First patient dosed in key trial of sickle cell treatment under review in US
Global study aims to confirm benefits of mitapivat for use in SCD
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The first participant has now been dosed in a global clinical trial designed to confirm the benefits of mitapivat, an oral therapy under regulatory review in the U.S. for the treatment of sickle cell disease (SCD), its developer Agios Pharmaceuticals announced.
The U.S. Food and Drug Administration (FDA) is due to decide by Nov. 1 whether or not to approve the treatment candidate — already cleared for use in other blood-related diseases — to treat SCD.
The Phase 3 trial, dubbed REIGNITE (NCT07656415), is mainly designed to determine whether mitapivat is superior to a placebo at reducing the need for blood transfusions in people with SCD. It’s expected to enroll 159 SCD patients, ages 12 and older, at sites around the world. Recruitment is underway at three U.S. locations.
REIGNITE is the confirmatory trial required by the FDA to allow the potential accelerated approval of mitapivat in the U.S., according to a press release from Agios that provided the company’s latest financial results and business updates. Accelerated approvals allow experimental therapies for serious diseases to reach patients sooner based on preliminary clinical trial evidence of their beneficial effects. Full approval is dependent on additional data from a confirmatory trial.
Agios submitted its application seeking mitapivat’s accelerated approval to the FDA earlier this year, after reaching an agreement with the agency on REIGNITE’s design. The FDA has granted the application priority review, which shortens the review period from the standard 10 months to six months.
The company also announced that an application seeking approval for mitapivat in Saudi Arabia for SCD has been submitted to the country’s regulatory authorities.
SCD is a rare inherited blood disorder in which an abnormal form of hemoglobin — the protein that carries oxygen in red blood cells — clumps together, causing the cells to become stiff and sickle-shaped.
These sickle cells break down more easily, leading to anemia, or low red blood cell counts, and are more likely to clump together and block blood flow, resulting in painful crises.
Trial
Mitapivat is an oral therapy designed to activate pyruvate kinase (PK), an enzyme that helps red blood cells produce energy. This is expected to increase energy stores needed to maintain red blood cell integrity and survival. PK activation also lowers levels of 2,3-DPG, a molecule that is elevated in SCD and promotes red blood cell sickling.
Through these effects, mitapivat is expected to reduce sickling and the premature hemolysis, or red blood cell destruction, potentially easing anemia and other SCD symptoms.
The treatment is approved in the U.S. as Pyrukynd for adults with pyruvate kinase deficiency, a genetic disorder marked by accelerated hemolysis, and as Aqvesme for anemia in people with thalassemia, another bleeding condition.
In the U.S. and Europe, mitapivat has been granted orphan drug designation for SCD, which is designed to accelerate the therapy’s development through incentives that can include certain fee reductions and a period of market exclusivity if the therapy is approved.
Applications seeking mitapivat’s approval for SCD are supported by findings from the Phase 2/3 RISE UP clinical trial (NCT05031780). A total of 286 adolescents and adults with SCD were enrolled in the study. All had low hemoglobin levels (between 5.5 and 10.5 g/dL) and had experienced two to 10 pain crises in the previous year.
In the trial’s Phase 2 portion, 79 participants were randomly assigned to receive oral tablets of either one of two therapy doses (50 or 100 mg) or a placebo, twice daily for about three months. Data showed that mitapivat significantly increased hemoglobin levels and reduced the frequency of pain crises compared with the placebo.
The one-year Phase 3 portion tested the optimal mitapivat dose (100 mg) against a placebo in 207 participants. Those results showed that mitapivat was associated with a significantly higher rate of hemoglobin responders — defined as patients with an hemoglobin increase of at least 1 g/dL — between six months and one year of treatment than the placebo (40.6% vs. 2.9%).
Among hemoglobin responders with mitapivat, meaningful reductions in pain crises, hospitalizations, and fatigue were also observed. The therapy’s safety profile was consistent with that seen in previous studies.
Participants who completed either portion could enter the trial’s open-label extension portion, in which all are receiving mitapivat for up to four years.
At least 1 blood transfusion needed for REIGNITE eligibility
In REIGNITE, eligible SCD patients must have hemoglobin levels between 5.5 and 10.5 g/dL, have experienced no more than 10 pain crises in the previous year, and have received at least one blood transfusion in that same period.
The participants are randomly assigned to receive either mitapivat or a placebo twice daily for 52 weeks, or about one year.
The trial’s main goal is to determine how many participants can remain free from blood transfusions between weeks four and 52, or approximately the one-month and one-year marks. Researchers will also assess how many units of red blood cells participants require, how many experience pain crises, and changes in hemoglobin and other markers of hemolysis.
Those who complete the study’s placebo-controlled portion may enter an open-label extension portion, in which all will receive mitapivat for 52 weeks.
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