Abstract Introduction: Thalassemia is caused by an imbalance of globin chains within red blood cells (RBCs) creating an excess of α-globins (β-thalassemia) or beta-globins (α-thalassemia). The excess globins form aggregates that cause cellular oxidative stress and damage, creating an increased metabolic burden within RBCs, and leading to ineffective erythropoiesis and premature hemolysis. Mitapivat is a first-in-class, oral, allosteric activator of pyruvate kinase (PK)—which includes the red cell-specific (PKR) and PKM2 isoforms—that enhances glycolytic production of adenosine triphosphate to support the increased energetic needs of thalassemic RBCs. In the Phase 3 ENERGIZE-T trial (NCT04770779) in patients (pts) with transfusion dependent (TD) α- or β-thalassemia, the primary and all key secondary endpoints of the study were met; mitapivat led to significant reductions in multiple measures of transfusion burden, with durability of response up to 36 weeks (wks) during the 48-wk double-blind period. Mitapivat was generally well tolerated in this study, with a low treatment discontinuation rate. Historically, there has been limited awareness of the disease burden experienced by pts with α-thalassemia in particular, including serious complications and early mortality. Further, there have been no approved disease-modifying therapeutic agents available for these pts, highlighting an unmet need. Aim: To assess the primary and secondary endpoints of mitapivat vs placebo in adults with TD α-thalassemia via a post hoc subgroup analysis of the ENERGIZE-T trial. Methods: In ENERGIZE-T, adults (≥18 years) with TD α- or β-thalassemia from 19 countries were randomized 2:1 to mitapivat 100 mg or placebo twice daily for 48 wks. Per study protocol, TD was defined as 6–20 RBC units transfused and a ≤6-wk transfusion-free period during the 24-wk period before randomization. In the present analysis, the following endpoints were assessed among the subgroup of pts with TD α-thalassemia: the primary endpoint of transfusion reduction response (TRR, defined as a ≥50% reduction in transfused RBC units and a reduction of ≥2 units of transfused RBCs in any consecutive 12-wk period through Wk 48 compared with baseline); key secondary endpoints: TRR2 (a ≥50% reduction in transfused RBC units in any consecutive 24-wk period through Wk 48 compared with baseline), TRR3 (a ≥33% reduction in transfused RBC units from Wk 13 through Wk 48 36-wk period compared with baseline), and TRR4 (a ≥50% reduction in transfused RBC units from Wk 13 through Wk 48 36-wk period compared with baseline); and the secondary endpoint of transfusion independence (TI), defined as transfusion-free for ≥8 consecutive wks through Wk 48. The proportion of pts who achieved TRR, TRR2, TRR3, TRR4, and TI were summarized for each treatment arm. The difference in proportion between the mitapivat arm and placebo arm, along with the 95% exact CI, are provided. Results: A total of 258 pts were randomized (mitapivat: N=171; placebo: N=87); 155 (90.6%) and 83 (95.4%) pts in the mitapivat and placebo arms, respectively, completed the 48-wk double-blind period. Twelve of the pts (9 and 3 in the mitapivat and placebo arms, respectively) had a confirmed diagnosis of TD α-thalassemia. Among the 12 pts with α-thalassemia, a TRR was achieved in 7 (77.8%) pts in the mitapivat arm vs 0 pts in the placebo arm (95% CI of difference: 2.6%, 97.2%). Also among these 12 pts, reductions in transfusion burden were observed in the mitapivat arm vs none in the placebo arm for all key secondary endpoints: TRR2 (7 77.8% vs 0; 95% CI of difference: 2.6%, 97.2%), TRR3 (6 66.7% vs 0; 95% CI of difference: –10.8%, 92.5%), and TRR4 (6 66.7% vs 0; 95% CI of difference: –10.8%, 92.5%). TI was achieved in 6 (66.7%) pts in the mitapivat arm vs 0 in the placebo arm (95% CI of difference: –10.8%, 92.5%). Conclusions: In this subgroup analysis, a higher proportion of pts with TD α-thalassemia in the mitapivat arm experienced reductions in transfusion burden, as determined by the primary and all key secondary endpoints, and achieved protocol defined TI, whereas no pts with TD α-thalassemia in the placebo arm achieved these endpoints. These data are consistent with the results of the overall population and support the beneficial effects of mitapivat in transfusion reduction in patients with α-thalassemia.
Kuo et al. (Mon,) studied this question.