Taher, A. T., Al-Samkari, H., Aydinok, Y., Besser, M., Boscoe, A. N., Dahlin, J. L., De Luna, G., Estepp, J. H., Gheuens, S., Gilroy, K. S., Glenthøj, A., Sim Goh, A., Iyer, V., Kattamis, A., Loggetto, S. R., Morris, S., Musallam, K. M., Osman, K., Ricchi, P., Salido-Fiérrez, E., … ENERGIZE investigators (2025). Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet (London, England), 406(10498), 33–42. https://doi.org/10.1016/S0140-6736(25)00635-X
Clinical Question
In adult patients with non-transfusion dependent (NTD) thalassemia, does the addition of mitapivat lead to an increase in hemoglobin and/or improve symptoms in a safe manner?
Background
Patients with NTD alpha and beta thalassemia have ineffective erythropoiesis and chronic hemolysis even if they do not meet transfusion thresholds. Therapeutic trials are limited in this disease group due to lack of transfusions as an end point, and many do not include patients with NTD alpha thalassemia. Mitapivat is an allosteric activator of pyruvate kinase, and has been approved for patients with inherited pyruvate kinase deficiency. This study asks if this medication can also improve hemoglobin as well as symptoms of fatigue in patients with NTD thalassemia.
Guidelines
There are no current published society guidelines specifically for treatment of non-transfusion dependent thalassemia. Recommended therapies include iron chelation therapy and treatment of anemia if indicated. ( Kattamis, A., Kwiatkowski, J. L. & Aydinok, Y. Thalassaemia. The Lancet 399, 2310–2324 (2022)).
Study Design
- Multinational, randomized, placebo-controlled phase 3 study
- n = 194 randomized 2:1
- 130 in mitapivat arm
- 64 in placebo arm
- Setting: 70 sites in 18 countries across South America, USA, Canada, Europe, and Asia
- Enrollment period: December 20, 2021 to November 13, 2023
- Analysis: Intention to treat
- Primary endpoint:
- Increase in hemoglobin greater than or equal to 1.0 g/dL averaged across four measurements (weeks 12, 16, 20, and 24).
- Key secondary endpoints:
- Change from baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) score from weeks 12 to 24
- Change from baseline of average hemoglobin concentration from weeks 12 to 24
Populations
- Inclusion Criteria
- Adult patients ≥ 18 years of age
- Documented diagnosis of thalassemia (beta-thalassemia with or without alpha-globin gene mutations, HbE/beta-thalassemia, or alpha-thalassemia/HbH disease)
- Hgb concentration of ≤10 g/dL on average of at least 2 measurements a minimum 7 days apart during screening period
- Non-transfusion dependance defined as: ≤5 RBC units during 24-week period before randomization, no RBC transfusions <8 weeks before informed consent and no RBC transfusions during screening period
- Hydroxyurea allowed if dose stable ≥ 16 weeks before randomization
- Key exclusion criteria:
- Adult patients ≥ 18 years of age
- Documented diagnosis of thalassemia (beta-thalassemia with or without alpha-globin gene mutations, HbE/beta-thalassemia, or alpha-thalassemia/HbH disease)
- Hgb concentration of ≤10 g/dL on average of at least 2 measurements a minimum 7 days apart during screening period
- Non-transfusion dependance defined as: ≤5 RBC units during 24-week period before randomization, no RBC transfusions <8 weeks before informed consent and no RBC transfusions during screening period
- Hydroxyurea allowed if dose stable ≥ 16 weeks before randomization
- Baseline characteristics
- Sex: 63% female, 37% male
- Mitapivat arm: mean age 42.4 yrs; mean hgb 8.3 g/dL; 32% alpha-thal and 68% beta-thal
- Placebo arm: mean age 38.9 yrs, mean hgb 8.39 g/dL, 31% alpha-thal and 69% beta-thal
Intervention
2:1 randomization of mitapivat 100mg twice daily or placebo for 24 weeks, with study visits every 4 weeks.
Outcomes
- Primary efficacy endpoint:
- In the mitapivat group, 42% (55 of 130 patients) had pre-specified hemoglobin response compared to 2% (1 of 64 patients) in the placebo group.
- Secondary efficacy endpoints:
- Statistically significant improvement in change from baseline in FACIT-Fatigue score in mitapivat group compared to placebo (increase in 4.85 least means squares change vs 1.46)
- Statistically significant improvement in average hgb concentration in mitapivat group compared to placebo (0.86 g/dL least means squares change vs –0.11 g/dL)
- Safety:
- No deaths in entire study period
- 4% of treatment related grade 3 events in mitapivat group
- Most common adverse events: headache (22%), insomnia (14%), nausea (12%) and upper respiratory tract infection (11%) of patients in mitapivat group.
Commentary and Intepretation:
In this study, patients who received mitapivat had a significantly increased hemoglobin level after 24 weeks compared with placebo. In addition, patients had improvement in fatigue symptoms as measured by the FACIT-fatigue score. Patients who received mitapivat had an average increase in hemoglobin concentration of 0.86 g/dL, and the earliest increase was seen at the first measured time point of 4 weeks and sustained through the 24-week study period.
These results are similar to the ACTIVATE study which led to the approval of mitapivat for patients with pyruvate kinase deficiency, though those patients had a higher average hemoglobin increase of 1.7 g/dL by 24 weeks. Despite a more moderate hgb increase, this study does show an improvement in fatigue scores, which has not been seen in similarly studied trials of luspatercept in the thalassemia population. One of the limitations of this study includes the limited 24-week period. It remains to be seen if the effects on hemoglobin can be sustained over a longer time. In addition, longer time periods could show if there could be any effect on reducing complications such as end organ damage. While not the primary focus of the study, there were no changes in ferritin levels between mitapivat or placebo at 24 weeks. There is an open-label extension arm of the study ongoing which may help to answer some of these questions.
In summary, patients with non-transfusion dependent thalassemia had a statistically significant improvement in hemoglobin levels and fatigue scores after taking mitapivat.
Peter Tonzi, MD, PhD, completed medical school, graduate school, and internal medicine residency at New York University School of Medicine. He is now a hematology focused fellow (HFFTP) at Beth Israel Deaconess Medical Center. He is passionate about all things hematology, with a particular focus on leukemias and myeloid disorders.
