Engasertib versus Placebo for Bleeding in Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) can cause recurrent, severe epistaxis, as well as anemia and reduced quality of life. The disease remains without licensed therapies worldwide.

In this proof-of-concept, multicenter, double-blind, placebo-controlled trial, we evaluated the safety and efficacy of oral engasertib, a new, allosteric, selective AKT inhibitor, in patients with HHT. Patients were randomly assigned in a 1:1:1 ratio to receive engasertib at a dose of 30 mg, engasertib at a dose of 40 mg, or placebo once daily for 12 weeks. The primary outcomes were the frequency and severity of adverse events. Key secondary outcomes included the frequency and duration of epistaxis. An open-label extension is ongoing.

A total of 75 patients were assigned to 30-mg engasertib (24 patients), 40-mg engasertib (25 patients), or placebo (26 patients). Among the patients who received at least one dose of the trial regimen, the most common on-target adverse events associated with engasertib included mild-to-moderate rash (5 patients [21%] in the 30-mg engasertib group, 10 [42%] in the 40-mg engasertib group, and 2 [8%] in the placebo group) and mild-to-moderate hyperglycemia (3 patients [12%] in the 40-mg engasertib group and no patients in the other two groups), which were reversible. The incidence of serious adverse events in each of the two engasertib groups was similar to that in the placebo group. From baseline to week 12, the mean (±SD) decrease in epistaxis frequency was 26.5±26.5% with 30-mg engasertib, 27.8±35.1% with 40-mg engasertib, and 18.0±36.0% with placebo; the mean decrease in epistaxis duration was 29.9±53.2%, 41.4±41.0%, and 23.8±53.4%, respectively.

The safety profile of engasertib was similar to that of placebo except for mild-to-moderate rash, which resolved in most patients who continued to receive the drug. Engasertib treatment was associated with decreases in epistaxis frequency and duration. (Funded by Vaderis Therapeutics; ClinicalTrials.gov number, NCT05406362.).