P1477: mitapivat efficacy in adults with pyruvate kinase deficiency and baseline hemoglobin levels >10 g/dl

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Pyruvate kinase (PK) deficiency is a chronic hereditary disorder characterized by hemolysis, ineffective hematopoiesis, and varying degrees of anemia. Patients (pts) with PK deficiency have a wide range of hemoglobin (Hb) levels, yet those with less pronounced anemia (Hb >10 g/dL) may still experience complications including iron overload, gallbladder disease, and osteopenia. Mitapivat is a first-in-class, oral, allosteric activator of PK approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, and by the European Medicines Agency for the treatment of adults with PK deficiency. In the phase 2, proof-of-concept DRIVE-PK (NCT02476916) study and the global, phase 3, randomized, placebo-controlled ACTIVATE and its long-term extension (LTE) (NCT03548220/NCT03853798) study, mitapivat demonstrated clinically meaningful improvements in Hb level. Aims: To evaluate changes in Hb and hemolysis after mitapivat treatment in adult pts with PK deficiency and baseline Hb >10 g/dL who were not regularly transfused and enrolled in the DRIVE-PK and ACTIVATE/LTE studies. Methods: For this analysis, adult (≥18 years) pts with post-screening baseline Hb >10 g/dL who received mitapivat 50 mg twice daily in the DRIVE-PK and ACTIVATE/LTE studies were included (data as of 28Aug2021 and 12Sep2021, respectively). The numeric change in Hb from baseline and the proportion of pts with increases in Hb from baseline of ≥1.0 and ≥1.5 g/dL, were evaluated to Week 48. Hb values within 61 days post-transfusion were excluded. Changes from baseline in markers of hemolysis (indirect bilirubin and reticulocyte percentage) were also measured. Results: Six pts from DRIVE-PK had baseline Hb >10 g/dL, ranging from 10.2 to 12.3 g/dL, as did 4 pts from ACTIVATE/LTE (range: 10.1 to 10.2 g/dL). The median change from baseline in Hb concentration at Week 48 (the latest timepoint with Hb assessments available for all pts) was 1.6 g/dL (range: −2.0 to 4.7; Figure). All 10 pts (100%) achieved improvements in Hb ≥1.0 g/dL by 16 weeks. Of these 10 pts, 7 (70%) had early increases in Hb concentration within 6 weeks (all improvements ≥1.5 g/dL). At Week 48, the majority of pts (7/10, 70%) had improvements in Hb ≥1.0 g/dL, with 5/10 (50%) having improvements ≥1.5 g/dL at this same time point. These 5 pts sustained this ≥1.5 g/dL Hb improvement throughout treatment from Weeks 6 to 48. At Week 48, indirect bilirubin levels were reduced from baseline in 9/10 pts (90% [data missing for 1 pt]; median change −35.1 μmol/L, range: –94.1 to −6.9 μmol/L; Figure) and reticulocyte percentage was reduced from baseline in 9/10 pts (90%; median change −5.5%, range: −25.3 to 0.5%; Figure). Summary/Conclusion: This analysis shows that mitapivat improved Hb levels in adults with PK deficiency and baseline Hb >10 g/dL who were not regularly transfused, indicating that this group of pts derived therapeutic benefit from this drug. Importantly, these pts also experienced a reduction in markers of hemolysis, indicative of improvements in the underlying pathophysiology of this condition. By improving red blood cell health, mitapivat may ameliorate the development of complications in this subset of pts with PK deficiency.Keywords: Pyruvate kinase deficiency, Hemoglobin, Anemia