Publication of phase II data in The Lancet demonstrating safety and efficacy of Pyrukynd in non-transfusion-dependent alfa- and beta-thalassemia

Data from this study were previously presented at the 2021 European Hematology Association (EHA) Annual Congress.

Pyrukynd is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variealfaty of mutated pyruvate kinase (PK) enzymes.

“Consistent with previously reported findings, the data reported underscore the potential of PK activation to improve hallmarks of alfa- and beta-thalassemia, including hemolysis and ineffective erythropoiesis,” said Kevin Kuo, M.D., hematologist at University of Toronto, Toronto General Hospital, and an investigator in the study. “Thalassemia is a rare, debilitating lifelong blood disorder characterized by severe complications, with no treatment options for those with alfa-thalassemia and limited options for those with beta-thalassemia. These data demonstrate the potential clinical benefits of mitapivat for a broad spectrum of thalassemia patients and support its continued investigation in pivotal trials.”

“We are encouraged by The Lancet’s publication of our Phase II thalassemia data for Pyrukynd, which has the potential to serve as several important firsts for patients: the first oral therapy for thalassemia, and first treatment for all types of thalassemia – alfa and beta, transfusion-dependent and non-transfusion-dependent,” said Sarah Gheuens, M.D., Ph.D., head of R&D and chief medical officer at Agios. “Enrollment is underway for the Phase III ENERGIZE and ENERGIZE-T studies of Pyrukynd in adults with non-transfusion-dependent or transfusion-dependent alfa- or beta-thalassemia, respectively, and we expect to enroll a substantial portion of patients in the trials by year-end.”

As reported in the publication, 16 of 20 patients (80%; p<0.0001), including five of five (100%) with alfa-thalassemia and 11 of 15 (73%) with beta-thalassemia, achieved the primary endpoint of hemoglobin response, a greater than 1.0 g dl increase in hemoglobin concentration from baseline at one or more assessment between weeks 4–12. the mean time to hemoglobin response was 4.5 weeks. of the 16 patients who achieved the primary endpoint, 13 had a sustained response, defined as greater than 1.0 g dl increase in hemoglobin at two or more assessments between week 12 and week 24. a trend in decreasing concentrations of markers of hemolysis (total bilirubin and ldh concentrations) was observed in both alfa- and beta-thalassemia patients, with decreases observed as early as week 2. decreases in erythropoietin concentrations were also observed in both alfa- and beta-thalassemia patients. the greatest change in markers of hemolysis and erythropoiesis was observed in the first 8 weeks of treatment, and improvements were maintained over the duration of the core period.

The most common adverse events were initial insomnia (50%, including 1 patient [5%] with Grade 3), dizziness (30%, all Grade 1) and headache (25%, all Grade 2 or lower). Initial insomnia was the only Grade 3 or worse treatment-emergent adverse event considered to be treatment-related. One patient who had beta-thalassemia discontinued after Week 4 due to a treatment-emergent adverse event deemed unrelated to the study drug.

Pyrukynd was approved in February 2022 by the 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. In addition, Pyrukynd has been granted FDA orphan drug designation for the treatment of thalassemia and sickle cell disease, for which enrollment for ongoing pivotal studies is underway.

See;_ The Lancet.VOLUME 400, ISSUE 10351, P493-501, AUGUST 13, 2022 "Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent alfa-thalassaemia or beta-thalassaemia: an open-label, multicentre, phase II study";Kevin H M Kuo, MD ,Prof D Mark Layton, MBBS,. Prof Ashutosh Lal, MD, Hanny Al-Samkari, MD, Joy Bhatia, MD, Penelope A Kosinski, et al. Published:August 13, 2022DOI:https://doi.org/10.1016/S0140-6736(22)01337-X.