Background

Bruton’s tyrosine kinase (BTK) is a key signalling node downstream of the B‑cell receptor (BCR) in B cells and Fc receptors (FcRs) in myeloid cells. Selective BTK inhibition may be beneficial for the treatment of MS by preventing B-cell and myeloid cell activation without immune cell depletion. BIIB091 is an orally active, selective, reversible (noncovalent), small molecule inhibitor of BTK in Phase 1 clinical development for the treatment of MS.

Objectives

Assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of BIIB091 in healthy adult participants.

Methods

This was a Phase I, randomized, double-blind, placebo-controlled, single ascending dose (SAD) and a multiple ascending dose (MAD) study in healthy adult participants (NCT03943056). Admitted participants were randomly assigned to BIIB091 or placebo (6:2). Participants received study drug orally at single dose levels of 50, 150, 300, 600, or 1200 mg in the fasted state during the SAD part. Participants completing 300 mg fasted dosing continued into a second period and received single dose 300 mg with a high fat meal. A separate group of participants enrolled in the MAD part and received doses of 50, 150, or 300 mg twice daily (BID) for 13 days, and a single dose on the morning of day 14. Safety (adverse events [AEs], vital signs, electrocardiograms [ECGs] and laboratory abnormalities), tolerability, and PK measures were assessed. The trial was ongoing as of February 2020. Preliminary results summarized here are based on a blinded data cut-off as of 20 Dec 2019, and include completed SAD cohorts, and 2 of 3 planned MAD cohorts.

Results

56 participants enrolled in the study (n=40 in SAD, n=16 MAD) and contributed to this analysis as of the data cut-off date. No deaths, serious AEs, severe AEs, cardiac related AEs, or AEs leading to study discontinuation were observed. All AEs were mild in severity. No clinically relevant changes in vital signs were reported as of the data cut-off date. BIIB091 PK was approximately dose linear, with median time to maximum plasma concentration ranging from approximately 0.8 to 1.4 hours after fasted dosing in SAD cohorts, with modest accumulation after multiple dosing. Food reduced C_max variability and increased AUC.

Conclusions

BIIB091 was well tolerated at single doses up to 1200 mg. No dose limiting clinical AEs were identified in the MAD as of the data cut-off. Complete study results will be described in the poster. Preliminary safety and PK profile supports continued development of BIIB091 for the treatment of MS.

Supported by: Biogen