Agios (AGIO) Q3 2026 Earnings Call: Umsatz erreicht 55,4 Mio. USD

Zentrale Erkenntnisse

• Agios Pharmaceuticals meldete für das dritte Quartal 2026 einen Rekord-Nettoumsatz mit Mitapivat von 55,4 Millionen US-Dollar – mehr als das Vierfache der im dritten Quartal 2025 verzeichneten 12,9 Millionen US-Dollar. Der US-Umsatz erreichte 48,7 Millionen US-Dollar.
• Die Markteinführung von AQVESME in den USA gewann bei Thalassämie weiter an Dynamik. Die kumulierte Zahl der Verschreibungen mit vollständig ausgefüllten Start-Formularen von Agios erreichte 619, was etwa 15 % der angestrebten Launch-Zielpopulation von rund 4.000 Patienten entspricht.
• Rund 75 % der AQVESME-Patienten blieben nach sechs Monaten weiter unter Therapie. Das Management bezeichnete die Therapieversistenz sowie eine breitere Akzeptanz im niedergelassenen Bereich und bei nicht-transfusionsabhängigen Patienten als zentrale Wachstumsprioritäten.
• Die FDA verlängerte das Prüfverfahren für Mitapivat bei Sichelzellkrankheit um drei Monate bis zum 1. Februar 2027, nachdem sie die Antwort des Unternehmens auf eine Anfrage nach zusätzlichen REMS-bezogenen Informationen als wesentliche Änderung eingestuft hatte.
• Agios schloss das Quartal mit liquiden Mitteln, Zahlungsmitteläquivalenten und marktgängigen Wertpapieren in Höhe von 907 Millionen US-Dollar ab. Das Management peilt für 2028 weiterhin die Profitabilität auf Non-GAAP-Basis an.
• Das Unternehmen baut die F&E-Belegschaft im Vergleich zu 2025 um mehr als 35 % bzw. über 100 Stellen ab. Der Großteil der damit verbundenen Einsparungen wird für 2027 erwartet.

Wichtigste Finanzdaten

Geschäftliche und operative Entwicklung

AQVESME verzeichnete im Bereich Thalassämie in den USA weiterhin eine anhaltende Dynamik. Im dritten Quartal erhielt Agios 177 Verschreibungen mit vollständig ausgefüllten Start-Formularen von 135 Ärzten. Bei weiteren 48 Verschreibungen waren die Formulare zum Quartalsende noch in Bearbeitung. Laut Management stellen 177 Verschreibungen möglicherweise eine realistischere quartalsweise Run-Rate dar, da die Markteinführung über die anfängliche Nachholnachfrage hinausgeht und sich auf niedergelassene Praxen sowie nicht-transfusionsabhängige Patienten ausweitet.

Das Unternehmen meldete eine solide Sechs-Monats-Persistenz von rund 75 % über alle Patientensegmente hinweg. Zudem baut Agios die Patientenansprache weiter aus: Die Nutzerinteraktion auf der Patienten-Website stieg nach dem Start der Direct-to-Consumer-Kampagne „Level Up with AQVESME“ im August um 65 %.

Außerhalb der USA profitierte der Mitapivat-Umsatz von europäischen Frühzugangsprogrammen, nachdem die Europäische Kommission im zweiten Quartal die Zulassung für Thalassämie erteilt hatte. Agios treibt die internationale Vermarktung über Partner voran, darunter Avanzanite in Europa und NewBridge Pharmaceuticals in den GCC-Staaten.

Die Sichelzellkrankheit bleibt für das Unternehmen die größte potenzielle kommerzielle Chance. Agios schätzt die Zahl der diagnostizierten US-Patienten ab 16 Jahren auf rund 75.000, wobei der anfängliche Launch-Fokus auf etwa 25.000 aktiv behandelten oder therapiebedürftigen Patienten liegt. Die Vertriebs-, Medizin- und Patientenbetreuungsteams sind geschult, während Produktion und Lieferkette auf eine potenzielle Verfügbarkeit ab dem ersten Tag ausgerichtet sind.

Agios hob zudem klinische Daten hervor, die die Differenzierung von Mitapivat untermauern. In der offenen Verlängerungsphase der RISE-UP-Studie erzielten 62,7 % der Patienten eine Hämoglobinverbesserung, darunter 39,7 % der anfänglichen Non-Responder, wobei das Ansprechen über einen Zeitraum von bis zu 115 Wochen beobachtet wurde. Post-hoc-Analysen zeigten zudem renale und kardiale Signale, die nach Ansicht des Managements auf potenzielle Vorteile über die Korrektur der Anämie hinaus hindeuten könnten.

Hinsichtlich der Pipeline plant Agios, bis Ende 2026 ein Phase-2/3-Programm für AG-236 bei Polycythaemia vera zu starten. Daten gesunder Probanden zeigten anhaltende pharmakodynamische Effekte über sechs Monate sowie keine schwerwiegenden unerwünschten Ereignisse, Therapieabbrüche oder unerwünschten Ereignisse über Grad 2 hinaus. Eine Phase-3-Studie für Sevidoplenib bei Immunthrombozytopenie ist für das erste Halbjahr 2028 geplant. Phase-1b-Proof-of-Mechanism-Daten für AG-181 bei Phenylketonurie werden noch vor Ende 2026 erwartet.

Ausblick des Managements

Agios rechnet für das Gesamtjahr 2026 mit weitgehend stabilen operativen Aufwendungen gegenüber 2025 – bereinigt um eine im zweiten Quartal erfasste Vorabzahlung von 25 Millionen US-Dollar für die Sevidoplenib-Lizenz sowie eine im vierten Quartal erwartete einmalige Belastung von rund 11 Millionen US-Dollar für den Personalabbau.

Das Management geht davon aus, dass der Großteil der Einsparungen aus dem F&E-Personalabbau im Jahr 2027 realisiert wird. Eine detaillierte Kosten- oder Umsatzprognose für 2027 gab das Unternehmen nicht ab.

Agios peilt weiterhin die Non-GAAP-Profitabilität im Jahr 2028 an. Das Management erklärte, dieses Ziel setze eine potenzielle Markteinführung bei Sichelzellkrankheit im Jahr 2027 sowie anhaltende Disziplin bei den operativen Aufwendungen voraus.

Risiken und wesentliche Faktoren

Die FDA prüft, ob für Mitapivat bei Sichelzellkrankheit ein REMS erforderlich sein wird. Agios reichte Sicherheitsdaten aus der offenen Verlängerungsstudie für rund neun zusätzliche Monate ein, und die Einstufung als Major Amendment durch die FDA verschob das PDUFA-Zieldatum auf den 1. Februar 2027.

Das Management betonte, dass das zusätzliche Follow-up keine Fälle von Leberschädigungen bei Sichelzellkrankheit gezeigt habe, die in Muster oder Schweregrad den bei Thalassämie beobachteten ähnelten. Die Verhandlungen über die Fachinformation (Labeling) einschließlich potenzieller REMS-Elemente dauern jedoch an, und die endgültige Struktur ist noch nicht festgelegt.

Der kommerzielle Launch bleibt von der Zulassung durch die FDA abhängig. Ein höherer Medicaid-Anteil bei der Sichelzellkrankheit könnte sich laut Management zudem auf das Brutto-Netto-Umsatzverhältnis (Gross-to-Net) auswirken.

Bei AG-236 muss sich die bei gesunden Probanden beobachtete Wirkungsdauer erst noch in einer anhaltenden Kontrolle des Hämatokritwerts und der Aderlasshäufigkeit bei Patienten mit Polycythaemia vera bestätigen. Der geplante Phase-2-Teil wird Dosierungen und Verabreichungsintervalle evaluieren, einschließlich der Möglichkeit einer Gabe alle sechs Monate.

Wichtigste Punkte aus der Fragerunde der Analysten

• REMS und kommerzielle Einsatzbereitschaft: Das Management stufte die Fristverlängerung der FDA eher als zeitliche Verschiebung und nicht als Schmälerung der Marktchancen ein. Agios erklärte, sich auf mehrere REMS-Szenarien vorzubereiten, nannte jedoch keine konkreten wahrscheinlichen Anforderungen.
• Positionierung bei Sichelzellkrankheit: Das Unternehmen plant, das antihämolytische Profil von Mitapivat, die gesammelte Sicherheitserfahrung und die Beziehungen zur Sichelzell-Community hervorzuheben. Zudem betonte das Management den dualen Aktivierungsmechanismus über PKR und PKM2.
• Studienübergreifende Vergleiche: Das Management riet Anlegern, beim Vergleich von Studien zur Sichelzellkrankheit die demografischen Ausgangsdaten, die Studienregionen, die anfänglichen Raten vasookklusiver Krisen sowie das Sicherheitsprofil zu berücksichtigen.
• AQVESME-Nachfrage: Das Management machte keine Angaben zur Aufteilung zwischen transfusionsabhängigen und nicht-transfusionsabhängigen Patienten, erklärte jedoch, dass Nachfrage und Persistenz in beiden Segmenten stark seien. Es bestätigte, dass es sich bei allen 619 abgeschlossenen Verschreibungen und den 48 Formularen in Bearbeitung um indikationsgerechte On-Label-Verschreibungen für Thalassämie handelte.
• Preisgestaltung: Agios zeigte sich zuversichtlich, dass Mitapivat bei Sichelzellkrankheit ähnlich wie Pyrukynd und AQVESME das Preisniveau für seltene Krankheiten beibehalten kann, auch wenn der Medicaid-Anteil den Brutto-Netto-Umsatz belasten könnte.
• Strategie für AG-181: Das Management stufte PKU als außerhalb des hämatologischen Kernfokus von Agios ein und erklärte, dass sich das Unternehmen nach Auswertung der anstehenden Phase-1b-Daten strategische Flexibilität bewahren werde.

Vollständiges Transkript der Telefonkonferenz

Vollständiges Transkript der Telefonkonferenz

Ausführungen des Managements

Operator

[Operator Instructions] This call is being recorded at Agios's request. I'd now like to turn the call over to Morgan Sanford, Vice President of Investor Relations at Agios. Please go ahead.

Morgan Sanford

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

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 the third quarter of last year. U.S. net revenue was $48.7 million, driven by the continued strong U.S. launch of AQVESME 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 mitapivat 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 a 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 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 AG-236 in polycythemia vera, where we plan to initiate a Phase 2/3 program by year-end, and sevidoplenib 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 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'll turn the call over to Cecilia to discuss financials. Cecilia?

Cecilia Jones

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 revenue 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 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 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 AQVESME 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 sevidoplenib in-licensing, which was recognized in the second quarter, and an approximately $11 million one-time expense 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

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 4x the third quarter of last year. In the U.S., net revenue was up 20% sequentially, driven by excess 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 AQVESME in thalassemia. As a reminder, an Agios 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 135 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'll 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 remain on therapy at about 6 months. This is exactly the foundation we want: a durable base of patients that builds over time. Looking ahead, we are focused on two things. 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 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. 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 AQVESME 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 broad thalassemia population, AQVESME 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 will use the additional time to prepare even further ahead of our February 1 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. 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 25,000 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. Thank you, Sarah.

Sarah Gheuens

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-Kids T have the potential to expand our addressable U.S. thalassemia population by approximately 2,000 pediatric patients.

Beyond mitapivat, we are advancing sevidoplenib in immune thrombocytopenia towards a Phase 3 trial planned for the first half of 2028, and AG-236 in polycythemia vera towards a Phase 2/3 program by year-end. Finally, we look forward to proof-of-mechanism data for AG-181 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. 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 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, 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 AG-236, our siRNA targeting 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 and 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 discontinuations.

This single-dose durability supports the potential for every-six-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 trial 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-responsive reductions in blood phenylalanine, and at 300 milligrams per kilogram, 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. 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 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

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, 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-236 in polycythemia vera and sevidoplenib in immune thrombocytopenia, both with clinically validated, de-risked mechanisms of action, and we have strategic optionality with AG-181 in PKU.

We are executing with discipline, right-sizing 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'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

[Operator Instructions] One moment for the first question. Our first question comes from the line of Alec Stranahan from Bank of America. Please go ahead.

Fragen und Antworten

Alec Stranahan

I have two questions: one on the PDUFA delay and one around the ASH presentations. Has the FDA raised anything outside of the REMS, such as the age range or any of the clinical endpoints? And if a REMS is required, how would this change your launch expectations around the curve versus what you've seen in thalassemia? And then around the ASH updates, the durable hemoglobin gains at up to 2 years, plus the kidney and heart signals, seem incremental to prior presentations. How do you think these benefits stack up versus competing drugs, especially around the PKM2 activation that you highlighted?

Brian Goff

Thanks, Alec. 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 and comment on where we are with FDA, and then Tsveta can talk about commercial aspects, and we'll take the second question separately.

Sarah Gheuens

Thanks, Alec. 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 working as quickly and as expeditiously as possible with the agency to get this very much needed drug to patients.

Tsveta Milanova

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 U.S., and it's going to be the largest indication that we're pursuing today. The 25,000, which we identified as an initial launch target, we are ready to launch in any scenario, and we already have a very well-established commercial infrastructure to do so.

Brian Goff

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

Sarah Gheuens

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 mortality in 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.

Alec Stranahan

Very good. Thanks again.

Operator

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

Samantha Lynn Semenkow

I have two questions as well, but both on sickle cell disease. I'm wondering if we can just 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's varying degrees for those requirements. And then on the competitive side, can you talk in more detail about how you see mitapivat positioned commercially? And as we look forward into ASH, 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?

Brian Goff

Thanks, Sam. Sarah, do you want to start with both of those questions?

Sarah Gheuens

And then maybe hand it to Tsveta as well for the positioning. 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 just on 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, an ETASU REMS, which is more like the AQVESME-style REMS. As we've highlighted, we are in negotiations with the FDA for a label which includes elements of a 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, when we're looking at any trial for sickle cell disease, 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. So those are things that I would definitely recommend when you are doing cross-trial comparisons. 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 regards to competitive positioning, I'll actually hand that over to Tsveta.

Tsveta Milanova

Absolutely. As I said, we're 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, and these are patients that are actually actively engaged with the healthcare system, seen by hematologists, and have potential to 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. It'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 Pyrukynd for several years now, and we have a well-established not only medical and clinical development, but commercial infrastructure, which is in place and engaging with these customers, and we'll leverage all of that.

Samantha Lynn Semenkow

Thanks very much.

Operator

Our next question comes from Eric Schmidt from Cantor. Please go ahead.

Eric Schmidt

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 break-even profitability?

Cecilia Jones

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 target non-GAAP profitability, we are including the potential launch of sickle cell in 2027 and a disciplined approach to managing our OPEX.

Eric Schmidt

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 of AQVESME, or would that require a third brand name if you had it at a slightly different range?

Sarah Gheuens

Thanks, Eric, for the question. Any options of those are always possible. There is a whole range of brand names and 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 options.

Eric Schmidt

Okay, thank you.

Operator

Our next question comes from the line of Gregory Renza from Truist Securities. Please go ahead.

Gregory Renza

It's Nishant for Greg. First on AQVESME, 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 6-month effects in healthy volunteers can translate into sustained phlebotomy control in PV without excessive iron restriction or anemia? Thanks so much.

Brian Goff

Tsveta, do you want to start with AQVESME and our continued progress?

Tsveta Milanova

Absolutely. We are very encouraged by the first three quarters of the launch. We are building the thalassemia market, and really, AQVESME is the first medicine approved for this broad thalassemia patient population. We're not giving the split on TDT and NTDT, 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 619 prescriptions that are coming from start forms—that is the completed start forms—which is about 15% of the total patient population, and an 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 persistency that we see right now for patients at 6 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 course, of new patients starting on therapy, but more and more patients continuing on therapy.

Brian Goff

And Nishant, we talk a lot internally about health of the launch and building on our rare disease experience. And I think what Tsveta 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, with breadth of prescribers and breadth of patient types. As Tsveta 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

Yep. And then in regards to your question on AG-236 and iron restrictive anemia from healthy volunteers going into patients, this is obviously why 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 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, once we have that data, to move seamlessly into Phase 3.

Gregory Renza

Thanks so much.

Operator

The next question comes from Douglas Tsao from HC Wainwright. Please go ahead.

Douglas Tsao

I guess maybe just on the AQVESME 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

Absolutely. We are very encouraged by the initial signs of persistency with 75% of the patients continuing beyond the 6-month mark. We're seeing a 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 Tsao

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

Yes, absolutely. I think in the real world, the benefit from AQVESME is defined 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 their hemoglobin increases. And here I just want to highlight also the fact that we have excellent payer coverage. The team has done a phenomenal job, and within 6 months of launch, we have payer coverage policies for 75% of covered lives, and they are very, very favorable for AQVESME, so we have no prior restrictions.

Douglas Tsao

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

Operator

Next question comes from Andrew Berens from Leerink Partners. Please go ahead.

Unknown Speaker

Hi, this is Amanda for Andrew Berens. 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

Thanks, Amanda. Tsveta, 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

Absolutely. So, you know, 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 on one level a rare disease pricing, which is very similar to what we have with Pyrukynd and 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.

Operator

The next questions will come from the line of Joseph Thome from TD Cowen. Please go ahead.

Joseph Thome

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 as an asset? Thank you.

Sarah Gheuens

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 development, and so we're excited about that.

Brian Goff

Yes, and I'll also add, as I mentioned in my comments earlier, PKU is high unmet need, though not hematology. And the 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 Thome

Great. Thank you.

Brian Goff

You bet.

Operator

Our next questions will come from the line of Tessa Romero from JPMorgan. Please go ahead.

Tessa Romero

I wanted to ask a question to Tsveta here. In the third quarter, 177 AQVESME prescriptions with completed Agios 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 6 months. What are you seeing in the marketplace in terms of why patients discontinue if they do? Thank you.

Tsveta Milanova

Sure. Absolutely. So on the first question, what I'll highlight is, look at the first three quarters first in totality: we reported 619 prescriptions with completed start forms and an additional 48 in progress, which kind of positions us at 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 EAP period.

We are now seeing the broadening, which we always expected and planned for, into the community 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 element for us that we're very excited about is also the hybrid system that we're seeing from initial 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.

Operator

Our next question will come from the line of Salveen Richter of Goldman Sachs. Please go ahead.

Salveen Richter

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

So, absolutely. We are obviously in regular contact with the physician community. The team is engaged, and we are doing extensive account profiling, but also Brian and I in the last few months had virtual meetings to connect with the sickle cell disease caregivers 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 hematologists, the three hemolytic anemias, really the 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 in the same center you might have hematologists who are focusing on hemolytic anemia, but some of them are specializing in thalassemia and might be specializing in sickle cell disease. Otherwise, in the community, every hematologist treats both conditions, both thalassemia and sickle cell disease.

Operator

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

Luca Issi

Maybe Tsveta, on the 619 cumulative prescriptions here for AQVESME and the additional 48, are all of these prescriptions coming from thalassemia, or are 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 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 a one-off or there is a mean proportion of that 619 that actually is already coming from sickle cell. So any color there is much appreciated. And then maybe Cecilia, to circle back on Eric's question, as the P&L continues 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

Tsveta, let's start with the question around the 619 and the 48.

Tsveta Milanova

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

Brian Goff

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

Cecilia Jones

It's a little early, Luca, to guide on 2027, but we look to provide guidance at the appropriate time.

Luca Issi

Got it. Thanks so much.

Cecilia Jones

Thank you.

Operator

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

Brian Goff

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 sickle cell disease 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, 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 AG-236, which, as Sarah commented on, supports every-six-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

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

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