Hemoglobin Improvement Fails to Differentiate, Agios Ends Tebapivat Development for Sickle Cell Disease

In the crowded field of sickle cell disease, demonstrating that a drug candidate is “effective” may no longer be enough. After reporting Phase 2 trial results, Agios Pharmaceuticals decided to discontinue development of the oral drug tebapivat. The key issue was not a complete lack of hematologic activity, but that its effects were insufficiently differentiated from those of other candidates in the same class.

The randomized, double-blind, placebo-controlled trial enrolled 59 patients aged 16 years or older. Participants received once-daily tebapivat at 2.5, 5, or 7.5 mg, or placebo, with the primary comparison based on mean hemoglobin concentration during weeks 10 through 12 of treatment. The study defined achievement of the primary efficacy endpoint as an increase in hemoglobin of at least 1 gram per deciliter from baseline.

The results showed that 43.8% of patients in the 2.5 mg group met the endpoint, compared with 47.1% in the 5 mg group and 29.4% in the 7.5 mg group. The rate in the placebo group was 33.3%. The highest dose did not produce a higher response rate, leaving the trial without a clear dose–response relationship and weakening the basis for selecting a dose for subsequent larger studies.

Agios said improvements in hemoglobin and markers of hemolysis were observed across all dose groups, consistent with the expected effects of pyruvate kinase activation. However, the company’s development criteria also included differentiation from other drugs in the same class. Only topline results were released, without statistical comparisons between groups, complete secondary endpoint results, or data on individual adverse events. The placebo group also included only nine patients, so the percentages alone cannot establish the precise magnitude of efficacy.

The company said tebapivat’s safety and tolerability were consistent with previous sickle cell disease trials, but did not provide details in the announcement. The 12-week study primarily measured hemoglobin response and therefore could not determine whether the drug could reduce, over the long term, outcomes that more directly affect patients’ lives, such as vaso-occlusive crises, hospitalizations, or organ damage.

Following the discontinuation of tebapivat, Agios will focus its work in the disease more heavily on another pyruvate kinase activator, mitapivat. Its supplemental new drug application is under priority review by the US FDA, with a target decision date of November 1, 2026. Novo Nordisk’s etavopivat is also advancing through late-stage development. With competitors already accumulating Phase 3 data, tebapivat’s lack of a clear dose response made it more difficult to justify continued investment. According to Agios’s publicly disclosed development pipeline at the time, the drug also had no other indications under investigation.