Drug Des Devel Ther. 2026 Apr 14;20:571780. doi: 10.2147/DDDT.S571780. eCollection 2026.
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 Tmax by ~5.2 hours and increased AUC and Cmax 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.
PMID:42016388 | PMC:PMC13092454 | DOI:10.2147/DDDT.S571780
