Agios’ Mitapivat Trial Meets Primary Endpoint in Patients with Pyruvate Deficiency

Mitapivat shows improvements in pyruvate deficiency patients. 

Topline results from Agios Pharmaceuticals’ Phase III ACTIVATE trial show that treatment with mitapivat was associated with a significantly greater hemoglobin response compared with placebo in patients with pyruvate kinase deficiency, suggesting the investigational first-in-class small molecule allosteric activator therapy could hold promise for patients with this rare and inherited form of anemia.

“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 Agios’ chief medical officer, Chris Bowden, M.D., in a statement. 

The rare, inherited disease presents itself as chronic hemolytic anemia, a disorder which results in the rapid destruction of red blood cells. Additionally, the mutations in pyruvate kinase R (PKR) genes lead to a cellular energy deficit within the red blood cell as well as a reduction in levels of adenosine triphosphate (ATP). Patients with a pyruvate kinase deficiency typically experience serious complications, such as gallstones, pulmonary hypertension osteoporosis and iron overload. Also, the disease substantially impacts quality of life and emotional and mental health. 

Supportive therapy is the only available treatment for patients with pyruvate kinase deficiency, indicating there is a significant unmet treatment need for this community. Red blood cell transfusions and splenectomy are current management strategies for pyruvate kinase deficiency, but these approaches increase the risk of both short- and long-term adverse events (AEs). 

Mitapivat, a first-in-class PKR activator developed by Agios, may be one solution to the current treatment landscape for pyruvate kinase deficiency. In summer 2020, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to mitapivat for the treatment of pyruvate kinase (PK) deficiency. And in mid-November 2020, the FDA also granted Orphan Drug Designation to the drug for patients with sickle cell disease. 

In the ACTIVATE trial, patients with pyruvate kinase deficiency were enrolled if they were not receiving regular transfusions. Patients were randomly assigned to mitapivat 5m or placebo twice daily.

Topline data revealed that 40% of patients in the mitapivat group achieved hemoglobin response (≥1.5 g/dL increase in hemoglobin concentration), the study’s primary endpoint, compared with zero patients in the placebo group by weeks 16, 20 and 24. 

Patients who received mitapivat also had significant improvements in markers of hemolysis and hematopoietic activity as well as improvements in the average change from baseline in hemoglobin concentrations up to 24 weeks. In terms of safety, the investigators observed a profile consistent with previously reported data. There were no reports of AEs that led to discontinuation in either arm.

“The results of this trial, which represent the first pivotal Phase III 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,” said Dr. Bowden, “We look forward to announcing ACTIVATE-T data in the first quarter of next year.”  

Based on these and other data, Agios says it expects to file for U.S. and EU regulatory approval for mitapivat in adults with pyruvate kinase deficiency in 2021. Pending approval, the company stated it believes the therapy could have a commercial launch in these regions by 2022.