AGIOS PHARMACEUTICALS, INC. Q3 2025 earnings call

Thank you, operator. Good morning, everyone. Thank you for joining us to discuss Agios Pharmaceuticals Third Quarter 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. 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 and 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. Our third quarter earnings call agenda is shown on the next slide. Joining me on today's call 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, please move to the next slide, and 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 to discuss our third quarter highlights. Beginning on the next slide. With steady progress and a focused strategy, we have a clear path to unlock long-term shareholder value. First, we have multiple high-value catalysts in the coming months that position PYRUKYND, our foundational PK activator, to achieve its multi-billion dollar potential across PK deficiency, thalassemia, and sickle cell disease. Following the FDA's recent request for a REMS program, our PDUFA date for PYRUKYND thalassemia supplemental NDA has been extended to December 7th. We are actively engaged with the FDA and are leveraging this additional time to strengthen our engagement with the thalassemia community and further refine our launch planning. Additionally, we look forward to sharing top-line results from the RISE UP phase III trial of PYRUKYND in sickle cell disease by year end.

Meanwhile, we continue to advance our early and mid-stage pipeline, which includes our other PK activator tebapivat for lower-risk myelodysplastic syndromes, or MDS, and sickle cell disease, AG-181 for phenylketonuria, and AG-236 for polycythemia vera. Importantly, our strong balance sheet with approximately $1.3 billion in cash and investments positions us to invest in a disciplined manner to both support our potential U.S. launches and advance our rare disease pipeline. Our third quarter highlights are summarized on the next slide. In the third quarter, we reported $12.9 million in net revenue, underscoring the strong value proposition of PYRUKYND. In August, we announced approval for PYRUKYND in adults with thalassemia in Saudi Arabia, our first global regulatory approval for this indication. Earlier this month, we also received a positive CHMP opinion recommending PYRUKYND for marketing authorization in Europe for the treatment of adults with thalassemia.

Lastly, we achieved a key R&D priority by completing enrollment in the phase II-B trial of tebapivat in lower-risk MDS, and we anticipate top-line data early next year. With continued momentum across our commercial portfolio and pipeline, our team has demonstrated strong execution and agility, keeping us firmly focused on our mission to deliver transformative medicines for patients. That agility is a competitive advantage as we work to transform the treatment landscape for thalassemia and sickle cell disease. Feedback from these communities through our recent global engagements reinforces the critical need for treatment innovation. Please move to the next slide and I'll turn the call over to Cecilia to provide commentary on our third quarter performance and full year outlook.

Cecilia, thank you, Brian. Next slide, please. Our third quarter 2025 financial results can be found in the press release issued this morning, and additional details can be found in our 10-Q, which will be filed later today. Let me now take a moment to provide some context and highlight a few key points. Third quarter net PYRUKYND revenue was $12.9 million, an increase of 44% compared to $9 million in the third quarter of 2024, and an increase of 3% compared to $12.5 million in the second quarter of 2025. Third quarter net revenue growth reflects continued commercial execution in PKD ahead of potential U.S. approval for thalassemia. Looking ahead, fourth quarter performance will benefit from an additional ordering week compared to the third quarter, and we anticipate PYRUKYND net revenue will continue to reflect continued focus on PK deficiency ahead of potential approval for thalassemia in the U.S.

on a full-year basis. Given the strong execution of our sales force to date, we anticipate net revenues in 2025 to show robust growth compared to 2024, although we recognize this growth is on a relatively small revenue base. Cost of sales for the quarter was $1.7 million. R&D expenses were $86.8 million, an increase of $14.3 million compared to the third quarter of 2024. This increase was primarily driven by increased clinical trial costs associated with our PK activation franchise. SG&A expenses were $41.3 million in the third quarter, an increase of $2.7 million compared to the prior year, driven by disciplined investment. Ahead of the potential commercial launch of PYRUKYND in thalassemia, we ended the third quarter with cash, cash equivalents, and marketable securities of approximately $1.3 billion. Next slide, please.

Our capital allocation strategy, backed by a strong balance sheet, enables strategic investment in future growth and delivery of our ongoing pipeline programs. First, we have built a capital-efficient global commercial model, prioritizing our investment in potential U.S. launches, which represent the largest commercial opportunities. We have executed partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe, both of which are structured as revenue-sharing arrangements that favor Agios. Over the long term, we will record our share of sales as net revenues. Second, we will continue to invest in our ongoing early and mid-stage clinical programs. Third, we are opportunistically looking for ways to expand and diversify our pipeline through internal efforts or externally sourced assets. In closing, I am confident that our balance sheet will enable us to continue to execute from a position of strength.

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. In the third quarter, we delivered $12.9 million in PYRUKYND net revenues, up 3% sequentially, once again reflecting strong execution by our commercial team. To date, 262 patients have completed prescription enrollment forms, including 14 in the third quarter, representing a 6% increase. Sequentially, this has translated into 149 patients currently on therapy, up 5% from the second quarter. These results underscore the strength of our commercial model and the foundation we are building for future growth. We are well positioned to deliver on potential U.S. launches for thalassemia and sickle cell disease. Please move to the next slide. Let's turn to thalassemia and our global commercialization strategy for PYRUKYND. Following the 3-month extension of our PDUFA goal date to December 7th, we remain confident in our ability to deliver a successful launch pending regulatory approval.

This confidence is further reinforced by our recent engagement with physicians, patients, and advocacy groups, which I will touch on shortly. Outside of the U.S., we have implemented a capital-efficient global commercialization strategy through partnerships with NewBridge Pharmaceuticals in the GCC and Avanzanite Bioscience in Europe. These partnerships allow us to retain full rights to PYRUKYND while preserving our capital investment for U.S. launches. In August, we announced SFDA approval of PYRUKYND for the treatment of adult thalassemia patients in Saudi Arabia, marking our first global approval for thalassemia. Launch activities are underway in Saudi. Our partner NewBridge is providing early patient access on a case-by-case basis, with the potential to expand access after securing a national procurement agreement over the next couple of years.

In Europe, we anticipate a European Commission regulatory decision in early 2026 following the positive recommendation from the CHMP, and we are actively working with our partner Avanzanite Bioscience to refine our launch strategy. Please move to the next slide. In the U.S., there are approximately 6,000 diagnosed adult thalassemia patients. It is important to remember that thalassemia is considered a spectrum of disease, not a single phenotype. Patients range from those who require regular transfusions to those who are non-transfusion dependent but still face debilitating fatigue and meaningful complications over time. The goal of treatment across the disease centers on three key to address patients, chronic anemia and hemolysis, increase their quality of life, and reduce the risk of comorbidities that can be caused by primary or secondary iron overload. Care for these patients happens in both academic centers and community hematology practices, and we're equipped to support both.

Over the past year, we have profiled and prioritized accounts across settings. We also engaged prescribers where patients are managed and delivered disease education to them. Following the announcement of our PDUFA goal date extension, we have taken the opportunity to continue our engagement with the thalassemia community. Through these ongoing interactions, stakeholders consistently recognize the clear and compelling potential of PYRUKYND. Advocacy leaders and clinicians emphasize the magnitude of the unmet needs facing thalassemia patients and continue to stress the urgency for novel treatments like PYRUKYND. Additionally, it has become clear that providers have strong familiarity and experience with REMS across both academic and community settings and do not view a potential REMS program as a barrier to prescribing. Our established rare disease infrastructure gives us a clear advantage in launching PYRUKYND in thalassemia.

With high-touch patient services and a single specialty pharmacy model, we are well positioned to execute swiftly and compliantly within a REMS framework. The team is ready, and we look forward to potential thalassemia approval before year end. We are confident in our ability to deliver a successful launch, and with that, please move to the next slide and I will hand the call over to Sarah to cover key R&D highlights from the quarter.

Thank you, Tsveta. Next slide, please. In the third quarter, we continue to make strong progress across our pipeline. In early August, we announced PYRUKYND's approval for adults with thalassemia in Saudi Arabia, and earlier this month, we received a positive CHMP opinion recommending PYRUKYND for marketing authorization in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha or beta thalassemia in Europe, and we look forward to a final regulatory decision by early next year. Finally, our reviews remain ongoing in the United Arab Emirates and in the U.S., where we continue to progress towards our new PDUFA goal date of December 7th. Beyond PYRUKYND, we were pleased to announce enrollment completion in the phase II-B trial of tebapivat for the treatment of low-risk MDS.

Tebapivat, our more potent PK activator, has the potential to be the first oral therapy to address anemia due to ineffective erythropoiesis in patients with low-risk MDS. I will share more on this potential opportunity shortly. Please move to the next slide. As we approach the anticipated top-line results for the phase III RISE UP trial, I wanted to take a moment to highlight the significant need in this community as well as our potential to deliver a disease-modifying novel treatment with PYRUKYND. There are approximately 100,000 diagnosed adult and pediatric patients with sickle cell disease in the United States and a significantly larger number worldwide. Sickle cell disease remains profoundly underserved. The lack of suitable treatment options contributes to a high mortality rate that has in fact worsened, with U.S. life expectancy in the late 30s.

Underscoring a significant opportunity for therapeutic innovation, PYRUKYND is a potential first-in-class oral therapy for sickle cell disease targeting both hemolysis and vaso-occlusion through a unique PK activation mechanism of action, activating both PKR and PKM2 isoforms, decreasing 2,3-DPG, limiting hemoglobin S polymerization, and increasing ATP to support red blood cell health. Please move to the next slide. Guided by extensive engagement with the sickle cell community, we designed the phase III RISE UP trial to align with clinical needs, positioning PYRUKYND to potentially reshape the treatment landscape for sickle cell disease. One of the two primary endpoints investigates hemoglobin increase, which addresses chronic anemia and thereby potentially reduces organ damage and improves how patients feel and function. Our other primary endpoint evaluates the reduction in analyzed rate of sickle cell pain crises, which are linked to organ dysfunction, early mortality, and a decreased quality of life for many patients.

Importantly, one of our key secondary endpoints will investigate potential improvement in fatigue, which is an overlooked symptom. In fact, chronic fatigue in sickle cell disease patients has been shown to be comparable to fatigue experienced by patients with other debilitating diseases like cancer and cystic fibrosis. In the trial, we will assess the improvement from baseline on the PROMIS Fatigue 13a scale, a validated measure of fatigue for this population. We look forward to sharing top-line results of the phase III RISE UP trial by the end of this year. Please move to the next slide where we present a high-level view of the trial design and statistical plan. As a reminder, since the trial includes two primary endpoints, the trial is positive if statistical significance is achieved on either one of the endpoints.

The pre-specified statistical testing strategy allows testing of the key secondary endpoints if at least one of the primary endpoints is met, thereby preserving the opportunity to show benefit on other key features of the disease, including fatigue. We remain confident in PYRUKYND's potential to become a transformative therapy for sickle cell patients, an underserved and underrepresented population with significant unmet needs. Next slide please. I'd like to take a moment to highlight our second, more potent pyruvate kinase activator, tebapivat, which is being investigated in ongoing phase II trials for two rare diseases indication: lower-risk myelodysplastic syndromes and sickle cell disease. Lower-risk MDS accounts for approximately 70% of all myelodysplastic syndromes. Symptomatic anemia is the primary concern for most patients. Therefore, the primary treatment goal is to improve quality of life by managing the underlying anemia caused by ineffective erythropoiesis.

Decreased glycolytic activity has been seen in MDS patients, where they may show decreased PK activity and an abnormal pyruvate kinase hexokinase enzymatic ratio. Tebapivat is designed to correct [RBC] metabolism by increasing ATP production and normalizing the PKHK ratio. Today there are limited treatment options to address low-risk MDS and we believe tebapivat has the potential to be the first oral medicine to address anemia due to ineffective erythropoiesis. We completed the phase II portion in November 2023 and progressed to the phase II-B portion, which evaluates three higher doses that were evaluated in phase II-A portion. This trial will investigate 10 mg, 50 mg, and 20 mg doses of tebapivat daily versus placebo over 24 weeks. Today we announced that we achieved enrollment completion and we continue to expect top-line data in early 2026. We are also investigating tebapivat for the treatment of sickle cell disease.

Enrollment remains ongoing in the phase II trial and we look forward to providing updates in the coming months. Please move to the next slide. We continue to advance our early-stage rare disease pipeline with AG-181, an oral PAH stabilizer intended for the treatment of phenylketonuria, and AG-236, a siRNA selectively targeting TMPRSS6 for the treatment of polycythemia vera. Our first early-stage program is AG-181 for the treatment of PKU. There are 15,000-20,000 patients diagnosed with phenylketonuria in the U.S. where patients' symptoms can range from mild to severe. Currently available treatment options have demonstrated limited efficacy or significant safety issues, leaving patients with a gap in treatment and limited to phenylalanine-restricted diets, therefore significantly impacting a patient's quality of life. Our phase I multiple ascending dose trial in healthy volunteers is currently ongoing and we look forward to providing updates on this trial in the future.

Our second early-stage program is AG-236 for the treatment of polycythemia vera, a rare hematologic disease that affects approximately 100,000 patients in the U.S. PV causes an excessive production of red blood cells, increasing blood volume and viscosity and can result in thrombosis, cardiovascular events, or death. Current treatment options are limited to phlebotomy, hydroxyurea, and other cytoreductive therapies. However, these medicines do not effectively control hematocrit for more severe patients. We believe AG-236 has the potential to address the remaining unmet need with a potentially improved safety and efficacy profile and less frequent dosing. Last quarter we received IND clearance and dosed the first subject in the phase I trial in healthy volunteers and look forward to providing updates as the trial progresses. 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. In the third quarter, we delivered meaningful progress across our 2025 R&D priorities, once again showcasing our ability to execute swiftly and effectively. Looking ahead, the fourth quarter holds exciting milestones. We are sharpening our launch planning in anticipation of the new December 7th, PDUFA goal date for PYRUKYND in thalassemia, and we expect to report top line results from the phase III RISE UP trial of PYRUKYND in sickle cell disease by year end. Please move to the next slide. Our fundamentals remain strong. Backed by a seasoned leadership team with a proven track record, we continue to advance our pipeline and deliver meaningful impact for the rare disease communities we serve, communities whose insights guide us and are vital to our success. We are operating from a position of strength, backed by a balance sheet that not only supports our potential U.S.

launches and advancement of existing clinical programs, but also enables us to pursue strategic business development opportunities to further expand and diversify our pipeline and ensure we can create long-term shareholder value. Before we move to Q&A, I want to take a moment to recognize the continued dedication of our employees, whose relentless focus and commitment continue to drive meaningful impact for patients with rare diseases. Their work, together with the voices of the communities we serve, is foundational to our mission. As we look ahead, we remain resolute in our pursuit of transformative medicines, advancing innovation with the aim of delivering long-term value for both patients and shareholders. With that, I'd like to open the call for questions. Operator, please open the line.