Mitapivat Safely Increases Hemoglobin Levels in SCD Patients, Phase 1 Trial Shows

Mitapivat (AG-348) safely increased the amount of hemoglobin and changed the levels of biomarkers of red blood damage and energy production in adults with sickle cell disease (SCD), early Phase 1 trial data show.

“These data build on our six years of clinical experience with this mechanism and establish proof-of-concept for mitapivat as a potential novel approach for the treatment of sickle cell disease,” Chris Bowden, MD, chief medical officer at Agios Pharmaceuticals, mitapivat’s developer, said in a press release. “Looking ahead, we are focused on advancing mitapivat to pivotal development, with the goal of initiating a pivotal study [in SCD] next year.”

Mitapivat is an oral, small molecule activator of piruvate kinase-R (PKR), an enzyme responsible for converting blood sugar, or glucose, into energy in the form of adenosine triphosphate (ATP) in red blood cells. During this process, known as glycolisis, PKR uses 2,3-diphosphoglycerate (2,3-DPG) and other compounds.

By increasing PKR activity and ATP production, mitapivat is designed to prevent the excessive accumulation of 2,3-DPG in red blood cells — an accumulation that’s thought to promote hemoglobin polymerization (hemoglobin molecules sticking to each other) and red blood cell sickling in SCD.

A Phase 1 proof-of-concept trial (NCT04000165) is currently investigating the safety, efficacy, and pharmacological properties of mitapivat in adults with SCD.

The study, which is being conducted in collaboration with the National Institutes of Health (NIH) as part of a Cooperative Research and Development Agreement, is expected to enroll approximately 25 participants. Patient recruitment is currently underway at a single site in Maryland.

During the study, patients will receive increasing doses of mitapivat — 5, 20, and 50 mg twice daily — each lasting two weeks, followed by a treatment tapering period. A recent protocol amendment introduced an additional dose of 100 mg.

To date, nine patients have been recruited, eight of whom received all planned doses of mitapivat, and one withdrew from the trial due to a pre-existing medical condition. Six received the three increasing doses (up to 50 mg) stated in the original trial protocol, and the other two were given all four doses described in the amended protocol, before tapering.

Seven of the eight patients (87.5%) who received the planned doses of mitapivat experienced increases in hemoglobin levels during the study. Five (62.5%) showed increases of 1 g/dL or higher from the study’s start while receiving 50 mg or lower doses of mitapivat.

The treatment decreased the levels of several biomarkers of red blood cell destruction, including bilirubin, lactic acid dehydrogenase, and reticulocytes. Mitapivat also lowered the levels of 2,3-DPG and increased the production of ATP, which was consistent with its proposed mechanism of action.

Additional analyses suggested that the treatment reduced red blood cell sickling and hemoglobin polymerization.

Mitapivat’s safety profile was in line with previous studies in patients with pyruvate kinase deficiency. One of the participants experienced a severe adverse event — a vaso-occlusive crisis — while tapering, which was deemed possibly related to treatment.

“The interim results from the Phase 1 study of mitapivat demonstrate for the first time that PKR activation has the potential to address chronic hemolytic anemia and impact markers of sickling in sickle cell disease patients as hypothesized based on the mechanism of action,” said Swee Lay Thein, chief of the Sickle Cell Branch of the National Heart, Lung, and Blood Institute at the NIH, and principal investigator of the study.

“The safety profile of mitapivat continues to be consistent with prior studies,” she added. “We are excited about these preliminary results, and I look forward to continuing to collaborate with Agios to advance this treatment.”

Mitapivat is also being tested in people with pyruvate kinase deficiency in Phase 2/3 clinical trials (NCT03548220, NCT03559699, and NCT02476916) and in those with thalassemia (NCT03692052).