Agios closed 2025 with worldwide PYRUKYND revenue of $20M in Q4 (up 86% year-over-year, up 55% sequentially) and $54M for the full year, and ended the year with roughly $1.2B in cash. The defining event was the December 23 FDA approval of ACTIVASE (mitapivat) for alpha and beta thalassemia, whose U.S. launch is underway with 44 REMS-certified prescriptions in the first five weeks and early dynamics tracking management's expectations, though revenue will lag demand given a 10-12 week prescription-to-initiation window. Management guided to FY2026 U.S. PK deficiency revenue of $45-50M and roughly flat operating expenses, and reiterated a clear path to profitability from the thalassemia and PK deficiency franchises. The pipeline is catalyst-rich for 2026: a Q1 pre-sNDA meeting for mitapivat in sickle cell disease (targeting full approval off RISE UP data), tebapivat phase 2b MDS data in H1 and phase II sickle cell data in H2, plus early-stage AG-236 and AG-181 readouts. The combined market opportunity across pipeline indications is cited at over $10 billion.
Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals' fourth quarter and full year 2025 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 on today's call. Next slide, please. Just last month, we outlined our 2026 strategic priorities, which are focused on delivering long-term shareholder value. First, we're focused on executing a high-impact launch of Pyrukynd for the treatment of thalassemia in the U.S. Second, we see meaningful opportunity to expand our PK activation franchise into additional high-value indications, including sickle cell disease and lower-risk myelodysplastic syndrome, with key catalysts this year for both opportunities. Third, through the advancement of our early-stage pipeline with AG-236 and AG-181, we have the potential to unlock future value in hematologic and other rare diseases. And finally, we remain committed to long-term sustainability, supported by disciplined capital allocation and continued operational efficiency.
Building on those priorities, the next slide maps key pipeline catalysts in 2026 across multiple high-value indication opportunities. The ACTIVASE launch in thalassemia is underway in the U.S., and we look forward to the potential to expand our PK activation franchise into sickle cell disease and lower-risk MDS. These milestones and continued progress in our early-stage pipeline position the portfolio for growth and long-term value creation. Next slide, please. We exited 2025 with solid momentum across the business, commercial execution, pipeline progress, and continued focus on financial discipline, which together provide a strong foundation to deliver on our 2026 strategic priorities. Starting with commercial performance, PYRUKYND delivered $20 million in net revenue in the fourth quarter, bringing full-year 2025 revenue to $54 million, reflecting robust year-on-year growth.
In the fourth quarter, we reported top-line data from the RISE UP phase III trial, and will meet with the FDA this quarter, as anticipated, for our pre-sNDA meeting to determine the regulatory path forward. Importantly, just before the end of the year, we received FDA approval for ACTIVASE, and the U.S. thalassemia launch is underway. Finally, we recently completed enrollment in the phase II sickle cell disease trial of tebapivat, with top-line results expected in the second half of this year. Importantly, we continue to operate from a position of strength, ending the year with approximately $1.2 billion in cash, providing flexibility to maximize the ACTIVASE thalassemia U.S. launch, pursue the path forward for mitapivat in sickle cell disease, and continue to advance our pipeline programs.
Please move to the next slide, and I'll turn the call over to Cecilia to provide additional details on our 2025 fourth quarter and full year performance, as well as our 2026 outlook.
Thank you, Brian. Next slide, please. Our fourth quarter and full year 2025 financial results can be found in the press release issued earlier this morning, and additional details can be found in our 10-K, which will be filed later today. Fourth quarter worldwide PYRUKYND revenue was $20 million, an increase of 86% compared to the fourth quarter of 2024, and a sequential increase of 55% compared to $13 million in the third quarter of 2025. In the U.S., fourth quarter revenues of $16 million were driven by continued commercial focus in PK deficiency ahead of FDA approval for ACTIVASE, an additional ordering week in the fourth quarter, and favorable growth to net adjustments. In 2026, we expect U.S. PK deficiency revenues to be in the range of $45-$50 million.
Outside of the US, revenue of $4 million in the fourth quarter primarily reflects inventory stocking ahead of demand-driven by PK deficiency patients in Europe, transitioning from our global managed access program, where PYRUKYND was provided free of charge, to commercial supply. We anticipate a sequential decline in ex-US revenues into the first quarter of 2026. Cost of sales for the fourth quarter was $1.9 million. R&D expenses were $88.1 million, an increase of $5.3 million compared to the fourth quarter of 2024, associated with the advancement of our earlier-stage pipeline program. SG&A expenses were $51.6 million in the fourth quarter and roughly flat year-on-year. We ended the fourth quarter with cash, cash equivalents, and marketable securities of approximately $1.2 billion.
As a reminder, in future quarters, we will report mitapivat revenue as a whole, breaking out U.S. and ex-U.S. performance. Next slide, please. We remain committed to financial discipline as we work toward our goal of becoming a sustainable rare disease company. We anticipate operating expenses in 2026 to be roughly flat with 2025. This guidance assumes investment to maximize launch of ACTIVASE in thalassemia in the U.S., gated investment for sickle cell disease, and operating model refinement. Importantly, we see a clear path to profitability through our existing commercial presence in thalassemia and PK deficiency. Please advance to the next slide, and I will turn the call over to Tsveta to share commercial highlights for the quarter.
Thank you, Cecilia. Next slide, please. As Cecilia noted, in the fourth quarter, PYRUKYND delivered $60 million in net revenue in the US, up 50% year-over-year, driven by continued demand in PK deficiency, an additional ordering week in the quarter, and certain gross-to-net adjustments. Fourth quarter ex-US revenue was roughly $4 million, which primarily reflects supply ahead of demand pull-through, as PK deficiency patients in Europe transition onto commercial supply. We expect this ordering to moderate in coming quarters. As expected, we continue to see quarterly variability driven by ordering patterns, inventory dynamics, and gross-to-net adjustments. Fourth quarter performance underscores the strength of our commercial model and the foundation we are building for future growth, starting with the recent US approval of ACTIVASE for the treatment of anemia in adults with alpha and beta thalassemia, regardless of transfusion burden. Please move to the next slide.
I am pleased to share that, as planned, the final implementation of PYRUKYND REMS was completed in late January to align with the approved FDA label, and we have already begun dispensing products. As of January thirtieth, we have seen 44 prescriptions written by REMS-certified physicians in the US, which reflects strong early recognition of PYRUKYND's clinical value and excellent execution by our field teams. What is especially encouraging is the healthy breadth of early prescribers at this stage of the launch, with its strong geographic distribution and, as expected, predominance of community physicians as early prescribers. We are also seeing, in these early days of launch, emergence of the patient profile we anticipated, largely transfusion-dependent patients, along with a group of highly engaged non-transfusion-dependent patients. These early signals speak not only to our launch readiness, but importantly, to our deep understanding of this patient community and their unmet needs.
Please move to the next slide. We are very encouraged by the early market response to ACTIVASE. Physicians consistently view its profile as addressing meaningful gaps in the current treatment landscape for thalassemia. Importantly, this aligns with what we heard ahead of FDA approval. We are not seeing the REMS as a barrier to prescribing, with early experience suggesting the certification process has been straightforward. We have also seen strong engagement with our patient support program. Initial experience indicates that patients do not view the REMS as burdensome, given the potential for meaningful clinical benefits, including reduction in transfusion burden and improvement in fatigue. Taken together, this early feedback reinforces both the significant unmet need in thalassemia and the value proposition of ACTIVASE. It also reflects the strength of our pre-launch planning.
On the next slide, I will take a few moments to discuss how we anticipate this demand will convert into treatment initiation and ultimately revenues in the first few quarters of launch. There are three key steps in the ACTIVASE REMS certification process. One of those steps, pharmacy education and certification, is already completed, as we use a single specialty pharmacy to dispense prescriptions and coordinate on delivery. Additionally, physicians are required to be educated and certified on the ACTIVASE brand. In parallel, once a prescription has been written, patients need to receive insurance authorization and complete a baseline liver test prior to initiating treatment. Our comprehensive patient support service, My Agios, has a strong track record assisting patients with the insurance authorization process for PK deficiency, which we expect to continue with thalassemia. Once these three components are completed, the pharmacy is authorized to dispense the prescription.
Patients will then complete monthly liver tests for the first six months and as clinically indicated thereafter. Initially, we expect the time from prescription to treatment initiation to be on average 10-12 weeks. As physicians are onboarded and access expands, we see opportunity to shorten this timeline as launch progresses. Turning to the next slide. The thalassemia opportunity presents a major potential growth inflection for Agios. To date, we have received approval of mitapivat for thalassemia in two regions, marketed as ACTIVASE in the US and Fyrokind in Saudi Arabia. Our capital-efficient global commercial model enables us to focus our investment on the US, which presents the most significant revenue opportunity. Outside of the US, we have executed commercialization and distribution agreements with Advanz Pharma in Europe and NewBridge Pharmaceuticals in the GCC.
Given access dynamics, we currently distribute Fyrokind in Saudi Arabia on a patient-by-patient basis, with potential to expand access following national procurement agreements. In Europe and UAE, regulatory reviews remain underway. We anticipate a potential EC decision in the coming months following the positive CHMP opinion received in October 2025. Across these regions, we see real potential to expand access and deliver meaningful growth as we scale the launch globally. 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. Next slide, please. Since we reported third quarter results, we have continued to make progress advancing our robust rare disease pipeline. We received the FDA approval of PYRUKYND for alpha and beta thalassemia, regardless of transfusion burden, on December 23 of last year. As you heard from Tsveta, the US launch is underway with strong reception from physicians. Following the RISE UP phase III top-line data of mitapivat in sickle cell disease, we will have our pre-sNDA meeting this quarter to inform the regulatory path forward. We continue to advance our more potent PK activator, tebapivat, in two phase II trials and anticipate results in lower-risk MDS in the first half of this year and in sickle cell disease in the second half.
We continue to advance our early-stage pipeline to important decision points this year and are on track to initiate a phase Ib proof of mechanism trial of AG-181, our phenylalanine hydroxylase stabilizer in PKU patients in the coming months, and report top-line data from the phase I healthy volunteer study of AG-236, our siRNA targeting TMPRSS6 for polycythemia vera in the first half. Please move to the next slide. Turning to tebapivat, we look forward to understanding more about the potential role of this more potent PK activator in low-risk MDS and sickle cell disease this year. We remain on track in low-risk MDS, where top-line data from the phase IIB trial are expected in the first half of this year.
This study will provide important insights into dose optimization, as well as the potential role of tebapivat in different patient subgroups, including low and high transfusion burden patients, as well as potential applications in later lines of treatment. In sickle cell disease, enrollment in the phase II trial is now complete, an important milestone that reflects the growing enthusiasm for PK activation following the RISE UP phase III results of mitapivat in this debilitating and deadly disease. This 12-week double-blind trial is designed to further explore tebapivat's potential to deliver meaningful improvements in hemoglobin, as well as broader markers of hemolysis. In turn, we see potential for higher hemoglobin response, building on the strength of the data established with mitapivat. Together, these programs underscore the potential for tebapivat to expand our leadership in hematology and address multiple high-value populations where unmet need remains significant.
We have an exciting year ahead of us, and we look forward to updating you on our pipeline progress throughout the year. 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. In closing, we have another pivotal, catalyst-rich year ahead of us. In line with our 2026 strategic priorities, we're focused on executing a high-value ACTIVASE US launch in thalassemia. In sickle cell disease, we're preparing for our pre-sNDA meeting for mitapivat this quarter, an important step toward defining our regulatory path. We also expect phase II top line data for tebapivat in sickle cell disease later this year, which will give us deeper insight into the potential of higher potency PK activation in this population. In lower-risk MDS, phase 2b top line data for tebapivat remain on track for the first half of 2026 and will be a key readout as we assess its ability to drive transfusion independence and broader improvements in anemia.
We also anticipate phase I top line data for AG-236 in polycythemia vera, and phase 1b proof of mechanism data for AG-181 in PKU, two important early-stage programs that expand our reach across hematologic and other rare diseases. Please move to the next slide. As we look beyond 2026, our opportunity set continues to expand. The combined global market potential across our current pipeline indications exceeds $10 billion, reflecting both the breadth of unmet need and potential to deliver transformative medicines to patients. Beginning in 2026, we're focused on delivering a high-impact US launch of ACTIVASE and thalassemia, which we believe has the potential to establish a strong foundation for our leadership more broadly in rare hematology. Our combination of near-term catalysts, disciplined investment, and a maturing pipeline creates a clear pathway to deliver long-term value.
Agios is well positioned for the next chapter of growth while advancing the next wave of innovation across our rare disease portfolio. Before we move into Q&A, I'd like to acknowledge the dedication of our employees, whose unwavering focus and commitment continue to make a meaningful difference for patients with rare diseases. With that, I'd like to open the call for questions. Operator, please open the line.