Agios Pharmaceuticals, Inc. presented detailed results from the Phase 2 portion of the global RISE UP study of mitapivat in sickle cell disease in an oral presentation (abstract #271) at the 65thAmerican Society of Hematology (ASH) Annual Meeting & Exposition, which is being hosted Dec. 9-12, 2023, in San Diego. During the Phase 2 double-blind, placebo-controlled study, treatment with mitapivat demonstrated statistically significant improvement in hemoglobin response across both mitapivat dose levels (50 mg and 100 mg BID), compared to placebo.

The safety profile for mitapivat observed in the study was generally consistent with previously reported data in other studies of sickle cell disease and other hemolytic anemias. Improvements were observed in annualized rates of sickle cell pain crises, and markers of hemolysis and erythropoiesis for both mitapivat treatment arms compared to placebo. Improvement in patient-reported fatigue scores was observed with mitapivat 50 mg BID compared to placebo.

Based on the Phase 2 data, Agios selected 100 mg BID as the Phase 3 dose and is currently enrolling patients in this portion of the RISE UP study. The operationally seamless Phase 2/3 study design allows Agios to leverage and create efficiencies in the start and conduct of the Phase 3 portion of RISE UP, with a goal of reporting the Phase 3 data in 2025 and potentially receiving U.S. approval in 2026. Results for the Phase 2 portion of RISE UP were as follows: A total of 79 patients were enrolled in the Phase 2 portion of the study, with 26 patients in the 50 mg BID mitapivat arm, 26 patients in the 100 mg BID mitapivat arm, and 27 patients in the placebo arm.

Demographics and baseline characteristics for the participants in each arm were as follows: Mean age (standard deviation) for participants in the 50 mg BID, 100 mg BID, and placebo arms, respectively, was: 29.9 (7.79), 30.2 (10.52), and 28.5 (10.30) years. Percentage of female participants in the 50 mg BID, 100 mg BID, and placebo arms, respectively, was: 57.7%, 61.5%, and 74.1%. Mean baseline hemoglobin (standard deviation) for participants in the 50 mg BID, 100 mg BID, and placebo arms, respectively, was: 8.76 (1.295), 8.82 (0.898), and 8.49 (1.141) g/dL.

Mean number of sickle cell pain crises during the previous year (standard deviation) for participants in the 50 mg BID, 100 mg BID, and placebo arms, respectively, was: 3.1 (1.83), 3.2 (1.65), and 3.4 (1.91). The study achieved its primary efficacy endpoint; treatment with mitapivat demonstrated a statistically significant increase in hemoglobin response rate compared to placebo. Hemoglobin response was defined as an increase of =1 g/dL in average hemoglobin concentrations from Week 10 through Week 12 compared with baseline.

46.2% of patients (n=12) in the 50 mg BID mitapivat arm and 50.0% of patients (n=13) in the 100 mg BID mitapivat arm achieved a hemoglobin response, compared to 3.7% of patients (n=1) in the placebo arm (2-sided p=0.0003 and 0.0001, respectively). Least-squares mean (95% confidence interval) for average change from baseline in hemoglobin levels, from Week 10 through Week 12, for participants in the 50 mg BID, 100 mg BID, and placebo arms, respectively, was: 1.11 (0.77, 1.45) g/dL, 1.13 (0.79, 1.47) g/dL, and 0.05 (-0.28, 0.39) g/dL. The annualized rate of sickle cell pain crises (95% confidence interval) for participants in the 50 mg BID and 100 mg BID, arms, respectively, was 0.83 (0.34, 1.99) and 0.51 (0.16, 1.59), compared to 1.71 (0.95, 3.08) for participants in the placebo arm.

Least-squares mean (95% confidence interval) for average changes from baseline in patient-reported fatigue score, from Week 10 through Week 12, for participants in the 50 mg BID, 100 mg BID, and placebo arms, respectively, was: -3.80 (-7.16, -0.45), -0.10 (-3.27, 3.08), and -0.17 (-3.40, 3.07). The safety profile for mitapivat observed in the study was generally consistent with previously reported data in other studies of sickle cell disease and other hemolytic anemias. The most common treatment-emergent adverse events (TEAEs) in the 50 mg BID, 100 mg BID, and placebo arms, respectively, were: headache (n=6, 6, 7), arthralgia (n=3, 5, 9), dysmenorrhea (n=0, 3, 0), pain (n=3, 3, 2), pain in extremity (n=1, 3, 6), back pain (n=4, 2, 3), nausea (n=1, 2, 4), fatigue (n=4, 1, 5), and influenza-like illness (n=1, 1, 3).

No serious TEAEs were attributed to mitapivat treatment. There were no adverse events leading to drug reduction, discontinuation, interruption or death in either the mitapivat or the placebo arms. Of the 79 patients enrolled in the study, 73 continued into the Phase 2 open-label extension period.