Mitapivat Produces Durable Hemoglobin Responses in Patients With Pyruvate Kinase Deficiency

Based on analysis of data from the ACTIVATE and ACTIVATE-T studies and their associated long-term extension (LTE) phases, mitapivat (AG-348) appeared to significantly improve hemoglobin (Hb), markers of hemolysis and hematopoiesis, and disease burden in patients with pyruvate kinase (PK) deficiency. It also significantly reduced transfusion burden in regularly transfused patients. The report was presented at the 2021 Annual Meeting & Exposition of the American Society of Hematology.

The study’s lead author, Rachael F. Grace, MD, from the Dana-Farber Boston Children’s Cancer and Blood Disorders Center in Boston, Massachusetts, concluded that the consistent and durable long-term responses observed supported mitapivat’s “potential to become the first disease-modifying drug therapy approved for PK deficiency.”

Pyruvate kinase (PK) deficiency, a rare hereditary anemia, is caused by mutations in the PKLR gene that encodes the red blood cell PK enzyme (PKR) and leads to chronic hemolytic anemia.

The ACTIVATE study administered mitapivat or a placebo to patients who were not regularly transfused. The primary endpoint was Hb response. The ACTIVATE-T study consisted of patients who were regularly transfused who all received mitapivat. The primary endpoint was transfusion response, and the secondary endpoint was transfusion-free status. Patients who completed either study’s fixed-dose period could continue to receive mitapivat in the LTE.

The authors reported that 40% of patients treated with mitapivat in ACTIVATE achieved a Hb response. Patients who switched from placebo to mitapivat between ACTIVATE and the LTE achieved similar improvements. Thirteen of 15 patients who received mitapivat in ACTIVATE and in the LTE maintained a ≥1.5 g/dL Hb increase from baseline over 19.5 months. The remaining two participants maintained a ≥1 g/dL Hb increase.

In ACTIVATE-T, 37% of patients experienced a transfusion response and 22% of patients achieved transfusion-free status. All six patients who achieved transfusion-free status in ACTIVATE-T maintained transfusion independence in the LTE, up to 21.9 months.

The study authors concluded that mitapivat effectively targeted underlying PKR defects and thereby improved symptoms and Hb and reduced transfusion burden in patients with PK deficiency.