More Positive Data Sets Up Agios' Mitapivat for Regulatory Filings This Year

Agios reported its second positive Phase III readout for small molecule mitapivat to treat pyruvate kinase deficiency, this time meeting its primary endpoint of reduced blood transmission burden.

The news preps the genetic diseases company for regulatory filings this year in U.S. and Europe, and sets up a play for mitapivat in the bigger thalassemia and sickle cell disease markets thereafter. The readout is also welcome news after the company sold off its cancer business last month.

In the open-label ACTIVATE-T trial, 10 of 27 pyruvate kinase deficiency patients receiving oral mitapivat met the primary endpoint, a 33% or better reduction in transfusion burden at 24 weeks of twice-daily treatment, compared with individual historical transfusion burden. Six of those responders were transfusion-free during that period.

In results announced last month in Agios’s ACTIVATE trial, 40% of patients in the group receiving mitapivat had a response of ≥1.5 g/dL increase in hemoglobin concentration, that trial’s primary endpoint, at weeks 16, 20 and 24.

Pyruvate kinase deficiency is a rare and debilitating hemolytic anemia caused by mutations in pyruvate kinase genes that encode for enzymes present in red blood cells (PKR). The mutations lead to low pyruvate kinase enzyme activity, energy deficits in red blood cells and a buildup of metabolites upstream.

Mitapivat is an allosteric activator of both wild-type and mutated pyruvate kinase enzymes present in red blood cells, which has been shown to increase adenosine triphosphate and reduce upstream metabolites. Agios intends to launch an additional Phase III study this year in patients with less severe disease who do not receive regular transmissions.

The company expects to file a biologics license application with U.S. Food and Drug Administration (FDA) in 2Q21 and file for regulatory approval in Europe shortly thereafter.

The therapeutic approach may work beyond pyruvate kinase deficiency as well. Mitapivat is in Phase II testing in adult patients with both α- and β-thalassemia, and a Phase III study in thalassemia patients receiving transfusions is planned for 2H21.

The company also reported preliminary safety data from a Phase I trial last month of mitapivat in sickle cell disease patients, consistent with findings in pyruvate kinase deficiency.

Chris Bowden, Agios’s chief medical officer, said the data supports continuing clinical evaluation in other hemolytic anemias like thalassemia and sickle cell disease.

“ACTIVATE-T represents our first study of mitapivat in regularly transfused patients, and these positive results may further de-risk our ENERGIZE-T pivotal study in regularly transfused thalassemia patients,” Bowden said.

Mitapivat received orphan drug designations by the FDA last year for treatment of pyruvate kinase deficiency, thalassemia, and sickle cell disease.

Mitapivat is an increasingly important asset following the sale of Agios’s cancer portfolio to Servier in December, who paid $1.8 billion up front. In the deal, Servier acquired Tibsovo, approved in the U.S. for leukemia and vorasidenib, in Phase III testing for glioma.