Background Bruton's tyrosine kinase (BTK) plays a role in signaling pathways of the B cell receptor, Fcγ receptor and Fcɛ receptor in non T-cell white blood cells and osteoclasts and thus represents an attractive target for autoimmune and inflammatory diseases. PRN1008 is a potent, oral, highly selective BTK inhibitor that targets cysteine through a reversible covalent interaction resulting in a slow off rate with prolonged inhibition of the target. PRN1008 has shown efficacy in a rat collagen induced arthritis model with trough BTK occupancy levels of 16% or more. Principia Biopharma Inc. is developing PRN1008 for the treatment of rheumatoid arthritis and other inflammatory diseases.

Objectives To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PRN1008 in single ascending dose (SAD) and multiple ascending dose cohorts (MAD) in healthy, adult volunteers.

Methods This first-in-human study consisted of two randomized, double-blind, placebo-controlled parts: Part A, 5 SAD cohorts (50-1200 mg) and in Part B, 4 MAD cohorts with 10 days treatment (300mg and 600mg QD, 300mg and 450mg BID). PRN1008 was administered as a liquid formulation in an inpatient facility. Safety was assessed clinically and by frequent ECG, vital sign and laboratory measurements. PRN1008 PD was assessed by BTK occupancy measured by a fluorescent probe competition assay and inhibition of anti-IgE-stimulated activation of basophils measured by surface expression of CD63.

Results PRN1008 was safe and well-tolerated in both parts of the study without changes in vital sign, ECG or laboratory measurements. In the MAD, treatment emergent adverse events (AEs) were reported by 50-88% of PRN1008-treated subjects, and 50% of placebo-treated subjects, with mild gastrointestinal AEs more common following PRN1008 vs. placebo. PRN1008 was rapidly cleared with a mean terminal half-life for all doses of approximately 4 hours on day 10. Maximal plasma concentrations ranged from 43 to 630ng/mL, 1-2 hours after dosing on day 1 or day 10. In these same subjects, BTK occupancy ranged from 75±7 to 90±6% (mean ± SD) at four hours on day 1, and 84±4 to 93±2% at four hours on day 10. BTK occupancy declined slowly and persisted at 12 and 24 hours. BTK occupancy at trough (12 or 24 hours) on day 10 ranged from 59±11 to 80±6%, at which time plasma PRN1008 concentrations were negligible. A reduction of basophil activation of up to 73±14.5% (mean ± SD) was observed 4 hours after PRN1008 administration, consistent with BTK pathway inhibition in these cells.

Conclusions PRN1008 was safe and well tolerated after single and 10 day dosing. BTK occupancy with a daily dose of ≥300mg reached therapeutic levels with little variability compared with the variability seen in systemic exposure. These data support further development of the reversible covalent BTK inhibitor PRN1008 for the treatment of RA and other inflammatory and autoimmune diseases.

Disclosure of Interest P. Smith Consultant for: Principia Biopharma Inc, J. Krishnarajah Grant/research support from: Principia Biopharma, P. Nunn Employee of: Principia Biopharma, R. Hill Shareholder of: Principia Biopharma, Employee of: Principia Biopharma, D. Karr Employee of: Principia Biopharma, D. Tam Employee of: Principia Biopharma, M. Masjedizadeh Shareholder of: Principia Biopharma, Employee of: Principia Biopharma, S. Gourlay Shareholder of: Principia Biopharma, Employee of: Principia Biopharma