Agios Pharmaceuticals announced mixed topline results from its RISE UP Phase 3 trial of mitapivat in sickle cell disease, with the oral pyruvate kinase activator meeting one primary endpoint while falling short on another key measure of clinical benefit.
The 52-week, double-blind, placebo-controlled trial enrolled 207 patients aged 16 years or older with sickle cell disease, randomized 2:1 to receive mitapivat 100 mg twice daily or placebo. The study was designed with dual primary endpoints to evaluate both objective measures of hemolysis improvement and clinical outcomes.
Primary Endpoint Results Show Split Outcomes
Mitapivat demonstrated statistically significant improvement in hemoglobin response, with 40.6% of patients achieving a ≥1.0 g/dL increase from baseline in average hemoglobin concentration from Week 24 through Week 52, compared to just 2.9% of placebo patients (p<0.0001). Among hemoglobin responders in the mitapivat arm, the mean change from baseline was 1.6 g/dL.
However, the drug showed only a trend toward reducing sickle cell pain crises (SCPCs), with an annualized rate of 2.62 events in the mitapivat arm versus 3.05 in the placebo arm (p=0.1213), failing to achieve statistical significance.
Secondary Endpoints Demonstrate Anti-Hemolytic Effects
Mitapivat met two of its five key secondary endpoints. The average change from baseline in hemoglobin concentration from Week 24 through Week 52 was 7.69 g/L in the mitapivat arm compared to 0.26 g/L with placebo (p<0.0001). The drug also significantly reduced indirect bilirubin levels, a marker of hemolysis, by -16.03 μmol/L versus an increase of 0.88 μmol/L with placebo (p<0.0001).
The trial did not meet its key secondary endpoint for fatigue improvement, with PROMIS Fatigue scores showing similar changes in both arms (-2.72 mitapivat versus -2.25 placebo, p=0.7112).
Hemoglobin Responders Show Clinical Benefits
A post hoc analysis revealed that patients achieving hemoglobin response experienced clinically meaningful benefits across multiple endpoints. These responders had an annualized SCPC rate of 2.20 compared to 2.98 for non-responders (rate ratio 0.74, 95% CI 0.58-0.94). Hospitalizations for SCPCs were also reduced, with rates of 1.16 versus 1.76 for non-responders (rate ratio 0.66, 95% CI 0.48-0.91).
Importantly, hemoglobin responders showed a -5.19 change in PROMIS Fatigue scores compared to -2.55 for non-responders, exceeding the -4.1 threshold for clinically meaningful improvement.
Safety Profile Remains Favorable
The safety profile was consistent with previous mitapivat trials in sickle cell disease. Similar proportions of patients experienced adverse events (97.1% mitapivat versus 98.6% placebo). Serious treatment-emergent adverse events occurred in 20.3% of mitapivat patients compared to 29.0% on placebo, with only 0.7% considered treatment-related in the mitapivat group.
Notably, liver abnormalities observed were not suggestive of drug-induced hepatocellular injury, unlike what was seen in the ENERGIZE and ENERGIZE-T trials in other conditions. Treatment discontinuation due to adverse events occurred in 4.3% of mitapivat patients versus 2.9% on placebo.
Clinical Significance and Next Steps
"Sickle cell disease is a complex and devastating condition that has long lacked innovation. As a result, patients have very few effective treatments, contributing to poor outcomes and shortened lifespans," said Biree Andemariam, M.D., Professor of Medicine at University of Connecticut Health and RISE UP trial investigator. "The data from RISE UP demonstrate that treatment with mitapivat significantly improved hemoglobin concentration and reduced hemolysis."
Sarah Gheuens, M.D., Ph.D., Chief Medical Officer at Agios, emphasized the drug's anti-hemolytic profile: "The RISE UP Phase 3 results further support mitapivat's strong anti-hemolytic profile, as demonstrated in other rare blood disease trials. These effects can help address debilitating features of sickle cell disease that can profoundly worsen quality of life and lead to early mortality."
Regulatory Path Forward
Agios intends to submit a marketing application for mitapivat in sickle cell disease after a pre-supplemental New Drug Application meeting with the FDA in the first quarter of 2026. The company also plans to present detailed analyses from the RISE UP trial at future medical congresses.
The company remains focused on other near-term milestones, including the potential U.S. approval of PYRUKYND (mitapivat) for thalassemia, anticipated in early December 2025.
About the Mechanism
Mitapivat is designed to enhance red blood cell energy production by increasing ATP levels and lowering 2,3-diphosphoglycerate (2,3-DPG) levels. In sickle cell disease, elevated 2,3-DPG increases the likelihood that red blood cells develop the abnormal "sickle" shape that triggers vaso-occlusive crises.
