Agios halts development of oral sickle cell drug following trial

Agios Pharmaceuticals is discontinuing development of its oral therapy candidate, tebapivat, for people with sickle cell disease (SCD).

The decision follows results from a small Phase 2 clinical trial (NCT06924970) showing that while tebapivat — an activator of the pyruvate kinase (PK) enzyme — reduced measures of red blood cell destruction in SCD patients, it did not offer enough advantages over other drugs in the same class to justify further development.

“These Phase 2 data further reinforce PK activation as a clinically validated mechanism in sickle cell disease, with tebapivat demonstrating [blood-related] activity consistent with this class of medicine,” Sarah Gheuens, MD, PhD, Agios’ chief medical officer and head of research and development, said in a company press release. “However, the results did not establish the level of differentiation we believe is necessary to support continued development.”

Instead, Agios will continue to focus on mitapivat, a first-generation PK activator approved in the U.S. for two other inherited disorders affecting red blood cells. Mitapivat is under U.S. Food and Drug Administration (FDA) priority review for sickle cell, and the agency is expected to make a decision by Nov. 1. If approved, mitapivat will become the first oral PK activator approved for SCD patients, according to the company.

“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,” Gheuens said.

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Activating energy-boosting enzyme

Sickle cell disease is caused when genetic mutations lead to the production of an abnormal form of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. The faulty hemoglobin tends to clump together, causing red blood cells to stiffen and become sickle-shaped.

These misshapen cells break apart more easily than healthy red blood cells, leading to anemia (a shortage of healthy red blood cells). They can also block blood vessels, triggering painful vaso-occlusive crises and other SCD symptoms.

Tebapivat was designed to activate PK, an enzyme that helps red blood cells produce energy. By boosting PK activity, the investigational once-daily oral therapy was intended to increase energy stores in red blood cells, helping stabilize their membranes.

PK activation also reduces levels of 2,3-DPG, a compound that tends to increase in SCD and contribute to the sickling process. All these effects were expected to reduce red blood cell sickling and ease symptoms.

The Phase 2 trial, which completed enrollment earlier this year, recruited 59 people ages 16 and older with SCD. Participants were randomly assigned to receive one of three doses (2.5 mg, 5 mg, or 7.5 mg) of tebapivat or a placebo, once daily for 12 weeks (about three months).

The main goal was to determine the dose-response relationship of tebapivat in SCD and to evaluate whether the therapy offered a clinically meaningful advantage over other PK activators.

Over the 12-week treatment period, tebapivat increased hemoglobin levels across all three dose groups, reflecting reduced red blood cell destruction, consistent with the way PK activators are expected to work.

Depending on the dose, 29.4% to 47.1% of tebapivat-treated participants achieved the study’s main goal — an increase of at least 1 g/dL in hemoglobin levels — compared with 33% of those given the placebo. The therapy’s safety profile was also consistent with earlier SCD studies, with no new safety concerns identified.

Despite these results, Agios concluded that the therapy did not demonstrate enough differentiation from other PK activators to support continued development and said it will instead remain focused on advancing mitapivat.

Mitapivat, which is taken orally twice daily, has so far shown positive results in SCD trials. In the global Phase 3 RISE UP trial (NCT05031780), the therapy proved superior to a placebo at boosting hemoglobin levels in adolescents and adults with SCD, meeting the study’s main goal. Participants who responded to the treatment also experienced fewer pain crises and related hospitalizations, as well as clinically meaningful reductions in fatigue.