Agios Completes Phase 3 RISE UP Enrollment for Mitapivat in Sickle Cell Disease

Agios Pharmaceuticals, Inc., a prominent firm in cellular metabolism and pyruvate kinase (PK) activation, has announced the completion of enrollment for its Phase 3 RISE UP study. This international, double-blind, randomized, placebo-controlled trial is focused on assessing the efficacy and safety of mitapivat, an oral PK activator, in patients aged 16 or older with sickle cell disease. The company anticipates releasing the topline data from this 52-week study towards the end of 2025.

Sickle cell disease is a genetic, lifelong blood disorder caused by mutations in hemoglobin, the key protein responsible for oxygen transport in red blood cells. In this condition, red blood cells assume a sickle shape due to genetic mutations affecting hemoglobin. These abnormally shaped cells are rigid and can obstruct blood flow, leading to chronic hemolytic anemia, pain, impaired quality of life, organ damage, and premature death. Additionally, sickle cell disease increases the energy needs of adenosine triphosphate (ATP) for red blood cell function and raises 2,3-diphosphoglycerate (2,3-DPG) levels, which heightens the likelihood of red blood cell sickling. Mitapivat aims to optimize the glycolytic pathway, thereby increasing ATP levels and reducing 2,3-DPG concentrations in red blood cells.

Sarah Gheuens, M.D., Ph.D., Chief Medical Officer and Head of R&D at Agios, emphasized the urgent need for new treatments that can improve the standard of care for those with sickle cell disease. She expressed gratitude to the patients, investigators, and advocates for their support and partnership in completing the enrollment for the Phase 3 RISE UP study. With enrollment finalized, the company is eager to complete the trial and share the results with the community by late 2025.

The Phase 3 RISE UP study included over 200 participants globally. The primary endpoints of the trial are hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 24 through Week 52 compared to baseline, and the annualized rate of sickle cell pain crises. These endpoints are crucial in sickle cell disease as anemia and pain episodes significantly affect a patient's quality of life.

The positive outcomes from the double-blind period of the RISE UP Phase 2 study, presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2023, encouraged Agios to further explore mitapivat's risk-benefit profile in sickle cell disease during the Phase 3 study.

The RISE UP Phase 2 and 3 studies are designed to evaluate the efficacy and safety of mitapivat in sickle cell disease patients aged 16 or older, who have experienced between two and ten sickle cell pain crises in the past year, with hemoglobin levels ranging from 5.5 to 10.5 g/dL during screening. The studies operate under a single seamless protocol, utilizing the same sites, vendors, and resources for operational efficiency.

The Phase 2 study featured a 12-week randomized, placebo-controlled period, where participants were assigned in a 1:1:1 ratio to receive either 50 mg or 100 mg of mitapivat twice daily, or a placebo. The primary endpoints were hemoglobin response and safety. The Phase 3 study entails a 52-week randomized, placebo-controlled period with participants randomized in a 2:1 ratio to receive 100 mg of mitapivat twice daily or a placebo. Upon completing the double-blind period, participants from both Phase 2 and Phase 3 studies have the option to enter a 216-week open-label extension period to continue receiving mitapivat.

Agios Pharmaceuticals remains committed to advancing transformative therapies for patients with rare diseases, leveraging its expertise in classical hematology and cellular metabolism to develop a robust pipeline of investigational medicines.