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FDA Approves Agios’ Pyrukynd for Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency

February 18, 2022

The U.S. Food and Drug Administration approved Agios Pharmaceuticals’ Pyrukynd (mitapivat) for the treatment of hemolytic anemia in adults with pyruvate kinase deficiency, the first approved disease-modifying therapy for this rare, debilitating, lifelong hemolytic anemia.

Pyruvate kinase (PK) deficiency is a rare, inherited disease that presents as chronic hemolytic anemia, which is the accelerated destruction of red blood cells. The inherited mutation in the PKLR gene can cause a deficit in 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, including 2,3-DPG (2,3-diphosphoglycerate).

PK deficiency is associated with serious complications, including gallstones, pulmonary hypertension, extramedullary hematopoiesis, osteoporosis and iron overload and its sequelae, which can occur regardless of the degree of anemia or transfusion burden. PK deficiency can also cause quality of life problems, including challenges with work and school activities, social life, and emotional health. Current management strategies for PK deficiency, including red blood cell transfusions and splenectomy, are associated with both short- and long-term risks.

“The successful ACTIVATE and ACTIVATE-T studies demonstrate the impact of mitapivat in significantly improving hemolysis and anemia in PK deficiency,” said Hanny Al-Samkari, hematologist and clinical investigator at the Mass General Cancer Center and Harvard Medical School, and an investigator in these pivotal phase 3 studies. “The FDA approval of mitapivat, a targeted agent and first disease-modifying medication in PK deficiency, is an encouraging step forward for these patients that addresses a significant unmet need.”

The FDA granted approval to Pyrukynd (mitapivat), a first-in-class oral PK activator, based on results from two pivotal studies, ACTIVATE and ACTIVATE-T, conducted in not regularly transfused and regularly transfused adults with PK deficiency, respectively.

The phase 3 ACTIVATE trial of mitapivat achieved its primary endpoint demonstrating a statistically significant increase in hemoglobin in patients with PK deficiency who are not regularly transfused—40 percent (n=16) of patients randomized to mitapivat achieved a hemoglobin response, compared to 0 patients randomized to placebo.

Statistically significant improvements compared to placebo were also demonstrated for all pre-specified secondary endpoints, including markers of hemolysis and ineffective erythropoiesis.

Serious adverse reactions occurred in 10 percent (n=4) of patients receiving mitapivat, including atrial fibrillation, gastroenteritis, rib fracture and musculoskeletal pain, which each occurred in 1 patient. The most common adverse reactions including laboratory abnormalities (≥ 10 percent) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males) and arthralgia.

The phase 3 ACTIVATE-T trial of mitapivat achieved its primary endpoint. Mitapivat demonstrated a statistically significant and clinically meaningful reduction in transfusion burden for patients who are regularly transfused—33 percent (n=9) of patients achieved a transfusion reduction response, defined as a ≥33 percent reduction in transfusion burden in the 24-week fixed dose period compared with individual historical transfusion burden standardized to 24 weeks and 22 percent (n=6) of patients were transfusion-free during the fixed-dose period. The adverse reactions reported in the ACTIVATE-T study were consistent with those observed in ACTIVATE.

A full analysis of these data was presented at the 2021 European Hematology Association (EHA) Virtual Congress. An extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T is ongoing and designed to evaluate the long-term safety, tolerability, and efficacy of treatment with mitapivat; initial results from the extension study were recently presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition.

In mid-2022, the company expects to initiate two pivotal studies – ACTIVATE-kids and ACTIVATE-kidsT – in pediatric patients with PK deficiency who are not regularly transfused and who are regularly transfused, respectively.

“For more than a decade, we have been pioneering the science of PK activation in order to bring Pyrukynd to people with PK deficiency and provide them with the first medication approved specifically to address this rare, debilitating blood disorder,” said Jackie Fouse, CEO of Agios Pharmaceuticals.

Agios said the average annual price of Pyrukynd would be $334,880 and it wouldn’t be raised for five years. The company also said it is offering a set of access programs aimed at reducing or eliminating patient out-of-pocket costs for the drug, including a copay program that lowers copays to $0 for eligible commercially-insured patients and a Patient Assistance Program that offers free prescriptions to eligible uninsured and underinsured patients.

Pyrukynd is expected to be available in the U.S. approximately two weeks after approval. It was reviewed by the FDA under Priority Review and was previously granted orphan drug designation. Pyrukynd is also under review by the European Medicines Agency as a potential treatment for adults with PK deficiency, and Agios expects a regulatory decision in the EU by the end of 2022.

Photo: Jackie Fouse, CEO of Agios Pharmaceuticals

Author: Rare Daily Staff

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