Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency

Abstract

BACKGROUNDPyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODSIn this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTSCommon adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONSThe administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.

Genotype‐phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

“…Due to the intrinsic difficulties of examining the relationship between genotype‐phenotype in PK deficiency, future studies should consider studying the relationship between residual PK protein level and clinical phenotype. Indeed, studies have shown that there is a relationship between residual PK protein and hemoglobin response to an oral PK activator in clinical development …”

Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

“…As shown in the companion manuscript (Lewandowski et al, 2019), the PK catalyzed reaction harnesses the free energy of PEP hydrolysis to cause ADP privation of both the mitochondria and KATP channels to depolarize the plasma membrane. The PK activator AG348 has been demonstrated to be well tolerated in Phase 1 healthy volunteer studies (Yang et al, 2018) and a Phase 2 trial in patients with PK deficiency (Grace et al, 2019;; Yang et al, 2019).…”

Molecular heterogeneity of pyruvate kinase deficiency

“… 34 , 35 This aspect has important implications, obviously from the diagnostic point of view, but also with regards to the possibility to access new specific therapies, as further discussed in the next paragraphs. 26 , 54 Laboratory confirmation of deep intronic variants is often difficult and may require specific testing such as loss of heterozygosity by analyzing an allele-specific cDNA, or the more complex minigene construct approach. 55 …”