Abstract Introduction: While regular transfusions and iron chelators have improved survival and outcomes in individuals with thalassemia, these therapies are supportive and do not address underlying ineffective erythropoiesis (IE) and hemolysis. Moreover, they can be associated with adverse effects, including transfusion reactions and iron overload, leading to high healthcare resource utilization, and negatively impacting quality of life. Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase (PK), which includes the red cell-specific (PKR) and PKM2 isoforms, facilitates adenosine triphosphate production through glycolysis. In thalassemia, this likely improves RBC health, IE, and hemolysis by addressing increased cellular energy demands. In the phase 3 ENERGIZE-T trial in transfusion-dependent (TD) thalassemia (NCT04770779), primary and all key secondary endpoints were met; mitapivat led to significant reductions in transfusion burden, with durability of response up to 36 weeks (wks) during the 48-wk double-blind period (DBP). A higher proportion of patient (pts) in the mitapivat arm achieved protocol-defined transfusion independence (TI) compared with placebo (mitapivat n=17 9.9%; placebo n=1 1.1%); 3/17 pts in the mitapivat arm remained transfusion free through Wk 48 of the DBP. Aim: Assess long-term duration of transfusion-free periods and potential real-world impact on transfusion-related burdens for pts who achieved protocol-defined TI during the 48-wk DBP of ENERGIZE-T. Methods: In ENERGIZE-T, adults with TD α- or β-thalassemia were randomized 2:1 to mitapivat 100 mg or placebo twice daily for 48 wks. Per protocol, TD was defined as 6–20 packed RBC (PRBC) units transfused and ≤6-wks transfusion-free period during the 24-wk period before randomization. Per protocol, TI, a secondary endpoint, was defined as transfusion free for ≥8 consecutive wks through Wk 48. Pts who completed the DBP could receive mitapivat for an additional 5 yrs in an open-label extension (OLE). Here, duration of transfusion-free periods was assessed based on cumulative data from the DBP and OLE, as of a data cut-off 90 days after the last pts first dose in the OLE (hereafter referred to as DBP+OLE). The DBP+OLE evaluation period included data for the 17 pts who were randomized to mitapivat and achieved protocol-defined TI during the DBP with up to 99.3 wks of mitapivat exposure. Transfusion-free duration was calculated as number of wks in the longest transfusion-free period starting on or after the first dose of mitapivat through the end of the DBP+OLE evaluation period. A transfusion visit was defined as the day when a transfusion was given. Transfusions (≥1 PRBC unit) given on consecutive days were counted separately as visits for each day. The total number of transfusion visits and PRBC units received in the evaluation period for each pt were annualized and compared with their respective annualized baseline values. The impact on transfusion-related burdens in terms of annualized reductions in number of hours and transfusional iron intake per yr were calculated with assumptions of 7 hours per transfusion visit and an assumed intake of 200 mg iron per transfused PRBC unit. Results: The mean (SD) duration of the longest transfusion-free period in wks among the 17 pts was 21.69 (16.892) in the 48-wk DBP and 30.49 (27.087) during the DBP+OLE evaluation period. The minimum and maximum number of wks of transfusion-free periods through the DBP+OLE evaluation period were 8.4 and 84.3 wks, respectively. The 3 pts in the mitapivat arm who did not receive any transfusions during the 48-wk DBP remained transfusion free during the OLE evaluation period. The 17 pts who achieved protocol-defined TI had mean (SD) 7.17 (4.163) reduction in annualized transfusion visits compared to annualized baseline, which represented a 56.0% (29.00%) reduction, and approximately 50.2 (29.14) hours saved in visits per yr. Pts received mean (SD) 14.01 (7.543) fewer PRBC units per yr, a 63.6% (27.45%) reduction from annualized baseline. This equates to mean (SD) 2802 mg (1508.6) less transfusional iron intake per yr. Conclusions: This analysis demonstrates long-term duration of prolonged transfusion-free periods of up to 84.3 wks achieved with mitapivat and its potential impact on clinical and humanistic transfusion-related burdens, further supporting use of mitapivat as an effective oral disease-modifying therapy for adults with TD α- or β-thalassemia.
Khaled M. Musallam (Mon,) studied this question.