P1424: one-year follow-up of a phase 2 study of mitapivat, an oral pyruvate kinase activator, for the treatment of sickle cell disease

Topic: 26. Sickle cell disease Background: Sickle cell disease (SCD) is a hereditary red blood cell (RBC) disorder characterized by a defective hemoglobin (HbS), which polymerizes upon deoxygenation. The poorly deformable, sickled RBCs cause potentially life-threatening complications. In SCD, 2,3-diphosphoglycerate (2,3-DPG), a glycolytic RBC intermediate, promotes deoxygenation by lowering oxygen affinity of hemoglobin (Hb). Mitapivat is an oral, allosteric activator of pyruvate kinase (PK). In SCD, activation of PK, a key enzyme in RBC glycolysis generating adenosine triphosphate (ATP) and reducing 2,3-DPG levels, provides a treatment rationale. Aims: Here, we report pre-specified safety and efficacy data of the 1-year fixed-dose extension period (FDEP) of mitapivat treatment in subjects with SCD enrolled in the ESTIMATE study (www.trialregister.nl NL8517; EudraCT 2019-003438-18). Methods: The ESTIMATE study is a phase 2, investigator initiated, open-label study. Eligibility criteria include: subjects ≥16 years with SCD (HbSS, HbS/β0 or HbS/β+), 1-10 vaso-occlusive crises (VOCs) in the prior year and/or prior SCD-related complications, a Hb level >4.0 g/dL and ≤11.1 g/dL, and not receiving chronic RBC transfusions. If eligible, subjects enter the 1-year FDEP after the previously reported 8-week dose finding period with similar endpoints (van Dijk et al. Am J Hematol, 2021). Safety Analysis Set (SAS) includes all subjects who received ≥1 dose in the FDEP. Per Protocol Set (PPS) includes all dosed subjects with Point of Sickling (PoS) and Hb assessments at the start and end of the FDEP. Post-hoc analysis includes the PPS without visits at which the subject was found to be study drug non-compliant 7 days before (<80% of pills taken). Results: Until Jan 2023, 9 subjects were treated with mitapivat in the FDEP (SAS), of which 6 subjects completed the FDEP (PPS) (n=1 ongoing, n=1 death, n=1 withdrew consent because of a pregnancy wish). Baseline characteristics (n=9): median (range) age was 30 years (16-59), 5/9 (56%) were female, and 6/9 (67%) used hydroxyurea. 7/9 (78%) had HbSS, 1/9 (11%) had HbS/β0, and 1/9 (11%) had HbS/β+. One non-treatment related SAE of massive pulmonary embolism due to COVID-19 resulted in death. No other SAEs or treatment-emergent AEs (TEAEs) grade ≥3 occurred in the FDEP. The most common (ongoing or firstly) reported TEAEs were (n>2 subjects): ALT or AST increase (resp. 6/9 (67%) or 5/9 (56%); all grade 1), headache (3/9 (33%); grade 1-2), and lymphocytosis (3/9 (33%); grade 2). 7/9 (78%) took 100 mg mitapivat twice daily in the FDEP, and 2/9 (22%) took 50 mg mitapivat twice daily after a single dose reduction because of ALT/AST increase. Table 1 summarizes mean changes in endpoints from baseline to the mean of 6 scheduled visits in the FDEP. Mean Hb level significantly increased, accompanied by a significant decrease in markers of hemolysis (reticulocyte count, total bilirubin, and lactate dehydrogenase). Mean PoS, p50, 2,3-DPG and ATP levels, and ATP/2,3-DPG ratio all significantly improved. In total, 4 VOCs occurred in 3 subjects with documented non-compliance 7 days before in 3/4 (75%) VOCs. There was a trend towards decreased annualized VOC rate and SCD-related hospital admission days compared to baseline (2-year historical data). Summary/Conclusion: One-year fixed-dose treatment with mitapivat in subjects with SCD was well tolerated and associated with general improvement of anemia, reduced hemolysis and sickling. Hence, these data further strengthen the potential benefit of mitapivat in SCD. Before EHA 2023, final analysis of the FDEP will be completed including data of one additional subject.Keywords: Pyruvate kinase, Therapy, Sickle cell disease