Agios Pharmaceuticals is stopping development of a drug for sickle cell disease after mid-stage clinical data showed the molecule failed to show sufficient differentiation from others in its class, including another Agios drug that’s currently under FDA review in this indication.
The failed Agios drug, tebapivat, is an oral small molecule designed to bind to an enzyme called pyruvate kinase-R (PKR), a form of the PK enzyme that’s found in red blood cells. Binding to and activating this enzyme was hoped to inhibit the process by which hemoglobin takes on the abnormal shape that gives sickle cell disease its name. Drugging PK already has validation. Agios’s mitapivat, brand name Pyrukynd, is a PK activator that’s approved for treating anemia caused by the rare disease PK deficiency.
Agios is seeking to add sickle cell disease to the label of Pyrukynd, a twice-daily pill. But the company developed the PKR activator tebapivat to offer the advantage of once-daily dosing. According to preliminary Phase 2 results reported Tuesday, the study led to improvement in the low hemoglobin levels and destruction of red blood cells that is characteristic of sickle cell disease.
However, the response was not dose dependent and the results for this Agios drug were not enough to stand out compared to the Phase 3 results achieved by Pyrukynd in this indication. They’re also undifferentiated from the Phase 3 results reported in April for etavopivat, a PKR-activator from Novo Nordisk.
Leerink Partners made no changes to its model for Agios, which did not include tebapivat for sickle cell disease. But analyst Andrew Berens said in a research note that this drug represented Agio’s primary opportunity to show competitiveness with Novo Nordisk’s PKR activator. He added that tebapivat’s shortfall in the sickle cell trial places greater importance on commercial execution for mitapivat. In addition to its approval in PK deficiency, the FDA last December approved the molecule as a treatment for alpha- and beta-thalassemia. For this rare hemoglobin disorder, the drug is marketed under the brand name Aqvesme.
Sickle cell disease has had a string of disappointing developments. In 2024, Pfizer voluntarily withdrew Oxbryta from the market after post-marketing studies showed higher risks of complications and deaths. Last year, a different Pfizer drug developed to treat a complication of sickle cell disease failed a Phase 3 study. And last month, Fulcrum Therapeutics stopped development of pociredir in sickle cell disease based on the FDA’s conclusion that all drugs in the molecule’s class posed a risk of causing cancer.
Two weeks ago, the FDA accepted Agios’s application seeking to expand mitapivat’s label to sickle cell disease. The agency set a Nov. 1 target date for a regulatory decision.
“We remain focused on mitapivat, our foundational PK activator, which is under FDA Priority Review in sickle cell disease with an expected U.S. approval later this year,” Sarah Gheuens, Agios’s chief medical officer and head of R&D, said in a prepared statement. “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.”
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