Deoxygenated hemoglobin S polymerization drives sickle cell disease (SCD) pathogenesis. Mitapivat (AG-348) boosts adenosine triphosphate (ATP) levels and reduces the concentration of 2,3-diphosphoglycerate (2,3-DPG), a precursor to glycolysis, to activate red blood cell pyruvate kinase and glycolysis. Both adjustments have the potential to be helpful for SCD patients. 

In the study, persons with SCD who had not recently received blood transfusions or made modifications to their hydroxyurea or l-glutamine medication underwent safety and tolerability evaluations of several ascending doses of mitapivat. Seventeen people were enrolled; 1 person withdrew from the research soon after it began. Mitapivat was administered to 16 patients in 3 ascending dosage levels of 5, 20, and 50 mg twice daily (BID) for 2 weeks each. As a result of a protocol change, the dose was increased to 100 mg BID in 9 subjects. 

The most frequent treatment-emergent adverse events (AEs) were sleeplessness, headaches, and hypertension. Mitapivat was well tolerated at all dosage levels. Four vaso-occlusive crises (VOCs), non-VOC-related shoulder discomfort, and a pre-existing pulmonary embolism were among the six serious adverse events (SAEs). No further SAEs were drug-related. However, two VOCs that happened during drug taper may have been drug-related. The average hemoglobin rose at the 50 mg BID dosage level was 1.2 g/dL, while 9 out of 16 patients (56.3%) saw a hemoglobin response of ≥1 g/dL increase from baseline. 

Additionally, mean decreases in hemolytic markers, dose-dependent reductions in 2,3-DPG, and increases in ATP were seen. Mitapivat may be able to change the course of the illness in SCD patients, according to the study’s proof-of-concept findings.