despite the fact that we have a very important launch underway, we're continuing our commercialization in PKD. And we have a very exciting pipeline that we're advancing we're guiding towards keeping our 2026 operating expenses flat to 2025.

Now depending on how the pipeline continues to read out, we may see even further operational efficiencies beyond 2026. The key components within this is, number one, we will ensure and we believe that we are fully funded to maximize the AQVESME, thalassemia launch opportunity. Two is just as we did with thalassemia, gating our investments until we had the strong data that read out, we're doing the same in sickle cell disease until we achieve regulatory clarity on our path ahead.

And third, we're very focused on our actual operating model inside Agios and striving for continued efficiencies. So the net of all this is that we see a clear path to profitability just based on our current commercial opportunity of PKD and now thalassemia. And we think that's really important for investors to know as a base case scenario for Agios.

So in closing, we're really excited about 2026 and beyond. I just want to do a quick reflection on 2025 without going through all these milestones, just to highlight the fact that, once again, I'm really proud of the team that I get to work with every day. We persevered through challenges as well as plenty of opportunities, and we delivered on every single one of our corporate milestones that we put forward.

And so once again, I'll just remind the strategic priorities are really focused on 2 key aspects. One is master this launch for thalassemia, and 2 is advance our exciting pipeline and throughout maintaining that financial discipline. And I'm going to land on, okay, so what are -- what's the catalyst rich environment for Agios in 2026. The top half shows first half of the year, and there, as I noted, we're eager to have our pre-sNDA meeting with the FDA to discuss the mitapivat data for sickle cell disease.

Secondly, getting that Phase IIb readout for tebapivat in low-risk MDS. And third, the Phase I healthy volunteer data for our TMPRSS6 inhibitor for polycythemia vera. Second half of the year will also be busy. There, we're looking forward to the tebapivat Phase II data for sickle cell disease as well as, very importantly, the Phase Ib proof of mechanism data for AG-181 for phenylketonuria.

So it's an exciting year. You can count on us to continue to lean in on continued excellence in execution and with that Tess. I'm going to stop here. And for Q&A I'll invite the power team of Sarah Gheuens, who is our Head of R&D, Chief Medical Officer; Cecilia Jone, our Chief Financial Officer; and Tsveta Milanova, our Chief Commercial Officer.

Thanks a lot, and over to you, Tess.

Great. Well, thank you so much, Brian, for the thorough presentation, and welcome everyone over to the stage here.

So I thought maybe we would start with the slide that you presented this morning that lays out over $10 million in total estimated global market size for your current pipeline indications by 2030. Can you talk about the inputs there and underlying assumptions and what your framework is across the opportunities in terms of risk adjustment?

Sure. I can start and then the team can fill in here, too. We've certainly validated these estimates. This is -- I should have noted this is an estimate for 2030. And this is across each of these indications on a worldwide basis, looking at both current opportunities -- or current treatments rather, for these patients as well as our forward look as to others that will be entering the space and how these markets will grow.

And again, I think the highlight is that what we have in front of us immediately is thalassemia which we've sized up to be $1 billion plus in worldwide potential. We expect to be a significant portion of that opportunity. And then beyond that, which I also talked about sickle cell disease and low-risk MDS, collectively on a worldwide basis are in excess of $7 billion.

The risks are, for us, continuing to advance our pipeline, we believe we're very well positioned, particularly on the consistency of data that we've seen across these 3 hemolytic anemias.

And just talking a little bit more in more detail about that $1 billion number for PKD and thalassemia together. Maybe can you just break that down for us just in terms of from a geography standpoint?

Yes. I'll -- and this is a good place for Tsveta to weigh in on how we rank order the geographies in thalassemia specifically.

Absolutely. So we are obviously very excited to have the approval for AQVESME in the U.S. and that followed up the approval for PYRUKYND for thalassemia in the KSA and we expect to have an easy decision for PYRUKYND and thalassemia in Europe soon earlier this year. The way we look at the $1 billion opportunity is a combination of PK deficiency and thalassemia. The majority of that is thalassemia, on a worldwide basis with the highest priority market for us being thalassemia for the U.S.

Given the approval and the power team behind the launch, we see that as a meaningful opportunity to scale up and U.S. leading the way, contributing to the majority of the $1 billion over time, as the pricing and reimbursement dynamics in Europe and the Gulf play out, we'll see the ex-U.S. contribution to start scale up. but that's going to come later in the launch trajectory. And when we look at ex U.S., we see the Gulf being the bigger opportunity followed up by Europe in certain selected geographies where we know the prevalence of thalassemia is higher.

Okay. And it sounds like, Brian, from your presentation, the priority of the company is really to maximize your launches and also continue to invest in your internal pipeline. Like what is your appetite for further BD in 2026?

Yes. Well, we're in a position of strength on many fronts. We have, as I noted, a very exciting internal pipeline. It really builds on as I said, our established credibility with discovering and developing very compelling assets. And so we'll continue to do that.

Likewise, our ambition is to continue to grow and be a leading rare disease company. And so we're always looking on the outside for opportunities that would fit our capabilities, particularly our expertise in hematology as long as these are differentiated, have a real transformative potential for patients.

But I think really importantly, from a discipline standpoint, whether it's internal or external, we maintain a very high bar and we always compare both sides against each other.

Okay. And you talked a little bit about your recent approval of -- AQVESME.

AQVESME. We can practice together.

This is my first time using it on the stage here, so bear with me.

What has been the early feedback from physicians upon approval here? And Tsveta, what are you most focused on getting right from a launch perspective?

Absolutely. I'm very excited to talk about the launch. And I can tell you that the clinician and the patient community is very excited about the potential of [ Equesmiand ] now having it available to the U.S. market.

Our first priority for the launch is demand generation. The moment we got the approval in -- on the 23rd of December, the team was trained immediately, and they're already in the field connecting with the community.

The second very important priority for Q1 right now is really to ensure the drug availability at the end of January. And the reason for that is we will just basically need to finalize the last aspects of the ramp, so we can put it in place and patients actually can start the therapy as well. We have engaged with the community and the excitement is palatable.

We really got so many inbound requests to learn more about AQVESME. The team is out there educating and we really look forward to a very strong start of the launch and really providing that very meaningful therapy to patients in the U.S.

Okay. And can you talk a little bit about the initial marketing message here? And are there specific elements of the label or REMS for liver monitoring that you think you will need to educate physicians on?

So in terms of the positioning of the product, we see AQVESME the standard of care in thalassemia. And what allows us to communicate on that positioning is really the strength of the data from the energized program and the breadth of our label. We have a label which covers the totality of thalassemia, and that's really the first product for that community covering alpha, data, transfusion-dependent and nontransfusion-dependent thalassemia.

The second aspect of it is really the strength of the clinical efficacy, which we've seen the trials delivered on a very clinically meaningful endpoint across both the transfusion-dependent and nontransfusion-dependent segment. And we hear from clinicians that, that data is really differentiating and will allow us to deliver on that standard of care and positioning for AQVESME.

When it comes to the REMS really, the main education is going to be around the actual paperwork of the REMS rather than what the clinicians and patients need to do from a clinical kind of management perspective. Our REMS is very similar to what it is to actually start and manage patients on a new therapy in thalassemia initially.

Basically, it requires liver monitoring on a monthly basis, for the first 6 months after the initiation of the therapy and what we hear from clinicians is that they would do that no matter of the REMS. They will monitor patients initially when they start on therapy for efficacy, they will monitor the liver parameters anyway for the thalassemia patients. And for us now is really ensuring that all of the elements of the REMS are in place. and then we can support the patients and the clinicians to getting certified and really going underway.

Really helpful. And how should we think about the ramp for AQVESME in 2026 on both revenues and new patient starts and which patients -- I think you've talked a bunch about this in the past, but who represents the best first candidates for the product?

So as Brian mentioned, we have identified about 4,000 patients who are our addressable patient population and we will target at launch. The way we see the launch trajectory early on is focused primarily on treatment initiation from the transfusion-dependent patients.

The main reason for that is that these patients are in content contact with the health care system they go for their transfusions every 3 to 4 weeks. So they are very likely to hear and consider initiating therapy first. As the launch progresses, we expect the NTD patients, the nontransfusion dependent patients to become a more meaningful contributor and allow us to scale up the launch.

From kind of a trajectory perspective, we don't expect to see bolus that will capture the majority of the patients earlier in the launch, and that's driven by 2 reasons. The first one, the drug is going to be available in January and it's going to take time from basically prescription to treatment initiation.

So we'll actually see an increase in demand, but we wouldn't see a very meaningful bolus of patients initiating therapy first. The second reason for that is as with every rare disease launch, which is not imminently life-threatening. We wouldn't expect all the patients to start therapy first, but we'll see the first adopters and over time, a continued growth trajectory as the launch progresses.

Okay. I'm going to have to hop around here just because we don't have a lot of time. But switching gears to talk a little bit about sickle cell. You top line your -- the Phase III portion of RISE UP in December. And that study hit on hemoglobin response, but missed on the annualized rate of sickle cell pain crises.

Big picture, what do you believe led to this outcome? And is it understood why certain patients were better hemoglobin responders than others and thus had better sickle cell pain crises related and promised fatigue outcomes?

I know Sarah is ready to go on this.

Sarah, over to you.

Thank you. First, the RISE UP trial generated for the third time, the third indication, a very strong anti-hemolytic profile. So the hemoglobin response is very consistent. The hemolysis improvement is very consistent with other hemolytic anemias, and that's important because hemolysis fundamentally drives a lot of the pathophysiology in the disease.

And so while we didn't observe the sickle cell pain crisis endpoints statistically in the overall patient population, we did observe a trend. But when we looked at the hemoglobin responders, we actually saw clinically meaningful benefits across all of the different endpoints.

So the sickle cell pain crisis-related endpoints and the fatigue. And so therefore, we're very excited about the data package generated that combined with the safety package is very compelling. And so we're looking forward to engage with the agency in Q1.

Okay. And Sarah, just on this engagement with the agency, can you elaborate a little bit more on that for us. What is the exact feedback or kind of line of questioning you're hoping to have with the FDA in that meeting?

Sure. So this is the sort of classic pre-sNDA meeting that we're having in Q1 of this year. And so what you do is you engage on the data generated. Again, there's a compelling data package here to discuss with them. So we're looking forward to gain their feedback.

And okay, thinking a little bit about prior history here, before the trial read out, did you ever speak to the FDA about a potential accelerated approval path based on hemoglobin response i.e., similar to what was done for Oxbryta? And why would or wouldn't the FDA allow you to have a similar move forward for that program?

Yes. So I think the situation with Oxbryta and us is different. We -- now this is a supplement. This is a supplemental NDA in which we have now are coming with very consistent data for the third time, which is very different from when Oxbryta for the first time went. And we fundamentally believe that we have a clinically meaningful package with the data generated in the RISE UP of Phase III. So that's what we're looking forward to discuss with them.

You're right that even recently, the FDA has said that hemoglobin by itself can be a surrogate endpoint, so which in that situation, can lead to an accelerated approval pathway, but that is something that would be discussed in the meeting. Our intent, based on the data that we have is to go in for a full approval.

Okay. And how are you thinking about informing all of us post this meeting, are you going to wait? Are there going to be minutes? Are we going to have to wait for the minutes and then you'll make a disclosure. If it's a material for Agios, do you have to make the disclosure right away? Like how are you thinking about it?

Yes. I think first steps first, first have the meeting and then determine the pathway, but then we would,, in due time, of course, give an update on the regulatory path.

Okay. Okay. well, where else do I go in 3 more minutes? Okay. What pipeline milestones in 2026 matter the most for Agios?

All of them.

Yes. I think, Tess, you can imagine we triage for this presentation. And so the 5 that you have represented here on this slide, our 2026 catalyst, we believe all of these are significant. And I should have noted, it's not a pipeline milestone, but the banner on the bottom of our catalyst slide indicates that -- what's exciting about 2026 is, we're going to do 2 things simultaneously.

As we advance our pipeline, we will continue to deliver on this exciting launch opportunity with AQVESME and thalassemia, but we refused to pick favorites at this time.

Okay. And you talked about flat OpEx in 2026 versus 2025. I did have a clarifying question. Just on what visibility do you have on how the launch of vorasidenib is going for Servier?

Well, they're a private company, and we're definitely. I must say, because of the legacy of Agios in discovering vorasidenib, we are cheering for Servier. We're really cheering for the patients. And periodically, we will, I'm sure, receive updates with how their launch is going even as a private company to guide us on the residual royalty that we retain. And anecdotally, we hear that not surprisingly, they continue to do well.

Okay. And last question just on tebapivat in the sickle cell disease program there. Is there a scenario that program doesn't move forward to Phase III? Or like what -- how are you thinking overall about how that program really fits in now given all the other things that you have going on?

Maybe Tsveta can speak on that one, too.

As I said, we keep a high bar for all of our assets in development, and we'll continue to assess that as we go. Tsveta, do you want to comment?

Absolutely. So sickle cell disease is a disease of high unmet need and really no many therapeutic options. We hear it loud and clear from the clinical communities that they won't need many treatment options because not every patient is going to respond to every therapy.

Having said that, I think the timing for the tebapivat data is perfect for us because we will know so much more about the sickle cell disease landscape to make an informed decision. If we were to move the product forward how to move it in the best possible way, so it adds value to the community.

We'll obviously start having interactions with FDA, and we are going to learn so much more as we continue to dig deeper into mitapivat data. We might have some updates from etavopivat, which is the Novo-Nordisk PK activator as well on their HIBISCUS study. And we'll continue to monitor the competitive environment as well and see how we can position the product. So it can add value both to patients and physicians.

Great. Well, the clock is telling me that we're basically done here. So I want to thank the entire Agios team so much for being here. We really appreciate it. And thanks to all the listeners for joining as well.

Thanks a lot, Tess. Thanks, everybody.

Good day, and welcome to Agios Pharmaceuticals' Investor Conference Call and Webcast. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss the FDA approval of mitapivat for the treatment of anemia in adults with alpha or beta thalassemia which will be marketed under the brand name AQVESME in the United States. You can access the slides for today's call by going to the Investors section of our website, agios.com. Next slide, please. Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements due to various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

On the next slide, you'll find the agenda for today's call. On the call with me today from Agios, we have Brian Goff, Chief Executive Officer; Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development; and Tsveta Milanova, Chief Commercial Officer. Following prepared remarks, we will open the call for questions for which we will be joined by Cecilia Jones, Chief Financial Officer. With that, please advance to the next slide, and I am pleased to turn the call over to Brian.

Thank you, Morgan. Good morning, everyone, and thank you for joining us on this historic day. Next slide, please. I am very excited to announce the FDA approval of AQVESME as the first and only medicine for the treatment of anemia in both non-transfusion-dependent and transfusion-dependent alpha or beta thalassemia regardless of transfusion burden. Importantly, maintaining a separate brand name enables us to isolate the AQVESME REMS to thalassemia ensuring regulatory clarity and confirming it does not apply to PYRUKYND for PK deficiency. This landmark approval represents a significant advancement for the thalassemia community and a proud moment for Agios. This achievement would not have been possible without the collaboration and trust of the thalassemia community, patients, caregivers, investigators and advocates, and we are deeply grateful for their partnership.

I also want to recognize the Agios team for their significant efforts in bringing this important medicine to patients. Next slide, please. This approval delivers a series of firsts for the treatment of thalassemia, establishing a clear and differentiated value proposition for patients and physicians. AQVESME is the first therapy indicated for both alpha or beta thalassemia regardless of transfusion burden. As Sarah will outline, its oral twice-daily dosing offers a far less burdensome alternative to frequent transfusions or subcutaneous therapies. Importantly, AQVESME is the first disease-modifying treatment for non-transfusion-dependent thalassemia and the first medicine to show quality of life improvements in non-transfusion-dependent patients which we understand to be of critical importance.

For transfusion-dependent patients, AQVESME delivered durable reductions in transfusion burden as demonstrated for up to 36 weeks in the ENERGIZE-T pivotal trial, a meaningful benefit for patients who may require transfusions as often as every 2 weeks. This compelling profile underscores both the significant commercial opportunity ahead, which Tsveta will provide more detail on shortly, as well as the transformative potential of AQVESME. And with that, please advance to the next slide, and I'll hand the call over to Sarah to review the unmet need in thalassemia, summarize the ENERGIZE and ENERGIZE-T pivotal trial supporting approval and walk through the AQVESME label. Sarah?

Thank you, Brian. We're thrilled about the opportunity to bring a first-in-class pyruvate kinase activator to adult patients with thalassemia regardless of genotype or transfusion requirements. Before we dive into the AQVESME label, I'd like to take a moment to highlight the significant disease burden these patients face and the clinical evidence that underpins our regulatory approval. Next slide, please. Thalassemia is an inherited blood disorder characterized by an imbalance in alpha and beta globin chain production, leading to defective hemoglobin synthesis. This imbalance drives ineffective erythropoiesis and chronic hemolysis, resulting in severe anemia and systemic complications. Patients often face significant life-threatening complications, including thrombosis, heart failure, liver injury and cardiopulmonary disease, which contribute to substantial disease burden and reduced quality of life.

Next slide, please. Until now, there were no approved disease-modifying therapies for the broad thalassemia population. Transfusion-dependent patients with beta thalassemia were heavily reliant on chronic transfusions and oral chelators, both associated with significant challenges, including secondary iron overload, compliance and tolerability concerns. Additionally, treatment with luspatercept requires in-office injections while gene therapy involves intensive conditioning, limiting access for most patients. For non-transfusion-dependent beta-thalassemia, treatment was largely restricted to occasional transfusions and chelation with no meaningful disease modification. Importantly, until the approval of AQVESME, there were no approved therapies for alpha thalassemia. Therefore, when you consider the historical treatment landscape, there is clear opportunity for AQVESME to transform care across the entire thalassemia spectrum.

As you can see on the next slide, we conducted 2 global placebo-controlled Phase III trials, ENERGIZE and ENERGIZE-T, investigating AQVESME in non-transfusion and transfusion-dependent alpha or beta thalassemia patients, which supported our sNDA filing in the U.S. ENERGIZE, our first trial, enrolled 194 non-transfusion-dependent alpha or beta thalassemia patients. The primary endpoint evaluated the proportion of patients who achieved a hemoglobin response defined as an increase of at least 1 gram per deciliter or more in average hemoglobin concentrations from week 12 through 24 compared with baseline. Key secondary endpoints measured FACIT-Fatigue scores, average hemoglobin concentration from week 12 through 24, safety and tolerability. Our second trial, ENERGIZE-T, enrolled 258 transfusion-dependent alpha or beta thalassemia patients.

As reduction in transfusion burden remains the primary treatment goal for patients, we designed our primary endpoint to evaluate a transfusion reduction response or TRR, defined as at least a 50% reduction in transfused red blood cell units with a reduction of at least 2 units over any consecutive 12-week period through week 48. The trial additionally evaluated other transfusion reduction measures in its key secondary endpoints and achievement of transfusion independence as a secondary endpoint, which was defined by at least 8 consecutive weeks without transfusion through week 48. These trials allowed us to assess the benefit of AQVESME across multiple aspects of thalassemia for both non-transfusion-dependent and transfusion-dependent patients. Next slide, please. In the ENERGIZE pivotal trial, AQVESME met the primary and key secondary endpoints. 42.3% of patients in the AQVESME arm achieved the primary endpoint of hemoglobin response.

And in these responders, the average increase in hemoglobin concentration from baseline was 1.56 grams per deciliter. This is a highly clinically meaningful result as an increase in hemoglobin by 1 gram per deciliter was shown to significantly reduce the risk of adverse morbidity outcomes as was seen in multiple observational studies that follow patients with thalassemia over multiple years. ENERGIZE also showed a statistically significant improvement in FACIT-Fatigue scores in non-transfusion-dependent patients, where there was a change of 4.85 points in the AQVESME arm compared with 1.46 points in placebo. This was the first trial to show improvement in quality of life measures for non-transfusion-dependent patients. AQVESME demonstrated improvement in hemolysis indicators such as indirect bilirubin and LDH, addressing a key contributor to organ damage.

Next slide, please. In our second trial, ENERGIZE-T, treatment with AQVESME reduced transfusion burden across transfusion-dependent alpha or beta thalassemia patients. Specifically, 30.4% of patients in the AQVESME arm met the primary endpoint of transfusion reduction response. AQVESME demonstrated statistical significance across all 3 key secondary endpoints, which further evaluated transfusion reduction. Lastly, we were pleased to see that 9.9% of patients in the AQVESME arm achieved transfusion independence, meaning these patients were transfusion-free for 8 or more consecutive weeks. In addition, as seen on the next slide, adverse reactions that occurred at a higher incidence in the AQVESME arm compared to placebo included headache and insomnia.

Next slide, please. We're very pleased with the final label for AQVESME, supporting broad use across all adult thalassemia patients regardless of genotype or transfusion burden. The label describes AQVESME as a novel mechanism of action as a pyruvate kinase activator as well as its oral administration, representing 2 of the novel attributes of this medicine for the treatment of thalassemia. Next slide, please. AQVESME's label has an associated risk evaluation and monitoring system to mitigate for adverse reactions suggestive of hepatocellular injury following observance in 5 patients across the ENERGIZE and ENERGIZE-T pivotal trials. On the left-hand side of the slide, you see an excerpt of the warnings and precautions language detailing the adverse reactions observed in the 5 patients. Each of these adverse reactions occurred within the first 6 months of exposure and liver tests improved upon discontinuation of AQVESME.

To date, there have been no HCI cases in other indications following the same pattern as was seen in the thalassemia pivotal trial. The final label details requirements of the REMS program, including physician, patient and pharmacist education and certification, a common element of many REMS programs as well as liver testing at baseline and every 4 weeks for the first 24 weeks of treatment and as clinically indicated thereafter. This liver monitoring requirement is consistent with current language in PYRUKYND PK deficiency label. This proposed REMS is unique and distinctive, requiring liver monitoring only for the first 6 months and then as clinically indicating, adding complexity and time to the regulatory review process.

Additionally, as is common when a REMS is implemented, the label includes a black box warning for potential serious hepatocellular injury advising against using patients with cirrhosis and recommending discontinuation if hepatic injury is suspected. In our discussions with KOLs and treating physicians, this type of black box warning is consistent with expectations for medicines requiring REMS and does not present additional hurdles for prescribing. We believe the label appropriately reflects the clinical data we have demonstrated to support AQVESME approval as well as adequate monitoring for safety concerns. We are thrilled to deliver a first-in-class medicine to address critical care gaps in the treatment of thalassemia. Please move to the next slide, and I'll turn the call to Tsveta to review the commercial launch strategy.

Thank you, Sarah. Next slide, please. As demonstrated by the ENERGIZE and ENERGIZE-T pivotal trials, AQVESME value proposition is firmly grounded in robust clinical evidence. In market research with treating physicians on the clinical profile, AQVESME was consistently rated highly across key attributes valued in a novel thalassemia therapy. Notably, 86% of survey physicians indicated they plan to prescribe AQVESME within 6 months of availability based on clinical profile. Following the PDUFA goal date expansion, we engaged with both KOLs and targeted HCPs with actively manage patients to gather insight on prior REMS experience. KOL has strong familiarity with REMS programs and therefore, did not view REMS for AQVESME as a prescribing barrier. Among community physicians where most thalassemia patients are treated, 94% of hematology oncologists reported prior REMS experience. Additionally, about 2/3 of HCPs anticipated no to minimal impact from REMS at launch.

Next slide, please. We have executed a capital-efficient global commercial model, maintaining full economics and strategic focus in the U.S., which represents the largest commercial opportunity. In the U.S., there are 6,000 diagnosed actively managed adult thalassemia patients. We have been able to verify this number through claims data and a comprehensive account profiling by our field teams. At launch, our initial addressable population is roughly 4,000 patients. This segment includes patients receiving transfusions and chelation therapy, older patients with comorbidities and individuals with hemoglobin levels at or below 10 grams per deciliter who experience anemia-related complications and fatigue.

Next slide, please. We remain sharply focused on executing a successful launch of AQVESME for thalassemia. This work is already well underway, driven by initiatives to raise disease awareness and understand more deeply the thalassemia treatment landscape. Through these efforts, we have developed a refined national target list of HCPs who are eagerly awaiting novel treatment options. The additional time from our previous PDUFA goal date in September has allowed us to deepen engagement with physicians, building familiarity with REMS requirements and strengthening patient and provider support services to streamline access. We are confident that we have the right infrastructure in place to ensure appropriate patients can start and stay on treatment with ease. Our ambition is clear: to establish AQVESME as the standard of care for thalassemia, anchored by its unique value proposition and ability to address critical treatment gaps.

Please move to the next slide, where I will provide more detail on how to think about the initial AQVESME launch curve. With the final label in hand, we can implement the final administrative processes of the REMS program with the aim of making the REMS fully operational in late January. Until then, no AQVESME prescriptions can be fulfilled. Between now and late January, our field teams will work towards educating physicians and patients on the REMS as well as generating prescription demand. From late January, the initial pace of adoption will be gated both by HCP REMS enrollment and the frequency of patient visits, which will likely determine completion of baseline liver testing required for REMS certification. In the initial quarters of launch, we expect the time between prescription and treatment initiation will be roughly 10 to 12 weeks. As prescriber enrollment accelerates and patient onboarding gets to a steady state, we expect prescription volume to more closely track and patient revenue.

Finally, we anticipate early skew towards transfusion-dependent patients given their higher frequency of provider interactions. Over time, we expect the mix to shift towards non-transfusion-dependent patients who represent over 2/3 of the total thalassemia population. Next slide, please. Given the significant unmet need and AQVESME's compelling value proposition, we see potential for each to become the standard of care for thalassemia. As Brian mentioned, this launch represents a series of firsts for the treatment of thalassemia, addressing broad patient population for the first time in the treatment of this rare disease. The market opportunity is meaningful with approximately 4,000 addressable patients at launch, diagnosed managed adults living with both non-transfusion-dependent and transfusion-dependent alpha or beta thalassemia. To capture this opportunity, we have approximately 40 dedicated sales representatives ready to go and have identified and refined a validated list of target prescribers.

Engagement with HCPs will begin now to ensure smooth onboarding where possible ahead of AQVESME availability in late January. AQVESME will be introduced at approximately $425,000 per patient per year on a WAC basis, reflecting its differentiated benefit and value to health care system value to the health care system in addressing critical gaps in thalassemia care. Our marketing and medical affairs teams have executed best-in-class disease awareness campaigns, driving strong engagement from both treating physicians and patients across transfusion and non-transfusion segments. Complementing this, our myAgios Patient Support program is designed to facilitate access and provide comprehensive support throughout the patient journey. With that, I'll turn back to Brian for closing remarks. Next slide, please.

Thank you, Tsveta. Next slide, please. In closing, the achievement of this historic approval reinforces our corporate priorities. First, we're focused on maximizing the value of mitapivat. With the thalassemia label now in hand, we'll work to implement final administrative elements of the REMS program with the aim of making AQVESME available in late January. In the meantime, the field team will work to educate physicians and patients on the REMS and focus on generating prescription demand. Additionally, we look forward to engaging with the FDA in the first quarter of next year to review the Phase III RISE UP data of mitapivat in sickle cell disease and determine the regulatory path forward.

Second, we'll continue to advance our mid- and early-stage pipeline, creating additional optionality within and beyond our foundation in nonmalignant hematology, critical steps towards achieving our goal of building a sustainable rare disease company. Finally, we remain committed to disciplined financial management. Early next year, we'll provide an update on proactive measures to reduce operating expenses and extend our cash runway while still ensuring appropriate investment behind the U.S. thalassemia launch. Our goal is clear, to become a sustainable rare disease company. This starts with delivering first on our core foundation in hematology, and we are executing with that objective in mind. With that, I'd like to now open the call for questions. Operator, please open the line.

[Operator Instructions] And our first question comes from Samantha Semenkow from Citi.

Happy holidays. Congratulations to the team for the approval. I just wanted to follow up a little bit. Can you speak a little bit more about the physician target list that you've generated? I'm wondering how many physicians are in that list? And what proportion of those 4,000 addressable patients are managed by these physicians?

Yes. Thanks a lot, Sam. I'm going to have Tsveta take that question. And we won't do so much quantification, but I think we can answer your question with a good qualification about the work we've done and generally the types of physicians that we'll be targeting first. Tsveta, you want to take that?

Absolutely. Thanks, Brian and Sam, for the question. As Brian mentioned, we're not going to be giving specific numbers of physicians, but what I want you to keep in mind is that the team has done a very comprehensive launch preparation and physician targeting for us to get ready and execute on a successful launch. The initial target physician will focus on 2 groups of physicians. These are the KOLs who are experts and manage thalassemia patients as well as HCPs who have thalassemia patients and have indicated their patients are likely to benefit from a novel therapy. So now when we have the approval, the team will be trained and they will be able to engage with those physicians immediately to educate on the product profile and educate on the REMS.

When we think about the initial launch trajectory, I want to stress that we don't expect bolus at the beginning of the launch, and that's driven by 2 things. The first, as we've mentioned in the past, thalassemia is not an imminently life-threatening disease. But also, as we mentioned on the call today, AQVESME due to the REMS implementation will not be available until late January. So initially, at the beginning of the launch, we'll see the prescriptions and the demand generation, but there will be lag between the prescriptions and the actual revenues at the initial quarters of the launch.

And over time, as the processes get smoother and more physicians get certified, we will expect the revenues and the demand to align closer with one another. One final thing is, as you would expect, initially, we would expect out of the 4,000 patients, the transfusion-dependent patients, which are about half of them to initiate therapy first, and this is because these patients are actually more engaged and have more frequent interactions with the health care system. But over the course of the launch, we would expect the proportion of non-transfusion-dependent patients to increase given that 2/3 of the 6,000 patients are actually non-transfusion dependent.

Very helpful.

Thank you.

And our next question comes from the line of Gregory Renza of Truist Securities.

Brian and team, happy holidays as well, and congrats on the great news. Brian, maybe just with respect to the outcome here on the label and also the details on the REMS program. In light of just the extra time that was utilized by the FDA and for you, your reference of being highly engaged with the agency over the last several weeks and of course, over this filing. Could you just comment a bit about how you're viewing where you all landed up on the label and the REMS program, how it sort of fits your expectations? And what maybe has had evolved over the last several weeks to the last few months with the extension that brings you to where you are today?

Yes. Sure, Greg. I'm going to let Sarah tackle that question. I will say I am very proud of the Agios team for the constructive engagement that we've had throughout. This is, as I think folks know, it's been a journey to work through the 2 very well-controlled, very impressive studies that back up the label. We're pleased with the outcome. But I'm going to let Sarah speak about the journey to get here and her thoughts ahead.

Thanks, Greg. So I think -- well, as you know, the REMS request came relatively late in the original review. I think once that occurred, we were able to really work collaboratively with the agency to get to this finish line. And I'm actually very proud of the outcome of the label because it truly reflects the data, both for efficacy, but also on the safety side. Again, on the efficacy side, very happy to be able to deliver AQVESME to all thalassemia patients independent of their transfusion need and genotype. So I think this is really a reflection of the rigor of the trial, the patient population enrolled and ultimately, that translates into a label for everyone.

And then as it relates to hepatocellular injury, I'm also actually very proud of that language. It completely reflects the data that we've observed with the cases occurring in the first 6 months as we had highlighted before. It also highlights that the monitoring indeed can be restricted to the first 6 months. So once a month for the first 6 months, which we believe is also a perfect reflection of the data, and I think the REMS reflects that as well. So I think we've landed in a great spot altogether in a very collaborative way. And again, this highlights the goal, both on the FDA side and on our side to deliver safe and effective therapies to patients.

That's fantastic. Sarah, congrats again.

Thank you.

Our next question comes from the line of Eric Schmidt from Cantor.

My congratulations as well, quite the achievement, many firsts for patients. Maybe first, could you -- once the REMS program is in place in late January, Tsveta, I was hoping you could just sort of walk us through what actually has to happen from the time a start form is in place to shipping the drug to patients, specifically with regard to the steps that the REMS provider and pharmacist and patient need to go through. And then the second question would be on pricing. I noticed there's a modest price discrepancy relative to the price of mitapivat in PKD. How do you police that or ensure no contamination across price utilization? Thanks, Eric. Fed, you want to get started on starting with the REMS process?

Thanks, Eric. Tsveta, you want to get started on starting with the REMS process?

Absolutely. So the REMS encompasses 3 steps. The first one is that the pharmacy needs to be certified. In our case, we have a single specialty pharmacy, so that will require one certification for the pharmacy. So that will be one time and one pharmacy. The second step is the physician certification, which requires education on the REMS and then being certified. It is important to note that once the physician is certified, the physician does not have to be certified again. And the third aspect is going to be the patient certification. The patient certification will require the patient to complete a liver test before they become certified. Once the 3 steps of the process for the REMS are completed and the patient has gone through their prior authorization aspect with the payers and their insurance company, then the drug can be dispensed by the pharmacy at that moment in time.

The team is very well positioned to handle all of the steps. As I mentioned at the moment, we're just working through the administrative steps of the process to ensure that the drug is going to be available in late January, but we are in a great place to start executing on demand generation immediately. On the second aspect of the pricing, both PYRUKYND and AQVESME are priced within the rare disease price band. Both of the products reflect rare diseases with -- diseases which are representing a high unmet need and a strong value proposition.

When it comes to AQVESME, as we mentioned, that price is reflective of the strong data and the fact that it is the first therapy to address the totality of the thalassemia patient population, given that both products are distributed through a single pharmacy at 2 different brand names, and we'll be able to ensure that patients actually receive products on label. And from a payer perspective, these are rare diseases, and we don't expect either of the category to be managed. So we have a very strong market access team, and I'm very confident we can execute on the AQVESME launch successfully and continue to support PYRUKYND for PK deficiency patients as well.

Thanks, Eric.

Next question comes from the line of Alec Stranahan of Bank of America.

Congrats from us on the approval, really great to see. Maybe 2 quick questions on just the launch dynamic piece. And then I've got a follow-up. I guess as we're modeling the launch, should we assume initial sales will likely happen in 2Q with little to none in 1Q, just given the lead time on the prescription to dose? And I guess, would you say the normalization on the new start to dosing could happen this year? Or is this more of a 2027 aspect for the launch?

Yes. Thanks, Alec. I think this is a good opportunity for Tsveta to take a break and Cecilia can comment on revenue expectations here.

Yes. Thanks, Alec. So in terms of the initial quarter, so as Tsveta mentioned, we have to finish implementing the last steps of REMS, and that would happen late January. What will happen probably in Q1 is you will see some initial orders coming in, in order to stock as well because as Tsveta mentioned, this is a different brand, different dose than what we have. So we'll have some shipments going in. And we do expect some prescriptions to be fulfilled as well in Q1. And then on your second question, as Tsveta has mentioned, like at the beginning, there will be prescriptions go ahead of revenues in a way. And I think we'll see that probably towards the later part of the year or early next year start to be more aligned with revenues as well.

Okay. That's helpful. And then maybe one quick one on sickle cell. I guess given you haven't seen the similar levels of liver AEs in RISE UP, I'm curious how you think about potential labeling if you were to see, say, a conditional approval here. Do you think there's a path to getting sickle cell added to the PYRUKYND label where there's no black box?

Sarah, you want to take that one?

Sure. So thanks, Alec. So first of all, it's important for us to go engage with the FDA on this in our sNDA -- pre-sNDA meeting in Q1. Of course, as you highlighted yourself, the data has not shown any hepatocellular injury cases in sickle cell disease like what we've seen in thalassemia. So that is what we will be walking the agency through and highlight what we believe is the right path. But as always, it will be a matter of review. Again, our assessment is that we have not seen any HCI in sickle cell disease. And so therefore, we believe there may be a path following pyruvate kinase deficiency.

All right. Congrats again on the approval.

Thank you.

Thanks, Alec.

Our next question will come from the line of Marc Frahm from TD Cowen.

Congrats on the approval. Maybe just following up on a few of the other questions. Just given there's maybe a bit of a disconnect between prescription demand and the ability to book revenue at least in the early stages, just will you be providing the TRx volumes as part of your kind of quarterly reporting? Is that expectations? And are there other metrics kind of along the certification process that you think are particularly key to -- for investors to be tracking the progress of the launch? And then related on the pricing question, just if you are successful in getting the FDA to ultimately agree to a sickle cell label based on the data, would this branding allow you, you think, also to keep a differentiated price for sickle cell that could potentially be even a bigger gap than the PYRUKYND pricing gap right now?

Yes. Thanks, Marc. I -- let's do 2 parts here. Cecilia, you can take the first one in terms of launch metrics. And then it's premature to say anything about pricing with sickle cell disease at this point, but Sarah can comment on the approach. Cecilia, you want to start?

Yes. Thanks, Marc. So our plan for next year, so with each quarter, we plan to share AQVESME prescription volume. And then from a revenue perspective, we plan to show mitapivat aggregate revenues, and we will split between U.S. and ex U.S.

Great. And Tsveta?

So we are excited about the opportunity and the potential to engage with the FDA on the sickle cell disease filing in early 2026. When it comes to pricing, as Brian mentioned, we'll look at the time of approval and the label. We'll look at the competitive space, and we'll make the right pricing decision at the time. It's a little bit premature for now to comment, but different brand names provide us different optionalities.

And again, I'll just reinforce, Marc, that we are pleased with the fact that this novel approach of having 2 different brands has really given us the opportunity to align the value that we see with thalassemia and the price. And of course, as we've already noted on this call, that's distinct now from PKD. So certainly pleased with the position that we're in.

Okay. Congrats again.

Thanks a lot.

And our next question will come from the line of Emily Bodnar of H.C. Wainwright.

Congrats on the approval. I guess, first one, if you could comment on how long that process for the REMS certification takes with the 3 elements that you discussed? And also curious on how common liver issues such as cirrhosis are in thalassemia patients. And then maybe if you can comment on ex U.S. launch process with some of your partners and how we should be thinking about that ramp-up?

All right. Thanks, Emily. So we'll batch together 2 of your questions, which are commercially oriented, and I'll ask Tsveta to comment. First, on the process for REMS certification, and maybe I'll expand the question a little bit, not so much for REMS itself, but the process from prescription all the way to treatment initiation, which Tsveta can comment on. And then Tsveta talk a little bit about ex U.S. and our partners, and then we'll turn it over to Sarah for thalassemia and incidence of cirrhosis.

Absolutely. So as we mentioned on the call, we expect initially the time from prescription to treatment initiation to take about 10 to 12 weeks. As Brian mentioned, this is driven by 2 things. The first one is the time it takes for the patient to complete the prior authorization with the insurance company. That's a highly variable process and really depends on the patient insurance, but that could take a month or even longer for some of the patients. And the second gating factor from prescription to initiation is going to be completing the REMS process, which has 3 elements: the physician certification, as we mentioned, the pharmacy certification, which will happen once at the beginning and the patient certification. From a patient certification perspective, they don't need to complete the liver test ahead of the spend. And our initial assessment initially that will take 10 to 12 weeks with the goal of shortening that time as more physicians get certified.

And I'll just remind you again, physicians need to get certified only once. and then they can prescribe the drug with the REMS. And of course, as the patient onboarding process gets to a steady state, we will be looking to shorten the time as we progress with the launch. When it comes to the ex U.S., we are very excited that we have an approval in KSA, which came in August of this year. Both Europe and the Gulf countries have a delay between actually initial approval and where we expect to see revenues. When it comes to specifically to the Gulf countries and KSA, that's driven by the fact that after you have an approval, the initial prescriptions come on a named patient basis. And these prescriptions need to be approved by the individual hospital and budgets need to be allocated to these prescriptions.

As the prescribing volume increase, then the national procurement process can start and that can open access significantly. That process can take about 2 years. So initially, in the Gulf countries and KSA specifically, we would expect a very slow demand generation and revenues then accelerating after the national procurement process is complete. When it comes to Europe, after we have the approval by the EMA and as we said, we expect an EC decision on the label for thalassemia early 2026, then we'll need to go through the individual country pricing and reimbursement processes, which can take 12 to 18 months themselves. And after that, once the product is available in the individual markets, we'll see revenue. So in that case, we wouldn't expect revenues coming from Europe early in 2026, if not even 2027.

Thanks, Tsveta. And then, Sarah, over to you just for the second part of the Emily's question about cirrhosis and how common that is in thalassemia.

Sure. So the natural history data of thalassemia, I think there is one publication that just recently came out that highlights in a cohort that was followed over 38 years, about 25% of patients ended up having cirrhosis in that untreated cohort. And this is where, of course, we have to remind ourselves that the cirrhosis typically comes because of iron overload in this condition in which patients get iron overload, secondary iron overload just because of transfusions and of course, primary iron overload from dysregulated iron metabolism plus hemolysis. And this is where we're excited that now mitapivat actually has shown that it reduces hemolysis as shown by positive impact on bili and LDH, and we have the transfusion reduction. So hopefully, these are 2 of the main sources of iron overload that we can tackle with this drug for thalassemia patients. And hopefully, in the long run, that also leads to similar observations that we have seen in PKD with an improvement on iron overload.

Thanks, Sarah.

And our next question will come from the line of Salveen Richter of Goldman Sachs.

This is [ Shrina John ] for Salveen. Congratulations on the approval. Could you comment on the path of getting from this 4,000 addressable population at launch to the 6,000 target TAM in the longer term and the expected drivers of growth that you believe will contribute to this?

Yes, sure. Tsveta had commented a little bit in her prepared comments, but maybe Tsveta, you put a little more color on that bridge from the 4,000 target thalassemia patient population and longer term, the broader 6,000 adult patients in the U.S.

Absolutely. So in the U.S., there are 6,000 diagnosed and actively managed patients with thalassemia. And we've been able to verify that number from the claims data and our extensive account profiling at launch. From the 6,000 patients, we have prioritized 4,000 patients for our initial launch focus. And these patients constitute the patients who are transfusion-dependent patients as well as non-transfusion-dependent patients who have already developed disease complications or are living with very low hemoglobin levels at about 10 or below 10 and are experiencing severe fatigue and are looking for additional therapies to help them manage their disease. When we think about the initial launch trajectory, we would expect the transfusion-dependent patients to consider and initiate therapy first.

And that is primarily driven by the fact that these patients are in a regular frequent interactions with the health care system. So they are more likely to actually have the conversation with their physicians and initiate therapy first. Over the lifetime of the product and the launch, we would expect the proportion of non-transfusion-dependent patients to increase, starting with more symptomatic non-transfusion-dependent patients who are currently actively looking to actually improve the management of their disease and are actively looking for new treatment options. And as the launch progresses, we will expand beyond the 4,000 addressable to the 6,000 patient population because ultimately, all of the 6,000 patients are on label. As we mentioned in the call, we have a broad label for thalassemia, which includes patients who are transfusion-dependent, patients who are non-transfusion dependent and patients who are with alpha or beta thalassemia as well.

Thanks, Tsveta.

And our final question comes from the line of Luca Issi of RBC Capital Markets.

Team, this is Cassie on for Luca. Congratulations on the approval. We have a question for the launch as well. On luspatercept, it generated $117 million and $224 million in revenue in year 1 and year 2 post launch in thalassemia alone according to Evaluate Pharma. Is that the right comp for us to think about as we think about the revenue for AQVESME in 2026 and 2027? Or would you advise us against that comp? And if you can also maybe speak to the alpha versus beta thalassemia breakdown in your 4,000 initial targeted population, that would be much appreciated.

Sure. So a 2-parter there, and we're keeping Tsveta joyfully busy today with all these commercial questions. Tsveta, first, maybe a commentary on why luspatercept, we believe, is not a compelling analog, and then we can talk about alpha versus beta.

Absolutely. I wouldn't use Reblozyl as a comparator here for 2 reasons. The first one is the company did not formally split the revenues between thalassemia and MDS. The only thing that they have commented on is that majority of their revenues are coming from MDS. So I wouldn't know if the Evaluate Pharma estimate for the indication split is accurate or not. The second thing that we want to stress is the fact that Reblozyl actually has a very low penetration in thalassemia, and that's driven by 2 things. The first aspect is the fact that Reblozyl has a narrow label. They focus only on transfusion-dependent beta thalassemia patients in the U.S. and do not cover the rest of the patient population.

And the second, what we've heard from treating physicians is the fact that even though a lot of the patients were eager to try Reblozyl, a lot of the patients actually opted out of continuing to stay on therapy with Reblozyl for thalassemia, driven either by lack of efficacy or the fact that the product is administered in the physician office every 3 weeks, which significantly increases the treatment burden for the patients. So they opted out not to stay on therapy. When you think about the 4,000 patient population that is our initial launch target, 50% of these 4,000 patients, they are transfusion-dependent patients.

Majority of the transfusion-dependent patients are beta thalassemia patients. So about -- when you think about it, majority -- around 2,000 of those will be transfusion-dependent beta-thalassemia patients. The non-transfusion-dependent patient population within the 4,000 is a mix between alpha and beta thalassemia. And that mix varies actually by region. For example, you see more alpha thalassemia patients in areas where it's like New York or L.A., where you have a lot of Asian patient population versus other parts of the country, but it's a mix of symptomatic non-transfusion-dependent alpha and beta thalassemia patients.

I would now like to turn the call back over to Brian Goff for closing remarks.

Well, thanks, [ Shibhan ], and thank you all for your thoughtful questions and for joining us today, especially during the holiday season. really love the fact that we had a lot of commercial questions, which I think speaks to recognition of the size of this opportunity in front of us. The FDA approval of AQVESME is clearly a landmark moment for both the thalassemia community and for Agios. And it has been truly heartening for us to have heard from many thought leaders and thalassemia advocacy leaders just in the past few hours since they read the news.

As noted, we expect the REMS program to be fully operational in late January. And as Tsveta has said a few times, our teams are already working diligently to ensure a seamless start for physicians and patients. Looking ahead, we're energized by the opportunity to deliver this first-in-class medicine to thalassemia patients in the U.S., and we look forward to keeping you updated on our progress. So on behalf of the entire Agios team, thank you very much for your continued interest and support. and we wish for you a wonderful holiday season. Thanks a lot.

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

Good morning, and welcome to the Agios Pharmaceuticals Investor Conference Call and Webcast. [Operator Instructions] Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Please go ahead.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss top line results from the pivotal Phase III RISE UP trial of mitapivat for the treatment of sickle cell disease. You can access the slides for today's call by going to the Investors section of our website, agios.com.

Next slide, please. Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

The next slide shows the agenda for today's call. On the call with me today from Agios, we have Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development.

Next slide, please. We are also joined on the call by Dr. Biree Andemariam, a thought leader in the sickle cell disease clinical community. Dr. Andemariam is a Professor of Medicine and the American Red Cross Endowed Chair in Transfusion Medicine at the University of Connecticut School of Medicine. She is the Founding Director of the New England Sickle Cell Institute and serves as Director of the Connecticut Bleeding Disorder Center.

Dr. Andemariam previously served as Chief Medical Officer and on the Board of Directors of the Sickle Cell Disease Association of America. We are pleased to have Dr. Andemariam provide her clinical perspective on the devastating nature of sickle cell disease and the RISE UP Phase III trial results. Following prepared remarks, we will open the call for questions.

With that, please advance to the next slide, and I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining today's call. At Agios, everything begins with connection. We partner closely with the rare disease communities we serve to deeply understand their challenges and priorities. This collaboration drives our ability to develop and deliver innovative medicines with the potential to transform lives.

As you'll be reminded on this call, sickle cell is a complex and devastating disease. In the U.S., median life expectancy for sickle cell patients is in the late 30s. Despite the staggering statistic, treatment options remain limited. Yet patients continue to advocate fiercely for progress, seeking partners who share their passion and commitment. We at Agios are proud to stand alongside them.

On the next slide, you'll see a quote from Cassandra, a sickle cell disease patient and advocate whose words reflect the reality faced by millions of patients worldwide. Her perspective underscores both the severe nature of this disease and the urgent need for new treatment options. As we announced in our press release this morning, the RISE UP Phase III trial of mitapivat in sickle cell disease achieved statistical significance on the primary endpoint of hemoglobin response.

And while mitapivat showed a reduction in the other primary endpoint of annualized rate of sickle cell pain crisis, this trend did not achieve statistical significance. On today's call, you'll hear from Dr. Biree Andemariam, who will provide an important perspective on the significant burden faced by patients living with sickle cell disease. Following her remarks, Sarah will do a deeper dive into the Phase III RISE UP trial results, after which Dr. Andemariam will share her clinical insights on the data.

Our goal is that by the end of this call, you'll share our conviction in the totality of data and understand the significant potential mitapivat holds in the treatment of sickle cell disease.

And with that, please advance to the next slide, and I'll hand the call over to Dr. Andemariam.

Thank you very much, Brian, and thank you, everyone, here at Agios for giving me the opportunity to lay the framework for how sickle cell disease affects the body and how it's deleterious affects and impede the quality of life.

First of all, I think it's important for us to remember that sickle cell disease, even though it's a hereditary disorder with a common genetic mutation across individuals, it really has heterogeneous presentation, clinical presentation. And this makes treatments as well as manifestations of the disease very complex to manage. Sickle cell disease affects the red blood cells, specifically the hemoglobin inside of the red blood cell. And since the red blood cells traverse the entire body through circulation, it is a multisystem disorder.

And in so doing, as the sickle cells traverse the vasculature, they have the ability to affect virtually every organ system. It's also important to understand the underlying pathophysiology of sickle cell disease. Well, first of all, there's a chronic underlying hemolytic anemia, red blood cells are fragile. They break open easily. The average lifespan of somebody born with sickle cell disease, their red blood cell average lifespan is only 1 to 2 weeks compared to the average person without sickle cell disease where the red blood cells last 3 to 4 months.

The other core part of the underlying pathophysiology of sickle cell disease is vaso-occlusion. This is blockage of blood flow at the microvascular level, again, impeding blood flow to all the vital organs. And together, the hemolytic anemia and the vaso-occlusive processes lead to the underlying severe morbidity and cumulative morbidity over the lifespan as well as the early mortality that you raised, Brian.

Hemolysis itself, breaking open of red blood cells leads to the release of toxic factors into the intravascular space. This includes free hemoglobin as well as the enzyme arginase. And these and other factors lead to endothelial dysfunction or vasculopathy, a depletion of nitric oxide as well as the activation of a number of inflammatory mediators. And together, this amplifies the risk of vaso-occlusive events. So hemolysis itself leads to vaso-occlusion.

So this has been very technical. It's focusing on pathophysiology and biology. It's very complex. But I think we'd be remiss if we didn't also touch on the fact that quality of life in persons with sickle cell disease is very much reduced. And in these people born with this condition, they face a lifetime of having to manage their chronic anemia, keeping in mind that the person living with sickle cell disease has about half the blood volume of someone born without sickle cell disease, and they have to function in society being very anemic and also managing the potential for the development of chronic organ damage over the lifetime as well as managing the vaso-occlusive pain crises that come out of nowhere and make it very difficult to lead fully productive lives.

With the next slide, I'd like to just orient us all to what treatment options we have for sickle cell disease. And first of all, what I think you'll appreciate is that we have very few dots on the time line. Sickle cell disease was first reported in the medical literature in 1910, but it wasn't until 1998 that the first drug was approved and that's hydroxyurea, which is the standard of care for all individuals with sickle cell disease. It wasn't until almost 20 years later that the second approved drug for sickle cell disease came on the market, L-glutamine for its ability to reduce vaso-occlusive pain crises.

But this has not had much uptake in the community for a number of reasons, including the fact that if you look at the Phase III trial, there was an imbalance in terms of dropouts in the treatment arm compared to placebo. And there's been some difficulty, I think, with understanding and communicating the mechanism of action of L-glutamine.

think we were all excited 2 years later when 2 new drugs were approved for sickle cell disease within 2 weeks of each other. 1 being crizanlizumab, which reduced vaso-occlusive crisis and 1 being voxelotor, which was an antihemolytic. And although these did benefit a substantial proportion of individuals living with sickle cell disease. Unfortunately, in a follow-up Phase III study of crizanlizumab, there was no difference compared to placebo, which led to it being withdrawn from the European market.

And with voxelotor, as many of us know, after 5 years in the market, it was withdrawn by the manufacturer globally due to some concerns regarding safety and ongoing Phase III studies. So this is where we are in terms of disease-modifying therapy with very few agents and many of us believe that really all we have is hydroxyurea. Just want to touch on the fact that, yes, gene therapies were approved about 2 years ago, but these are complex to give, even though all patients are theoretically a candidate for gene therapy because it does not require a bone marrow donor.

Every patient is their own donor. It is hard to access these therapies. They have to be given through authorized treatment centers and require not only hematological expertise, but also bone marrow transplant expertise, and they're also costly. So there's been limited uptake despite some excitement for them becoming on the market.

Next slide, please. I'd like to close by just addressing some of the ongoing challenges in treating individuals with hemolytic anemia and vaso-occlusive crisis and sickle cell disease. First of all, with respect to the hemolytic anemia, this is very burdensome to patients. The anemia itself makes it very difficult to function at a high level. There is the ongoing vaso-occlusive risk, endothelial dysfunction as well as end-organ damage that are driven by the underlying hemolytic burden. There are -- and I can tell you, as a clinician, very few options to improve hemoglobin in individuals with sickle cell disease, particularly since voxelotor came off of the market.

And really, the mainstay of treatment for anemia is either hydroxyurea for which we only see modest increases in hemoglobin and not in everybody and blood transfusions. And blood transfusions can be very complex, leading to the development of red blood cell alloantibodies that can make it hard to find appropriately matched blood for patients in the future. They also can lead to significant iron overload. And in some parts of the world, particularly those where sickle cell disease is most prevalent, transfusions are not necessarily safe from an infection standpoint or readily available.

And in terms of vaso-occlusive crisis, it's important to remember that these are the leading cause of acute morbidity and for people seeking acute medical care, whether that's an emergency department [indiscernible] office or through hospitalization. It's also important to note that right now, the only thing that I as a clinician can do to try to treat somebody that's in the midst of a vaso-occlusive crisis is really [ payload ]. We have nothing that can stop a vaso-occlusive crisis once it's begun. All we do is give patients IV fluids, some oxygen and high doses of opioids until the underlying pathophysiological process dissipates. And this is unacceptable.

And some of the existing therapies that we have limitations, as I've mentioned. So I really believe that we are still in a period of time where there's a strong need for physiologically anchored, well-tolerated and predictable therapies for this population.

And with that, I'd like to hand the call to Sarah. Next slide, please.

Thank you, Biree. Before I review the results of the RISE UP Phase III trial, I would like to take a moment to review the mechanism of action of mitapivat on the next slide.

Mitapivat is an oral allosteric activator of red blood cell pyruvate kinase, which is the enzyme responsible for converting phosphoenolpyruvate to pyruvate and thereby converting ADP to ATP, the main source of energy for the red blood cell. So in activating pyruvate kinase, ATP levels increase and upstream in the glycolytic pathway, 2,3-DPG levels are decreased.

In hemolytic anemias, higher ATP improves red blood cell membrane integrity and overall health and thereby reducing hemolysis. And then in sickle cell disease, patients also have higher levels of 2,3-DPG and lowering 2,3-DPG decreases hemoglobin S polymerization, minimizing sickling and microvascular obstruction. These data, which I'll detail shortly, indicate that effectively targeting the last step of the glycolytic pathway, which is important to increasing hemoglobin levels, help achieve upstream benefits, including decreased 2,3-DPG to potentially reduce red blood cell sickling and vaso-occlusion.

Next slide, please. Here, you'll see our RISE UP Phase III trial design. As you can see, we conducted a 52-week trial comparing 100 milligram mitapivat twice daily to match placebo with a 2:1 randomization. Patients were stratified based on the number of sickle cell pain crises in the 12 months prior to informed consent and concomitant hydroxyurea use.

As we have said previously, we designed this trial with 2 primary endpoints and 5 key secondary endpoints to evaluate objective measures of hemolytic anemia as well as vaso-occlusion. This comprehensive design enables a broad assessment of the potential benefits of mitapivat across multiple aspects of the disease that Dr. Andemariam referenced earlier.

Next slide, please. Here, we showed baseline characteristics in the trial. While you can see there was a slightly younger patient population enrolled in the mitapivat arm than in the placebo arm, generally, baseline characteristics were well balanced across the 2 arms. On the next slide, we continue to show disease characteristics, including genotyping, number of sickle cell pain crises observed in the 12 months prior to informed consent, transfusion burden and prior disease-modifying therapy.

Again, disease characteristics were well balanced across both arms and highlight that we enrolled a patient population experiencing pain crises and that was not heavily transfused. The next slide reinforces that the patients enrolled in the trial demonstrated characteristics of hemolytic anemia, including measures of hemoglobin, bilirubin, LDH and reticulocyte count. These data depict what we would naturally expect from a sickle cell disease patient population.

Moving on from baseline characteristics. On the next slide, we've shown our statistical testing strategy, including the key secondary endpoint hierarchy. As we have said previously, if one or both primary endpoints achieved statistical significance per our statistical analysis plan, the level of alpha would be transferred to key secondary endpoint testing in a hierarchical fashion.

Importantly, on the next slide, you can see our patient disposition data. We observed a low discontinuation rate with 85% of patients completing the 52-week double-blind treatment period. And similar to what we've observed in our PK deficiency and thalassemia trials, we saw a very high rollover rate of 99% of patients that completed the trial, they decided to enroll into the open-label extension, which is exceptional.

So now moving on to our efficacy results, beginning with the first of our 2 primary endpoints on the next slide. First, I'm going to orient you to the slide format as all of the next slides will have a similar layout. So on the left-hand side of the slide, you'll see a legend, which follows the statistical testing hierarchy. And on the right-hand side, you'll see relevant data tables for each endpoint.

So sickle cell patients are anemic and chronic hemolytic anemia leads to poor clinical outcomes, as Dr. Andemariam just highlighted. And therefore, we chose a hemoglobin response as the primary endpoint to be able to assess if mitapivat could improve anemia. In the placebo arm, 2 patients achieved a hemoglobin response, which was defined as at least 1 gram per deciliter increase or more in average hemoglobin concentration from week 24 through week 52 compared to baseline. And in the mitapivat arm, 56 patients achieved that endpoint. Basically being 40.6% of the trial population. So that is a highly statistically significant result on the hemoglobin response.

So when we move to the next endpoint, the next primary endpoint, which is the annualized rate of sickle cell pain crisis, we chose that endpoint because, of course, as you heard, sickle cell pain crises are manifestations of vaso-occlusion, and they represent a major cause of morbidity and mortality.

And therefore, we chose that as the other primary endpoint. As you can see in the data table here, we observed an annualized rate of 3.05 pain crises in the placebo arm and 2.62 in the mitapivat arm. While we did not achieve statistical significance in the total trial population, we did observe a trend with a 14% reduction in observed crises for mitapivat compared to placebo. The p-value is 0.12. So there is a trend favoring mitapivat versus placebo.

So now we're moving on to the secondary endpoints, and we are going to begin with the average in hemoglobin concentration from baseline to week -- from week 24 through week 52. And this is the first key secondary endpoint, which further examines the impact of mitapivat on anemia. So on this endpoint, we show a statistically significant difference of 0.7 grams per deciliter in the average hemoglobin concentration compared to placebo.

Again, a highly statistically significant result. And on the next slide, you can see the waterfall plot depicting that average change from baseline hemoglobin concentration from week 24 through week 52, which highlights that the mitapivat patients are clearly responding well and it's very much in line with our other hemolytic anemias.

So as Dr. Andemariam highlighted, sickle cell disease anemia is hemolytic in nature. And so our mechanism of action improves red blood cell membrane integrity and health. So therefore, we looked at indirect bilirubin as a marker of hemolysis. And so this slide depicts the endpoint of average change in indirect bilirubin from week 24 through week 52 compared to baseline.

So here, you can see that we demonstrated a mean difference of 16.91 micromoles per liter in the mitapivat arm compared to placebo, again, highly statistically significant.

Moving on to the next slide. So as fatigue is considered an important symptom in sickle cell disease, we measured fatigue in this patient population. We used the PROMIS Fatigue 13a short form to capture fatigue, and we measured an average change in T scores from week 24 through week 52 compared to baseline in the total trial patient population.

So first, more background on the endpoint itself. Scoring is through a normalized T-score and scores that represent fatigue actually can vary depending on the condition. And so when you look at the baseline numbers presented here, 52.72 in placebo and 53.49 in mitapivat, that means that for this disease, the trial enrolled a mildly fatigue patient population. So the patients reported mild fatigue at baseline, and we did not achieve statistical significance on this measure.

So because now we are no longer showing statistical significance on the endpoint, we can no longer transfer alpha to the next endpoint, and we can no longer draw statistical conclusions on the next 2 key secondary endpoints.

So on the next slide, we report analyzed rate of hospitalizations for sickle cell pain crises and hospitalizations, of course, they often represent the primary driver of health care utilization for patients. So that's why we chose that as the key -- another key secondary endpoint. And in this table, you can see that the analyzed frequency of hospitalizations was 1.81 in placebo versus 1.56 in the mitapivat arm leading to that rate ratio of 0.86, again, representing a 14% reduction in hospitalizations favoring mitapivat.

And on the last slide on the key secondary endpoints. So the last endpoint we tested in our statistical hierarchy is the average change in percent reticulocytes. Again, no longer possible to draw statistical conclusions on this endpoint. But we chose reticulocytes because often you see an elevation of reticulocytes in sickle cell disease, and that is truly because it's a compensatory mechanism to address chronic hemolysis.

But in addition, the reticulocytes are more adhesive. These are the young red blood cells. They're more adhesive and they're more likely to come together and thereby actively participate in the vaso-occlusive phenomena.

And therefore, when hemolysis improves, this can reduce reticulocytes, placing less stress on bone marrow and in turn, reduce also vaso-occlusion. So when you look at this data table, you can see a substantial decrease from baseline in the mitapivat arm compared to placebo. And while we cannot draw statistical conclusions on this endpoint, it's the nominal p-value is 0.001 (sic) [ 0.0001 ], showing that this is a robust data point, and it continues to support the PK activation mechanism.

So then when we go to the next slide, we looked at the hemoglobin responders, so the 40.6% of hemoglobin responders in the mitapivat arm. And importantly, in that group, we saw a 1.6 gram per deciliter mean increase from baseline in hemoglobin concentration in mitapivat compared to placebo. And then we continue to look at the sickle cell pain crisis-related endpoints and the PROMIS Fatigue, and this slide highlights that we observed clinically meaningful benefits.

So when you look at the hemoglobin responders, we saw an annualized rate of pain crisis of 2.2 compared to 2.98 in the nonresponder group, representing a 26% reduction. Then for the analyzed rate of hospitalizations for sickle cell pain crisis, we observed a 34% reduction for hemoglobin responders compared to nonresponders.

And then importantly, when you look at the rate ratio confidence intervals of both of those endpoints, you can see that one is not included. So that reinforces the robustness of these results.

And then finally, when we look at the average change in PROMIS Fatigue T-scores in hemoglobin responders compared to nonresponders, we can also see there an improvement of minus 5.19 in the responders versus minus 2.55 in the nonresponders. And the minus 5.19 on average is bigger than the minus 4.1% decrease that was considered clinically meaningful for a meaningful change analysis within this trial.

So therefore, we review the data as important findings from the RISE UP trial, suggesting that there are clinically meaningful benefits on sickle cell pain crises related endpoints and PROMIS Fatigue in hemoglobin responders.

So finally, we're going to review the safety data, and that data supports the mitapivat's favorable safety profile. So in this overall summary of safety table, you can see that adverse events overall were generally well balanced across mitapivat arm and placebo arms. I remind -- I want to remind you, this is a year-long trial. So it is very normal for almost everybody to report an adverse event.

Then when you look at the serious adverse events, there were more events reported in the placebo arm than in the mitapivat arm. And then further down in the TEAEs leading to death, you'll see that there was 1 on placebo and 2 on mitapivat 2:1 randomization, so well balanced there. I want to spend a little bit of time here because, in fact, this data highlights the severe nature of this disease. We had 2 additional deaths in the trial that were not captured as safety event per protocol, but they were part of efficacy endpoints, which leads to a total of 2.2% in the mitapivat arm and 2.9% in the placebo arm of fatal cases.

But we also had 2 deaths in the screening period before a patient was even exposed to placebo and mitapivat, again, highlighting the seriousness of this disease. And then on the next slide, we also spent some time highlighting the key summary findings of the liver events analysis.

So first, as with other hemolytic anemias in sickle cell disease, patients often have abnormal and fluctuating liver enzymes as part of this -- as part of the underlying disease. And so while we observed liver abnormalities across both treatment arms, any event that met prespecified criteria was reviewed for severity and causality for the likelihood of drug-induced liver injury.

And so in the RISE UP trial, we did not observe an imbalance between patients in the mitapivat and placebo arms with lab values meeting lab constellations of concurrent lab values that have the highest sensitivity for drug-induced liver injury. And then upon review of the totality of the data, both by us and by independent hepatologists, there were no similar cases of drug-induced hepatocellular injury as what was observed in the mitapivat thalassemia trials.

And therefore, there is no change to the safety profile the way we currently understand it. So in closing, on the next slide, I want to summarize the key takeaways of the Phase III RISE UP trial. So first, mitapivat showed a strong anti-hemolytic profile in the total trial population with a sickle cell pain crises strength. So 40.6% of the patients achieved significant hemoglobin response, and there was a statistically significant improvement in other markers of hemolysis, both on hemoglobin concentration and indirect bilirubin.

And then we saw clinically meaningful benefits in hemoglobin responders. So on average, we saw a 1.6 gram per deciliter increase in this group. We saw improvements in sickle cell pain crises-related endpoints with a 26% decrease in the annualized rate of sickle cell pain crises and a 34% reduction in the analyzed rate of hospitalizations for sickle cell pain crises and a reduction in the PROMIS Fatigue T-score.

And then we have a favorable safety profile. There were no similar cases of HCI as observed in thalassemia. There was a low discontinuation rate in the double-blind period. And then very importantly, the patients that completed the trial, the 99% of those patients opted to roll over into the open-label extension.

So with this data, we intend to submit a marketing application for mitapivat in the U.S. for sickle cell disease after having a pre-sNDA meeting with the FDA in Q1 of 2026.

And with that, I want to hand the call back over to Dr. Andemariam to put some clinical perspective on this data package.

Thank you, Sarah. Thank you for the opportunity to do just that. I think that I'm extremely encouraged by these results, particularly the analysis of the hemoglobin responders. Of course, I'm sure there are many people listening that we're hoping that the intention to treat group, that is the entire cohort would have hit on both endpoints.

But I think that this is just fine. I think the notion that we were going to be able to develop a treatment for sickle cell disease that can manage the multifaceted pathophysiology of all patients all of the time is just not reasonable. And not every medication has to work in all patients. We don't expect that for other conditions. Why would we expect that for sickle cell disease.

But I want to take a deeper dive on what the hemoglobin responder subgroup analysis showed us. 41% of patients in this cohort had a hemoglobin response and your threshold was a hemoglobin response of 1 gram per deciliter or more. But if you look at the mean hemoglobin increase in the responder group, 1.6 grams per deciliter and that was sustained over a year. And to put that into clinical context, we don't have anything else to offer patients that can have us achieve a mean increase of 1.6 grams per deciliter sustained over a year aside from blood transfusions.

And what that would translate into is giving someone with sickle cell disease approximately 2 units of blood every couple of weeks per year, which is not sustainable. And blood transfusions, as you know, have multiple downstream clinical consequences, like I said, red blood cell antibodies, the development of iron overload, limited IV access, not to mention that those units could have gone to someone else who almost very desperately needed them. So there's a societal cost there.

But I'm very encouraged by what I'm seeing in 41% of the patients. That magnitude of hemoglobin increase being sustained is clinically meaningful. When you look further at other endpoints within the hemoglobin responder group, a 26% reduction in vaso-occlusive crises. That is substantive. I would like people to understand that most of the deaths that occur in individuals with sickle cell disease occur within the context of one of these painful vaso-occlusive crises. So any reduction in the frequency of vaso-occlusive painful crises has a translational benefit in terms of prolonging survival.

Health care utilization. We know that health care utilization is high in this population. When looking at costs, there was a study performed published over 10 years ago that looked at acute care costs in America for individuals living with sickle cell disease and acute care costs alone, that is hospitalizations and ER visits across Americans living with sickle cell disease approximated $2 billion per year. That doesn't include their longitudinal care, their pharmacy costs, just going to the ER in the hospital.

Look at this. This drug approximated a 1/3 reduction in hospitalizations, which is meaningful on many levels. Now looking at quality of life. The improvement in fatigue in the hemoglobin responder group is fantastic. When you talk to patients, they will tell you that fatigue is their #1 symptom. It gets in the way of everything. And it's directly related to the anemia. So it's not surprising that a drug that works as an antihemolytic and has a substantial increase in the hemoglobin would confer not only reduced vaso-occlusive rate, lower health care utilization as a consequence of reduced vaso-occlusion but also improve the #1 symptom of fatigue.

I think what's also important to highlight, and this was near the end of your presentation, Sarah, is that mitapivat is safe in this study. It's well tolerated by the patients. And I think looking forward, if mitapivat were to be available on the market for individuals with sickle cell disease, since it's so safe, I think you could have shared decision-making with your patients, offer it to patients and expect that a substantial proportion would have a hemoglobin response as well as a reduction in vaso-occlusive crisis.

And because it's so safe, I think that you could be pretty generous in terms of who you would offer it to. So I think that this is very encouraging. I'm excited by the results, and I hope that those who are listening are as well. So I'd like to hand it back to you, Brian.

Well, thank you very much, Dr. Andemariam, for your clinical context, which is really important to hear following Sarah's very comprehensive review of the data. On the next slide, I want to reinforce the key points that Sarah made in her prepared remarks. First, mitapivat demonstrated a strong anti-hemoglytic profile in the total patient population, as you just heard, with a trend towards reduction in annualized rate of sickle cell pain crisis.

Second, we observed a clinically meaningful benefit in hemoglobin responders, which represented 40.6% of patients in the mitapivat arm. And third, mitapivat demonstrated an encouraging safety profile, which, as you just heard from Dr. Andemariam, is an important feature of a potential new disease-modifying agent.

Let's go to the next slide. Our corporate priorities are clear. First, we intend to maximize the value of mitapivat. We are roughly 2 weeks from our thalassemia PDUFA goal date of December 7. And I'll add, we've had positive recent labeling discussions with the FDA. We clearly remain excited about the potential to bring this transformative medicine to thalassemia patients in the U.S. And additionally, we will focus on preparing for the potential sNDA filing in sickle cell disease, as you just heard from Sarah.

Second, we will continue to advance our pipeline programs. These data validate the mechanism of PK activation, and we look forward to results from the ongoing Phase II trials of tebapivat, our more potent PK activator in lower-risk MDS and in sickle cell disease. We also continue to advance our Phase I programs for AG-236. This is our siRNA targeting TMPRSS6 intended for the treatment of polycythemia vera and AG-181, our phenylalanine hydroxylase stabilizer intended for the treatment of phenylketonuria. Underscoring these first 2 priorities is a commitment to financial discipline with the aim of maximizing shareholder value.

To that effect, we will take proactive steps to reduce operating expenses to extend our cash runway and intend to provide an update early next year. Our goal is to become a sustainable rare disease company, and we will continue to work to deliver on that objective.

In closing, I want to express my deep gratitude to our employees for their unwavering commitment to our mission and to the investigators and patients whose collaboration made this trial possible. The RISE UP trial represents years of commitment. And with these results, we see a potential path toward delivering a meaningful therapy for sickle cell disease, one that has the potential to create value for patients and stakeholders.

With that, I'd now like to open the line for questions. Operator, please open the line.

[Operator Instructions] Our first question comes from Eric Schmidt with Cantor.

Thank you for the very detailed review of the Phase III data. Maybe for the company and Sarah, first on safety, you mentioned no sign of liver injury, but were there any Grade 2 or Grade 3 increases in liver enzymes? And then for Dr. Andemariam, it sounds like you're quite convinced of the benefits here, though with lack of statistical significance on some of the clinical outcomes, how would you communicate the benefits to your patient with this drug to be approved?

Sure. I'll start with Sarah on the safety question.

Eric, so across the trial in both treatment arms, there are like a variety of different liver enzyme elevations. But as I mentioned, upon selecting very broad net of events to review, both our internal review plus an independent review by hepatologists did not see any drug-induced liver injury in the same way that we saw on thalassemia. So therefore, we feel very confident to say that the safety profile to date hasn't changed.

Thank you. And interesting question, Eric. So Dr. Andemariam, maybe you can comment on, given what you now have seen and discussed, how would you explain the benefits of mitapivat to your patients?

Yes. So thinking forward, if mitapivat is approved and I was having conversations with my patients in clinic, I would say that given sort of an overview of the RISE UP clinical trial results, and I would do this in plain language, which I think I'm very used to doing and I think most doctors are. And I would say, this was given to a number of individuals. And compared to those who were receiving placebo, there was an improvement in their anemia and about 40% of patients who were given this treatment for a year, there was an increase in hemoglobin by almost 2 points. And that would be sort of equivalent to giving you 2 units of blood every few weeks.

I would say that in those patients who had a response in terms of their hemoglobin that they translated into reduced episodes of acute vaso-occlusive pain, a reduction in their hospitalizations and improvement in the fatigue symptoms. And so I would say that even though mitapivat didn't necessarily work to improve the anemia in all patients that a 40%, 41% response rate is substantial. And given that it has been shown to be a safe drug that it's worth giving it a try to try to improve the patient [indiscernible] hemoglobin. So that's really how I would guide the conversation.

But at the end of the day, it's shared decision-making and the patients will be the ones at the end of the day to make that decision.

Our next question comes from Salveen Richter with Goldman Sachs.

I was just wondering what the registrational path forward is here and what you would tend -- what you think the focus of the pre-sNDA meeting with the FDA will be in the first quarter.

Thanks, Salveen. Sarah, do you want to start with that?

Yes, sure. So from our perspective, when we go to a pre-sNDA meeting, our goal is to highlight the data package that we have obtained in a clinical trial and to highlight our intent to file and make sure that when we do so, that this is in a format that the agency finds good to review.

And so that would be here the same goal as any other pre-sNDA meeting that we do prior to submitting. And so here, what we would highlight is that sickle cell disease has a huge unmet need. I think Biree just highlighted it beautifully earlier, why there is such an unmet need and that there are really no treatment options available today, as you just actually mentioned in the previous question that can raise the hemoglobin in such a way that it is building on a consistent data package in other hemolytic anemias as well as it relates to those aspects.

And that this clinical trial data package when you actually look at the hemoglobin responders really provides clinically meaningful benefits in that group of patients with reduced reduction on the sickle cell pain crisis-related endpoints and the PROMIS Fatigue. So on the benefit side, there's a very clear clinical compelling story that can be told with this data package. And then the safety side as well, of course, you see serious adverse events and fatal events in this clinical trial patient population, which are consistent with this horrible disease.

So on the safety side, it's a clear story to tell as well. So I think from that perspective, in the current landscape and the unmet need, that is how we would present the data package. I don't know if you have anything to ask...

Our next question comes from Ellen Horste with TD Cowen.

I'm on for Marc. I'm wondering if this drug is approved, how long might you treat a patient waiting for a response given that 40% of patients do seem to do really well? I guess, how long would the duration of treatment have to be before you decide this is not benefiting the patient?

I think that's an excellent question for Dr. Andemariam and it's a guest that you're in the room, and you can help give your perspective on that.

Yes. It is an important question, but I think my answer would be really speculative at this point. I think that, as Sarah pointed out, in the intention to treat analysis, there was a statistically significant increase in hemoglobin across the entire cohort that approximated 1 gram per deciliter. And so I think that the -- it's hard to predict what the exact time line of response would be. It's also entirely possible that since this illness is so heterogeneous, that the time to response may be variable between patients. So I think it would be really trial and error with each patient to see whether or not they have that hemoglobin response.

And this might be a good opportunity. And Sarah, you might want to comment, too, that the finding that we talked about in sickle cell disease is, in fact, consistent that we've seen across now 3 different hemolytic anemias. And so we have a similar dynamic with PKD and thalassemia as well. Sarah, anything you want to add?

Right. And so this is the beauty of this package because it's building upon previous data packages as well in different hemolytic anemia and the drug behaves the same way as it has done before, meaning there is a relatively quick onset of action in hemoglobin and then it's a sustained response throughout. And as you know, we already in our PKD label have some language guiding physicians and patients on how to have the discussion around how to assess benefit. So we think that would be something similar. And it's actually very much in line with how Dr. Andemariam just described how to approach it with the patients.

Our next question comes from Alec Stranahan with Bank of America.

Maybe one for the team and then one for Dr. Andemariam. I guess first, one for Brian and Sarah. When you think about potential differentiation with tebapivat versus mitapivat, I guess, do you think a functional benefit is still in the realm of possibility with tebapivat now that you've seen the data from RISE UP? And if so, what's driving that confidence?

And then one for Dr. Andemariam. I appreciate the disease characteristics were fairly balanced between placebo and mitapivat arms, which I think speaks to the quality of the study overall. But I guess, how does the 3.05 pain crises on the placebo arm sort of compare to what you'd expect for this patient population broadly? And same thing on fatigue score. Did this, I guess, maybe seem higher than you would expect for placebo?

Yes. Thanks, Alec. Sarah, would you like to start on mitapivat and tebapivat? Starting first with the concept that we believe it's an advantage to have 2 PK activators not 1 as we pursue ever-expanding portions of the population that could benefit from 1 of our PK activators but differentiation options.

Yes. So first of all, I want to bring it back to mitapivat because I do -- it does -- this trial really highlights that a PK activator improves hemolytic anemia. So this is to be anticipated for tebapivat as well because it's a peak activator that it has -- that is of the same thing.

However, we do know it's a more potent PK activator and it's currently in a Phase II to really understand how it would influence hemoglobin response. Each drug needs to, of course, work towards its own efficacy and safety profile. And then that data will guide for a big part how we can differentiate. Obviously, here, with this data set, we learned how on the RISE UP trial, we learned that this threshold of 1 gram per deciliter of hemoglobin is confirmed to be an important threshold, an important clinically meaningful threshold.

This is already well known across different hemolytic anemias. And then each grant per deciliter that you can improve is associated with better clinical outcomes. So we are really excited about that hemoglobin response that we see. It's 41% of -- so there is like a lot of patients who can still stand to benefit of more potent or more deep hemoglobin responses.

We are also very excited that the magnitude of the hemoglobin response is actually leading to these observed clinical benefits in that group. I think this takes away part of the concerns around is too much hemoglobin leading to potentially negative consequences in sickle cell disease. That is not what we see in our data that we see with an improvement of hemoglobin, and you saw the waterfall plot that there is really a clinical benefit in that group.

So the data will continue to guide us. And then maybe I can comment also a little bit on the data aspect because the 3.05, if that was expected, what we would see. This was our intent, right? We've always highlighted that we were hoping to enroll a patient population that, on average, have about 3 pain crises in the placebo group. So 3.05 is spot on, I would say. So it does speak to the inclusion and exclusion criteria that these were appropriate and that our assumptions for the whole trial were import -- were correct and appropriate.

And then as it relates to the fatigue score, the improvement -- so indeed, like the fatigue reported by patients using this tool highlights that they were mildly fatigued as captured by this tool. But I think it speaks to the complexity of fatigue in this disease. And what you see is an improvement in the placebo group over time and also in the mitapivat intent-to-treat group, which was a little bit more in comparison to placebo. You can see patients improve on the context of having -- being part in the clinical trial. But with that, I would like to actually hand it over to you to comment more on that.

Yes. Thank you, Sarah. And I think this is an important question when we're taking deeper dives into patient-reported outcomes in clinical trials in sickle cell disease, specifically the fatigue score. I think it's important to understand what it takes to be able to take part in a clinical trial.

So for patients to be able to take part in a clinical trial, what we do is to go over them what the schedule of events are. And so they have to come in for frequent visits, and they have to meet certain clinical parameters or eligibility parameters. They can't be too sick, they can't be too well. You can imagine that for a patient to be able to commit to frequent visits that they can't have a very significant baseline fatigue level. It would just make it very difficult for them to participate. So I think it's almost like when we conduct these clinical trials, we are selecting for a population that perhaps has more energy than the more representative population.

I also really believe that when we give these baseline assessments, patients don't know what it's like to feel better. So I think there can be an underestimate in reporting when we take the baseline fatigue measurements, and then there's not an opportunity to give your answer over again at the end. So that the magnitude or the delta that we're able to measure is minimized artificially.

Our next question comes from Emily Bodnar with H.C. Wainright.

I guess first one, were there any trends in certain baseline characteristics that were more likely to be hemoglobin responders? And then also curious on the blood transfusion comment. What percent of sickle cell disease patients get blood transfusions or have more severe anemia? And do you see that as a subset of patients to maybe focus commercialization on?

Well, thanks, Emily. So we'll start with Sarah on the question about baseline characteristics, any differences with respect to hemoglobin response.

So no, there was not a specific subgroup that was driving the overall efficacy results, which is in line with our other clinical trial experience.

And then a real-world question for Dr. Andemariam about what transfusions.

Yes. So virtually all individuals with sickle cell disease at some point in their life will be transfused. There are a subset of patients who get more frequent transfusions. This includes patients who are either hepat stroke or at risk for stroke or have had other complications like the acute chest syndrome. Sometimes chronic transfusions are used in patients who have frequent vaso-occlusive pain crises as a way to try to reduce that frequency when all else fails.

So the -- if you -- for example, if you look at my population, I would say about 10% of my adult patients, so I focus on taking care of adults with sickle cell disease, about 10% of my patients are on chronic transfusions, which means they're getting somewhere between 5 and 10 units of blood every 3 to 6 weeks for life. So the transfusion burden is high. Whether or not that's a subset of patients to target with mitapivat, I think, is a really good question and something that maybe can be explored later.

Yes. Maybe I can comment commercially as well. We -- with the current product profile, we actually see a very compelling commercial opportunity, and that's really driven by the unmet need in the disease that you've seen, the fact that the trial population enrolled a representative sample, and we showed a strong antihemolytic benefit in the responder population. So from a commercialization perspective, of course, we'll need to engage with the FDA and see the label, but the opportunity, it continues to be very, very compelling for us.

Our next question comes from Tess Romero with JPMorgan.

So 2 from us. In your view, does this result qualify as hemoglobin and, which I think you've been talking about for a while. Given the PROMIS Fatigue score did not get met here in the eyes of regulators and this endpoint seemed to rise to the top for KOLs in terms of level of significance. And then my second question is, should we expect the price of PYRUKYND to change on the approval in thalassemia or not?

Sure, Tess. I'm going to go back to Sarah for perspective on hemoglobin and well, she's already recapped a few times how we see the data and the strength of the data, but hemoglobin and then with the responders, what that profile really looks like. And again, we have a KOL in the room. So certainly, Dr. Andemariam can comment on that as well. And then we'll go to Tsveta for the second part.

Yes. Thanks, Tess. So indeed, like from an intent-to-treat perspective, we did not meet statistical significance on the promised fatigue. But this is where you -- when you look at the hemoglobin responders and you've seen that actually you see a robust data on the sickle cell pain crisis-related endpoints and the PROMIS Fatigue score, which goes beyond what was considered clinically meaningful change within the trial. It's really very, very good clinical data for that subgroup of patients. So to us, this is a very, very compelling clinical story. But I'll hand it over to Dr. Andemariam to comment on that.

Yes, I agree. I think you have to look at -- really look at the subgroup of responders, and there's a clear relationship between an increase in hemoglobin, reduction in hemolytic markers, reduction in vaso-occlusive events, whether you measure them by hospitalization or events and entirety and an improvement in fatigue that's clinically meaningful.

When you look at the whole cohort, the whole intention to treat cohort, something I think you have to keep in mind with sickle cell disease is that the symptom of fatigue is multifactorial. It's not only related to anemia. It's related to mood issues, whether that's related to depression or anxiety, PTSD, all of these run high in the sickle cell community. A lot of that is related to living with a chronic condition for which there are few available therapies, knowing from the time of childhood that you were probably not going to live as long as your siblings and your peers.

There's a fatigue associated with living with sickle cell disease that is sort of psychosocial in nature and not necessarily only due to underlying anemia. That said, the hemoglobin responder subgroup, there seems to be a relationship between that almost 2 gram per deciliter sustained increase over a year of hemoglobin and a clinically meaningful reduction in fatigue, which I'm very excited about. And I think the KOLs that you're talking about will be excited, too.

Yes. And this whole discussion is such a reminder about how complicated sickle cell disease is and the profound unmet need. And of course, test, we would have hoped to have the whole population benefit, but we are inspired by the responder analysis that we've talked so extensively about this morning, and we think it's both the commercial opportunity that Sarah talked about as well as our responsibility for this community to take a step forward and have a thoughtful discussion with the regulators. Sarah, the second part on price whoever work too soon, but...

Absolutely. Too soon, but not too soon for the PDUFA date. So close to 2 weeks to the PDUFA date, and I can tell you that the team is ready and excited to deliver on a very successful launch for thalassemia, pending the FDA approval. From a pricing perspective, of course, we'll have that discussion at the time of approval, but I can tell you, we are very well positioned given the unmet need in thalassemia, the strong product profile that we've demonstrated across the ENERGIZE program.

And the fact that thalassemia from a payer perspective is a rare disease. So we don't expect that category to be managed, and we are looking forward to the potential launch coming soon.

And our last question comes from Luca Issi with RBC.

Maybe, Sarah, if I can circle back on maybe prior question, maybe ask a little bit differently. Can you just talk about your confidence that this drug actually gets approved by the FDA at the end of the day? Is your understanding that hitting 1 of the 2 primary endpoints and 2 of the secondary endpoints that are at the top of the hierarchical analysis sufficient to get this over the finish line? Or do you think that the FDA was looking for this trial to hit more than 2 secondary endpoints? Any context there, much appreciated.

And then maybe second, on fatigue, if I may, and apologies if I missed it, but can you talk about fatigue when compared to placebo and not maybe baseline? Again, it looks like there was no effect in the ITT population, but there was a benefit in the responder population. So does that imply the fatigue went all the way around in the nonresponder population? Or is that not the right way to think about it?

Okay. So for the first question around the likelihood of approval and all that, you're always going to hear this from me. I'm not going to comment on what the FDA will do or not do or as always, it will be a matter of review. And that is something that happens when you feel you have a data package, and you go talk to the regulators. Ultimately, they do, do their own independent reviews and engage and make their own independent assessment.

As we mentioned, we really feel we have a very compelling data package to go and have that engagement with the agency because, again, like we see very consistent data on how mitapivat acts that hemolytic anemia improvement. The clinical context just around the hemolytic anemia improvement was highlighted by Dr. Andemariam very well a couple of times. I think it's really by itself already meaningful in this patient population that if you remember the slides from our presentation, if you look at the treatment options for this horrible disease, it's a very bare landscape.

But then to see actually that there is robust data that speaks to clinical benefit in the hemoglobin responders on so-called hard-core endpoints as it relates to sickle cell disease with sickle cell pain crisis-related endpoints and fatigue is really a compelling clinical story to tell. And obviously, we hope the regulator will see it the same way. But as always, it's a matter of review because we're not the FDA, obviously, or any other regulator.

So -- but we are looking forward to hopefully collaborating as we've always done in a similar fashion. So in regards to the second question and the complexity of fatigue and placebo and the mitapivat arm, I think I look at this multiple ways. One way was just highlighted by Dr. Andemariam in the context of how fatigue is really multifactorial, very complex in the context of sickle cell disease, and there are more components to fatigue than just physical fatigue. You do also see that patients by this scale report being mildly fatigued.

Again, Dr. Andemariam spoke to it as well, like people don't have an opportunity to go back. So when people actually feel better, they can go change their baseline score. So that is a little bit of a problem with these types of tools. But I also think it really does establish the importance of a 1 gram per deciliter increase threshold that is now a very common way to look at a meaningful improvement in hemoglobin for a multitude of reasons. And when you do that, you actually do see you can push past that clinically meaningful threshold in that group.

So again, it's like -- it's a compelling clinical story within this data set, and I'm very proud of the data that we delivered with this clinical trial. And most importantly, very grateful to the patients and physicians and our team who have delivered these results.

There are no further questions. I'd like to turn the call back over to CEO, Brian Goff, for closing remarks.

All right. Thanks, Michelle. And again, I want to thank Sarah for the very comprehensive review of the data and to Dr. Andemariam for spending time with us this morning to give us the appropriate clinical context in parallel. And also, thanks, everyone, for listening in. We were pleased to be able to provide an update on the RISE UP trial this morning. This has been years in the making. And I also will remind everybody, we have an action-packed fourth quarter at Agios.

As Sarah had noted in her comments, we have, in about 2 weeks' time, our PDUFA date for thalassemia review, which is on December 7. So I'm sure we're going to have plenty to talk about. So thanks a lot, and we definitely look forward to connecting again real soon. Thank you.

Thank you for your participation. You may now disconnect. Everyone, have a great day.

Good morning, and welcome to Agios Pharmaceuticals Third Quarter 2025 Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Agios' request.

I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Please go ahead, ma'am.

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals third quarter 2025 financial results and business highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com.

Next slide, please. Please note we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC.

Our third quarter earnings call agenda is shown on the next slide. Joining me on today's call are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions.

With that, please move to the next slide, and I am pleased to turn the call over to Brian.

Thanks, Morgan. Good morning, everyone, and thank you for joining us on today's call to discuss our third quarter highlights beginning on the next slide.

With steady progress and a focused strategy, we have a clear path to unlock long-term shareholder value. First, we have multiple high-value catalysts in the coming months that position PYRUKYND, our foundational PK activator to achieve its multibillion-dollar potential across PK deficiency, thalassemia and sickle cell disease.

Following the FDA's recent request for a REMS program, our PDUFA date for PYRUKYND thalassemia supplemental NDA has been extended to December 7. We are actively engaged with the FDA and are leveraging this additional time to strengthen our engagement with the thalassemia community and further refine our launch planning.

Additionally, we look forward to sharing top line results from the RISE UP Phase III trial of PYRUKYND in sickle cell disease by year-end. Meanwhile, we continue to advance our early and mid-stage pipeline, which includes our other PK activator, Tebapivat, for lower-risk myelodysplastic syndromes, or MDS and sickle cell disease, AG-181 for phenylketonuria and AG-236 for polycythemia vera.

Importantly, our strong balance sheet with approximately $1.3 billion in cash and investments positions us to invest in a disciplined manner to both support our potential U.S. launches and advance our rare disease pipeline. Our third quarter highlights are summarized on the next slide.

In the third quarter, we reported $12.9 million in net revenue, underscoring the strong value proposition of PYRUKYND. In August, we announced approval for PYRUKYND in adults with thalassemia in Saudi Arabia, our first global regulatory approval for this indication.

And earlier this month, we also received a positive CHMP opinion recommending PYRUKYND for marketing authorization in Europe for the treatment of adults with thalassemia. And lastly, we achieved a key R&D priority by completing enrollment in the Phase IIb trial of Tebapivat in lower-risk MDS and we anticipate top line data early next year.

With continued momentum across our commercial portfolio and pipeline, our team has demonstrated strong execution and agility, keeping us firmly focused on our mission to deliver transformative medicines for patients.

That agility is a competitive advantage as we work to transform the treatment landscape for thalassemia and sickle cell disease. Feedback from these communities through our recent global engagements reinforces the critical need for treatment innovation.

Please move to the next slide and I'll turn the call over to Cecilia to provide commentary on our third quarter performance and full year outlook. Cecilia?

Thank you, Brian. Next slide, please. Our third quarter 2025 financial results can be found in the press release issued this morning and additional details can be found in our 10-Q, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points.

Third quarter net PYRUKYND revenue was $12.9 million, an increase of 44% compared to $9 million in the third quarter of 2024 and an increase of 3% compared to $12.5 million in the second quarter of 2025. Third quarter net revenue growth reflects continued commercial execution in PKD ahead of potential U.S. approval for thalassemia.

Looking ahead, fourth quarter performance will benefit from an additional ordering week compared to the third quarter and we anticipate PYRUKYND net revenue will continue to reflect continued focus on PK deficiency ahead of potential approval for thalassemia in the U.S.

On a full year basis, given the strong execution of our sales force to date, we anticipate net revenues in 2025 to show robust growth compared to 2024, although we recognize this growth is on a relatively small revenue base.

Cost of sales for the quarter was $1.7 million. R&D expenses were $86.8 million, an increase of $14.3 million compared to the third quarter of 2024. This increase was primarily driven by increased clinical trial costs associated with our PK activation franchise.

SG&A expenses were $41.3 million in the third quarter, an increase of $2.7 million compared to the prior year, driven by disciplined investments ahead of the potential commercial launch of PYRUKYND in thalassemia. We ended the third quarter with cash, cash equivalents and marketable securities of approximately $1.3 billion.

Next slide, please. Our capital allocation strategy backed by a strong balance sheet enables strategic investment in future growth and delivery of our ongoing pipeline programs.

First, we have built a capital-efficient global commercial model, prioritizing our investment in potential U.S. launches, which represents the largest commercial opportunities. We have executed partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe, both of which are structured as revenue sharing arrangements that favor Agios over the long term. We will record our share of sales as net revenues.

Second, we will continue to invest in our ongoing early and mid-stage clinical programs. And third, we are opportunistically looking for ways to expand and diversify our pipeline through internal efforts or externally sourced assets.

In closing, I am confident that our balance sheet will enable us to continue to execute from a position of strength.

Please advance to the next slide and I will turn the call over to Tsveta to share commercial highlights for the quarter.

Thank you, Cecilia. Next slide, please. In the third quarter, we delivered $12.9 million in PYRUKYND net revenues, up 3% sequentially, once again reflecting strong execution by our commercial team.

To date, 262 patients have completed prescription enrollment forms, including 14 in the third quarter, representing a 6% increase sequentially. This has translated into 149 patients currently on therapy, up 5% from the second quarter.

These results underscore the strength of our commercial model and the foundation we are building for future growth. We are well positioned to deliver on potential U.S. launches for thalassemia and sickle cell disease.

Please move to the next slide. Let's turn to thalassemia and our global commercialization strategy for PYRUKYND. Following the 3-month extension of our PDUFA goal date to December 7, we remain confident in our ability to deliver a successful launch, pending regulatory approval.

This confidence is further reinforced by our recent engagement with physicians, patients and advocacy groups, which I will touch on shortly.

Outside of the U.S., we have implemented a capital-efficient global commercialization strategy through partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe. These partnerships allow us to retain full rights to PYRUKYND while preserving our capital investment for U.S. launches.

In August, we announced SFDA approval of PYRUKYND for the treatment of adult thalassemia patients in Saudi Arabia, marking our first global approval for thalassemia. Launch activities are underway in Saudi.

Our partner, NewBridge, is providing early patient access on case-by-case basis with the potential to expand access after securing national procurement agreements over the next couple of years.

In Europe, we anticipate a European Commission regulatory decision in early 2026, following the positive recommendation from the CHMP and we are actively working with our partner Avanzanite Bioscience to refine our launch strategy.

Please move to the next slide. In the U.S., there are approximately 6,000 diagnosed adult thalassemia patients. It is important to remember that thalassemia is considered a spectrum of disease, not a single phenotype.

Patients range from those who require regular transfusions to those who are non-transfusion-dependent, but still face debilitating fatigue and meaningful complications over time. The goal of treatment across the disease centers on 3 key aspects: to address patients' chronic anemia and hemolysis, increase their quality of life and reduce the risk of comorbidities that can be caused by primary or secondary iron overload.

Care for these patients happens in both academic centers and community hematology practices and we are equipped to support both. Over the past year, we have profiled and prioritized accounts across settings.

We also engaged prescribers where patients are managed and delivered disease education to them. Following the announcement of our PDUFA goal date extension, we have taken the opportunity to continue our engagement with the thalassemia community.

Through these ongoing interactions, stakeholders consistently recognize the clear and compelling potential of PYRUKYND. Advocacy leaders and clinicians emphasize the magnitude of the unmet need facing thalassemia patients and continue to stress the urgency for novel treatments like PYRUKYND.

Additionally, it has become clear that providers have strong familiarity and experience with REMS across both academic and community settings and do not view a potential REMS program as a barrier to prescribing.

Our established rare disease infrastructure gives us a clear advantage in launching PYRUKYND in thalassemia. With high-touch patient services and a single specialty pharmacy model, we are well positioned to execute swiftly and compliantly within a REMS framework.

The team is ready and we look forward to potential thalassemia approval before year-end and we are confident in our ability to deliver a successful launch.

And with that, please move to the next slide and I will hand the call over to Sarah to cover key R&D highlights from the quarter.

Thank you, Tsveta. Next slide, please. In the third quarter, we continued to make strong progress across our pipeline. In early August, we announced PYRUKYND approval for adults with thalassemia in Saudi Arabia.

And earlier this month, we received a positive CHMP opinion recommending PYRUKYND for marketing authorization in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha or beta thalassemia in Europe and we look forward to a final regulatory decision by early next year.

Finally, our reviews remain ongoing in the United Arab Emirates and in the U.S., where we continue to progress towards our new PDUFA goal date of December 7. Beyond PYRUKYND, we were pleased to announce enrollment completion in the Phase IIb trial of Tebapivat for the treatment of lower-risk MDS.

Tebapivat, our more potent PK activator has the potential to be the first oral therapy to address anemia due to ineffective erythropoiesis in patients with lower-risk MDS. I will share more on this potential opportunity shortly.

Please move to the next slide. As we approach the anticipated top line results for the Phase III RISE UP trial, I wanted to take a moment to highlight the significant need in this community as well as our potential to deliver a disease-modifying novel treatment with PYRUKYND.

There are approximately 100,000 diagnosed adult and pediatric patients with sickle cell disease in the United States and a significantly larger number worldwide. Sickle cell disease remains profoundly underserved.

The lack of suitable treatment options contributes to a high mortality rate that has, in fact, worsened with U.S. life expectancy in the late 30s, underscoring a significant opportunity for therapeutic innovation.

PYRUKYND is a potential first-in-class oral therapy for sickle cell disease, targeting both hemolysis and vasal occlusion through a unique PK activation mechanism of action, activating both PKR and PKM2 isoforms, decreasing 2,3-DPG, limiting hemoglobin S polymerization and increasing ATP to support red blood cell health.

Please move to the next slide. Guided by extensive engagement with the sickle cell community, we designed the Phase III RISE UP trial to align with clinical needs, positioning PYRUKYND to potentially reshape the treatment landscape for sickle cell disease.

One of the 2 primary endpoints investigates hemoglobin increase, which addresses chronic anemia and thereby potentially reduces organ damage and improves how patients feel and function.

Our other primary endpoint evaluates the reduction in annualized rate of sickle cell pain crises, which are linked to organ dysfunction, early mortality and a decreased quality of life for many patients. Importantly, one of our key secondary endpoints will investigate potential improvement in fatigue, which is an overlooked symptom.

In fact, chronic fatigue in sickle cell disease patients have been shown to be comparable to fatigue experienced by patients with other debilitating diseases like cancer and cystic fibrosis. In the trial, we will assess the improvement from baseline on the PROMIS Fatigue 13A scale, a validated measure of fatigue for this population. We look forward to sharing top line results of the Phase III RISE UP trial by the end of this year.

Please move to the next slide, where we present high-level view of the trial design and statistical plan. As a reminder, since the trial includes 2 primary endpoints, the trial is positive if statistical significance is achieved on either one of the endpoints.

The prespecified statistical testing strategy allows testing of the key secondary endpoints if at least one of the primary endpoints is met, thereby preserving the opportunity to show benefit on other key features of the disease, including fatigue.

We remain confident in PYRUKYND's potential to become transformative therapy for sickle cell patients and underserved and unrepresented population with significant unmet need.

Next slide, please. I'd like to take a moment to highlight our second more potent pyruvate kinase activator, Tebapivat, which is being investigated in ongoing Phase II trials for 2 rare disease indications, low-risk myelodysplastic syndrome and sickle cell disease.

Low-risk MDS accounts for approximately 70% of all myelodysplastic syndrome. Symptomatic anemia is the primary concern for most patients. Therefore, the primary treatment goal is to improve quality of life by managing the underlying anemia caused by ineffective erythropoiesis.

Decreased lipolytic activity has been seen in MDS patients where they may show decreased PK activity and an abnormal pyruvate kinase [indiscernible] kinase symptomatic ratio. Tebapivat is designed to correct red blood cell metabolism by increasing ATP production and normalizing the PK/HK ratio.

Today, there are limited treatment options to address low-risk MDS and we believe Tebapivat has the potential to be the first oral medicine to address anemia due to ineffective erythropoiesis.

We completed the Phase II portion in November 2023 and progressed to the Phase IIb portion, which evaluates 3 higher doses than were evaluated in the Phase IIa portion. This trial will investigate 10 milligrams, 50 milligrams and 20-milligram doses of Tebapivat daily versus placebo over 24 weeks.

Today, we announced that we achieved enrollment completion and we continue to expect top line data in early 2026. We are also investigating Tebapivat for the treatment of sickle cell disease. Enrollment remains ongoing in the Phase II trial and we look forward to providing updates in the coming months.

Please move to the next slide. We continue to advance our early-stage rare disease pipeline with AG-181, an oral PAH stabilizer intended for the treatment of phenylketonuria and AG-236, our siRNA selectively targeting TMPRSS6 for the treatment of polycythemia vera.

Our first early-stage program is AG-181 for the treatment of PKU. There are 15,000 to 20,000 patients diagnosed with phenylketonuria in the U.S. where patient symptoms can range from mild to severe.

Currently available treatment options have demonstrated limited efficacy or significant safety issues, leaving patients with a gap in treatment and limited to phenylalanine restricted diet, therefore, significantly impacting the patient's quality of life.

Our Phase I multiple ascending dose trial in healthy volunteers is currently ongoing and we look forward to providing updates on this trial in the future.

Our second early-stage program is AG-236 for the treatment of polycythemia vera, a rare hematologic disease that affects approximately 100,000 patients in the U.S. PV causes an excessive production of red blood cells, increasing blood volume and viscosity and can result in thrombosis, cardiovascular events or death.

Current treatment options are limited to phlebotomy, hydroxyurea and other cytoreductive therapies. However, these medicines do not effectively control [indiscernible] for more severe patients.

We believe AG-236 has the potential to address the remaining unmet need with a potentially improved safety and efficacy profile and less frequent dosing.

Last quarter, we received IND clearance and dosed the first subject in the Phase I trial in healthy volunteers and look forward to providing updates as the trial progresses.

With that, please move to the next slide, and I will hand the call back to Brian for closing remarks.

Thank you, Sarah. Next slide, please. In the third quarter, we delivered meaningful progress across our 2025 R&D priorities, once again showcasing our ability to execute swiftly and effectively.

Looking ahead, the fourth quarter holds exciting milestones. We are sharpening our launch planning in anticipation of the new December 7 PDUFA goal date for PYRUKYND in thalassemia and we expect to report top line results from the Phase III RISE UP trial of PYRUKYND in sickle cell disease by year-end.

Please move to the next slide. Our fundamentals remain strong, backed by a seasoned leadership team with a proven track record. We continue to advance our pipeline and deliver meaningful impact for the rare disease communities we serve, communities whose insights guide us and are vital to our success.

We are operating from a position of strength, backed by a balance sheet that not only supports our potential U.S. launches and advancement of existing clinical programs, but also enables us to pursue strategic business development opportunities to further expand and diversify our pipeline and ensure we can create long-term shareholder value.

Before we move to Q&A, I want to take a moment to recognize the continued dedication of our employees whose relentless focus and commitment continue to drive meaningful impact for patients with rare diseases.

Their work, together with the voices of the communities we serve is foundational to our mission. As we look ahead, we remain resolute in our pursuit of transformative medicines, advancing innovation with the aim of delivering long-term value for both patients and shareholders.

With that, I'd like to open the call for questions. Operator, please open the line.

[Operator Instructions] Our first question comes from the line of Eric Schmidt with Cantor.

Maybe first, just on the thalassemia review process. It's been almost 2 months now since you've got the PDUFA extension. Do you have a better sense of what type of a REMS program the FDA is interested in here? I know there's a spectrum of maybe more or less onerous REMS programs.

And then just a second follow-up question. I think both Cecilia and Brian mentioned actively looking for external assets. What type of BD makes sense for the company at this stage? And would you wait until the sickle cell readout to transact?

I'll have Sarah take the first one and then I can pick up with the external pursuit question. And Sarah, let me turn it over to you.

Yes. So in regards to REMS and label, as you know, the review is ongoing with our extended PDUFA date of December 7. We per process don't comment on the details of REMS in the label.

However, indeed, to your point, there are many different forms of REMS. And as you know, the REMS is requested because of hepatocellular injury. So you can anticipate that it will include monitoring and some form of education.

And Eric, on your second question in terms of continuing to expand our pipeline, our pursuit really is not timed to anything in particular. I'm really proud of the work that the team does to cast the net wide and continue to look at a number of different opportunities.

And this goes externally, but it's also organically internally to see if there are other indications, for example, that we should pursue. But again, that's not timed to anything per se.

In general, I mean, our sweet spot, of course, is rare diseases. We look for therapies that have transformative potential for patients, early derisking opportunities, if we're talking about earlier [indiscernible] assets.

And then I would say another opportunity would be if we find something that doesn't have to be first-in-class, but we always set the bar for best-in-class, which we feel very proud of with our current organic pipeline.

So that work continues ongoing. And like I said, I'm really proud of the capabilities that our team has, both with internal opportunities as well as external.

Our next question comes from the line of Alec Stranahan with Bank of America.

Just a couple from us. It's been interesting to see how the different geographies have approached the risk of liver injury for mitapivat in thalassemia. Maybe could you just remind us what sort of liver monitoring requirements are so far being required in Saudi and potentially in EU if it's approved as well?

And do you think this could change depending on the U.S. label? And then maybe second, as a follow-up, curious how this monitoring requirement is changing maybe your commercial approach in these different areas.

Yes. Again, Sarah can start with the labeling so far. And I'll just preempt by saying the label we have right now, of course, at this point, only exists in Saudi Arabia and Sarah can comment on that. And then we're still in process with FDA.

And in Europe, it's a CHMP positive opinion, but we're still awaiting the conclusion of that review in the coming couple of months and expect that by early next year. And then I'll have Tsveta comment in terms of the impact of some of these scenarios. Sarah, do you want to start?

Sure. So in regards to the label, yes, indeed, for Saudi, it's in line with our proposal of once-a-month monitoring for the first 6 months and that label is now available.

For the European Union, we indeed are very pleased that we received a positive CHMP opinion, which from their perspective, confirms the benefit risk profile that we saw. We are -- obviously, the label will only be final when you have the EC decision.

So the details will become available at that point in time. And to Brian, Brian already mentioned it, but the U.S. -- the review is still ongoing.

And then Tsveta comments on potential impact of REMS.

Absolutely. So as we all know and there are very few treatment options for the thalassemia patients across the board and with regards to non-transfusion-dependent, transfusion-dependent patients.

We remain very convicted behind the strong benefit risk profile of PYRUKYND for these patients and that has been reiterated and confirmed by all of our stakeholders, including all the clinicians that interacted with recently in the field after the announcement of REMS for the potential U.S. label.

I can tell you the team is prepared for the launch. We are taking advantage of the additional time to continue the engagement with the community and do disease education. And when it comes to REMS in the U.S., we don't anticipate that to be a barrier to prescribing or have an impact on our commercial opportunity because we know that both the academic as well as the community hematology, oncology practices, they have an experience with REMS.

And when I connected both with academics and the community prescribers, they confirmed that to me and the team is confirming that in the field on a daily basis.

[Operator Instructions] Our next question will come from the line of Emily Bodnar with H.C. Wainwright & Co.

This is [ Joey ] on for Emily. Congrats for a great quarter. Shifting focus to Tebapivat. How are you guys looking at what be considered positive data in LRMDS given the data for luspatercept and imetelstat?

And then a follow-up, could you also remind us of the Avanzanite strategy for the European thalassemia launch and how the cadence could look like for that?

Yes. I think we're going to follow the same order of entry here. So Sarah can get started on Tebapivat and how we think about the potential in low-risk MDS, which is a very high unmet need area with -- is classic across all of our diseases that we're pursuing very limited treatment options.

And then Tsveta can comment on Avanzanite and also probably tuck in some comments about NewBridge too. We have 2 very valued partners outside the U.S. Sarah, do you want to start?

Sure. So in regards to the positive data for lower-risk MDS. So we are very pleased that we were able to announce enrollment of our Phase IIb trial today.

So more data will come at the beginning of next year for our program. Obviously, we are going to take the ecosystem around us into account when we look at the data that this program will generate.

But what is important, I think, is what Brian just mentioned, there is a huge unmet need for this patient population, specifically as the goal for this population tends to be really also now more and more focused on quality of life.

And as you know, like for PK activators, quality of life has been an important component of their benefit profile. So that is something that we were definitely hoping to deliver to.

And, Tsveta, pivoting then to Avanzanite. And since you've also spent some time outside the U.S. recently in Saudi Arabia, maybe you can comment on NewBridge as well and the preparation of our partners.

Absolutely. So starting with Avanzanite, first of all, we are very [Technical Difficulty] about the potential EC decision and approval of PYRUKYND for thalassemia in Europe coming early next year.

We're working very closely with Avanzanite team to refine our strategy for Europe. It's important to remember that in Europe, after a regulatory decision and approval, each of the countries needs to undergo a pricing and reimbursement process.

So at the moment, we are going with Avanzanite, assessing the market opportunities, prioritizing market where to submit for pricing and reimbursement first. But the pricing and reimbursement process in the European countries can take 12 to 18 months.

So just keep in mind that we wouldn't see kind of the immediate impact of an approval on the commercial opportunity in Europe after a EC decision is announced.

But we prioritize Avanzanite as our selected partner because they have a very strong rare disease capabilities and expertise as well as the pricing and market access capabilities and we look forward to continue to work with them to provide access to patients in Europe.

As Brian mentioned, I actually had the opportunity to spend some time with the team in Saudi towards the FDA approval in August. And again, very senior team here in Saudi Arabia.

We consistently hear the high unmet need for thalassemia patients, the strong excitement about the benefit risk profile of PYRUKYND and the value it can bring to that community.

But as a reminder, again, in Saudi Arabia, the process after approval starts with one-on-one requests from physicians for individual patients for PYRUKYND early and patient access and market access. And it's going to take about a couple of years until we get to the stage of a national procurement agreement, which will open access more broadly and see the commercial opportunity there.

Our next question will come from the line of Marc Frahm with TD Cowen.

Just back on the liver events. Can you maybe just as you've continued to dose people and follow them for longer and longer, just kind of comment on if any additional events have been observed kind of across the PKR trials?

And to the extent any have, have they continued to conform to the kind of description before of occurring within 6 months and importantly, the patient returning to baseline whenever they do stop mitapivat as a result?

And then maybe on the commercial side, if you -- I recognize it will take quite a while to work through case-by-case access and actually get to revenue for any of those patients, let alone the reimbursement negotiations. But maybe can you comment on just any level of demand you're already seeing kind of in the Gulf to kind of start that process?

Sure. Sarah, maybe you could just start then with the question Marc has around the hepatocellular injury and have there been additional cases that have met the pattern that we observed in thalassemia. And then Tsveta again can talk about the green shoots, I could say, of demand so far.

Sure. So in regards to the observations that we had in the thalassemia program that allowed us to determine the hepatocellular injury risk for thalassemia specifically, so nothing has changed the way we have assessed the risk.

So safety profile remains exactly the same as when we declared this hepatocellular injury risk and we have not observed anything across the program that warrants us to update the safety profile the way we currently understand it.

Tsveta?

So yes, I actually had the opportunity to meet with some key customers in Saudi Arabia this week in some of the biggest hospitals. And as I said, we definitely hear the interest in PYRUKYND profile, the desire to try it in individual patients and gain experience with the product.

At the very beginning in the country, it's a very burdensome process, which actually takes months from an individual patient prescription and a request until approval at the hospital level and securing the budget.

So we expect that to be the slow process, slow and steady as the individual patient requests get approved, the experience gets stronger and stronger. But definitely, the interest from the community is there and it's high. It's just the process in the country takes time.

And Marc, what I would add is what's unique about Saudi Arabia is, of course, the prevalence is quite different from what we see in the U.S. on a per capita basis, it's about 8 to 9x more common.

So on the less rare side, for sure, most people -- most clinicians certainly have a good working knowledge of thalassemia. However, the common denominator that we see across all geographies really is a function of the limited treatment options available is the need for us to continue to educate, particularly the burden that non-transfusion-dependent thalassemia patients face on a daily basis because they're subjected to chronic hemolysis and all the downstream consequences that come from that, we're doing our part to make sure that clinicians have that top of mind as they think about the potential that mitapivat, PYRUKYND could offer.

So that's one thing that's not unique to geography. It's across all markets in the world.

[Operator Instructions] Our next question comes from the line of Tessa Romero with JPMorgan.

So for the Phase III portion of RISE UP, has the last patient exited the trial yet? And what are any considerations in terms of the steps and timing to get to your top line? And then I have a follow-up.

Okay. Well, I will allow Sarah to comment. I will just remind that we will not be more refined on our timing guidance for the RISE UP data that we're also eagerly awaiting, we'll be more refined by saying that we're on track for that data by year-end. And Sarah, I'm not sure if you want to say anything additional about where we are on that process.

No, I think you summarized it, Brian. So indeed, like we're not commenting on individual patient status, but we are indeed on track to deliver the top line data by year-end.

And since we are very -- like we have delivered several Phase III clinical trials per our milestone. So we are a well-oiled machine at this point in time to get from database locks to top line results.

And I'll just say -- I mean, Tess, if I can just add, I am really pleased with the continued excellence in operations from the team because, of course, we have a lot of moving parts underway simultaneously.

We have launch preparation. You've heard from Tsveta. We've got Sarah's team working on labeling for our PDUFA date that's approaching for thalassemia, December 7 and then, of course, getting ready for a data readout for RISE UP. So we're -- this team is really delivering and I'm really pleased with the operational excellence.

Okay. So you can't tell us if your top line will be before or after your PDUFA date?

What an excellent follow-up question and I'm going to stick to it by year-end.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

This is [ Lydia ] on for Salveen. Maybe just another one on the REMS program. Do you anticipate the requirements to apply kind of across the label to PKD and sickle cell as well?

And have you received any physician feedback on how this might impact uptake, particularly with sickle cell where some of these treatment centers might not see PKD and thalassemia patients as well?

Yes. I think, Lydia, I might just start on this one to say, first of all, the REMS request has been specific to thalassemia. So that's an important point.

And with respect to any potential outcome or impact rather in sickle cell disease, the most important step is what we literally just had discussed is getting to the point of the RISE UP Phase III data. That's the most important next step. And then from there, we'll be better guided around the benefit risk profile.

And I'm showing no further questions at this time. And I would like to hand the conference back over to Brian Goff for closing remarks.

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Well, thanks, Michelle, and thank you very much, everyone, for joining us on this morning's call. As you've seen, and as I just mentioned, we've delivered on many of our milestones this year.

So we have 2 of our most anticipated inflection points approaching by year-end. As you can imagine, this is a very exciting time at Agios and we truly believe that we are poised to deliver transformative new therapies for patients and create significant long-term value for shareholders.

So thanks again and we look forward to speaking with you again soon.

This concludes today's conference call. Thank you for participating and you may now disconnect. Everyone, have a great day.