Agios (AGIO) 2026年第三季度业绩电话会：营收达5540万美元

核心要点

• Agios Pharmaceuticals公布2026年第三季度mitapivat净营收达到创纪录的5540万美元，是2025年第三季度1290万美元的四倍多。其中美国市场营收达4870万美元。
• AQVESME在美国地中海贫血市场的商业化推广持续扩大。已完成Agios启动表格（Start Forms）的累计处方量达到619张，约占约4000名目标上市患者群体的15%。
• 约75%的AQVESME患者在接受治疗6个月后仍坚持用药。管理层将提高用药依从性以及在社区和非输血依赖型患者群体中扩大应用列为关键增长重点。
• 在将公司对补充REMS（风险评估与减低策略）相关信息要求的回复定性为重大修订后，FDA将mitapivat用于镰状细胞病的审评期限延长了三个月，至2027年2月1日。
• 截至该季度末，Agios拥有9.07亿美元的现金、现金等价物及有价证券。管理层继续将2028年实现Non-GAAP盈利作为目标。
• 与2025年相比，该公司正在削减超过35%的研发人员，涉及100多个岗位。预计大部分相关开支节约将在2027年显现。

关键财务数据

业务与经营业绩

AQVESME在美国地中海贫血市场保持了持续的增长势头。第三季度，Agios收到来自135位医生的177张附带完整启动表格的处方。截至季度末，另有48张处方的表格正在处理中。管理层表示，随着上市度过被压抑需求的释放阶段，并逐步拓展至社区诊所及非输血依赖型患者，177张处方可能代表了更为合理的季度常态化水平（run rate）。

该公司报告称，各患者群体的6个月用药坚持率均表现强劲，约为75%。Agios还在加大患者触达力度：在8月份推出直接面向消费者（DTC）的“Level Up with AQVESME”宣传活动后，其患者网站的互动量增长了65%。

在美国以外地区，继欧盟委员会在第二季度批准其地中海贫血适应症后，mitapivat的营收受益于欧洲的早期准入计划。Agios正通过合作伙伴推进国际商业化，包括欧洲的Avanzanite以及海湾阿拉伯国家合作委员会（GCC）地区的NewBridge Pharmaceuticals。

镰状细胞病仍是该公司最大的潜在商业化机会。Agios估计美国16岁及以上已确诊患者约为75,000人，初始上市重点针对约25,000名正在接受积极治疗或需要治疗的患者。其销售、医学和患者支持团队均已培训到位，生产和供应也已做好在获批首日即可供货的准备。

Agios还着重介绍了支持mitapivat差异化优势的临床数据。在RISE UP开放标签拓展研究中，62.7%的患者实现了血红蛋白改善，其中包括39.7%的初始无应答者，应答持续时间最长观察至115周。事后分析还显示出肾脏和心脏指标信号，管理层认为这可能支持其在改善贫血之外的潜在获益。

在在研管线方面，Agios计划在2026年底前启动针对真性红细胞增多症的AG-236 2/3期临床试验项目。健康受试者数据显示，其药效学效应可持续6个月，且未出现严重不良事件、停药或2级以上不良事件。用于治疗免疫性血小板减少症的sevidoplenib 3期临床试验计划于2028年上半年开展。用于苯丙酮尿症的AG-181 1b期机制验证数据预计将在2026年底前公布。

管理层业绩指引

Agios预计2026年全年营业费用将与2025年基本持平，这不包括第二季度确认的2500万美元sevidoplenib授权许可首付款，以及预计在第四季度产生的约1100万美元一次性裁员费用。

管理层预计削减研发人员带来的大部分费用节约将在2027年显现。该公司未提供详细的2027年费用或营收指引。

Agios继续以2028年实现Non-GAAP盈利为目标。管理层表示，该目标的设定基于2027年镰状细胞病药物可能上市以及持续严格控制营业费用的假设。

风险与关注重点

FDA正在评估mitapivat在镰状细胞病治疗中是否需要制定REMS（风险评估与减低策略）。Agios补充提交了约9个月的开放标签拓展研究安全性数据，而FDA将其定性为重大修订，导致PDUFA目标审评日期延后至2027年2月1日。

管理层表示，补充随访中未发现与地中海贫血中观察到的模式或严重程度相似的镰状细胞病肝损伤病例。不过，包括潜在REMS要素在内的药品标签谈判仍在进行中，最终方案尚未确定。

商业化上市仍取决于FDA的批准。管理层还指出，镰状细胞病患者中较高的医疗补助（Medicaid）占比可能会影响总营收向净营收的转化。

对于AG-236，在健康受试者中观察到的疗效持久性仍需转化为真性红细胞增多症患者体内对红细胞比容及静脉放血的持续控制。计划开展的2期部分将评估剂量和给药频率，包括每6个月给药一次的潜力。

分析师问答要点

• REMS及商业化就绪情况：管理层将FDA延期定性为时间进度的调整，而非商业机会的改变。Agios表示，公司正在为多种REMS预案做准备，但未明确具体的要求。
• 镰状细胞病定位：公司计划重点强调mitapivat的抗溶血特性、积累的安全性经验以及与镰状细胞病群体的良好关系。管理层还着重强调了其PKR和PKM2双重激活机制。
• 跨试验对比：管理层建议投资者在对比各项镰状细胞病试验时，应综合考虑基线人口统计学特征、入组地区、基线血管闭塞危象发生率及安全性。
• AQVESME需求：管理层未提供输血依赖型与非输血依赖型患者的拆分数据，但表示这两类人群的需求和用药依从性均表现强劲。管理层确认，所有619张已完成处方及48张处理中表格均为符合适应症的地中海贫血处方。
• 定价：Agios表示，相信mitapivat在镰状细胞病适应症上能够保持罕见病定价水平，类似于Pyrukynd和AQVESME，尽管Medicaid的占比可能会对总营收向净营收的转化产生一定压力。
• AG-181战略：管理层表示苯丙酮尿症（PKU）不属于Agios的核心血液学业务范畴，并称公司将在评估即将公布的1b期临床数据后保持战略灵活性。

财报电话会议完整实录

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完整财报电话会议逐字稿

管理层陈述

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.

分析师问答

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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