FDA Approves First Drug for Rare Inherited Anemia

Zosia Chustecka

February 18, 2022

A new drug that is both the first in its class and the first disease-modifying agent for hemolytic anemia in adults with pyruvate kinase (PK) deficiency has been approved by the US Food and Drug Administration (FDA).

The new drug, mitapivat (Pyrukynd,from Agios Inc), was approved on the basis of clinical trials that showed that it significantly improved hemolysis and anemia in patients with PK deficiency.

PK deficiency is rare. In clinical practice, its frequency is approximately three to nine cases per one million people, the FDA noted. However, PK deficiency likely is misdiagnosed or undiagnosed, making it difficult to determine its frequency in the general population

PK deficiency is an inherited disorder that causes premature red blood cell destruction, leading to anemia, the agency explained in its announcement. Symptoms of PK deficiency range in severity and include fatigue, unusually pale skin, jaundice, shortness of breath, and a fast heart rate. Patients can also develop an enlarged spleen, can have too much iron in their blood from repeated blood transfusions, and can develop gallstones.

"Pyrukynd is the first approved therapy for PK deficiency and marks an important milestone for these patients, who may face tremendous challenges and debilitating symptoms throughout the course of this lifelong disease," said Rachael Grace, MD, pediatric hematologist and director of hematology clinical research at Boston Children's Hospital.

She was an investigator in the clinical trials that led to the approval. In a statement from the manufacturer, she added that "partnering with Agios and the PK deficiency community to improve understanding of the natural history of this rare disease and bring a new medicine to patients has been an honor, and I look forward to additional collaboration in the future."

Clinical Data

Clinical data that formed the basis of the approval came from two trials, one of which was a randomized placebo-controlled trial, and the other a single-arm study, the FDA noted. In these studies, patients received up to 50 mg of mitapivat orally twice daily after an initial dose titration period

The randomized trial involved 80 adults with PK deficiency who were not having regular blood transfusions. They were allocated to receive either mitapivat or placebo and were followed for an average of 24 weeks. The primary endpoint was the number of patients who achieved a hemoglobin response (defined as a 1.5 g/dL or greater increase in hemoglobin concentration that was sustained at two or more scheduled assessments). At the end of the study, 40% of participants who received mitapivat had a hemoglobin response, compared with no participants who received placebo.

The single-arm study involved 27 adults with PK deficiency who were receiving regular blood transfusions. They took mitapivat for an average of 40 weeks. In this study, the primary endpoint was the reduction in transfusion burden, defined as at least a 33% reduction in the number of red blood cell units transfused during the last 24 weeks of treatment compared with the historical transfusion burden on the individual participant (standardized to 24 weeks). The results show that 33% of participants who received mitavipat met this reduction in transfusion burden; 22% of participants did not require any transfusions over the last 24 weeks of treatment.

The most common side effects reported were decreases in estrone and estradiol in men, increased urate level, back pain, and joint stiffness. The effects of estrone and estradiol could not be reliably assessed in women because of normal changes in these hormone levels during the menstrual cycle and use of hormonal contraception.

The FDA warns of drug interactions that could necessitate dose adjustments, and also that abruptly stopping mitapivat could worsen premature red blood cell destruction.

The agency noted that this application received orphan drug designation, fast track designation, and priority review.

Agios is offering access programs aimed at reducing or eliminating patient out-of-pocket costs. Further details are on the myAgios patient support services program.

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

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