Agios Pharmaceuticals Q3 2026 Earnings Call Transcript

Agios Pharmaceuticals (NASDAQ:AGIO) reported third-quarter financial results on Thursday. The transcript from the company’s third-quarter earnings call has been provided below.

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Summary

Agios Pharmaceuticals reported record third-quarter product revenue of $55.4 million, a significant increase from the previous year, driven by the U.S. launch of mitapivat in thalassemia.

The company is preparing for the potential launch of mitapivat in sickle cell disease, addressing an FDA request for additional safety data and aiming for approval by February 2027.

Agios reduced R&D headcount by over 35% to focus on rare hematology and anticipates cost savings in 2027, targeting non-GAAP profitability by 2028.

Third-quarter net loss was reduced to $65 million from $103.4 million the previous year, with $907 million in cash reserves to support ongoing projects.

Agios plans to advance AG236 in polycythemia vera and sevdoplenib in immune thrombocytopenia, with potential new clinical data presentations at upcoming medical conferences.

Full Transcript

OPERATOR

Good morning and welcome to Agios Pharmaceuticals third quarter 2026 conference call. At this time all participants are in the 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.

Morgan Sanford (Vice President of Investor Relations)

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals’ third 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. 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. 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.

Brian Goff (Chief Executive Officer)

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 four times the third quarter of last year. U.S. net revenue was $48.7 million, driven by the continued strong U.S. launch of mitapivat 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’ll speak to the status of our sNDA in a moment. We ended the quarter with $907 million in cash, 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 9th 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 nine 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 three 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 continue 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 support 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 2027. Second, advance a focused rare hematology pipeline that includes AG236 in polycythemia vera, where we plan to initiate a phase 2/3 program by year-end, and sevdoplenib in immune thrombocytopenia, with a phase 3 trial planned for the first half of 2028.

Importantly, both programs have clinically validated and de-risked mechanisms of action. To support that focus, we have right-sized our operating model. Over the course of 2026 we will have reduced R&D headcount by more than 35% 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 hematology programs, and we are pursuing opportunities to unlock value from non-core assets, including our vorosidenib royalty and AG181.

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’ll turn the call over to Cecilia to discuss financials. Cecilia.

Cecilia Jones (Chief Financial Officer)

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 revenues in the third quarter of 2025. 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 2025, primarily reflecting reductions in spend associated with mitapivat and tevapivat 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 U.S. launch in thalassemia and preparation for a potential U.S. sickle cell disease launch. Net loss for the third quarter of 2026 was $65 million compared to a net loss of $103.4 million in the third quarter of 2025. We ended the quarter with $907 million in cash, cash equivalents and marketable securities, which we believe provides the financial strength to support the mitapivat 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 sevdoplenib in-licensing which was recognized in the second quarter, and approximately $11 million of one-time expenses associated with the headcount reduction to be recognized in the fourth quarter. Please advance to the next slide and I’ll turn it over to Tsveta to cover commercial highlights.

Tsveta Milanova (Chief Commercial Officer)

Thank you, Cecilia. Next slide, please. The third quarter was a record quarter for mitapivat, and I’m proud of the execution across the teams, with total mitapivat revenues increasing more than four times the third quarter of last year. In the U.S., net revenue was up 20% sequentially, driven by access and 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 partners Avanzanite in Europe and NewBridge Pharmaceuticals in the GCC. Next slide, please. Now turning to U.S. demand for mitapivat in thalassemia. As a reminder, an Agios Start Form is submitted with a mitapivat 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 4,000 patients, only three quarters into launch.

This is the last quarter we will report this metric, so for a complete picture, another 48 prescriptions had start forms in process at quarter end. We communicated previously that first-quarter start forms benefited from pent-up demand built 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 six months. This is exactly the foundation we want: a durable base of patients that builds over time. Looking ahead, we are focused on two priorities. On persistency, making sure prescribers know the long-term clinical data 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 non–transfusion-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 mitapivat, our first direct-to-consumer campaign, a targeted omnichannel effort. This month we are expanding with multilingual assets to reach the diverse thalassemia community. Early 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 mitapivat in thalassemia.

Recent market research shows broad enthusiasm across both transfusion-dependent and non–transfusion-dependent segments. We are encouraged by the momentum three quarters into launch. As the first medicine approved for the broader thalassemia population, mitapivat is well positioned for continued growth, and I’m 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 1st PDUFA goal date. There are approximately 75,000 diagnosed patients age 16 and older in the U.S. Our initial launch focus is approximately 25,000 patients who are actively treated 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 six times larger—roughly 25,000 patients compared with approximately 4,000 in thalassemia. Our dedicated sales, medical and patient support teams are hired and trained, our manufacturing and supply chain are staged for day-one availability, and we have mapped priority physicians.

Pending 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.

Sarah Gheuens (Chief Medical Officer)

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 and sickle cell disease. We are in active 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-Kids-T have the potential to expand our addressable US thalassemia population by approximately 2,000 pediatric patients beyond mitapivat.

We are advancing sevidoplinib in immune thrombocytopenia towards a Phase 3 trial planned for the first half of 2028 and AG236 in polycythemia vera towards a Phase 2/3 program by year-end. Finally, we look forward to proof-of-mechanism data for AG181 in phenylketonuria before the end of the year as well. Next slide, please. We’re excited to share new clinical data at the 2026 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’s 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 a hemoglobin improvement in the open-label extension period, including 39.7% 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. 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 non-responders and 4.6 on placebo. Left atrial volume was also reduced, supporting the potential for disease-modifying benefit. Taken together, these data suggest mitapivat’s unique action on PKM2 may address organ damage and a key driver of premature mortality in sickle cell disease.

Next slide, please. Also at ASH 2026, we will present the first clinical data for AG236, our siRNA targeting TMPR6 inhibitor for polycythemia vera, from our Phase 1 study in healthy volunteers. AG236 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. AG236 also reduced transferrin saturation and hematocrit, with effects on iron, transferrin saturation, hemoglobin, and hematocrit sustained through month six.

AG236 was well tolerated with all adverse events grade one or two and no serious adverse events or discontinuations. This single-dose durability supports the potential for every six months 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 six-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 AG181, our novel PAH stabilizer for the treatment of phenylketonuria, or PKU. In our preclinical model of classical severe PKU, AG181 produced significant dose-responsive reductions in blood phenylalanine, and at 300 mg per kg we achieved a 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.

AG181 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 AG181 offers a meaningfully differentiated mechanism for the treatment of PKU supported by compelling preclinical data and Phase 1 data in healthy volunteers. We look forward to building on that foundation with Phase 1b proof-of-mechanism 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.

Brian Goff (Chief Executive Officer)

Thank you, Sarah. Next slide, please. Agios is a focused rare hematology company approaching its next phase of growth in thalassemia. Akvesmi is the first medicine approved for the broad thalassemia population, and the US launch delivered record net product revenue this quarter. With strong momentum, Akvesmi 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 1st, 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 AG236 in polycythemia vera and sevidoplinib in immune thrombocytopenia, both with clinically validated de-risked mechanisms of action, and we have strategic optionality with AG181 in PKU.

We are executing with discipline, right-sizing our operating model and allocating capital to the opportunities where we believe Agios Pharmaceuticals can create the most value for patients and shareholders. Before we open the call for questions, I’d 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.

OPERATOR

Thank you. We will now begin the question and answer session. If you would like to ask a question on the phone, please press star followed by 1 on the telephone and wait for your name to be announced. To cancel your request, please press star 1 again. One moment for the first question. Our first question comes from the line of Alex Shanahan from Bank of America. Your line is open. Please go ahead.

Alex Shanahan (Analyst)

Hey, guys, thanks for taking my questions and congrats on the progress in the quarter. I guess two questions, one on the PDUFA delay and one around the ASH presentation. I guess, 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 REMS is required, how would this maybe change your launch expectations around the curve versus what you’ve seen in thalassemia? And then just around the ASH updates, I guess the durable hemoglobin gains — I think it was up to two years — plus the kidney and heart signals seem incremental to prior presentations.

How do you think these benefits maybe stack up versus competing drugs, especially around the PKM2 activation that you highlighted? Thanks.

Brian Goff (Chief Executive Officer)

Thanks, Alex. So we’ll take that in sequence, then start with your question on the PDUFA. And that’s going to be a two-parter. Sarah can begin, comment on where we are with FDA, and then Sveta can talk about commercial aspects, and we’ll take the second question separately.

Sarah Gheuens (Chief Medical Officer)

Thanks, Alex. So in regards to the PDUFA delay and the potential other questions raised, the engagement with the agency is going very well. We highlighted we are in labeling negotiations. We feel confident in the benefit-risk profile of our drug and are looking forward to work as quickly and expeditiously as possible with the agency to get this very much needed drug to patients.

Tsveta Milanova (Chief Commercial Officer)

Absolutely. And the way that we see the PDUFA delay is really a change of timing and not a change in the commercial opportunity. As we know, sickle cell disease affects approximately 100,000 patients in the US and is going to be the largest indication that we’re pursuing today, with 25,000 which we identified as an initial launch target. We are ready to launch in any scenario, and we have already a very well-established commercial infrastructure to do so.

Brian Goff (Chief Executive Officer)

Yeah, and I’ll put an exclamation point on the last thing Sveta said, too. Sveta and her team always prepare for multiple scenarios. And I think this quarter in particular is a good demonstration of all the preparation that went into thalassemia with Akvesmi. And here we are with continued progress, and we’ll do the same with sickle cell.

Sarah Gheuens (Chief Medical Officer)

And then in regards to your other question around incremental data, I’m 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 two major 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 PKM2, which of course is a unique mechanism that we have.

We are a pan-PK activator, so there is not really any competitor that has this mechanism available. So we’re going to continue to highlight these data, differentiate via the dual mechanism of action, and we are very much looking forward to ASH.

Alex Shanahan (Analyst)

Very good. Thanks again.

OPERATOR

Thank you for the questions. Our next question comes from the line of Samantha Samanco from Citi. Please go ahead.

Samantha Samanco (Analyst)

Hey, good morning. Thanks very much for taking the question and congratulations on all the Akvesmi launch progress. I have two questions as well, but both on sickle cell disease. I’m wondering if we can just maybe elaborate a little bit more on some of the potential scenarios for what a REMS could look like for sickle cell disease. Our understanding is that there are varying degrees for those requirements. And then just on the competitive side, can you 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.

Brian Goff (Chief Executive Officer)

Thanks. Thanks, Sarah. You want to start with actually both of those questions. I think you can.

Sarah Gheuens (Chief Medical Officer)

Yeah, I can start and then maybe hand it to Sveta as well for the position. So in regards to your first question, Sam, around potential scenarios for REMS, you’re right that there is a huge range of different REMS. Some of them are focused on just educational components — so a medication guide, for instance — versus then you have a whole range that goes to a REMS with Elements to Assure Safe Use and REMS which is more like the Akvesmi-style REMS.

As we’ve 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 comparison: so when we’re looking at any trial for sickle cell disease, then of course we 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 are doing cross-trial comparison.

And then, of course, one of the other aspects beyond efficacy is safety data because ultimately it’s about a benefit-risk profile for a drug. And then, in regard to competitive positioning… I’ll actually hand that over to Sveta.

Tsveta Milanova (Chief Commercial Officer)

Absolutely. As I said, we are launch-ready, and we’re excited about the potential approval for sickle cell disease. As I mentioned, we have identified about 25,000 patients which are our initial launch targets. We are benefiting from very good data in sickle cell disease. These are patients that are actively engaged with the healthcare system, seen by hematologists, and of potential show need of therapy, which is fantastic. The three elements that we are going to look to position the drug around are, starting of course with the clinical data. The clinical data is very well recognized and accepted by the treating hematologists. We have 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 substantiate 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’s important, of course, for clinicians to have confidence in the profile, but it’s critically important in a disease like sickle cell disease where patients themselves are very safety conscious, and we see that as a strength. And last but not least is the trust that we have built with this community. We’ve been on the market with mitapivat for several years now, and we have a well-established not only medical and clinical development but commercial infrastructure which is in place in engaging with these customers, and we’ll leverage all of that.

OPERATOR

One moment for our next question. Our next question comes from Eric Smith from Cantor. Your line is open. Please go ahead.

Eric Smith (Analyst)

Thank you for taking my questions. Maybe on the financial side and the R&D cost savings for Cecilia, can you share an estimate for the degree of cost savings or where you think that 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?

Cecilia Jones (Chief Financial Officer)

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

Eric Smith (Analyst)

Okay, maybe if I could add a 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? Or would that require a third brand name if you had a slightly different REMS? Thanks.

Sarah Gheuens (Chief Medical Officer)

Thanks, Eric, for the question. Like any options, those are always possible. There is a whole range of the brand names and the types of REMS. We can’t comment at this point on ongoing label negotiations. We will really look forward to completing these. I think Sam touched upon the range of potential REMS and so all of those are, you know… Okay, thank you.

Eric Smith (Analyst)

Thanks, Sarah.

OPERATOR

One 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.

Aneesh (Analyst)

Hey team, it’s Aneesh on for Greg. Congrats on the progress this quarter and for taking our questions. First on Akfesmi, just how much of the 177 completed START forms and 48 new ones came from NTD versus TD patients, and what is driving the sequential moderation? And second, on AG-236 and the therapeutic window: what gives you confidence that the six-month effects in healthy volunteers can translate into sustained phlebotomy control in PV without excessive iron restriction or anemia? Thanks so much.

Brian Goff (Chief Executive Officer)

Want to start with Akfesmi and our continued progress?

Tsveta Milanova (Chief Commercial Officer)

Absolutely. We are very encouraged by the first three quarters of the launch. We are building the thalassemia market, and really Akfesmi is the first medicine approved for this broad thalassemia patient population. We’re not giving the split on NTD and TDT, but I’m very pleased to see the demand continue to broaden in both segments — the transfusion-dependent patients as well as the expansion in the non–transfusion-dependent patients. And that is great.

When I look at the performance in totality, it’s 609 prescriptions that are coming from START forms — 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 are part of the demand funnel. So for us that’s very, very encouraging. But very importantly, moving forward, I just want to emphasize the point on persistency. We reported that the initial kind of persistency that we see right now for patients at six months is 75%, and that is probably one of the most important elements given that thalassemia is a chronic disease. And revenues moving forward will be really comprised of, of course, new patients starting on therapy, but more and more patients continuing on therapy.

Brian Goff (Chief Executive Officer)

And Aneesh, 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’re three quarters in, we’re making continued really good progress into a very significant opportunity. We’re seeing breadth of prescribers, breadth of patient types — as Sveta just said, we gave some color on that today — persistency, and all of that stacks together for very healthy dimensions that we’re quite pleased about.

And of course all these learnings we’re going to look to amortize into a potential sickle cell disease launch as well. And Sarah?

Sarah Gheuens (Chief Medical Officer)

Yep. And then in regards to your question on AG-236 and iron-restrictive anemia from healthy volunteers going into patients: obviously we’re running the phase 2 to do proper dose finding in patients. We’re 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 six-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’re very excited that once we have that data, to move seamlessly in a phase two.

Aneesh (Analyst)

Thanks so much.

OPERATOR

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

Douglas Chow (Analyst)

Hi, good morning. Thanks for taking the questions and congratulations on the progress. I guess maybe just on the Akfesmi launch: I’m just curious, in terms of the 75% persistence, which is really impressive, is there any difference between the non–transfusion-dependent and transfusion-dependent patients right now?

Tsveta Milanova (Chief Commercial Officer)

Absolutely. We are very encouraged by the initial signs on persistency. With 75% of the patients continuing beyond the six-month mark, we’re seeing strong persistency across patient segments. And that was actually also true for the PK deficiency indication. So it’s wonderful to see that also in thalassemia as well.

Douglas Chow (Analyst)

And as a follow-up, I’m just curious, in terms of the data that was presented at EHA last year, have you had a sense that clinicians are more willing to sort of extend trialing with patients than perhaps they were ahead of that data set?

Tsveta Milanova (Chief Commercial Officer)

Yeah, absolutely. I think in the real world the benefit from Akfesmi we find a lot broader than what we see in the clinical trial. The clinical trial criteria are very, very specific and well defined for regulatory purposes. But people are looking, of course, at how patients feel as well as also their hemoglobin increases. And here I just want to highlight also the fact that we have an excellent payer coverage. The team has done a phenomenal job and within six months of launch we have payer coverage policies for 75% of coverage, and they are very, very favorable for Akfesmi.

So we have no payer restrictions.

Douglas Chow (Analyst)

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

OPERATOR

Thank you for the questions. Please hold for our next. Next question comes from Andrew Behrens from Leerink Partners. Your line is open. Please go ahead.

Amanda (Analyst at Leerink Partners)

Hi, this is Amanda on for Andrew Behrens. A question that I think you’ve touched on a little bit already, but just to get a little bit more color: could you outline the potential options around pricing and brand strategy if you do get a REMS during the sickle cell review? Thanks.

Brian Goff (Chief Executive Officer)

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

Tsveta Milanova (Chief Commercial Officer)

Absolutely. So, when you think about sickle cell disease from a payer perspective, it’s still a rare disease — a rare disease with very high unmet need and no treatment options. We are preparing, as we said, for all the launch scenarios, but irrespective of the launch scenarios, we think we can maintain a level of rare disease pricing which is very similar to what we have with our other products, 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.

OPERATOR

Thank you for the questions. One moment for our next question. The next question will come from the line of Joseph Tom from TD Cowen. Please go ahead.

Joseph Tom (Analyst)

Hi there. Good morning, and thank you for taking my question. Actually one 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&D focus and headcount reduction, is this something that remains in your focus, or would you look to out-license this asset? Thank you.

Sarah Gheuens (Chief Medical Officer)

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

Brian Goff (Chief Executive Officer)

Joe, I’ll just add: as I mentioned in my comments earlier, obviously PKU is high unmet need, though not hematology. And first step of course is get the data, which we’re eager to see. And I had noted that we maintain optionality, so 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’re in a position of strength to have that option.

Joseph Tom (Analyst)

Great, thank you.

OPERATOR

One moment for our next question. Our next question will come from the line of Tess Romero from JP Morgan. Your line is open.

Tess Romero (Analyst)

Hi Brian and Team, thanks for taking our question this morning. I wanted to ask a question to Sveta here. You know, in the third quarter, 177 prescriptions with completed start forms were written. What is the right way to think through the run rate for that script add per quarter as we move ahead in your launch? And then my second question was just around the 75% of patients that remain on therapy after six months. What are you seeing in the marketplace in terms of why patients discontinue if they do?

Thank you.

Tsveta Milanova (Chief Commercial Officer)

Sure. Absolutely. So Tess, on the first question what I’ll highlight is look at the first quarter first. In totality we reported 619 prescriptions with completed start forms and additional 48 in from risk, which kind of positions us 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 imminently life-threatening disease. When you kind of look at the quarter-over-quarter evolution, Q1, as we already have highlighted, and to a lesser extent Q2, really benefited from that pent-up demand which was built during the extended FDA period. We are now seeing the broadening which we always expected and planned 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 appropriate run rate as we continue to penetrate these markets.

I’m going to highlight it again. Given the chronic nature of the disease, an important element for us that we’re very excited about is also the hyper efficiency that we’re seeing in the initial stages of the launch because, moving forward, of course the revenues will be driven by both the new patient start and patients on therapy as well.

OPERATOR

Thank you for the questions. Our next questions will come from the line of Salvin Richter of Goldman Sachs. Your line is open. Please go ahead.

Salvin Richter (Analyst at 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?

Tsveta Milanova (Chief Commercial Officer)

So absolutely. We are obviously in regular contact with the physician community. The team is in place and we are doing an extensive account profiling. But also Brian Sr. and I in the last few months had an opportunity to connect with the sickle cell disease care wells at different forums and I can tell you that there is a very high level of engagement and excited both on the profile and the potential approval for the product. When we think about the hematologies, the three hemolytic anemias, really the kind of what we call an overlap will exist mainly in the academic setting. We haven’t given specifics on the overlap and this is mainly driven by the fact that if in the same center you might have hematologists who are focusing on hemolytic anemia, but some of them might be specializing on thalassemia, 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.

OPERATOR

Thank you for the questions. And our final question comes from Luca Isi from RBC Capital. Please go ahead.

Luca Isi (Analyst)

Oh great. Thanks so much for taking my question. Congrats on the progress. Maybe, Sveta, again congrats on the 619 cumulative prescriptions here and the additional 48. Are all of these prescriptions 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 versus she claims that there’s much more pushback on Medicare and commercial.

So wondering if that doc is just kind of one-off or there is a meaningful proportion of that 619 that actually is already coming from sickle cell. So any color there, much appreciated. And then maybe, Cecilia, circling back on Eric’s question, as the P&L continue to mature here and you’re 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? Thanks so much.

Brian Goff (Chief Executive Officer)

So, let’s start with the question around the 619 and the 48.

Tsveta Milanova (Chief Commercial Officer)

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

Brian Goff (Chief Executive Officer)

Yep. And then, Cecilia, question around the P&L and future guidance and so forth.

Cecilia Jones (Chief Financial Officer)

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

Luca Isi (Analyst)

Got it. Thanks so much. Thank you.

OPERATOR

With that we conclude our Q and A sessions and now I’d like to turn the call back to Brian Goff, Chief Executive Officer, for closing remarks.

Brian Goff (Chief Executive Officer)

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. We are 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 14th, where 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 AG236 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.

OPERATOR

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

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