Mitapivat Achieves Phase 3 Endpoint in Non-Transfusion-Dependent Thalassemia

Ali Taher, MD, PhD

Credit: LinkedIn

Positive results from the Phase 3 ENERGIZE study demonstrated the efficacy of oral mitapivat (PYRUKYND) for the treatment of adult patients with non-transfusion-dependent alpha- or beta-thalassemia.¹

Announced by Agios Pharmaceuticals on June 15, 2024, ENERGIZE met its primary endpoint, with oral mitapivat achieving a statistically significant increase in hemoglobin response rate compared with placebo. These data were presented at the European Hematology Association (EHA) 2024 Hybrid Congress in Madrid, Spain.

“I am pleased to present the results of the ENERGIZE study to my esteemed colleagues and believe they will share my enthusiasm for the positive impact mitapivat may have for patients with non-transfusion-dependent alpha- or beta-thalassemia,” said investigator Ali Taher, MD, PhD, professor of medicine, hematology & oncology and director of the Naef K. Basile Cancer Institute, American University of Beirut Medical Center.¹ “Based on the data collected in the ENERGIZE study, mitapivat has the potential to become a foundational treatment for non-transfusion-dependent thalassemia.”

Mitapivat is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States and the treatment of PK deficiency in adults in the European Union.²

The Phase 3 ENERGIZE trial enrolled 194 patients, including 130 randomized to twice-daily mitapivat 100 mg and 64 randomized to matched placebo.¹ A total of 122 (93.8%) patients in the mitapivat arm and 62 (96.9%) in the placebo arm completed the 24-week double-blind period of the study. Baseline demographics and characteristics were well-matched between the cohorts.

The study met its primary endpoint of hemoglobin response – an increase of ≥1 g/dL in average hemoglobin concentrations from Week 12 through Week 24 compared with baseline. Approximately 42% (n = 55) of patients in the mitapivat arm achieved a hemoglobin response, compared with 1.6% (n = 1) patients in the placebo arm (2-side P <.0001).

Among those who achieved a response, the mean change from baseline in average hemoglobin concentration from Week 12 to 24 was 1.56 g/dL in the mitapivat arm. Hemoglobin response rates were higher among those treated with mitapivat versus placebo across all prespecified subgroups, including by thalassemia genotype (alpha - or beta-thalassemia) and baseline hemoglobin concentration (≤9.0 g/dL or 9.1 – 10.0 g/dL).

Mitapivat treatment also demonstrated statistically significant improvements for both key secondary endpoints, compared with placebo. The average change from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale score from Week 12 to 24 was 4.85 (95% CI, 3.41 - 6.30) in the mitapivat arm, compared with 1.46 (95% CI, –0.43 to 3.34) in the placebo arm (P = .0026).

Meanwhile, the average change from baseline in the average hemoglobin concentration from Week 12 to 24 was 0.86 (95% CI, 0.73 - 0.99) g/dL in the mitapivat arm, compared with –0.11 (95% CI, –0.28 to 0.07) g/dL in the placebo arm (P <.0001).

Improvements were also identified in patients treated with mitapivat across various measures of health-related quality of life, including the 6-minute walk test, Patient Global Impression of Change (PGIC) fatigue, walking capacity, and thalassemia symptom subscales.

Safety results revealed a similar incidence of adverse events between the mitapivat and placebo arms during the 24-week double-blind period. Approximately 83% (n = 107) of patients in the mitapivat arm and 79% (n = 50) of patients in the placebo arm experienced treatment-emergent adverse events (TEAEs).

Agios has also announced positive results from the Phase 3 ENERGIZE-T study of mitapivat in adults with transfusion-dependent alpha- or beta-thalassemia.³ The company intends to file for regulatory approval by the end of 2024 based on available data from both studies.

“Together with the recently announced positive results from the ENERGIZE-T study of mitapivat in adults with transfusion-dependent thalassemia, the detailed ENERGIZE results underscore mitapivat’s potential to become an important treatment option for all subtypes of thalassemia – alpha- and beta-thalassemia, transfusion-dependent and non-transfusion-dependent – with the convenience of a pill,” said Sarah Gheuens, MD, PhD, chief medical officer and head of R&D at Agios.¹

References

1. _{Agios presents positive results from phase 3 energize study of mitapivat in non-transfusion-dependent thalassemia in plenary session at the European Hematology Association 2024 hybrid Congress. Agios Pharmaceuticals, Inc. June 15, 2024. Accessed June 17, 2024. https://investor.agios.com/news-releases/news-release-details/agios-presents-positive-results-phase-3-energize-study-mitapivat.}
2. _{Zhuang-Yan A, Shirley M. Mitapivat: A Review in Pyruvate Kinase Deficiency in Adults. Drugs. 2023;83(17):1613-1620. doi:10.1007/s40265-023-01961-x}
3. _{Agios announces phase 3 Energize-T Study of Mitapivat met primary endpoint and all key secondary endpoints in adults with transfusion-dependent alpha- or beta-thalassemia. Agios Pharmaceuticals, Inc. June 3, 2024. Accessed June 17, 2024. https://investor.agios.com/news-releases/news-release-details/agios-announces-phase-3-energize-t-study-mitapivat-met-primary.}