Results of the first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study of BIIB113 in healthy volunteers.

Background: Preclinical studies have demonstrated that inhibition of the O-linked β-N-acetylglucosaminidase enzyme increases tau O-linked β-N-acetylglucosaminylation and may attenuate tau pathology in Alzheimer's disease.

Objectives: To examine the safety, tolerability, pharmacokinetics, and target occupancy of single- and multiple-ascending oral doses of the small-molecule O-linked β-N-acetylglucosaminidase inhibitor, BIIB113.

Design: Study 276HV101 was a first-in-human, multicenter, Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose trial.

Setting: 72 participants were enrolled from February 2022 through July 2023.

Participants: Adult healthy female and infertile/vasectomized male participants.

Intervention: In the single-ascending dose substudy, participants received a single dose of placebo or BIIB113 0.5, 3, 15, or 50 mg. In the 14-day multiple-ascending dose substudy, participants received placebo or BIIB113 15 or 50 mg once daily. In the target occupancy substudy, participants received either a single dose of BIIB113 0.5 or 3 mg or a once-daily dose of BIIB113 0.5 mg.

Measurements: Safety and tolerability were measured by incidence of adverse events. Pharmacokinetic and concentration-time profiles were assessed. Target occupancy was evaluated using the carbon-11 BIO-1819,578 radioligand.

Results: BIIB113 was generally well tolerated. Pharmacokinetics were linear over the dose range, with a half-life of approximately 30 h. Administration with food decreased the rate but did not affect the extent of absorption. There were no clinically meaningful differences in pharmacokinetics between elderly and nonelderly participants. Multiple once-daily doses of BIIB113 0.5 mg maintained a target occupancy of ≥90 % up to 48 h.

Conclusions: BIIB113 was well tolerated and achieved high levels of target occupancy.