Agios Pharmaceuticals has discontinued development of tebapivat in lower-risk myelodysplastic syndromes (LR-MDS) after a Phase 2b trial failed to meet efficacy thresholds, though the next-generation PK activator remains in development for sickle cell disease with topline data expected in 2H 2026.
Written By: Farha Farheen, PharmD
Reviewed By: Pharmacally Editorial Team
Agios Pharmaceuticals has discontinued development of tebapivat for patients with lower-risk myelodysplastic syndromes (LR-MDS) and anemia after a Phase 2b study failed to meet the company’s predefined threshold for further advancement.
The open-label, multicenter, 24-week trial (NCT05490446) evaluated once-daily tebapivat at 10 mg, 15 mg, and 20 mg in 65 patients. Although tebapivat showed biological activity, it failed to generate enough clinical benefit to support continued development in LR-MDS.
Study Design and Patient Population
The study enrolled a heavily pretreated and clinically heterogeneous population, reflecting the biological complexity of lower-risk MDS. Patients with LR-MDS often develop chronic anemia and may become dependent on repeated red blood cell transfusions despite available therapies, highlighting the need for additional treatment options.
The trial’s primary endpoint was transfusion independence, defined as at least eight consecutive weeks without a red blood cell transfusion during the 24-week treatment period. Clinical responses were not observed in a sufficient proportion of patients or within any identifiable subgroup to support continued development in the indication.
Mechanism of Action
Tebapivat is a next-generation oral pyruvate kinase (PK) activator that targets both PKR and PKM2 isoforms expressed in red blood cells. By enhancing cellular energy metabolism, PK activation has emerged as a clinically validated therapeutic strategy in hematologic disorders, supported by the success of PK activators in diseases such as pyruvate kinase deficiency and thalassemia.
Clinical pharmacology studies have supported once-daily dosing without the need for dose tapering, potentially offering a convenient treatment approach for patients with chronic hematologic conditions.
Safety Profile
Across all evaluated dose levels, tebapivat was generally well tolerated. Investigators reported no new safety signals, and the overall safety profile remained consistent with previous studies. However, the favorable tolerability profile was not sufficient to offset the limited efficacy observed in the trial.
Company Perspective
Sarah Gheuens, M.D., Ph.D., Chief Medical Officer and Head of Research and Development at Agios, said the findings highlight the biological complexity of LR-MDS and the challenges of identifying patients most likely to benefit from PK activation. She also acknowledged the contributions of patients, caregivers, investigators, and advocacy organizations that participated in the study.
Clinical Path Forward
While the LR-MDS program has been discontinued, Agios continues to advance tebapivat in sickle cell disease. The company expects topline results from an ongoing Phase 2 trial in the second half of 2026.
Future development of tebapivat will now depend largely on the outcome of that study. Despite the setback in LR-MDS, Agios continues to view PK activation as an important therapeutic mechanism with potential applications across rare hematologic diseases.
Reference
About the Writer
Farha Farheen, PharmD (LinkedIn) is a pharmacy professional with a strong interest in pharmacovigilance and clinical research. She has completed her Doctor of Pharmacy (Pharm.D) along with her internship as a Clinical Pharmacist. She has hands-on experience in adverse drug reaction (ADR) reporting, safety data documentation, and pharmacovigilance workflows, and is proficient in using VigiFlow. She is also a patent holder for an antibacterial formulation enriched with bioactive substances, granted by the German Patent and Trademark Office.