Proof of Concept for the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non–Transfusion-Dependent Thalassemia: Interim Results from an Ongoing, Phase 2, Open-Label, Multicenter Study

Background: Thalassemias are characterized by compromised red blood cell (RBC) survival due to mutations in the genes encoding α- and/or β-globins. Imbalanced globin chain production results in excess α- or β-globin precipitation, reduced RBC fitness, and ineffective erythropoiesis and hemolysis. Adenosine triphosphate (ATP) levels are reduced in thalassemic RBCs, despite increased energy demands to clear globin precipitates and maintain cell membrane integrity. Mitapivat (AG-348) is a first-in-class, small-molecule, oral activator of RBC pyruvate kinase (PKR), a key enzyme regulating ATP production via glycolysis. Glycolysis is the primary means of RBC energy generation. Increasing ATP synthesis via PKR activation by mitapivat may improve thalassemic RBC fitness and survival, thus ameliorating anemia and other clinical sequelae. In a phase 2 study of PK deficiency caused by mutations in PKR, BID dosing with mitapivat increased hemoglobin (Hb) by > 1.0 g/dL in 50% of patients (pts). Studies in β-thalassemia mouse models and healthy adults suggested benefits from activating wild-type PKR.

Objective: To report interim results from an ongoing study of mitapivat in adults with non-transfusion dependent thalassemia (NTDT).

Methods: This open-label, phase 2 study (NCT03692052) evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with NTDT in a 24-week (wk) core treatment period plus optional 2-year extension. Key inclusion criteria are presence of β-thalassemia ± α-globin gene mutations, HbE β-thalassemia, or α-thalassemia (HbH disease); Hb ≤ 10.0 g/dL; ≤ 5 RBC units transfused in preceding 24 wks and none in 8 wks prior to study drug. Pts were to receive mitapivat 50 mg orally twice daily (BID) for 6 wks with a possibility to increase to 100 mg BID at the wk 6 visit, depending on safety. Primary endpoint is % pts who achieve a Hb response (increase ≥ 1.0 g/dL from baseline (BL) any time between wks 4–12, inclusive). Key secondary/exploratory endpoints include sustained or delayed Hb response, markers of hemolysis and hematopoietic activity and safety.

Results: Eighteen pts (13 female), had received mitapivat as of 03March2020 (data cut). Median age was 43.5 years (range 29–67); median BL Hb was 8.4 g/dL (range 5.6–9.8). Full BL demographics and characteristics are shown in the Table. All pts were able to be escalated to 100 mg BID at the wk 6 visit; at data cut, 13 pts had completed 12 wks of treatment and were evaluable for the primary endpoint. Twelve of these pts (92.3%, 90% confidence interval 68.4, 99.6) achieved a Hb increase from BL ≥ 1.0 g/dL after a median of 3.1 wks (range 1.4–7.1), including 4/4 pts with α-thalassemia and 8/9 pts with β-thalassemia. Of the 13 pts, mean Hb increase from BL during wks 4–12 was 1.34 g/dL (standard deviation [SD] 0.70). Directional improvements in markers of erythropoiesis and hemolysis were observed. Mean increase in ATP from BL to wk 12 was 86.7%, similar to that previously observed in healthy subjects. Nine of 13 pts had completed 24 wks of treatment as of the data cut; all had β-thalassemia. Among this group, mean (SD) change in Hb from BL during wks 4–24 was 1.43 (0.8) g/dL. A sustained response (defined as achieving ≥ 2 Hb increases of ≥ 1 g/dL vs BL during wks 12–24 among those achieving a primary Hb response during wks 4–12) was achieved in 7/8 pts. Hb change over time in pts who completed at least 12 wks of treatment is shown in the Figure.

The safety profile was consistent with that of previously published mitapivat studies. As of the data cut, there were no serious adverse events (AEs) or AEs leading to treatment discontinuation. AEs occurring in > 3 pts were insomnia, dizziness, cough, dyspepsia, fatigue, headache, nasal congestion, nausea and upper respiratory tract infection. Post data cut, 1 serious AE of renal dysfunction was reported, which resolved upon treatment discontinuation. Dose escalation up to 100 mg BID was well tolerated and not associated with increased AEs.

Conclusions: These data demonstrate proof of concept that activation of wild-type PKR by mitapivat improved Hb and associated markers of hemolysis and erythropoiesis in pts with either α- or β-thalassemia and support its further investigation; pivotal trials are in development. This is the first clinical study evaluating PKR activation as a therapeutic option in α- and β-thalassemia, and the first drug trial aimed at treating α-thalassemia.