S116: LONG-TERM EFFICACY AND SAFETY OF THE ORAL PYRUVATE KINASE ACTIVATOR MITAPIVAT IN ADULTS WITH NON—TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA
Authors: K Kuo, D Layton, A Lal, H Al-Samkari, J Bhatia, P Kosinski, B Tong, M Lynch, K Uhlig, E Vichinsky
Journal: HemaSphere (2022)

Background: Thalassemia is characterized by ineffective erythropoiesis and hemolysis that occur due to imbalanced production and precipitation of globin chains.1,2 Thalassemic red blood cells (RBCs) have insufficient levels of ATP to meet increased energy demands associated with globin chain imbalance, protein degradation, and cellular oxidative stress responses.3,4 Mitapivat is an oral activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme regulating ATP production.5 In a phase (ph) 2, open-label trial of mitapivat in adults with α- or β-non–transfusion-dependent (NTD) thalassemia (NCT03692052), 80% of patients (pts) met the primary endpoint of a hemoglobin (Hb) response (≥1.0 g/dL increase from baseline [BL] at ≥1 assessments between Weeks (Wks) 4–12, inclusive). Improvements in markers of hemolysis and ineffective erythropoiesis were also observed and mitapivat was generally well tolerated.6 Aims: To report data from the ongoing long-term extension (LTE) period (up to Wk 72; data cutoff 27Mar2021). Methods: Pts aged ≥18 yrs with a known medical history of α- or β-thalassemia, Hb concentration ≤10.0 g/dL, and ≤5 RBC units transfused in prior 24 wks and none in 8 wks prior to study drug were eligible. All pts started mitapivat 50 mg twice daily (BID), escalating to 100 mg BID based on individual safety and Hb assessments. After completion of the 24-wk core period, pts with a Hb response, or delayed Hb response (after Wk 12), with no ongoing study drug-related grade ≥3 treatment-emergent adverse events (AE) continued on mitapivat in the LTE at the same dose as the Wk 24 visit. Study visits occur every 12 wks for ≤10 yrs. Results: Of 19 pts who completed the core period, 17 entered the LTE (mitapivat 100 mg BID, n=16; 50 mg BID, n=1). As of data cutoff, 1 pt discontinued (pt decision). Median duration of treatment for pts in the LTE was 70.9 wks (range 54.7, 105.6), with 8 pts receiving ≥72 wks of treatment as of data cutoff. Median pt age in the LTE was 44 yrs (range 29, 67). Mean BL (SD) Hb, total bilirubin and lactate dehydrogenase (LDH) was 8.1 (1.2) g/dL, 40.1 (26.2) μmol/L and 272.4 (121.7) U/L, respectively. Median BL erythropoietin (EPO) was 70.5 (range 15, 11191) IU/L. Hb improvements achieved in the core period were sustained in the LTE (Figure). Mean Hb (SD) increase from BL to Wk 60 (α-thalassemia, n=4; β-thalassemia, n=9) and Wk 72 (β-thalassemia, n=8) were 1.5 (0.4) and 1.7 (0.5) g/dL, respectively. Improvements in markers of hemolysis and ineffective erythropoiesis observed in the core period were maintained in the LTE up to Wk 72 (mean [SD] bilirubin and LDH, –15.8 [16.6] μmol/L and –63.6 [216.0] U/L, respectively; median [range] EPO, –33.0 [–72.0, –16.0] IU/L). The safety profile was consistent with that observed in the core period. AEs in ≥15% of pts were headache (5/17) and back pain (3/17), none were grade ≥3. No trends for decreases in bone mineral density were observed. No treatment-related serious AEs occurred. Conclusions: A favorable efficacy-safety profile was observed with long-term mitapivat in pts with α- or β-thalassemia. Data show sustained improvements in Hb, hemolysis and ineffective erythropoiesis despite globin genotypic heterogeneity, and no new safety findings. Mitapivat, through its unique mechanism of action, may represent a novel therapeutic approach for this condition. Two ph 3 trials of mitapivat in α- and β-thalassemia, (NTD and transfusion-dependent pts), are enrolling.References 1. Taher et al. Lancet 2018; 391:155–67. 2. Galanello et al. Ophanet J Rare Dis 2010; 5:11. 3. Khandros et al. Blood 2012; 119:5265–75. 4. Shaeffer. J Biol Chem 1988; 263:13663–9. 5. Kung et al. Blood 2017; 130:1347–56. 6. Kuo et al. HemaSphere 2021; Abstract S267.