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Mitapivat for the Treatment of Pyruvate Kinase Deficiency
Pyruvate kinase (PK) deficiency is an inherited, rare chronic form of hemolysis resulting in anemia and, potentially, pigmented gallstones and iron overload, among other complications. Mutations involving the PKLR gene are common, though there are many pathogenic variants involving this gene. Treatment is typically supportive and includes transfusions, splenectomy, and cholecystectomy for those with gallstones.
In a prior phase 2 study of mitapivat, an activator of red cell pyruvate kinase, roughly half the patients experienced an increase in hemoglobin level of at least 1 g/dL. Now, in an industry-sponsored phase 3 study (ACTIVATE), researchers compared mitapivat to placebo in 80 patients with PK deficiency. Included patients had PKLR mutations, baseline hemoglobin ≤10 g/dL, and lack of transfusion dependence. The primary endpoint was a sustained increase in hemoglobin of at least 1.5 g/dL.
Among the findings:
- Patients had a mean age of 36 (mitapivat) and 37 years (placebo) and mean baseline hemoglobin level of 8.6 and 8.5 g/dL, respectively.
- Most patients had undergone splenectomy as well as cholecystectomy.
- The most common genetic profile in both groups was missense/missense.
- The primary endpoint was met in 16 of 40 patients treated with mitapivat, compared with none of 40 patients in the placebo group.
- Among responders, the mean change in hemoglobin level was 3.5 ± 1.4 g/dL.
- The most common adverse events in the mitapivat group included nausea in 7 patients (18%) and headache in 6 (15%) — incidences similar to or lower than those in the placebo group.
This phase 3 study demonstrates safety and efficacy for a novel treatment for PK deficiency. Although the condition is rare, access to such an agent would obviate the need for splenectomy and chronic transfusion support, which can lead to excess morbidity. There was no clear clinical characteristic that predicted response. In the prior phase 2 study, a lack of response was noted in patients with the R479H mutation as well as those with non-missense mutations involving PKLR. Such patients were excluded from the current study. The authors note that due to hundreds of PKLR variants, it is unclear that the drug would be effective in all patients. The recent FDA approval of this drug represents an important advance for those with this rare condition.
Al-Samkari H et al.
Title: Mitapivat versus placebo for pyruvate kinase deficiency.
Source: N Engl J Med 2022 Apr 14; [e-pub]. (Abstract/FREE Full Text)