The First Drug for an Inherited Anemia Receives FDA Approval

For the treatment of a rare, inherited hemolytic anemia in adults caused by a deficiency of the enzyme pyruvate kinase (PK), which is critical to cellular processes, a new first-in-class drug has received FDA (United States Food and Drug Administration) approval.

The new drug, mitapivat (brand name Pyrukynd, from biotechnology company Agios), was approved on the basis of clinical trials showing significant improvements in hemolysis (the breakdown of large numbers of red blood cells) and anemia in patients with PK deficiency.

Pyruvate kinase (PK) is an enzyme with a critical role in cellular energy production, and its deficiency is rare. Its prevalence is estimated to be about three to nine cases per million people. However, PK deficiency is probably misdiagnosed or undiagnosed, making its exact prevalence in the general population difficult to determine.

What Is Pyruvate Kinase Deficiency?

PK deficiency is an inherited disorder that causes premature death/breakdown of red blood cells, leading to anemia. Symptoms of PK deficiency vary with the severity of anemia and include fatigue, unusually pale skin, jaundice, shortness of breath and a rapid heart rate. Patients may also develop an enlarged spleen, excessive iron accumulation in the blood from repeated transfusions, and gallstones.

Pyrukynd is the first approved treatment for PK deficiency and is an important milestone for these patients, who may face tremendous challenges and debilitating symptoms throughout this lifelong disease.

Clinical Trials Leading to FDA Approval

The FDA stated that the clinical data supporting approval came from two studies, one a randomized, placebo-controlled trial and the other a single-arm study. In these studies, patients received oral mitapivat at up to 50 mg twice daily after an initial dose-titration period.

The randomized clinical trial (in which patients were assigned at random) included 80 adults diagnosed with PK deficiency who were not receiving regular blood transfusions. Patients were randomly assigned to two arms to receive mitapivat or placebo and were followed for an average of 24 weeks. The primary endpoint was the number of patients achieving a hemoglobin response (defined as an increase in hemoglobin concentration of 1.5 g/dL or more sustained at two or more scheduled assessments). At the end of the study, 40% of participants receiving mitapivat had a hemoglobin response, whereas no participants receiving placebo had an increase in hemoglobin.

The single-arm study included 27 adults with PK deficiency who received regular blood transfusions. Patients received mitapivat for a median of 40 weeks. The primary endpoint in this study was a reduction in transfusion burden, defined as at least a 33% reduction in the number of red blood cell units transfused during the final 24 weeks of treatment compared with the individual participant’s historical transfusion burden. The results show that 33% of participants receiving mitavipat met this reduction in transfusion burden; 22% of participants did not need any transfusion during the final 24 weeks of treatment.

The most commonly reported side effects were decreased estrogen hormones in men, increased urate levels, back pain and joint stiffness. The effects on estrogen hormones could not be reliably assessed in women because of normal changes in these hormone levels during menstruation and oral contraceptive use.

The FDA warns about drug interactions that may require dose adjustment and that abruptly discontinuing mitapivat may worsen premature red blood cell destruction.

The FDA noted that the application received orphan drug designation, fast track designation and priority review.

The company also noted that mitavipat was awaiting approval in the European Union. A decision was expected before the end of 2022.