Thalassemic red blood cells (RBCs) have insufficient levels of adenosine triphosphate (ATP) to meet increased energy demands associated with globin chain precipitation and oxidative stress responses. Mitapivat is a first-in-class, small molecule, oral activator of pyruvate kinase (PK), a key glycolytic enzyme regulating ATP production. In a phase 2, open-label trial of mitapivat in adults with α- or β-non–transfusion-dependent (NTD) thalassemia (NCT03692052), 80% (16/20) 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 (Wk) 4–12, inclusive). Improvements in markers of hemolysis and ineffective erythropoiesis were also observed and mitapivat was generally well tolerated. Here we report data from the ongoing long-term extension (LTE) period (≤Wk 72; data cutoff 27Mar2021).

Pts aged ≥18 years (y) with α- or β-thalassemia, Hb concentration ≤10.0 g/dL, and ≤5 RBC units transfused in prior 24 wk and none in 8 wk 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. Pts with a Hb response or a delayed Hb response (after Wk 12), with no ongoing study drug-related grade ≥3 treatment-emergent adverse events (AE), could continue on mitapivat in the LTE at the Wk 24 visit dose. LTE study visits occur every 12 wk.

Twenty patients started treatment; 19 pts completed the core period, 17 entered the LTE. As of the data cutoff, 1 pt discontinued (pt decision). Median treatment duration for pts in the LTE was 70.9 wk (range 54.7, 105.6); 8 pts received ≥72 wk of treatment as of data cutoff. Baseline values for patients who continued in LTE were: median age 44 y (range 29, 67), mean (standard deviation [SD]) Hb 8.1 (1.2) g/dL, total bilirubin 40.1 (26.2) μmol/L, lactate dehydrogenase (LDH), 272.4 (121.7) U/L, and median erythropoietin (EPO) 70.5 (range 15, 11191) IU/L. Hb improvements achieved in the core period were sustained in the LTE. Mean (SD) Hb 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 (change in mean [SD] bilirubin and LDH, –15.8 [16.6] μmol/L and –63.6 [216.0] U/L, respectively; change in 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), 0 were grade ≥3. No treatment-related serious AEs or trends for decreases in bone mineral density were observed.

In pts with either α- or β-thalassemia, a favorable efficacy-safety profile was observed with long-term mitapivat treatment. Data show sustained improvements in Hb, hemolysis, and ineffective erythropoiesis across a spectrum of globin genotypes, and no new safety findings.

Mitapivat's mechanism of action may represent a novel therapeutic approach for thalassemia. Two phase 3 trials of mitapivat in α- and β-thalassemia for both NTD (ENERGIZE, NCT04770753) and transfusion-dependent (ENERGIZE-T, NCT04770779) pts are enrolling.