Prepared remarks
Good morning, and welcome to Agios Pharmaceuticals Second Quarter 2026 Conference Call. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios.
Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals Second Quarter 2026 Financial Results and Business Highlights. You can access the slides for today's call by going to the Investors section of our website, agios.com. Please note, we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements because of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. On the call with me today from Agios are Brian Goff, Chief Executive Officer; Cecilia Jones, Chief Financial Officer; Tsveta Milanova, Chief Commercial Officer; and Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development. Following prepared remarks, we will open the call for questions. With that, I am pleased to turn the call over to Brian.
Thanks, Morgan. Good morning, everyone, and thank you for joining us. Before we review our second quarter results, I'd like to take a step back and highlight the strong position from which Agios is executing as we continue advancing toward our goal of building a multibillion-dollar rare disease business. We are executing against multiple drivers of value creation, including the launch of AQVESME in thalassemia, the potential expansion of Mitapivat into sickle cell disease and a pipeline that continues to grow through both internal innovation and disciplined business development. During the quarter, we further strengthened our portfolio with the addition of cevidoplenib, a next-generation, highly selective oral SYK inhibitor that expands our rare hematology franchise into immune thrombocytopenia or ITP. We also advanced AG-236 into an operationally seamless Phase II/III program in Polycythemia Vera, adding another potential growth driver within hematology. Beyond hematology, AG-181 continues to progress, and we expect Phase Ib proof of mechanism data in phenylketonuria patients in the second half of the year. We also continue to apply a disciplined approach to portfolio management, making focused investment decisions and directing resources toward opportunities with the greatest potential to create value for patients and shareholders. As you'll hear throughout today's call, our progress this quarter reflects the strength of that strategy, combining commercial execution, pipeline advancement, disciplined capital allocation and strategic business development to position Agios for sustainable long-term growth. Turning to our second quarter highlights on the next slide. We delivered a quarter marked by strong commercial performance, meaningful pipeline progress and continued portfolio discipline. First, we delivered sustained commercial momentum with $44.7 million in total net revenue, including $40.9 million in the U.S. and 442 cumulative AQVESME prescriptions for REMS-certified physicians. Second, we further diversified our pipeline through the in-licensing of cevidoplenib, a next-generation, highly selective oral SYK inhibitor for ITP, progressing towards Phase III and strengthening our rare hematology pipeline. Third, we advanced Mitapivat toward a potential new indication in sickle cell disease. During the quarter, we received FDA acceptance of our sNDA with priority review and were assigned a PDUFA goal date of November 1, bringing us one step closer to delivering a first-in-class medicine in an area of significant unmet need. And finally, we ended the quarter with approximately $1 billion in cash, cash equivalents and marketable securities, providing financial flexibility to support both commercial growth and pipeline progression. Overall, we entered the second half of 2026 with strong commercial delivery, a more diversified pipeline, an important near-term regulatory catalyst and the capital position to execute on our strategy. With that, please advance to the next slide, and I'll turn the call over to Cecilia to discuss financials.
Thank you, Brian. Next slide, please. Turning to our second quarter financial results. Total Mitapivat net revenue was $44.7 million, including $40.9 million in the U.S. and $3.8 million outside the U.S. Cost of sales for the quarter was $3 million and research and development expense was $100.8 million compared to $91.9 million in the second quarter of 2025, primarily due to an increase in-process research and development of $15 million, driven by a $25 million up-front payment associated with the agreement with Oscotec. Selling, general and administrative expense was $51.5 million compared to $45.9 million in the prior year period, reflecting an increase in commercial-related activities as we executed launch of AQVESME in thalassemia. Net loss for the second quarter of 2026 was $100.7 million compared to a net loss of $112 million for the second quarter of 2025. We ended the quarter with approximately $1 billion in cash, cash equivalents and marketable securities, which we believe provides financial flexibility to support commercial execution, advancement of our pipeline and continued investment in opportunities to create long-term value. Turning to our outlook for 2026. We continue to expect approximately $45 million to $50 million from PK deficiency revenues in the U.S. Full year operating expenses are expected to remain approximately flat versus 2025, excluding the $25 million upfront payment associated with the cevidoplenib in-licensing transaction recognized in the second quarter and include investments to prepare for a potential sickle cell disease launch aligned with our November 1 PDUFA date. Our priorities for the remainder of the year remain clear: driving the AQVESME launch, preparing for potential sickle cell disease approval, advancing our pipeline and maintaining financial discipline. Please advance to the next slide, and I'll turn it over to Tsveta to cover commercial highlights AQVESME U.S. thalassemia launch progress.
Thanks, Cecilia. Next slide, please. With 6 months of launch experience now behind us, we are encouraged by the underlying drivers of performance. What we have seen so far continues to reinforce our confidence in the long-term AQVESME opportunity in thalassemia. Importantly, the strong execution across our commercial and patient-focused organization further strengthen our confidence in future launch opportunities. In the U.S. performance reflected continued growth in thalassemia demand and solid commercial execution. Net revenue in the quarter reflected approximately $5 million of one-time benefits related to stocking in thalassemia, along with modest gross-to-net favorability. We continue to expect gross-to-net within our previously guided 10% to 20% range with quarter-to-quarter variability. Outside the U.S., we delivered $3.8 million in net sales, reflecting anticipated demand for thalassemia in Europe following approval and continued consistent early demand for thalassemia in the GCC. As we've been seeing consistently across rare disease launches, the shape of new patient starts naturally moderates as adoption broadens beyond the earliest wave of highly motivated patients and prescribers. We continue to expect quarter-to-quarter revenue variability, reflecting order timing, inventory movement and gross-to-net dynamics. Next slide, please. I'm very pleased with the continued U.S. launch performance of AQVESME. During the second quarter, we generated an additional 200 prescriptions from REMS-certified physicians, bringing cumulative prescriptions to 442 as of June 30. As a reminder, this metric captures unique prescriptions for patients with completed start forms from REMS-certified physicians and serves as an early indicator of underlying demand. Importantly, the underlying launch dynamics remain healthy. While demand continues to come from highly motivated patients, we saw a growing proportion of non-transfusion-dependent patients in the second quarter, a profile consistent with the therapy moving beyond the earliest, most motivated cohort of transfusion-dependent patients. We continue to see strong conversion from prescription to treatment initiation. Time to start is naturally trending towards our anticipated 10- to 12-week range as adoption broadens across the NTDT population where treatment decisions often involve more deliberate clinical discussions and patients may have less frequent interactions with the health care system. Access continues to strengthen, and we now have approximately 75% of thalassemia lives covered under payer policies. Additionally, physician REMS certification continues to progress in step with prescribing activity, and it's not a barrier to patient access. As the launch matures, prescriptions with completed start forms become a less informative measure of performance, whereas revenue increasingly reflects both new patient starts and persistence on therapy. For that reason, in anticipation of a potential FDA approval for Mitapivat in sickle cell disease, we plan to discontinue reporting prescriptions from REMS-certified physicians after the third quarter and transition to revenue as our primary measure of commercial performance. Upon a potential sickle cell disease approval, we will assess the most meaningful metrics to communicate the progress and outlook of the broader Mitapivat franchise. Next slide, please. I wanted to take a few moments to highlight thalassemia launch considerations in the second half of this year. The first half reflected a distinct initial phase of the launch. The first quarter benefited from a strong prelaunch anticipation and momentum built in the period leading to approval following the more than 3-month PDUFA delay. Second quarter demand continues to reflect adoption from highly motivated patients and prescribers with time to treatment initiation beginning to approach our anticipated 10- to 12-week average at launch maturity. Looking ahead, we expect the shape of the launch to naturally evolve. Adoption is expanding into a broader non-transfusion-dependent population where patients are typically seen less frequently and treatment decisions may take more time. As the patient mix continues to shift towards non-transfusion-dependent patients, we expect time to treatment initiation to move well within the 10- to 12-week range we consistently discussed. We are also mindful that the first cohort of patients who initiated therapy in the earliest months of launch is approaching 6 months of treatment, a natural point at which physicians assess clinical response. This is an important part of the treatment journey, and it is the period during which we will begin to build a broader real-world understanding of how physicians and patients evaluate response and integrate Mitapivat into long-term care. Taken together, these dynamics reinforce that AQVESME is delivering a healthy launch that is successfully progressing beyond the initial wave of adoption and into a broader expansion phase. As we move through the second half of the first launch year, our focus remains on expanding reach across the thalassemia community, expanding adoption in the non-transfusion-dependent segment while continuing to add new prescribers. We remain highly confident in the long-term opportunity for AQVESME and in our ability to build a durable growing thalassemia franchise over time. Please move to the next slide. We are actively preparing for a potential sickle cell disease launch in the U.S. and are encouraged by both the commercial opportunity and the unmet need we see in this community. Our initial launch focus is on approximately 25,000 patients who are actively treated or in need of therapy today. We believe that population alone represents a meaningful opportunity for Mitapivat with potential to expand beyond the initial segments over time. Importantly, we are leveraging the capabilities, relationships and insights we have developed through the thalassemia launch while continuing to invest in market access, education and community engagement activities ahead of the PDUFA goal date. Pending FDA approval, we believe these efforts position us well to support a successful launch and to deliver Mitapivat to patients in need of innovative treatment options. Please move to the next slide. And with that, I will hand the call over to Sarah to cover key R&D highlights from the quarter.
Thank you, Tsveta. Turning to our pipeline on the next slide. Following recent portfolio prioritization decisions, we remain focused on advancing a diversified rare hematology portfolio with opportunities across multiple stages of development. Mitapivat continues to anchor the portfolio with approved indications in pyruvate kinase deficiency and thalassemia and a potential accelerated approval in sickle cell disease later this year. During the first half of this year, we achieved an important milestone with thalassemia approvals in Europe and the UAE, completing regulatory approvals across all 4 priority launch geographies following prior approvals in the U.S. and KSA. Since first quarter results, we filed and received acceptance in the U.S. for the Mitapivat sNDA in sickle cell disease with priority review and a PDUFA goal date of November 1. We remain committed to bringing Mitapivat to patients with sickle cell disease and recently dosed the first patient in REIGNITE, our Phase III confirmatory trial, an important milestone in advancing the program. We also strengthened the pipeline during the quarter through the in-licensing of cevidoplenib, a next-generation SYK inhibitor that expands our reach within rare hematology and adds a compelling opportunity in immune thrombocytopenia. Beyond Mitapivat and cevidoplenib, we continue to invest in future growth drivers, including AG-236 in polycythemia vera and AG-181 in Phenylketonuria. Taken together, we believe the pipeline reflects a focused allocation of capital and resources towards programs where we see the greatest potential to create long-term value for patients and shareholders. Please move to the next slide. As we discussed when we announced the in-licensing of cevidoplenib, our interest in the program is grounded in its potential to address some of the limitations that have historically constrained the SYK inhibitor class. Cevidoplenib was designed to optimize both selectivity and pharmacokinetics, supporting sustained target inhibition while maintaining a tolerability profile suitable for chronic use. The clinical data generated to date are encouraging and support this design rationale, demonstrating dose-dependent activity, no dose-limiting toxicities through Phase II and evidence of durable platelet responses. Taken together, these data support the rationale for advancing cevidoplenib as a next-generation highly selective SYK inhibitor. We're looking forward to engaging with the FDA in the coming months to align on progression to Phase III. Next slide, please. At EHA in June, we were pleased to share a broad body of data across both thalassemia and sickle cell disease that continues to strengthen our confidence in Mitapivat. Across the portfolio, we have 10 abstracts accepted, including the RISE UP Phase III study, which was selected for the EHA oral plenary session. In sickle cell disease, RISE UP demonstrated hemoglobin responses consistent with the mechanism of PK activation with hemoglobin responders experiencing clinically meaningful improvement in sickle cell pain crisis related endpoints and fatigue. At EHA, we presented new data showing clinically meaningful reductions in transfusion burden and red blood cell unit transfused across the total trial population, exceeding historical experience with hydroxyurea. Importantly, outcomes from the subgroup of patients with at least one transfusion in the 52 weeks prior to enrollment directly informed the treatment effect and powering assumptions for the ongoing REIGNITE confirmatory trial supporting accelerated approval. We also presented additional patient-reported outcomes data showing clinically meaningful improvement in how hemoglobin responders feel and function, including reductions in physical pain. In addition, 56-week follow-up data from the SATISFY Phase II investigator-sponsored trial in related membranopathies showed robust hemoglobin response rate and mean hemoglobin improvement as well as suggesting decreased iron burden. In non-transfusion-dependent thalassemia, we shared open-label extension data showing that 60% of patients continuing on Mitapivat met criteria for hemoglobin response and 60% of patients who switched on to Mitapivat in the open-label extension achieved hemoglobin response. Additionally, subgroup analyses indicate high hemoglobin response rates for non-transfusion-dependent patients with high baseline hemoglobin levels, indicating that less severely anemic NTD patients achieved improvement in hemoglobin levels and fatigue. These data were received very favorably by the thalassemia community and reinforced the value of Mitapivat in non-transfusion-dependent patients, which comprise the majority of the diagnosed adult patients in the U.S. Taken together, these data reinforce the consistency of Mitapivat's profile across indications and further strengthen our confidence in the long-term potential of Mitapivat in hemolytic anemia. While we continue to advance and expand the Mitapivat opportunity, we're also focused on building the next generation of potential growth drivers within rare hematology. AG-236 is an important example of that strategy. Next slide, please. Following encouraging Phase I data, we're advancing AG-236 into an operationally seamless Phase II/III development program in polycythemia vera. What continues to differentiate AG-236 is its potential profile with an evolving treatment landscape. The molecule demonstrated hepcidin induction through day 57 and favorable effects on iron parameters in extended follow-up, supporting the potential for an every 6-month dosing regimen without titration. The Phase II portion of the study is designed to identify the optimal therapeutic window across multiple dose levels while enabling efficient progression into the registrational portion of the program. More broadly, the seamless Phase II/III strategy reflects our commitment to disciplined execution while advancing development as efficiently as possible with Phase II initiations planned for the second half of 2026. We believe AG-236 has the potential to further diversify our rare hematology leadership and contribute to our long-term growth beyond Mitapivat. With that, please move to the next slide, and I will hand the call back to Brian for closing remarks.
Thank you, Sarah. Next slide, please. As we look across the business, we continue to make meaningful progress against the strategic priorities we established for 2026. We're building commercial momentum with AQVESME in thalassemia, reaching 442 cumulative prescriptions as of June 30. We're advancing Mitapivat toward a potential approval in sickle cell disease, which represents an important opportunity to expand our PK activation franchise and a potential next growth driver for the company. We're also advancing AG-236, our siRNA TMPRSS6 inhibitor for polycythemia vera into an operationally seamless Phase II/III program expected to begin in the second half of this year. And during the quarter, we further diversified our portfolio through the addition of cevidoplenib, a next-generation, highly selective SYK inhibitor in ITP progressing toward Phase III. Importantly, our progress this year reflects both execution and discipline. We're investing behind the opportunities where we believe Agios can have the greatest impact for patients and create the strongest long-term value for shareholders. Next slide. Taken together, we entered the second half of the year with a growing commercial foundation, a meaningful near-term regulatory catalyst and an increasingly diversified pipeline and the financial strength to execute on our strategy. Next slide, please. Today, Agios is anchored by a growing commercial business and supported by a pipeline spanning multiple development stages and disease areas. Across the portfolio, we are pursuing opportunities where differentiated biology, meaningful patient unmet need and disciplined execution can support durable long-term growth. Collectively, these opportunities represent rare disease markets estimated at more than $10 billion in 2030. Before we open the call for questions, I'd like to thank the entire Agios team for their unwavering commitment to patients and their continued dedication to executing on our strategy. Their passion, resilience and focus have been instrumental in the progress we've made this year. And with that, thank you all for joining us today. Operator, we're ready to begin the question-and-answer session.
Questions and answers
Our first question comes from the line of Alec Stranahan with Bank of America.
Congrats on the really strong quarter here. Two questions from me. First, on time on treatment in the commercial setting, do you think the ENERGIZE studies are a good barometer here? Just trying to think about how the dynamic of patients potentially coming off therapy could play into second half sales. And then, when you look at the time to treatment, did this change at all between 1Q to 2Q? Did it move closer or further away from that 10- to 12-week average range that you're setting out? And I guess, are you starting to see any repeat prescriptions under the REMS program at this point?
Thanks, Alec. Two-parter. Tsveta, you can take the first one. Actually, you'll take both of these: the time on treatment and whether ENERGIZE is a good analog. And then the second one, I think, Alec, you're asking about not time on treatment, but time to treatment from demand to initiation. Tsveta, do you want to take that?
Absolutely. We are very pleased with the strong initial start of the AQVESME launch, Alec. As we mentioned, we had in total 442 prescriptions from REMS-certified physicians for the first two quarters of the launch. In the first couple of quarters, we benefited from faster-than-anticipated time to treatment initiation, so it was faster than the 10 to 12 weeks given that we had prescriptions coming from highly motivated patients and physicians. We will reach the natural point at which physicians and patients evaluate benefit and continuation, which will be more in the second half of the year, and we will monitor that closely. Currently, what we see from the market is very strong feedback from the community. We expect continuation rates to be in line with the ENERGIZE study, and we'll continue to monitor that, but product performance is very strong in the market. Regarding time-to-treatment initiation, as we penetrate into the NTDT setting, we are moving closer to what we initially expected, the 10- to 12-week range. As we move into the second half of the year, we expect to be well within the 10 to 12 weeks given the strong penetration in the NTDT setting. On repeat prescriptions for the REMS, of course, we have patients who have been on therapy for multiple months, so we are starting to see repeat prescriptions and patients and physicians are going through the ramp process smoothly.
Our next question comes from the line of Andrew Berens with Leerink.
Congrats on the strong execution. I want to expand on persistence since it's so important going forward. Is there anything you can tell us about the expanded access program at all, what the experience will be like for these patients in the real world? And then the other thing that's obviously very important is going to be a sickle cell label, whether it's on AQVESME or PYRUKYND. What factors will go into that? And is there anything you can tell us in these early days ahead of the November 1 PDUFA that gives us confidence that you won't have a REMS or have to potentially reduce the pricing for AQVESME in thalassemia?
Thanks, Andy, and thanks for the comments about the strong quarter. I'm really pleased and proud of the continued execution from Tsveta and the team. On persistency, Andy, maybe we'll start with Sarah reflecting on the clinical trial, the open-label extensions and what we saw, because it's still early days to quantify persistence, but the trials and OLEs are an important proxy.
Thanks, Brian. Andrew, we can look at the open-label data we recently presented at EHA. We have very high continuation rates for people who finish clinical trials and then go into the open-label extension. We've now followed them for a period of time post randomized controlled trial, and what you see is good maintenance of response—patients continue on the drug and maintain hemoglobin and antihemolytic responses and continue feeling better. It was also exciting to see that patients with higher hemoglobin responded, which is important as we expand to non-transfusion-dependent patients in the launch. So the clinical trial data is the best way to look at that question right now.
Yes, and I'd add that I've been spending a lot of time with clinicians in the field and hearing their feedback on the EHA data. As we begin to see real-world evaluation of persistency in the second half, I'm confident we'll see continuation rates similar to the trials at six months.
I was just going to ask, can you give us a number, a percentage that you saw in the open-label extension study of patients who stayed on?
For ENERGIZE, we had over 90% continuation from the clinical trial. Of course, as time continues, there is some drop, but it's very good persistence for PKD, thalassemia and sickle cell disease in the clinical trials. Another notable point is that with longer exposure some non-responders converted into responders—for thalassemia we moved from early 40% to about 60% response. So the clinical trial data is very supportive.
We know persistency is an important metric going forward. We're still early into launch—second full quarter—and that matches the period for the ENERGIZE trial. We'll continue to monitor and implement patient services support to help patients continue on therapy. Andy, could you repeat the second part of your question?
Yes. Obviously, I don't think anyone expects sickle cell pricing to be as resilient as thalassemia or PKD. It depends on whether sickle cell is added to AQVESME or PYRUKYND. What do you think will drive that decision? Any insights now, several months away from the PDUFA, about which brand sickle cell may be added to if approved?
The PDUFA is November 1 with priority review, and we're excited about that. We have not yet discussed which brand name will be used. As you know, the clinical trial data looks very good and we did not observe hepatocellular injury in the sickle cell disease patients, so it may not warrant a REMS. Either way, our teams are ready to execute the launch with or without a REMS. More to come.
Absolutely. We'll provide specifics at the time of launch once we have the label. We'll price the product for that indication and across the portfolio to maximize the opportunity based on the clinical data and the market environment at the time. We are in a strong position given it's a potential third indication, there's high unmet need in sickle cell disease, and we have a very strong market access team. I'm proud of the progress we've made in thalassemia with payer policies and we'll continue to build from here.
Congrats again on the strong quarter. It looks like it's going to continue.
Our next question comes from the line of Gregory Renza with Truist Securities.
Congrats to the team on an excellent quarter. My question is two parts. As we enter the second half of 2026 and we move beyond the initial wave of highly motivated transfusion-dependent patients, how should we think about the run rate of new patient starts, particularly in the broader non-transfusion-dependent population? And second, where are you at in terms of gross-to-net? I know it was favorable this quarter; where are you within the 10% to 20% expected range now that you have 75% covered lives?
Tsveta, maybe you can start with the NTDT dynamics. Tsveta, do you want to take that and then we'll cover gross-to-net?
Absolutely. We're seeing a healthy start to the launch, with penetration into the community setting where most prescribers manage patients and growing adoption in the NTDT segment—the larger commercial opportunity. In the second quarter we added 200 prescriptions from REMS-certified physicians. As we move into the second half, prescription growth and revenue growth may not correlate perfectly because of time to treatment initiation, REMS onboarding and persistency. In NTDT, we expect time to treatment initiation to move into the 10- to 12-week range since these patients have less frequent visits and need insurance verification and REMS processes. We are encouraged by patient adoption, conversion and positive clinician feedback.
Cecilia, do you want to comment on gross-to-net?
Yes. We expect gross-to-net to continue to be within the 10% to 20% range as we've guided before. There will be quarter-over-quarter variability, but on aggregate, that's the range we continue to expect.
Our next question comes from the line of Marc Frahm with TD Cowen.
Thanks. Regarding the conversion of prescriptions into actual revenue and the potential drop-off of patients in the back half, do you view the 200 patient additions at the top of the funnel as a sustainable rate? Or does that still partly reflect a bolus from the backlog of REMS certifications and highly motivated patients from the Q1 launch?
Maybe I'll start. A good way to think about this is that engaged patients and clinicians exist on a gradient. We're still early in the build. As we move further into the NTDT population—who by definition have less frequent clinical interactions—that dynamic changes. Tsveta, what would you add?
As I said earlier, prescription growth and revenue growth may not correlate quarterly due to time to treatment initiation, refill and persistency dynamics and inter-quarter ordering variability. That's why we'll move away from prescriptions after Q3 and focus on revenue, which better reflects new patient starts, time to initiation, refills and continuations. The first half benefitted from early adopters and anticipation from the PDUFA delay, and as we move into the next phase, we'll see more steady-state dynamics as we penetrate NTDT and move to the 10- to 12-week average initiation.
On discontinuation, do you think the initial highly motivated patients who started in Q1 and early Q2 are more likely to stay on drug because of that motivation, or might they be harder-to-treat and have a higher discontinuation rate than the long-term average?
We'll provide more real-world color as the launch matures. For now, clinical trials are a good proxy for continuation and we'll continue to learn. I'm pleased with payer policies that allow flexibility for patients and physicians to make informed treatment choices on continuation. For now, use clinical trial persistence as a proxy.
Our next question comes from the line of Samantha Semenkow with Citi.
Let me add my congrats on the strong quarter. Could you speak more to the clinical evaluation after six months of treatment you referenced in the prepared remarks? What are physicians viewing as an acceptable clinical bar for continuing treatment? Is the six-month clinical mark strict, or is there flexibility when physicians assess clinical progress?
Thanks. This is another good question for Tsveta and draws from our experience with PKD in assessing benefit and continuation in clinical practice.
There is variability in how physicians and patients define benefit. They'll often evaluate benefit beyond the primary endpoint in trials. For transfusion-dependent patients, they'll look at transfusion reductions, both by expanding time between transfusions and reducing units transfused, and decisions are patient-by-patient. Many physicians mentioned six months as a practical time point to evaluate initial benefit, driven by the trial timelines and clinical practice. They won't strictly adhere to a 50% reduction threshold; decisions are individualized, including how patients feel between transfusions. For NTDT, they'll look at hemoglobin improvement—while a 1 g/dL increase is a useful benchmark, physicians also consider hemolytic parameters and, importantly, patient-reported outcomes like fatigue reduction. So there's flexibility, and decisions are individualized. We're encouraged by clinician feedback and look forward to learning more in the second half of the year.
Great. As a follow-up, on the evolution of the prescriber base, are you seeing physicians write scripts for multiple patients they manage? Any dynamics you can share from the first two quarters?
When I look at our prescriber base, I'm focused on breadth of prescribing since most thalassemia patients are managed in the community. I'm pleased to see very strong breadth across the country from different clinicians. We do have a small number of key opinion leaders who have written for more than one patient, and we continue to see prescriptions from these prescribers. They have stable patient bases, but our main opportunity is continued penetration in the community setting.
Our next question comes from the line of Eric Schmidt with Cantor.
Congrats on the progress. I want to be clear about what's in the 442 cumulative prescriptions you're reporting. Historically that metric was for individual patients mapped to individual start forms and didn't include refills. Is that still the case?
Absolutely. They are unique patient prescriptions—equivalent to a start form—written by REMS-certified physicians.
Do you have insight into how many refills have been written so far?
Refill rates continue as patients reach their second and third month of therapy. Refills are coming in according to plan. We're not providing specific refill dynamics or total patients on therapy now. Moving forward, we'll shift from start forms to revenue reporting because that captures new starts, time to initiation, refills and continuations.
Do you have a sense of whether many patients dropped out of the queue as they awaited therapy?
We have positive payer policies and early access in key regions. Our fill rate—the conversion from prescriptions to patients starting therapy—is very high and consistent with other rare disease launches. Nothing unanticipated there.
I'll add that our PKD experience informs this: often the translation from a start form to a patient starting therapy is a timing issue rather than a loss issue. As we penetrate NTDT more deeply, it may take longer, which makes the translation from start forms to revenue less direct quarter-to-quarter.
Our next question comes from the line of Emily Bodnar with H.C. Wainwright.
Congrats on the positive quarter. On Europe sales for thalassemia, were any of the 2Q revenues driven by Europe specifically? How do you think about ex-U.S. revenue growth for the remainder of the year? Second, with the sickle cell PDUFA in November, are you expecting to launch by year-end, and should we expect any initial revenues for 4Q?
For the quarter, ex-U.S. revenue was a combination of continued consistent demand in the GCC and anticipated demand in Europe following approval in May. The vast majority of revenues are still expected to come from the U.S. in upcoming quarters as we're ramping up other regions. Given the November PDUFA, a potential sickle cell approval would not be a material contributor to full-year 2026 revenues.
We are enthusiastic about the priority review PDUFA on November 1. We're also at an important sickle cell KOL and community physician meeting, and I'm proud of the work the team is doing to prepare for that launch while leveraging learnings from thalassemia.
Our next question comes from the line of Salveen Richter with Goldman Sachs.
Congrats on the progress. Could you speak broadly to the current split between transfusion-dependent and non-transfusion-dependent patients and when you anticipate the non-transfusion population to make up a majority of patients on treatment? And once you reach that 10- to 12-week range, do you expect it to be the run rate going forward?
Tsveta?
We're seeing a growing proportion of the NTDT segment as anticipated. In the first quarter and part of the second quarter, many patients were TDT because they have more frequent interactions with the health care system. NTDT growth increased in the second quarter and we expect that to continue. Our initial launch focus included about 4,000 patients with roughly 60% NTDT, so we'll continue penetrating that segment. We expect the 10- to 12-week average time to treatment initiation to stabilize and remain constant over time.
Our next question comes from the line of Tess Romero with JPMorgan.
Quick housekeeping: what is the right way to think about the loss of exclusivity for Mitapivat? Second, how should cumulative scripts for AQVESME evolve from end of 2Q to end of 3Q? And when might you be in a position to guide to revenues if script count will no longer be reported after 3Q?
On LOE, you can think of Mitapivat composition-of-matter LOE around 2035, with potential extensions beyond that.
From 2Q to 3Q we expect continued penetration into the NTDT segment. These patients have less frequent visits, so time to treatment initiation will be a key dynamic and we expect movement into the 10- to 12-week range. We are reaching the six-month evaluation point for early patients, which is one reason we'll transition beyond Q3 to providing revenue rather than prescription metrics. If we receive sickle cell approval on November 1, we'll provide more information about characterizing the Mitapivat franchise across indications at the time of launch.
With potential sickle cell on board upon approval in November, we'll evaluate the appropriate timing to provide guidance for the franchise going forward.
Our final question comes from the line of Luca Issi with RBC Capital Markets.
On commercial preparation for a potential sickle cell launch: I believe this population has a higher Medicaid mix versus thalassemia and PKD. Is that correct? How are you thinking about gross-to-net dynamics and net revenue per patient in sickle cell relative to existing products? Does de novo competitive dynamics factor into your pricing approach?
We'll provide specific pricing details at the time of approval; pricing will be driven by the label and competitive environment then. Sickle cell does have a higher Medicaid proportion, which implies a mandatory rebate of 23% that will influence gross-to-net and likely make it higher than PKD and thalassemia. We're excited about the PDUFA date and our team is ready for launch.
Ladies and gentlemen, at this time, I would like to turn the call back over to Brian Goff for closing remarks.
All right. Thanks, everyone, for your questions and for joining us today. Tsveta was in the hot seat today, which we quite enjoy. To close, we're really pleased with the progress we made in the second quarter. That includes delivering on continued AQVESME launch momentum, advancing Mitapivat toward a potential sickle cell disease approval, strengthening our pipeline with cevidoplenib and AG-236 and maintaining the financial flexibility to execute. We enter the second half of the year focused, disciplined and confident in our ability to build long-term value for both patients and shareholders. Thanks a lot, and we look forward to speaking with you all soon.
Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.