First-in-Human Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of BIIB091, an Oral BTK Inhibitor, in Healthy Adult Participants.

Introduction: Multiple sclerosis (MS) affects 2.8 million people globally. Despite available disease-modifying therapies (DMTs), more effective treatments are needed to prevent/slow disability progression. BIIB091 is a selective, non-covalent oral Bruton's tyrosine kinase (BTK) inhibitor. This Phase 1, first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BIIB091. Methods: Participants received single ascending doses (SAD; 50-1200 mg) or multiple ascending doses (MAD; 50-300 mg twice daily [BID] for 14 days) of BIIB091 or placebo. Safety assessments included labs, vitals, physical examinations, electrocardiograms, and adverse event (AE) recordings. PK was evaluated through blood and urine samples; PD was evaluated through blood samples, including BTK phosphorylation and B-cell receptor-mediated CD69 upregulation. Additional objectives assessed PK/PD relationship and food's effect on PK. Results: Sixty-four participants were randomized (SAD n=40; MAD n=24). BIIB091 showed rapid absorption, dose-proportional PK, and no significant accumulation. BIIB091 suppressed B cell activation, achieving >90% inhibition of CD69 expression on CD19+ within 1 hour at all study doses; inhibition was sustained up to 24 hours at 1200 mg. A high-fat meal delayed T Conclusion: BIIB091 was well tolerated at single doses up to 1200 mg and repeated doses up to 300 mg BID, showing dose-linear PK and sustained effective B cell activation suppression. BIIB091 PK appeared to be sensitive to food effect. These important insights support its continued development for MS.