FDA delays decision on potential treatment for sickle cell

The U.S. Food and Drug Administration (FDA) has extended the review period for mitapivat as a potential treatment for sickle cell disease (SCD), with a decision now expected by Feb. 1, 2027.

The delay follows the FDA’s request for additional information to determine whether a Risk Evaluation and Mitigation Strategy (REMS) is needed for mitapivat, Agios Pharmaceuticals, the therapy’s developer, said in a press release. A REMS is a drug safety program that may require measures such as patient monitoring or additional safety information to help ensure a treatment’s benefits outweigh its risks.

The FDA requested the information three weeks before the application’s original Nov. 1 decision deadline. Agios Pharmaceuticals, the therapy’s developer, submitted its response on Oct. 19.

The company said its response included approximately nine months of updated safety data from the ongoing extension periods of the global Phase 2/3 RISE UP clinical trial (NCT05031780), the placebo-controlled periods from which formed the basis of the regulatory application.

The FDA informed the company on Oct. 28 that its response constituted a major amendment to its application and extended  the review period by three months.

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‘Potential to transform care’

“We have strong conviction in mitapivat’s potential to transform care for people living with sickle cell disease, grounded in the comprehensive data from the RISE UP clinical program and further supported by the additional data we submitted in response to the FDA’s recent request,” said Brian Goff, Agios’ CEO.

Agios submitted the application in May under the FDA’s  accelerated approval pathway, and the agency accepted the application in July. Accelerated approval allows a therapy to be marketed based on preliminary evidence supporting its clinical benefits. Full approval is dependent on additional clinical trial data confirming such benefits.

The application was based on RISE UP data that demonstrated mitapivat significantly boosted levels of hemoglobin, the oxygen-carrying protein in red blood cells, in people with SCD.

Agios began the global Phase 3 REIGNITE trial (NCT07656415) as a potential confirmatory study designed to assess whether mitapivat reduces the need for blood transfusions in people with SCD. The first participant was dosed in July, and the trial is actively enrolling up to 159 participants, ages 12 and older.

SCD is caused by genetic mutations that lead to the production of abnormal forms of hemoglobin, causing red blood cells to acquire a sickle-like shape. The sickled cells are stiff and sticky and can block small blood vessels, reducing oxygen delivery and triggering painful crises. They are also more prone to destruction, or hemolysis.

Mitapivat is an oral small molecule that activates pyruvate kinase (PK), an enzyme involved in producing ATP, the cells’ main energy source that is essential for red blood cell survival. It also reduces the levels of 2,3-DPG, a molecule linked to red blood cell sickling. These effects may prevent red blood cell sickling and death, which is expected to ease SCD symptoms.

The treatment is approved in the U.S. under the brand name Pyrukynd for adults with PK deficiency and as Aqvesme for adults with alpha- or beta-thalassemia, two blood diseases that reduce the body’s ability to produce hemoglobin.

RISE UP enrolled 286 SCD patients, ages 16 and older, who had low hemoglobin levels and experienced two to 10 pain crises in the previous year. In its Phase 2 part, mitapivat was shown to increase hemoglobin levels and reduce the frequency of painful crises relative to a placebo.

The trial’s Phase 3 part, in which 207 participants received either mitapivat or a placebo twice daily for 52 weeks (about one year), also met one of its main goals. Specifically, mitapivat-treated participants were significantly more likely to achieve a hemoglobin response — defined as a hemoglobin increase by at least 1 g/dL — relative to those on the placebo (40.6% vs. 2.9%).

The therapy also significantly reduced blood levels of a marker of hemolysis and the proportion of participants requiring blood transfusions during the study, compared with the placebo (23.9% vs. 40.6%).

Although the Phase 3 portion did not meet its other primary goal of significantly reducing the annual rate of pain crises, a subsequent analysis found that participants who achieved a hemoglobin response experienced fewer pain crises and related hospitalizations than those who did not.

With the additional safety follow-up, there continued to be no cases of liver cell damage with mitapivat similar to those observed in clinical trials testing the therapy in adults with thalassemia. “The benefit-risk profile of mitapivat in sickle cell disease remains unchanged,” the company said.

“We are launch-ready, building on our commercial infrastructure and the strong relationships we have established over several years with hematologists, sickle cell centers, and patients,” Goff said. “We will continue to work expeditiously with the goal of bringing mitapivat to patients with sickle cell disease as soon as possible.”