Mitapivat showed positive safety and efficacy outcomes in patients with pyruvate kinase deficiency, according to results from a phase 2 trial.
After 24 weeks of treatment, the therapy was associated with a rapid rise in hemoglobin levels in 50% of study participants, while the majority of toxicities reported were transient and low grade.
“The primary objective of this study was to assess the safety and side-effect profile of mitapivat administration in patients with pyruvate kinase deficiency,” wrote Rachael F. Grace, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. The findings were published in the New England Journal of Medicine.
The uncontrolled study included 52 adults with pyruvate kinase deficiency who were not undergoing regular transfusions.
The median age at baseline was 34 years (range, 18-61 years), 62% of patients were male, and the median baseline hemoglobin level was 8.9 g/dL (range, 6.5-12.3 g/dL). In addition, 73% and 83% of patients had previously undergone cholecystectomy and splenectomy, respectively.
Study patients received oral mitapivat at 50 mg or 300 mg twice weekly for a total of 24 weeks. Eligible participants were subsequently enrolled into an extension phase that continued to monitor safety.
At 24 weeks, the team reported that 26 patients – 50% – experienced a greater than 1.0-g/dL rise in hemoglobin levels, with a maximum mean increase of 3.4 g/dL (range, 1.1-5.8 g/dL). The first rise of greater than 1.0 g/dL was observed after a median duration of 10 days (range, 7-187 days).
Of the 26 patients, 20 had an increase from baseline of more than 1.0 g/dL at more than half of the assessment during the core study period. That met the definition for hemoglobin response, according to the researchers.
“The hemoglobin response was maintained in the 19 patients who were continuing to be treated in the extension phase, all of whom had at least 21.6 months of treatment,” they wrote.
With respect to safety, the majority of adverse events were of low severity (grade 1-2) and transient in nature, with most resolving within 7 days. The most frequently reported toxicities in the core period and extension phase were headache (46%), insomnia (42%), and nausea (40%). The most serious reported toxicities were pharyngitis (4%) and hemolytic anemia (4%).
“Patient-reported quality of life was not assessed in this phase 2 safety study, although such outcome measures are being evaluated in the ongoing phase 3 trials,” Dr. Grace and colleagues wrote. “This study establishes proof of concept for a molecular therapy targeting the underlying enzymatic defect of a hereditary enzymopathy,” they concluded.
Agios Pharmaceuticals funded the study. Dr. Grace reported research funding from and consulting for Agios, and several authors reported employment, consulting, or research funding with the company.
SOURCE: Grace RF et al. N Engl J Med. 2019;381:933-44.