Agios Pharmaceuticals, Inc. (AGIO) Q3 2026 Earnings Report, Transcript and Summary

Good morning, and welcome to Agios Pharmaceutical third Quarter 26 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford Vice President of Investor Relations at Agios.

Thank you. Please go ahead. Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals Third Quarter 2020 financial results and business highlights. You can access the slides for today's call by going to the section of our website, agios.com. Next slide, please. Please note we will 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 next slide, we have the agenda for today's 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. The third quarter delivered record product revenue for Agios and is a clear demonstration of our commercial execution. We delivered $55.4 million in total net revenue more than 4x that of the third quarter of last year. US net revenue was $48.7 million driven by the continued strong US launch of AKPESB in thalassemia. To put that in perspective, in a single quarter, we generated more total revenue than we did in all of 2025. This performance reflects what we are building. A focused rare hematology company with a scalable commercial foundation. Thalassemia is the first launch to leverage that foundation. Sickle cell disease, our largest opportunity, is next. And I will speak to the status of our mitapivat sNDA in a moment. We ended the quarter with $907 million in cash equivalents and marketable securities. And are well capitalized to support commercial launches and development of our focused pipeline. Next slide, please. As I mentioned, we have the pieces in place to deliver on the commercial launch of mitapivat in sickle cell disease. Let me take a moment to directly address our recent update on our sNDA. As we disclosed last week on October 9, the FDA asked for additional information to evaluate whether a risk evaluation and mitigation strategy or REMS is necessary for mitapivat in sickle cell disease. We responded within 10 days, including approximately 9 months, of additional safety data from the Rise Up open-label extension period. The FDA classified our response as a major amendment, which procedurally extends the review timeline by 3 months to February 1, 2027. Let me be clear on why we remain confident in a potential approval in sickle cell disease. With this additional follow-up, there continues to be no cases of liver injury in sickle cell disease. Similar in pattern or severity to those seen in thalassemia. The benefit risk profile for mitapivat in sickle cell disease is unchanged. The FDA granted this application priority review recognizing the serious unmet need. And that urgency has not changed. We are in ongoing labeling negotiations with the agency including elements of a potential REMS. And we are launch ready. Our commercial, medical, market access, and patient teams are in place, and we continue to engage closely with the sickle cell community. Our focus is on bringing mitapivat to patients as quickly as possible. Next slide, please. Looking ahead, we are sharpening our focus to drive the next phase of growth. Our strategy is clear. First, maximize the mitapivat franchise. Which is now approved in PK deficiency and thalassemia with sickle cell disease serving as another growth driver from early 27. Second, advance a focused rare hematology pipeline. That includes AG 36 and polycythemia vera, where we plan to initiate a phase 3 program by year end. And cevidoplenib in immune thrombocytopenia with a phase 3 trial planned for the first half of 28. Importantly, both programs have clinically validated and derisked mechanisms of action. To support that focus, we have rightsized our operating model. Over the course of 2026, we will have reduced R&D headcount by more than 35 percent compared with 2025, or more than 100 roles and we expect associated cost savings to be realized in 2027. We are concentrating our clinical investment on differentiated rare programs, and we are pursuing opportunities to unlock value from noncore assets including our vorasidenib royalty and AG-181. As a result, we will continue to manage operating expenses as we prioritize investment behind our commercial launches and rare hematology pipeline opportunities and are targeting non GAAP profitability in 2028. With that, please advance to the next slide and I will turn the call over to Cecilia to discuss financials. Cecilia?

Thank you, Brian. Next slide, please. Turning to our third quarter financial results, Total mitapivat net revenue was $55.4 million including $48.7 million in the U.S., and $6.6 million outside the U.S., compared with $12.9 million in total net in the third quarter of 25. Cost of sales for the quarter was $2.5 million compared to $1.7 million in the prior year period. Research and development expense was $73.5 million compared to $86.8 million in the third quarter of 25 primarily reflecting reductions in spend associated with metapivat and tebapivat process development and certain clinical trials. Selling, general, and administrative expense was $56.5 million compared to $41.3 million in the prior year period, reflecting commercial activities supporting the AQVESME U.S. Launch in thalassemia and preparation for a potential US sickle cell disease launch. Net loss for the third quarter of 26 was $65 million compared to a net loss of $103 million in the third quarter of 25. We ended the quarter with $907 million in cash equivalents and marketable securities, which we believe provides the financial strength to support the Agvestme launch, a potential sickle cell disease launch, and progression of our focused pipeline into non GAAP profitability in 2028. Turning to our 2026 outlook, full year operating expenses are expected to remain approximately flat versus 2025 excluding the $25 million upfront payment associated with the cevidoplenib in licensing, which was recognized in the second quarter, and an approximately $11 million onetime expense associated with the headcount reduction to be recognized in the fourth quarter. Please advance to the next slide, and I will turn it over to Tsveta to cover commercial highlights.

Thank you, Cecilia. Next slide, please. The third quarter was a record quarter for mitapivat. And I am proud of the execution across the teams with total mitapivat revenues increasing more than 4x that of the third quarter of last year. In the U.S., net revenue was up 20% sequentially driven by a sales mix demand across the broad thalassemia population which I will cover in more detail shortly. Outside the U.S., net revenue increased 74% versus the prior quarter. Driven by early access programs in Europe following the European Commission approval for thalassemia in the second quarter. This is an early signal of the global opportunity for mitapivat which we are pursuing through a capital efficient model with our partner Avanzanite in Europe and Newbridge Pharmaceuticals in the GCC. Next slide, please. Now turning to US demand for AQVESME in thalassemia. As a reminder, an myAgios Start form is submitted with an AQVESME prescription when the patient and physician opt into our support program. In the third quarter, we added 177 prescriptions from REMS certified physicians with completed start forms. Bringing the total to 619 since launch. Which is roughly 15% of our target launch population of about 4 thousand patients. Only 3 quarters into launch. This is the last quarter we will report this metric. For a complete picture, another 48 prescriptions have started for and in process at quarter end. We communicated previously that first quarter start forms benefited from pent up demand during the extended thalassemia FDA review period. We are now seeing the steady broadening we planned for. Into community practices and non transfusion dependent patients where treatment decisions take more time. On persistency, approximately 75% of patients remained on therapy at about 6 months. This is exactly the foundation we want. A durable base of patients that built over time. Looking ahead, we are focused on 2 things. On persistency making sure prescribers know the long term clinical date we have generated so patients stay on treatment long enough to benefit. On demand, we are expanding our reach in the community setting, deepening adoption in transfusion dependent patients, and driving uptake in nontransfusion dependent patients. We are also activating patients themselves through the first direct to consumer campaign. Next slide, please. In August, we launched Level Up with AQVESME, our first direct to consumer campaign. A targeted omnichannel effort. This month, we are expanding with multilingual assets to reach the diverse thalassemia community. Earlier results are encouraging, and after the launch, we saw a 65% increase in engagement on our patient website. Please move to the next slide. Feedback from treating physicians continues to reinforce the value of AQVESME in thalassemia. Recent market research shows broad enthusiasm across both transfusion-dependent and non transfusion dependent segments. We are encouraged by the momentum 3 quarters into launch. As the first medicine approved for the broad thalassemia population, AQVESME is well positioned for continued growth. And I am confident in our team's ability to deliver. Next slide, please. Turning to sickle cell disease. As Brian said, we are launch ready and we will use the additional time to prepare even further. Ahead of our February 1, 2024 PDUFA goal date. There are approximately 75 thousand diagnosed patients aged 16 and older in the U.S. Our initial launch focus is approximately 25 thousand who are actively treated for or in need of therapy. And we will prioritize these patients with a hemolytic profile. Defined by low or declining hemoglobin. This focused approach is designed to drive speed of adoption. This launch builds on the commercial foundation we established for thalassemia. In an initial launch population more than 6x larger roughly 25 thousand patients, compared with a approximately 4 thousand in thalassemia. Our dedicated sales, medical, and support teams are hired and trained, Our manufacturing and supply chain are staged for day-1 availability, and we have mapped priority physicians. Spanning FDA approval, we are well positioned to bring mitapivat, the first oral PK activator to people living with sickle cell disease. Please move to the next slide. And with that, I will hand the call over to Sarah to cover R&D highlights.

Thank you, Sveta. Next slide, please. Our pipeline is focused on advancing our leadership in rare hematology. Mitapivat anchors the portfolio with broad global approvals in PK deficiency and thalassemia. In sickle cell disease, we are in labeling discussions with the FDA, including elements of a potential REMS, and we have filed for approval in Saudi Arabia. We also continue to advance our pediatric thalassemia program. ENERGIZE-Kids and ENERGIZE-KidsT have the potential to expand our addressable US thalassemia population by approximately 2,000 pediatric patients. Beyond mitapivat, we are advancing cevidoplenib in immune thrombocytopenia towards a phase 3 trial planned for the first half of 28 and AG-236 in polycythemia vera toward the phase 3 program by year end. Finally, we look forward to proof of mechanism data for AG-181 in ketonuria before the end of the year as well. Next slide, please. We are excited to share new clinical data at the 26 American Society of Hematology Annual Meeting next month across our rare hematology portfolio, which were highlighted by abstracts released yesterday. In December, we will present new clinical data from the RISE UP Phase 3 trial that we believe meaningfully differentiates mitapivat profile in sickle cell disease, both on hemoglobin and beyond. Potentially driven by mitapivat's unique mechanism of action, targeting both PKR expressed in red blood cells and PKM2 expressed in organ tissues. First, durability. In the open-label extension period, hemoglobin increases are maintained and more patients continue to show response with continued treatment. 62.7% of patients achieved the hemoglobin improvement in the open-label extension period, including 39.7 percent of patients who were initially non responders. And hemoglobin response reaching up to 115 weeks in the open-label period. Second, we are seeing emerging kidney and cardiac data from post hoc analyses of RISE UP. In sickle cell disease, hyperfiltration as measured by an abnormally high eGFR is an early sign of kidney damage. In patients with hyperfiltration, mitapivat reduced eGFR towards normal, a mean change of -14.7 versus -4.9 with placebo at week 52. Importantly, this kidney effect was independent of hemoglobin response suggesting the potential for a PKM2 mediated effect beyond anemia correction. In the heart, hemoglobin responders showed favorable remodeling with a mean reduction in left ventricular mass index of -5.9 grams per meter squared, compared with increases of +5.8 in nonresponders and +4.6 on placebo. Left atrial volume was also reduced supporting the potential for disease modifying benefits. Taken together, these data suggest mitapivat's unique action on PKM2 may address organ damage, a key driver of premature mortality in sickle cell disease. Next slide, please. Also at ASH 26, we will present the first clinical data for AG-236, our siRNA-targeted TMPRSS6 inhibitor for polycythemia vera. From our Phase 1 study in healthy volunteers. AG-236 is designed to raise hepcidin and limit the iron available for red blood cell production, which can control hematocrit in polycythemia vera. A single dose increased hepcidin by up to 24 micrograms per liter at day 29 compared with a decrease on placebo. AG-236 also reduced transferrin saturation in hematocrit, with effects on iron, transferrin saturation, hemoglobin, and hematocrit sustained through month 6. AG-236 was well tolerated with all adverse events Grade 1 or 2 and no serious adverse events or discontinuation. This single dose durability supports the potential for every-6-month dosing and global key opinion leader feedback describes this as a potential paradigm shift in the treatment of polycythemia vera. We look forward to presenting the full 6-month data at ASH next month and updating you on the progress of this program with Phase 2/3 initiation anticipated by the end of this year. Next slide, please. Ahead of Phase 1b proof of mechanism data, we are sharing for the first time preclinical data for AG-181, our novel PAH stabilizer for the treatment of phenylketonuria or PKU. In our preclinical model of classical severe PKU, AG-181 produced significant dose response reductions in blood phenylalanine, and at 300 milligrams per kilogram, we achieved the clinical target of below 360 micromolar without diet modification. In our Phase 1 healthy volunteer study presented at the Society for the Study of Inborn Errors of Metabolism 2026 Annual Symposium, human exposures at our Phase 1b doses were comfortably within the range of efficacious exposures in mice. AG-181 was well tolerated with no serious or Grade 3 or higher adverse events and no discontinuations. And its pharmacokinetic profile supports twice daily dosing in our ongoing Phase 1b study in PKU patients. We believe AG-181 offers a meaningful mechanism for the treatment of PKU supported by compelling preclinical data and phase 1 data in healthy volunteers. Look forward to building on that foundation with Phase 1b proof-of-concept data in PKU patients before the end of the year, which we believe will position the program for further development and its potential to become a transformative medicine for this community. 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. Agios is a focused rare hematology company approaching its next phase of growth. In thalassemia, AQVESME is the first medicine approved for the broad thalassemia population, and the U.S. launch delivered record net product revenue this quarter. With strong momentum, AQVESME continues to drive growth heading into year end. In sickle cell disease, we are launch ready in advance of our PDUFA goal date of February 1, 2024 with a growing body of data supporting mitapivat's strong anti-hemolytic profile, and differentiated organ health benefits. Behind mitapivat, we have a focused pipeline with AG 36 and polycythemia vera, and cevidoplenib in immune thrombocytopenia both with clinically validated derisked mechanisms of action and we have strategic optionality with AG-181 and PKU. We are executing with discipline rightsizing our operating model, and allocating capital to the opportunities where we believe Agios can create the most value for patients and shareholders. Before we open the call for questions, I would like to thank the entire Agios team. Their focus and dedication delivered a record quarter. While preparing for our next potential launch. With that, thank you all for joining us today. Operator, we are ready to begin the question-and-answer session.

Thank you. We will now begin the question-and-answer session. Cancel your request, please press *11 again. 1 moment for the first question. First question comes from the line of Alec Stranahan from Bank of America. Your line is open. Please go ahead.

Hey, guys. Thanks for taking my questions and congrats on the progress in the quarter. I guess 2 questions. 1 on the PDUFA delay and 1 around the ASH presentation. I guess, you know, has the FDA raised anything maybe outside of the REMS such as the age range or any of the clinical endpoints. I guess if a REM is required, I guess, how would this maybe change your launch expectations around the curve versus what you have seen in thalassemia? And then just around the ASH update, I guess, you know, the durable hemoglobin gains, I think, was up to 2+ years plus the kidney and heart signals seems incremental to prior presentations. I guess, how do you think you know, these benefits maybe stack up versus competing drugs especially around the PKM 2 activation that you highlighted? Thanks.

Thanks, Alec. So we will take that in sequence then. Start with your question on the PDUFA, and that is going to be a 2-parter. Sarah can begin comment on where we are with FDA, and then Tsveta can talk about commercial aspects, and we will take the second question separately.

Thanks, Alec. So in regards to the PDUFA delay and the potential other questions raised, so. No. So the engagement with the agency is going very well. We highlighted we are in labeling negotiations. We negotiations We feel confident in the benefit risk profile of our drug, and are looking forward to work quickly and as expeditiously as possible with the agency to get this very much needed drug to patients.

Absolutely. And the way that we see the PDUFA delay is really a change in timing and not a change in the commercial opportunity as we know sickle cell disease affects approximately 100 thousand patients in the U.S., and it is going to be the largest indication that we are pursuing today. With 25 thousand, which we identified as an initial launch target We are launch-ready to launch, in any scenario, and we have already a very well established commercial influx infrastructure to do so.

Yeah. And I will put an exclamation point in the last thing, Svetta said too. Setta and her team always prepare for multiple scenarios. And now, you know, I think this quarter, in particular is a good demonstration of all the preparation that went into thalassemia with AQVESME and we are with continued progress, and we will do the same with sickle cell.

And then in regards to your other question around incremental data, so I am actually very proud of the data I think this is new data highlighting that mitapivat has potential benefit to improve organ health both on kidney and cardiac which, of course, are 2 major you know, organs that contribute to killing patients with sickle cell disease. So seeing this data for us was very exciting. It highlights also the potential of PKM 2, which, of course, is a unique mechanism that we are pan PK activator, so there is not really any competitor that has this mechanism available. So we are gonna continue to highlight these data, differentiate via our, but then, like, via the dual mechanism of action, and we are very much looking forward to ASH.

Very good. Thanks again. Thank you for the questions.

Our next question comes from the line of Samantha Semenkow from Citi. Please go ahead.

Congratulations on all the AQVESME launch progress. I have 2 questions as well, but both on sickle cell disease I am wondering if we can just maybe elaborate a little bit more on some of the potential scenarios for what a REMS could look like sickle cell disease. Our understanding is that there is varying degrees for those requirements. And then just on the competitive side, can you just talk a little bit in more detail about how you see mitapivat positioned commercially? And as we look forward into ASH, and when we go and make our cross trial comparisons versus, competitors, is there anything we should keep in mind in terms of trial design considerations when we do that exercise? Thanks very much.

No. Thanks. Thanks, Samantha. Sarah, you wanna start with. Actually, both of those questions, I think you can Yeah.

I can start and then maybe hand it to Sarah as well for the positioning. So in regards to your first question, Samantha, around potential scenarios for REMS, you are right that there is a huge range of different REMS. Some of them are, folks on just educational components, so a medication guide, for instance. Versus then you have a whole range that goes to a REMS with elements for to assure safe use and the ETASU REMS, which is more like the AQVESME style REMS. As we have highlighted, we are in negotiations with the FDA for label which includes elements of potential REMS, and that is really all that we can comment on at this point in time. In regards to ASH and cross trial comparisons, so when we are looking at any trial for sickle cell disease, then, of course, we would be looking at baseline demographics of a patient population where patients were enrolled, baseline VOC rates, to be able to understand treatment effects that have been discussed. And so those are things that I would definitely recommend when you were doing cross trial comparison. And then, of course, 1 of the other aspects beyond efficacy is safety data, because ultimately, it is about benefit risk profile for a drug. And then in regards to competitive positioning, I will actually hand that over to Sarah.

Absolutely. As I said, we are launch-ready, and we are excited about the potential approval for sickle cell disease. Then, as I mentioned, we have identified about 25 thousand patients, which are our initial launch targets. We are benefiting from very good data in sickle cell disease, and these are patients that are actually actively engaged with the health care system, seen by hematologists, and, of potential of showing a need for therapy, which is fantastic. The 3 elements that we are going to look to position the drug around our starting, of course, with the clinical data. The clinical data is very well recognized and accepted by the treating hematologist. We have a very positive feedback both on the consistency and the strength of the anti-hemolytic profile. And as Sarah mentioned, we continue to generate data both in the open label extension and additional data to the clinical differentiation. A second very important element is also our market experience and the totality of our safety exposure accrued throughout the years. that is important, of course, for clinicians to have confidence in the profile, and it is critically important in disease like sickle cell disease, where patients themselves are very safety conscious. And we see that as a strength. Last but not least is the trust that we have built with the community. We have been on the market with mitapivat. For several years now, we have a well established not only medical and clinical development, but commercial infrastructure, which is in place and engaging with this customers, and we will leverage all of that Thanks very much.

Our next question comes from Eric Schmidt from Cantor. Your line is open. Please go ahead.

Thank you for taking my questions. Maybe on the financial side and the R and D cost savings for Cecilia. Can you share an estimate for, the degree of cost savings or where you think this R&D spend might end up on a 2027 basis or even what type of revenue you need in 2028 to achieve that non GAAP breakeven profitability?

Great. Thanks, Eric. On the OpEx front, what we highlighted is we have we will be reducing our R&D headcount by approximately 100 heads or 35% during the course of 2026. And we will see a onetime charge in 2020. In Q4 of 20 of $11 million The impact of the cost savings from those will be seen in 2027 since the majority was towards the end of 26. We are not providing guidance yet. it is a little early for 2027. On the 2028, target non GAAP target profitability, We are including the potential launch of sickle cell in 2027 and a disciplined approach to managing our OpEx.

Okay. Maybe, if I could add a maybe somewhat technical question for Sarah on the elements of the REMS program in sickle cell that are being discussed. Is it possible to have a different REMS program in sickle cell versus what you have in thalassemia? And still be approved under the same brand name of AQVESME, or would that require sort of, yeah, a third brand name if you had a slightly different range? Thanks.

So we thanks, Eric, for the question. But, like, any options of those are always possible. There is a whole range of the brand names and the types of rims. We cannot comment at this point on ongoing label negotiations. We will really you know, look forward to completing these. I think Samantha touched upon the range of potential REMS, and so all of those are possibilities.

Okay. Thank you. Thanks, sir.

1 moment for our next question. The next question comes from the line of Gregory Renza from Truist Securities. Your line is open. Please go ahead.

Hey, team. it is Danish on for Gregory. Congrats on the progress this quarter and for taking our questions. First on how much of the 177 completed start forms and 48 new ones came from NTD versus TD patients What is driving the sequential moderation And second, on 36 in the therapeutic window, what gives you confidence that the 6 month effects in healthy volunteers can translate into sustained phlebotomy control in PV without excessive iron restriction or anemia. Thanks so much.

So Tsveta, want to start with PYRUKYND and, or continue progress.

Absolutely. We are very encouraged by the first 3 quarters of the launch. We are building the thalassemia market and really is the first medicines approved for this broad thalassemia patient population. We are not giving the split on NTD and TD, but I am very pleased to see the demand continue to broaden in both segments, the transfusion dependent patients as well as the expansion in the nontransfusion dependent patients and that is great. When I look at the performance in totality, it is 619 prescriptions, that are coming from a start form. That is the completed start forms. Which is about 15% of the total launch patient population. And the additional 48 prescriptions are really the upstream demand, which still are in process. And, you know, and are part of the demand funnel. So for us, that is very, very encouraging, but very importantly, moving forward, I just wanna emphasize the point of persistency. We reported that the initial kind of persistency that we see right now for patients every-6-months is 75%. And that is probably 1 of the most important elements given that the is a chronic disease and revenues moving forward will be really comprised of, of course, of new patients starting on therapy, but more and more patients continue on therapy.

And Anish, we talk a lot internally about health of the launch and, you know, building on our rare disease experience and I think what Sveta just described is what we look for, which is we are 3 quarters in. We are making continued really good progress into a very significant opportunity We are seeing breadth of prescribers, breadth of patient types, As Svetta just said, we gave some color on that today. Persistency, and all of that stacks together for very healthy dimensions that we are we are quite pleased about. And, of course, all of these learnings, we are gonna look to amortize into a potential sickle cell disease launch as well. And Sarah?

Yep. And then in regards to your question on AG-236, and iron-restrictive anemia from healthy volunteers going into patients. So this is. Obviously, we are running the phase 2 to do proper dose finding in patients. We are very excited about the data that are going to be presented at ASH, which allows us to move forward into patients. We believe based on that data, and we have really an opportunity to bring this dosing frequency to an every-6-month dose. That will be the goal of the phase 2, to test this across a range of doses and a range of frequencies. And then we are very excited, like, once we have that data, to move seamlessly in a phase 3.

Thanks so much.

Please hold for our next question. The next question comes from Emily Bodnar from H.C. Wainwright. Your line is open. Please go ahead.

Hi, good morning. Thanks for taking the questions and congratulations on the progress. I guess maybe just on the AQVESME launch, I am just curious In terms of the 75% persistence, which is really impressive, is there any difference between the nontransfusion dependent and transfusion dependent patients right now?

Absolutely. We are we are very encouraged by the initial signs on persistent with the 75 percent of the patients continuing beyond the 6 month mark. We are seeing a strong persistency across patient segments. And that was actually also true for the PK deficiency indication. So it is wonderful to see that also in thalassemia as well. And as a as a follow-up, I am just curious. In terms of the data that was presented at EHA last year, have you had a sense clinicians are more willing to sort of extend filing with patients than perhaps they were ahead of that data set? Yeah. Absolutely. I think in the real world, the benefit from AQVESME defined a lot broader than what we see in the clinical trial. The clinical trial criteria very, very specific and well defined for regulatory purposes. But people are looking, of course, of how patients feel as well as also their hemoglobin increases. And here, I just wanna highlight also the fact that we have an excellent payer coverage. The team has done a phenomenal job. Within 6 months of launch, we have payer coverage policies for 75%. Of coverage wise, and they are very, very favorable for AQVESME. So we have no bear restrictions.

Okay. Great. Thank you so much, and congrats on the progress.

Thanks for the questions.

Please hold for our next question. Next question comes from Andrew Berens from Leerink Partners. Your line is open. Please go ahead.

This is Amanda on for Andrew Berens. A question that I think you have touched on a little bit already, but just to get a little bit more color. Could you outline the potential options around pricing and strategy if you do get a REM during the sickle cell review? Thanks.

Thanks, Amanda. Do you wanna take that? Of course, we never get specific on pricing, but I think we can dimensionalize how we think about it.

Absolutely. So from know, when you think about sickle cell disease from a payer perspective, it is still a rare disease. A rare disease with very high unmet need. And no treatment options. We are preparing for, as we said, for all the launch scenarios. But irrespective of the launch scenarios, we think we can maintain on what level of rare disease pricing, which is very similar to what we have with thalassemia, AQVESME. Given the strength of the value proposition, of mitapivat in the sickle cell disease indication. Of course, sickle cell disease has a little bit more Medicaid patient population, and that will impact the gross to net. But we are very well positioned from a pricing perspective.

Thank you for the questions.

1 moment for our next question. The next questions will come from the line of Marc Frahm from TD Cowen. Please ahead. Go ahead.

There, good morning, and thank you for taking my question. Actually, 1 on the pipeline What should we expect from the upcoming proof of concept data in PKU? What would be encouraging there? And maybe given your updated R and D focus and headcount reduction, is this something that remains in your focus, or would you look to license this asset? Thank you.

So in regards to proof of mechanism data in PKU patients, obviously, we are looking for safety because it is a phase 1b, but then also looking at fee reductions the classic way 1 would look, at it from a PKU perspective. We believe this program then know, gives us the potential for further development and so we are excited about that.

Yeah. And Joe, just add, you know, this is. As I mentioned in my comments earlier, it is obviously. PKU is high unmet need. Though not hematology. And first step, of course, is get the data, which we are eager to see. And I had noted that we maintain optionality So know, we have certainly the option of keeping that in our portfolio. We know that there is also a lot of interest in PKU in general as a market that continues to develop and grow. And so we feel like we are in a position to strengthen to have that option. Great. Thank you. You bet.

1 moment for our next question. Our next questions will come from the line of Tessa Romero from JPMorgan. Your line is open.

Thanks for taking our question this morning. I wanted to ask a question to Tsveta here. You know, in the third quarter, 177 AQVESME prescriptions was completed myAgios start forms were written. What is the right way to think through the run rate for that script ad per quarter as we move ahead in your launch? And then my second question was just around the 75 percent of patients that remain on therapy after 6 months You know, what are you seeing in the marketplace in terms of why patients discontinue if they do? Thank you.

Sure. Absolutely. So Tessa, on the first question, what I will highlight is look at the first quarter first in totality where it was 119 prescriptions. We have completed 5 forms and additional 48 in progress, please? Kind of conditions is roughly about 15% of the total addressable patient population for thalassemia, for our launch target. Which is a very good start for, a chronic not imminent, like, life threatening disease. When you kind of look at the quarter over quarter evolution, Q1 as we already have highlighted, yeah, and to a lesser extent, Q2 really benefited from that pent up demand, which was built during the expanded NDA period. We are now seeing the broadening, which we always expected and plan for into the community practices as well as the non transfusion dependent patients where treatment decisions take more time. Looking ahead, the 177, is probably the more run rate as we continue to penetrate these markets. I am gonna highlight it again given the chronic nature of the disease, an important element for us that we are very excited about also the high persistency that we are seeing in this. In this stages of the launch. Because moving forward, of course, the revenues will be driven by both the new patient starts and patients on therapy as well.

Thank you for the questions.

Our next questions will come from the line of Salveen Richter of Goldman Sachs. Thank you.

Good morning. Ahead of the PDUFA in sickle cell disease Could you just speak to the physician overlap with thalassemia and their comfort around a potential REMS inclusion here?

So, absolutely, we are obviously in a regular contact with the physician community, the team is in place, and we are doing an extensive account profiling but also brands are in the last few months. I got an opportunity to connect with the sickle cell KOL at different forums. And I can tell you that there is a very high level of engagement and excitement both on the profile and the potential approval for the product. When we think about the hematologist, the 3 hemolytic anemias, really the kind of what we call an overlap will exist mainly in the academic setting We have not given specifics on the overlap, and this is mainly driven by the fact that if in the same center, you might have hematologists focusing on hemolytic anemia, but some of them might specializing on the leukemia. Some of them might be specializing in sickle cell disease. Otherwise, in the community, every hematologist treats both conditions, both thalassemia and sickle cell disease.

Thank you for the questions.

And our final question comes from Luca Issi from RBC Capital. Please go ahead.

Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe for Tsveta. again, congrats on the 619 cumulative prescriptions here for AQVESME and, you know, the additional 48. Are all of these prescription coming from thalassemia, or are there any of them actually coming already from sickle cell disease We spoke to a doc the other day, and she claimed that she already has put 10 to 15 of her patients, her sickle patients, on this drug, and she had actually little pushback from Medicaid, whereas she claims that there is much more pushback on Medicare and commercial. So wondering if that doc is just kind of a 1-off or there is a meaningful proportion of that 619 that actually is already coming from sickle cell. and the closer there. Much appreciated. And then maybe Cecilia, circling back on Eric's question. You know, as the p and l continue to mature here and you are starting to see non GAAP profitability on the horizon for 2028. Is there a plan to actually guide the top- and maybe the expense line in 2027, or would that be maybe too premature?

So much. With Tsveta, let's start with the question around the 619 and the 2048.

Absolutely. I just wanna be very clear. Both the 619 and the 48 are on-label thalassemia prescriptions.

Yep.

And then, Luca, your question around the p and l and future guidance and so forth.

Yes. it is a little early, Luca, to guide on 2027, but we look to provide guidance at the appropriate time.

Got it. Thanks so much.

Thank you.

With that, we conclude our q and a session. And I would like to turn the call back to Brian Goff, Chief Executive Officer, for closing remarks.

Great. Great. Thanks a lot. Thank you, everyone, for joining us today. So as we talked about the third quarter delivered record product revenue for Agios. AQVESME is building a durable growing base of patients in thalassemia and in sickle cell disease which is our largest potential opportunity, we are launch ready ahead of our February 1, 2027 PDUFA goal date. We have over $900 million in cash a disciplined operating model, and we are well positioned to execute as we target non GAAP profitability in 2028. So we look forward to updating you on our progress, including at our upcoming virtual ASH investor event. That will be on December 14. We will be featuring new clinical data for mitapivat in sickle cell disease further strengthening our profile as well as 6 month healthy volunteer data for AG-236. Which as Sarah commented on, supports every-6-month dosing, meaning we have the potential to deliver a best in class medicine for the treatment of polycythemia vera. Thank you very much, and look forward to speaking soon.

That concludes today's conference call. Thank you for your participation. You may now disconnect. Disconnect your lines.