Mitapivat improves Hb, decreases hemolysis in pyruvate kinase deficiency: NEJM

USA: Mitapivat significantly increases the hemoglobin level, improves patient-reported outcomes, and decreases hemolysis in patients with pyruvate kinase deficiency, a recent study has found. The researchers identified no new safety signals in the patients who received mitapivat. The study appears in the New England Journal of Medicine. 

"The lifelong anemia associated with pyruvate kinase deficiency results in chronic fatigue, reduced exercise tolerance, and a reduced ability to concentrate at work or school, which can make it a challenge to get through even a normal day," says lead author Hanny Al-Samkari, MD, a hematologist and clinical investigator at MGH and an assistant professor of Medicine at Harvard Medical School. "Moreover, most patients develop other potentially serious complications, like iron overload in the liver and/or heart (which can cause cancer or death), osteoporosis, gallbladder disease, blood clots, and other issues."

Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is tied to hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase was shown to increase the hemoglobin level in patients with pyruvate kinase deficiency.

Hanny Al-Samkari and colleagues evaluated the safety and efficacy of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. They were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or a placebo for 24 weeks. 

A hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24 was the primary endpoint. 

The findings confirm that through its novel mechanism of up-regulating the enzymatic activity of pyruvate kinase and thus increasing ATP levels in red cells, mitapivat successfully addressed the underlying cause of chronic hemolysis and hemolytic anemia in some patients with pyruvate kinase deficiency. The clinical efficacy of mitapivat and its benefit with respect to health-related quality of life is further supported by improvements in the pyruvate kinase deficiency–specific patient-reported outcome measures. 

"Patients who received mitapivat had substantially greater decreases in symptom severity and disease effects at 24 weeks compared to those who received placebo," wrote the authors. "A longer follow-up is warranted to assess the durability of these improvements."

Reference:

The study titled, "Mitapivat versus Placebo for Pyruvate Kinase Deficiency," was published in the New England Journal of Medicine.

DOI: 10.1056/NEJMoa2116634