Agios Announces Publication of Phase 3 ACTIVATE-T Data Demonstrating Benefits of PYRUKYND for Adults With Pyruvate Kinase Deficiency

Agios Pharmaceuticals, Inc. recently announced data from the core period of the pivotal Phase 3 ACTIVATE-T study of PYRUKYND (mitapivat) in adults with pyruvate kinase (PK) deficiency who receive regular transfusions were published on August 18, 2022, in The Lancet Haematology. Data from this study were previously presented at the 2021 European Hematology Association (EHA) Annual Congress. PYRUKYND is a first-in-class, oral PK activator and the first and only approved disease-modifying treatment for this rare, debilitating, lifelong hemolytic anemia.

“The results of the ACTIVATE-T study confirm that treatment with mitapivat substantially reduced the need for transfusions in PK deficiency patients who regularly receive them,” said Andreas Glenthøj, MD, PhD, Associate Professor, Department of Hematology, Rigshospitalet, Copenhagen, Denmark, an investigator in the pivotal ACTIVATE-T Phase 3 study and first author of this publication. “Improvements in the PK deficiency–specific patient-reported outcome measures further support the clinical efficacy of mitapivat and its benefits on health-related quality of life and reduction in symptom severity.”

“With the approval of PYRUKYND for the treatment of hemolytic anemia in adults with PK deficiency earlier this year, we delivered the very first approved medicine for patients who previously had no disease-modifying treatment options,” said Sarah Gheuens, MD, PhD, Head of R&D and Chief Medical Officer at Agios. “The results of the ACTIVATE-T study underscore the clinical value of PYRUKYND, particularly for patients who require regular transfusions to manage their disease, and support our current efforts to deliver this medicine to as many patients as possible who may benefit from it.”

As reported in the publication, the ACTIVATE-T study met its primary endpoint, with 10 of 27 patients (37%; p=0.0002) receiving PYRUKYND achieving a transfusion reduction response, defined as a ≥33% reduction in transfusion burden in the 24-week fixed dose period compared with individual historical transfusion burden standardized to 24 weeks. Nine of these responders achieved a ≥50% reduction. Additionally, six patients (22%) reached transfusion-free status during the fixed-dose period, and three patients (11%) achieved hemoglobin concentrations in the normal range at least once, eight weeks or more after a transfusion, during the fixed dose period. Improvements were also observed for two PK deficiency–specific patient-reported outcome measures. The safety profile of mitapivat was consistent with previously reported data. The most frequently reported adverse events in patients receiving mitapivat included alanine aminotransferase increase (37%), headache (37%), aspartate aminotransferase increase (18.5%), fatigue (18.5%) and nausea (18.5%). Adverse events of Grade 3 or higher occurred in 8 patients (30%) who received PYRUKYND. No serious adverse events were considered by the investigator to be related to study treatment, and only one patient experienced an adverse event leading to dose reduction.

PYRUKYND was approved in February 2022 by the US FDA for the treatment of hemolytic anemia in adults with PK deficiency. PYRUKYND is also under review by the European Medicines Agency (EMA) as a potential treatment for adults with PK deficiency, and Agios expects a regulatory decision in the EU by the end of 2022. Both the FDA and EMA have granted orphan drug designation to PYRUKYND in PK deficiency.

ACTIVATE-T is a Phase 3 global, open-label study to evaluate the efficacy and safety of mitapivat as a potential treatment for adults with PK deficiency who are regularly transfused, defined as receiving six or more transfusions in the past 52 weeks. The trial enrolled 27 patients.

The study was designed with two parts. Part 1 was a dose escalation period in which patients started at 5 mg twice daily of mitapivat, with two potential dose increases to 20 mg twice daily and 50 mg twice daily for up to 16 weeks. After the dose escalation period, patients received a fixed dose for an additional 24 weeks in Part 2.

The primary endpoint of the study was reduction in transfusion burden, defined as a reduction of ≥33 percent in the number of red blood cell units transfused during the 24-week fixed dose period compared with the historical transfusion burden standardized to 24 weeks. Participants who discontinued the study before completing at least 12 weeks of treatment in the fixed dose period were considered non-responders. The p-value is based on the binomial exact test of H0: transfusion reduction response rate ≤10% vs. H1: transfusion reduction response rate >10% at a 1-sided α=0.025.

Agios conducted an additional pivotal Phase 3 study, ACTIVATE, in adults with PK deficiency who do not receive regular transfusions; these data were published in April 2022 in the New England Journal of Medicine. The company is conducting an ongoing extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T, which is designed to evaluate the long-term safety, tolerability and efficacy of treatment with PYRUKYND.

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. For more information, please visit the websites of two U.S.-based independent patient advocacy groups dedicated to PK deficiency: PK Deficiency Foundation and Thrive with PK Deficiency.

Agios is a biopharmaceutical company that is fueled by connections. The Agios team cultivates strong bonds with patient communities, healthcare professionals, partners and colleagues to discover, develop and deliver therapies for genetically defined diseases. In the US, Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company’s leadership in the field of cellular metabolism, Agios is advancing a robust clinical pipeline of investigational medicines with active and planned programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency and MDS-associated anemia. In addition to its clinical pipeline, Agios has multiple investigational therapies in preclinical development and an industry-leading research team with unmatched expertise in cellular metabolism and genetics. For more information, visit www.agios.com.