Phase 1b Dose-ranging Study Demonstrates Tolerability and Pharmacokinetics (PK) of Oral Epetraborole at the Predicted Therapeutic Dosage for Mycobacterium avium Complex (MAC) Lung Disease

ABSTRACT

Background. Epetraborole (EBO) - an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria - is under clinical development for treatment of MAC lung disease. We conducted a Phase 1b dose-ranging study of EBO tablets in healthy adult volunteers, to inform dose selection in the treatment of MAC lung disease. Methods. In this double-blind, placebo-controlled trial, EBO or placebo tablets were administered (n=8/cohort, 31 randomization) at dosages of 250-1000 mg q24h or 500 mg or 1000 mg q48h for up to 28 days. Standard Ph1 clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Based on prior human studies using significantly higher EBO daily doses, gastrointestinal (GI) events and anemia were predetermined AEs of special interest (AESIs). Plasma concentrations of EBO were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods. Results. A total of 43 subjects were enrolled;the 1000 mg q24h cohort was terminated early due to local COVID restrictions. Overall, 80.6% EBO subjects and 83.3% placebo subjects experienced >=1 TEAE, none of which was serious or severe (Table). Most TEAEs were mild in severity (90%), and the remainder were moderate (10%). No TEAE leading to withdrawal from study was reported. The most frequent types of TEAEs were GI events (48.4% EBO, 41.7% placebo subjects), the most common being mild nausea. Two subjects had premature discontinuation of EBO due to a TEAE (asymptomatic liver enzyme elevations in a 250 mg q24h subject and mild nausea in a 1000 mg q48h subject). One 1000mg q24h subject had a TEAE of anemia. No clinically significant findings or TEAEs were observed for physical examinations, ECGs, or urine laboratory tests. Plasma Cmax and AUC0- of EBO increased in a linear, dose-proportional manner across cohorts. Tmax was observed at ~1 h post dose;mean t1/2 ranged from 7.63 to 11.1 h. Conclusion. * Oral EBO administered for 28-day dosing was generally well tolerated at the predicted therapeutic dose (500mg q24h) * Predictable PK characteristics facilitate its use in MAC lung disease * Further evaluation in a Phase 2/3 treatment-refractory MAC lung disease study is planned.