To evaluate the safety, tolerability and pharmacokinetics of fenebrutinib and its effect on cardiac repolarization in healthy participants.

Part A was a randomized, double-blind, placebo-controlled, single ascending dose study. Participants received fenebrutinib 400 or 700 mg orally or placebo following an ≥8-hour fast. Part B was a randomized, double-blind, single-dose, placebo- and positive-controlled, four-way crossover study that included four treatment sequences: fenebrutinib therapeutic dose (400 mg), fenebrutinib supratherapeutic dose (700 mg), a positive control (moxifloxacin 400 mg) and placebo. The QT interval was corrected for heart rate using the Fridericia formula (QTcF).

Part A included 16 participants. Both doses were well tolerated, and no serious adverse events (AEs), AEs of special interest or Grade ≥2 AEs were reported. Part B included 85 participants. At all time points, all upper bounds (UBs) of one-sided 95% CIs for the least-squares (LS) mean placebo-adjusted ΔQTcF (ΔΔQTcF) values were <10 ms. The maximum effect was observed at 1 hour post dose, with LS mean ΔΔQTcF of 3.8 ms (UB of 95% CI, 5.3 ms) at the therapeutic dose and 6.6 ms (UB of 95% CI, 8.2 ms) at the supratherapeutic dose. All predefined time points after moxifloxacin administration, a positive control, had a lower bound 99% CI of ΔΔQTcF of >5 ms, which confirmed assay sensitivity in the study. In the regression analysis, UBs of one-sided 95% CIs for ΔΔQTcF at the maximum concentration for fenebrutinib were <10 ms: 4.4 ms for the therapeutic dose and 7.8 ms for the supratherapeutic dose.

Single therapeutic and supratherapeutic doses of fenebrutinib were well tolerated. Fenebrutinib had no clinically meaningful impact on QT/QTc interval.