PII-014 - SAFETY , TOLERABILITY, AND PHARMACOKINETICS OF SM17 IN HEALTHY VOLUNTEERS, A NOVEL IL-17 RECEPTOR B TARGETING ANTIBODY IN PHASE I DEVELOPMENT FOR THE TREATMENT OF ASTHMA

S. Paglialunga¹, G. Xu², X. Qian², R. Ding², K. Webster³, A. van Haarst³, C. Engel⁴, C. Hui², L. Lam², W. Li², W. Wu², A. Hunt⁵, S. Leung²; ¹Celerion, Tempe, AZ, USA, ²SinoMab BioScience Limited, Hong Kong, Hong Kong, ³Celerion, Belfast, UK, ⁴Celerion, Montreal, Canada, ⁵Celerion, Lincoln, NE, USA.

Background: Alarmin cytokines such as interleukin-25 (IL-25) mediate type 2 T helper cell (Th2) inflammation and serve as upstream signaling elements in allergic inflammation and autoimmune responses. IL-25 binds to the IL-17 multi-domain receptor A and B (IL-17RA and IL-17RB), resulting in the release of Th2 cytokines such as IL-4, IL-5, IL-9 and IL-13 to drive an inflammatory response. Therefore, blockage of IL-17RB is an attractive therapeutic target for Th2-mediated diseases, such as asthma. SM17 is a novel humanized monoclonal antibody against IL-17RB being developed for the treatment of asthma. In an animal model of asthma, SM17 demonstrated beneficial effects in improving allergic asthma. Therefore, these encouraging nonclinical findings support the clinical drug development of SM17.

Methods: This first-in-human (FIH) randomized, double-blind, placebo-controlled, dose-escalation study, evaluated the safety, pharmacokinetic and immunogenicity of intravenous (IV) doses of SM17 in healthy adult subjects. In Part A, 53 healthy participants received a single IV dose of SM17 (2, 20, 70, 200, 400, 600, 1200 mg) or placebo. In Part B, 24 healthy subjects received a single IV dose of SM17 every two weeks (Q2W) (200, 400, 600 mg Q2W) or placebo for a total of 3 doses.

Results: Treatment-emergent adverse events (TEAEs) occurred in 11 (28%) participants in the SM17 groups and 4 (29%) participants in the placebo groups in Part A, and in 11 (61%) participants in the SM17 cohorts and 5 (83%) participants in the placebo groups in Part B. The most frequently reported drug-related TEAE was headache and there were no drug-related serious adverse events observed. Total SM17 exposure increased by approximately 60- to 188-fold with a 60-fold increase in dose from 20 to 1200 mg SM17. The elimination half-life (t½) appeared to increase with increasing dose levels, up to 452 hours at 1200 mg. Upon administration of the third dose, mean accumulation ratios over 200-600 mg was 1.5 to 2.1, which confirms moderate accumulation of SM17. After Q2W dosing of SM17 over 4 weeks, total exposure increased in a dose-proportional manner from 200 mg to 600 mg SM17.

Conclusion: In this FIH study, a single IV dose of SM17 up to 1200 mg and three Q2W doses up to 600 mg were well tolerated in healthy participants, demonstrating a favorable safety profile and supports further drug development.