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

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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 max by ~5.2 hours and increased AUC and C max about 2.046- and 1.420-fold. A single 300 mg dose prolonged the CD69 inhibition duration, maintaining > 90% 24 hours post-dose versus 42% in fasted state. MAD > 150 mg BID maintained rapid and consistent CD69 inhibition over 14 days. Mild AEs were reported in 14 participants, with no dose-limiting AEs, serious AEs, or withdrawals. Nausea and headache were the most common AEs. 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. Keywords: Bruton’s tyrosine kinase, non-covalent, reversible, Phase 1, BIIB091, multiple sclerosis dose-escalation study, CD69 inhibition

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