Agios Pharmaceuticals has announced the completion of enrollment for its Phase 3 RISE UP study, a global, double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of mitapivat in patients with sickle cell disease. The study focuses on individuals aged 16 years or older and aims to address the critical need for novel regimens to improve the standard of care for this debilitating condition.
The RISE UP study enrolled over 200 patients worldwide. Topline results from this 52-week Phase 3 study are expected in late 2025. The trial's primary endpoints are hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 24 through Week 52 compared with baseline, and the annualized rate of sickle cell pain crises.
Rationale for Mitapivat in Sickle Cell Disease
Sickle cell disease is an inherited blood disorder characterized by mutations in hemoglobin, leading to sickle-shaped red blood cells that block blood flow. This results in chronic hemolytic anemia, pain, organ damage, and reduced quality of life. In sickle cell disease, red blood cells have an increased energy demand of adenosine triphosphate (ATP) and elevated 2,3-diphosphoglycerate (2,3-DPG) concentrations, increasing the likelihood of red blood cell sickling.
Mitapivat, an oral, small molecule pyruvate kinase (PK) activator, is designed to optimize the glycolytic pathway. This dual-action mechanism aims to increase ATP levels and decrease 2,3-DPG concentrations in red blood cells, potentially mitigating the effects of sickle cell disease.
Clinical Endpoints and Prior Data
The primary endpoints of the RISE UP trial, hemoglobin response and annualized rate of sickle cell pain crises, are clinically significant as anemia and pain episodes are hallmark symptoms that severely impact patients' quality of life. Positive results from the double-blind period of the Phase 2 RISE UP study, presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2023, supported the further exploration of mitapivat's risk-benefit profile in sickle cell disease.
Study Design and Patient Population
The Phase 3 study includes a 52-week randomized, placebo-controlled period where participants are randomized in a 2:1 ratio to receive 100 mg of mitapivat twice daily or a matched placebo. Patients eligible for the RISE UP studies had between two and ten sickle cell pain crises in the past 12 months and hemoglobin levels within the range of 5.5 to 10.5 g/dL during screening.
About Mitapivat (PYRUKYND®)
PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States and for the treatment of PK deficiency in adult patients in the European Union. It is important to note that acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND. The prescribing information advises to avoid abruptly discontinuing PYRUKYND and to gradually taper the dose when discontinuing treatment, monitoring patients for signs of acute hemolysis and anemia.
Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios, expressed gratitude to the patients, study investigators, and patient advocates for their support and partnership in completing enrollment of the Phase 3 RISE UP study. She stated, "There is a critical need for novel regimens that elevate the standard of care for patients suffering from sickle cell disease, a burdensome and debilitating disease. With enrollment now complete, we look forward to completing the trial and sharing topline results with the community in late 2025."
