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This research investigates the safety, tolerability, and pharmacokinetics of BIIB091, a new oral BTK inhibitor, in healthy adults.

April 16, 2026Open Access

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

Key Points

This research investigates the safety, tolerability, and pharmacokinetics of BIIB091, a new oral BTK inhibitor, in healthy adults.
Participants received either single or multiple ascending doses of BIIB091 or placebo.
Safety was assessed via lab tests, physical exams, and adverse event recordings.
Pharmacokinetics were measured through blood and urine samples, while pharmacodynamics were evaluated by studying B cell activation markers.
BIIB091 was well tolerated; no serious adverse events were reported.
Significant inhibition of CD69 expression on B cells was achieved, indicating effective target engagement.
Pharmacokinetic data showed rapid absorption and dose-proportional behavior with a notable food effect.

Abstract

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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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

Key Points

Abstract

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