RARE Daily

Agios Reports Positive Late-Stage Results of Therapy for PK Deficiency

December 1, 2020

Rare Daily Staff

Agios Pharmaceuticals reported that its late-stage study of its experimental therapy mitapivat in adults with the rare blood disorder pyruvate kinase deficiency who do not receive regular transfusions met its primary endpoint.

Treatment with mitapivat demonstrated a statistically significant, sustained increase in hemoglobin compared to placebo. The safety profile observed in the study was generally consistent with previously published data.

Pyruvate kinase (PK) deficiency is an inherited disease that presents as chronic hemolytic anemia, which is the accelerated destruction of red blood cells. The inherited mutations in PKR genes cause a deficit in cellular energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate (ATP) levels and a build-up of upstream metabolites.

Mitapivat is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated PKR enzymes. It has been granted orphan drug designation for the treatment of PK deficiency by the U.S. Food and Drug Administration and the European Medicines Agency. Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and sickle cell disease.

The phase 3 ACTIVATE trial was a global, double-blind, placebo-controlled trial with a 1:1 randomization evaluating the efficacy and safety of mitapivat as a potential treatment for adults with PK deficiency who do not receive regular transfusions. Patients were required to have a hemoglobin concentration less than or equal to 10.0g/dL. The trial randomized 80 patients.

The study was designed with two parts. Part 1 was a dose escalation period in which patients started at 5 mg of mitapivat or placebo twice daily, with two potential dose escalations to 20 mg twice daily and 50 mg twice daily over a 12-week period. After the dose escalation period, patients received a fixed dose for an additional 12 weeks in part 2. The primary endpoint of the study was hemoglobin response that is sustained at two or more scheduled assessments at weeks 16, 20, and 24 during part 2 of the trial.

Some 40 percent of patients randomized to mitapivat achieved a hemoglobin response (defined as a ≥1.5 g/dL increase in hemoglobin concentration from baseline) that is sustained at two or more scheduled assessments at Weeks 16, 20, and 24 during the fixed-dose period, compared to 0 patients randomized to placebo.

Treatment with mitapivat demonstrated statistically significant improvements over placebo across pre-specified key secondary endpoints, including average change from baseline in hemoglobin concentration at Weeks 16, 20, and 24 during the fixed-dose period.

The safety profile observed in the study was generally consistent with previously reported data. There were no adverse events leading to discontinuation in either the mitapivat or the placebo arm.

Agios anticipates filing for regulatory approval in the United States and European Union in adults with PK deficiency in 2021, with a potential 2022 commercial launch in both geographies.

“The robust, clinically meaningful efficacy and safety results from the ACTIVATE study underscore mitapivat’s potential to be the first disease-modifying therapy for people with pyruvate kinase deficiency, a chronic, lifelong hemolytic anemia that often leads to serious physical and quality of life complications,” said Chris Bowden, chief medical officer at Agios. “The results of this trial, which represent the first pivotal phase 3 clinical data for mitapivat, support our hypothesis that mitapivat can improve the health, energy and longevity of red blood cells in patients with hemolytic anemias.”

Photo: Chris Bowden, chief medical officer at Agios.

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