One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study.

Targeting the primary pathogenic event of sickle cell disease (SCD), polymerization of sickle hemoglobin (HbS), may prevent downstream clinical events. Mitapivat, an oral pyruvate kinase (PK) activator, has therapeutic potential by increasing adenosine triphosphate (ATP) and decreasing 2,3-diphosphoglycerate (2,3-DPG), a glycolytic red blood cell (RBC) intermediate. In the previously reported 8-week dose-finding period of this phase 2, investigator initiated, open-label study, mitapivat was well tolerated and showed efficacy in SCD. Here, the 1-year fixed-dose extension period is reported in which 9/10 (90%) included patients 16+ years with SCD (HbSS, HbS/β0 or HbS/β+) continued with mitapivat. Mostly mild treatment-emergent adverse events (most commonly: transaminase increase and headache) were still reported. Apart from the reported non-treatment-related serious adverse event (SAE) of a urinary tract infection in the dose-finding period, one non-treatment-related SAE occurred in the fixed-dose extension period in a patient who died of massive pulmonary embolism due to COVID-19. Importantly, sustained improvement in Hb level (mean increase: 1.1 +/- 0.7 g/dL; p=0.0014) was seen, which was accompanied by decreases in markers of hemolysis. In addition, the annualized rate of vaso-occlusive events reduced significantly from a historic baseline of 1.33 +/- 1.32 to 0.64 +/- 0.87 (p=0.0489) when combining the dose-finding period and fixed-dose extension period. Cellularly, the ATP/2,3-DPG ratio and Hb-oxygen affinity significantly increased, and RBC sickling (Point of Sickling) non-significantly reduced. Overall, this study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18) demonstrated 1-year safety and efficacy of treatment with mitapivat in SCD, supporting further evaluation in ongoing phase 2/3 study (RISE UP, NCT05031780).