Agios’ Pyrukynd Approved in the EU for the Treatment of PK Deficiency in Adult Patients

Rare Daily Staff

The European Commission has granted marketing authorization for Agios Pharmaceuticals’ Pyrukynd for the treatment of pyruvate kinase deficiency in adult patients.

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.

Pyrukynd (mitapivat) is a first-in-class, oral PK activator and the first approved disease-modifying therapy for patients in the EU with this rare, debilitating, lifelong hemolytic anemia.

“With today’s EU approval, we are proud to expand the positive impact of Pyrukynd for more patients with PK deficiency around the globe,” said Brian Goff, CEO at Agios. “We are dedicated to continued innovation on behalf of people with rare and genetically defined diseases and are working to further expand the impact of Pyrukynd through our ongoing investigational pivotal programs in pediatric PK deficiency, thalassemia and sickle cell disease.”

The EU marketing authorization was 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. Pyrukynd demonstrated a statistically significant increase in hemoglobin in patients with PK deficiency who are not regularly transfused. Forty percent (n=16) of patients randomized to Pyrukynd 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.

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. Thirty seven percent (n=10) 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. Twenty two percent (n=6) of patients were transfusion-free during the fixed-dose period.

The most common adverse reaction across both studies was insomnia (19.4 percent), and the most common laboratory abnormalities observed were oestrone decreased (males) (43.5 percent) and oestradiol decreased (males) (8.7 percent).

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

The company is enrolling pediatric PK deficiency patients in two pivotal studies – ACTIVATE-kids and ACTIVATE-kidsT – in patients who are not regularly transfused and who are regularly transfused, respectively. Agios also continues to advance its phase 3 ENERGIZE and ENERGIZE-T studies in non-transfusion-dependent and transfusion-dependent adults with thalassemia, respectively, as well as its phase 2/3 RISE UP study in sickle cell disease.

Pyrukynd was previously granted orphan drug designation by the EMA, which is maintained at the time of EU marketing authorization. Agios has also applied for a marketing authorization for Pyrukynd as a treatment for PK deficiency in adult patients in Great Britain under the European Commission Decision Reliance Procedure (ECDRP) with the Medicines and Healthcare Products Regulatory Agency.

Pyrukynd was approved by the U.S. Food and Drug Administration in February 2022 for the treatment of hemolytic anemia in adults with PK deficiency.

Photo: Brian Goff, CEO at Agios Pharmaceuticals