Mitapivat, a pyruvate kinase-R activator, in SCD is safe with early efficacy results

Early phase 1 trial data show that mitapivat safely increased the amount of haemoglobin and decreased biomarkers of erythrocyte damage in adults with sickle cell disease (SCD).

In this phase 1 proof-of-concept study, 25 patients will ultimately be enrolled, presented Dr Kevin HM Kuo (Princess Margaret Cancer Centre, Canada) [1]. The rationale of the study is based on the fact that mitapivat is an oral, small molecule activator of pyruvate kinase-R (PKR), an enzyme which consumes 2,3-diphosphoglycerate (2,3-DPG) in glycolysis. Accumulation of 2,3-DPG in red blood cells is thought to promote haemoglobin polymerisation, and thus the hypothesis is that mitapivat will mitigate that process.

Patients receive increasing doses of mitapivat in this study — 5, 20, 50, and 100 mg twice daily — each lasting 2 weeks, followed by a treatment tapering period. To date, 9 patients have been recruited, 8 of whom received all planned doses of mitapivat.

As anticipated, mitapivat lowered 2,3-DPG levels in red blood cells, with consequent increases in ATP. Initial efficacy results look promising: 87.5% who received the planned doses of mitapivat experienced increases in haemoglobin levels during the study; 62.5% showed increases of 1 g/dL or higher from baseline while receiving 50 mg or lower doses of mitapivat. Other disease biomarkers including bilirubin, lactic acid dehydrogenase, and reticulocytes decreased on treatment. Whether the treatment reduced red blood cell sickling or haemoglobin polymerisation are not yet conclusive, but the preliminary data point to that mechanism.

Mitapivat’s safety profile was in line with previous studies in patients with pyruvate kinase deficiency; with common adverse events including transient headache and insomnia at time of drug initiation and resolving within 7 days. A single severe adverse event, a vaso-occlusive crisis which occurred during the tapering phase, was deemed possibly related to treatment.

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   1. Kuo K, et al. 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. EHA25 Virtual, 11-21 June 2020, Abstract S297.

 



Posted on 28 August, 202016 February, 2024