Agios to seek accelerated approval in US of oral mitapivat for SCD
Regulatory submission plans follow meeting with FDA on new trial data
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Agios Pharmaceuticals is planning to file an application with the U.S. Food and Drug Administration (FDA) in the coming months that will seek accelerated approval of its oral therapy mitapivat for sickle cell disease (SCD).
This decision by Agios follows a prefiling meeting with the regulatory agency in which the developer presented new data from its global Phase 2/3 RISE UP clinical trial (NCT05031780). The data show mitapivat significantly increased levels of hemoglobin — the oxygen-carrying protein in red blood cells — and led to other clinical benefits in people with SCD.
“The clinically meaningful benefits observed in the RISE UP clinical program, combined with our ongoing, constructive, and collaborative dialogue with the FDA, reinforce our confidence in mitapivat’s potential in sickle cell disease,” Sarah Gheuens, MD, PhD, Agios’ chief medical officer and head of research and development, said in a company press release. “We are focused on advancing mitapivat as rapidly as possible with the rigor required for potential U.S. accelerated approval.”
Accelerated approval allows experimental therapies to be marketed in the U.S. based on preliminary clinical trial data supporting their safety and efficacy. Full approval of such medications is dependent on additional supporting data from a confirmatory trial.
The company has already submitted to the FDA the proposed design of such a confirmatory trial, which would be required for filing for accelerated approval. According to Agios, its main goal would be different from those used in the RISE UP clinical program, and was based on analyses of trial data and discussions with the FDA.
“Our engagements with the FDA continue to underscore both the unmet need in sickle cell disease and the importance of expeditiously advancing new treatment options for patients living with this complex, debilitating, and deadly disease,” Gheuens said.
SCD is caused by faulty hemoglobin that causes red blood cells to acquire the sickle-like shape that gives the disease its name. That altered shape makes these cells more prone to destruction — a process known as hemolysis — and more likely to clump together and block blood flow, leading to symptoms like anemia, marked by low red blood cell levels, and painful crises.
Trial tested mitapivat in over 250 people with SCD
Mitapivat works by activating pyruvate kinase, an enzyme in red blood cells that supports cell integrity and survival. By boosting pyruvate kinase’s activity, the medication also reduces levels of 2,3-DPG, a molecule known to promote red blood cell sickling.
The treatment is approved under the brand name Pyrukynd for adults with pyruvate kinase (PK) deficiency, a genetic condition marked by accelerated hemolysis. It’s also under review in the U.S. for another bleeding condition called thalassemia.
Mitapivat has been granted orphan drug designation in the U.S. and the European Union for SCD. This status aims to incentivize companies to develop treatments for rare diseases, providing benefits like exemptions from certain fees and a period of market exclusivity if the therapy is ultimately approved.
The RISE UP study enrolled 286 SCD adolescents and adults with low hemoglobin levels (between 5.5 and 10.5 g/dL) who had experienced two to 10 pain crises in the prior year.
Its Phase 2 portion involved 79 participants who received either one of two mitapivat doses or a placebo, twice a day. Three-month results demonstrated that the therapy was superior to the placebo at increasing hemoglobin levels and reducing the frequency of pain crises.
Therapy’s use led to more patients experiencing hemoglobin response
The ongoing Phase 3 part of the trial is evaluating the one-year safety and effectiveness of mitapivat, at a dose of 100 mg, against a placebo. It involves 207 patients.
The results have demonstrated that mitapivat was associated with a significantly higher proportion of patients experiencing a hemoglobin response, defined as at least 1.0 g/dL increase, between six months and one year of treatment, relative to the placebo (40.6% vs. 2.9%). This meant the study met its main goal.
Treatment also led to a greater reduction in the annualized rate of pain crises (2.62 vs. 3.05), though this difference was not statistically significant. That means the finding could be due to chance; as such, this other main goal was not attained.
Participants treated with mitapivat who showed a hemoglobin response also experienced clinically meaningful hemoglobin raises and reductions in pain crises and related hospitalizations, according to the data. These individuals also reported reductions in fatigue.
The treatment’s safety profile was consistent with that reported in previous mitapivat trials in SCD.
Overall, 87% of mitapivat-treated participants and 81% of those on the placebo completed the trial’s one-year, placebo-controlled Phase 3 portion. All except two chose to enter RISE UP’s open-label extension, where all will receive the treatment for as long as four years.
