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Agios ends tebapivat development in sickle cell disease after phase 2 results show no differentiated benefit.
Topline results from a phase 2 trial of tebapivat in patients aged ≥16 years with sickle cell disease (SCD) showed improvements in hemoglobin and markers of hemolysis but did not demonstrate sufficient differentiation to support continued development of the pyruvate kinase (PK) activator, prompting Agios to discontinue the program.
"These phase 2 data further reinforce PK activation as a clinically validated mechanism in sickle cell disease, with tebapivat demonstrating hematologic activity consistent with this class of medicine," said Sarah Gheuens, MD, PhD, chief medical officer and head of research and development at Agios, in a statement. "However, the results did not establish the level of differentiation we believe is necessary to support continued development."
The phase 2 trial was designed to characterize the dose-response relationship of tebapivat in SCD and evaluate whether the therapy demonstrated a differentiated profile relative to other PK activators.
The 12-week, double-blind, placebo-controlled study randomized 59 patients in a 2:2:2:1 ratio to receive once-daily tebapivat at doses of 2.5 mg, 5.0 mg, or 7.5 mg or placebo QD.
The primary endpoint was hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration during Weeks 10 through 12 compared with baseline.
According to Agios, the primary endpoint was achieved by 43.8% (n = 7/16), 47.1% (n = 8/17), and 29.4% (n = 5/17) of patients receiving 2.5 mg, 5.0 mg, and 7.5 mg tebapivat, respectively, compared with 33.3% (n = 3/9) receiving placebo.
The company also reported improvements in hemoglobin levels and markers of hemolysis across tebapivat dose groups, findings it said were consistent with the established mechanism of PK activation. Safety and tolerability were consistent with prior SCD studies.
Although tebapivat demonstrated hematologic activity, Agios stated that the phase 2 findings did not establish the level of differentiation it considered necessary to support continued development in SCD. The company did not cite safety or tolerability concerns as a reason for discontinuing the program.
PK activators increase pyruvate kinase activity in red blood cells to improve cellular energy metabolism, with the goal of reducing hemolysis and improving anemia in patients with SCD. Agios noted that the results further support PK activation as a clinically validated therapeutic mechanism despite its decision not to advance tebapivat.
Agios said it will continue to prioritize mitapivat, its lead oral PK activator, which is currently under US Food and Drug Administration (FDA) Priority Review for SCD.
Earlier this month, the Agency accepted the company's supplemental New Drug Application (sNDA) for mitapivat and assigned a Prescription Drug User Fee Act (PDUFA) target action date of November 1, 2026.
"We remain focused on mitapivat, our foundational PK activator, which is under FDA Priority Review in sickle cell disease with an expected US approval later this year," Gheuens said. "We look forward to bringing this first-in-class medicine to the sickle cell community and building on the extensive clinical experience generated to date as we work to address the significant unmet need in this debilitating disease."
