Mitapivat Demonstrates Safety, Tolerability Among Sickle Cell Disease Patients


The ongoing phase I study also demonstrates that the drug is associated with an increase in Hb from baseline with a concomitant decrease in hemolytic markers.

Julia Xu, MD, MS

Julia Xu, MD, MS

A new study found that mitapivat—an oral, small molecule, allosteric activator—demonstrated a positive safety profile in patients with sickle cell disease.

Furthermore, the data indicated potential efficacy as demonstrated by an Hb increase from baseline with simultaneous decreases in hemolytic markers.

The ongoing Phase I study, presented at the American Society of Hematology (ASH) 2020 Annual Meeting, is led by Julia Xu, MD, MS, of the National Institutes of Health, and is currently assessing the tolerability and safety, in addition to the pharmacokinetics and pharmacodynamics, of multiple ascending doses of the drug.

Mitapivat, also known as AG-348, has the capability to activate “both mutant and wild type red cell pyruvate kinase (PKR), thus decreasing 2,3- diphosphoglycerate (DPG) and increasing adenosine triphosphate (ATP) levels in red cells and potentially acting as an anti-sickling agent," the investigators noted.

Thus, they initially enrolled a total of 9 individuals ≥18 years of years, who were confirmed with sickle cell disease. Additionally, all patients had adequate organ function, baseline Hb ≥ 7 g/dL, and had not undergone transfusions or erthyropoietin therapy 3 months prior to start of treatment.

During the course of the study period, 1 patient discontinued treatment and was subsequently lost to follow-up.

The investigators then administered 3 or 4 ascending dose levels (5 mg, 20 mg, 50 mg, 100 mg, all twice daily) for 2 weeks at each level. Treatment was then followed by a 12-15 day drug taper.

The primary endpoint sought by the investigators was safety and tolerability, which they assessed according to frequency and severity of adverse events and laboratory parameters.

Secondary endpoints were changes in hematological parameters, 2,3-DPG and ATP levels, and markers of Hb S polymerization.

The mean age of the remaining 8 patients was 43.6, 5 were male, and 7 were stabilized on hydroxyurea.

Of the total, 6 reached a maximum dosage of 50 mg, while the remaining 2 reached a maximum dosage of 100 mg. 

All patients reported adverse events. The most common events were hypertension (n = 3; Grades 1-3), insomnia (n = 3, Grade 2), and asymptomatic heart rate increase on vital signs (n = 3, Grade 1).

Furthermore, 5 serious adverse events occurred in 4 individuals. However, only 1 of the events was due to the drug itself: A vaso-occlusive event during the drug taper period.

In terms of secondary endpoints, mean 2,3-DPG levels decreased and ATP levels increased according to dosage.

In 5 of the 8 patients, ATP levels remained elevated following drug taper. However, the investigators observed that at 4 weeks post-drug taper, both 2,3-DPG and ATP levels returned to near baseline levels.

Xu and team also noted that mitapivat increased Hb levels in a dose-dependent manner along with a decrease in hemolytic markers. Thus, the mean change in Hb baseline for all individuals at the 50 mg dosage level was 1.2 g/dL (range,-0.3 to 2.7 g/dL).

Of the 8, 3 achieved an Hb increase ≥1 at 20 mg dosage, while 5 achieved a similar increase at 50 mg dosage level.

Both Hb levels and hemolytic markers returned to near baseline following drug taper.

“A small dose-dependent increase in mean corpuscular volume (MCV) was also observed, suggesting a potential alternative mechanism of mitapivat, acting through the ATP-dependent Gardos channel to increase red cell hydration, decrease hemolysis, and improve red cell survival in sickle cell disease,” the investigators wrote.

They indicated that they will increase their sample size to 15 subjects, all of whom will complete 6-8 weeks of treatment. The investigators plan to present pharmacokinetics-related data.

The study, Phase 1 Multiple Ascending Dose Study of Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Mitapivat (AG-348) in Subjects with Sickle Cell Disease,” was presented at ASH 2020.

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