THU0185 Safety, Pharmacokinetics and Proof-of-mechanism of an Oral Bruton's Tyrosine Kinase Inhibitor HM71224 in Healthy Adult Volunteers

Background HM71224 is an orally available, irreversible and highly selective small molecule inhibiting Bruton9s Tyrosine Kinase (BTK) which plays key roles in B-cell receptor (BCR) and Fc receptor (FcR) signaling cascades and B cell development and activation. HM71224 showed strong efficacy in mice and rat collagen induced arthritis models, dose-proportional pharmacokinetic (PK) profile and acceptable tolerability in healthy male volunteers. Therefore, HM71224 may provide a new therapeutic option for active rheumatoid arthritis (RA). We hereby report updated data from the first in man clinical study with HM71224 (NCT01765478). Objectives To evaluate safety, tolerability, PK and pharmacodynamics (PD) of HM71224 following once daily or twice daily multiple ascending dose (MAD) in healthy volunteers. Methods MAD part was performed in a randomized, double-blind, placebo-controlled design in which subjects were administered HM 71224 once daily (10 mg ∼120mg) or twice daily (5mg ∼ 60mg) for 14 days. Adverse events (AEs) were monitored throughout the study. Blood samples were collected to measure HM71224/metabolites concentration and explore PD effect such as BTK occupancy. Results HM71224 showed good safety profile up to once daily MAD of 80 mg HM71224. No drug-related serious AEs were reported in twice daily MAD dosing. Following multiple ascending administration of HM71224, exposure in plasma (C max and AUC 0-t ) increased approximately dose-proportionally. BTK occupancy was increased with blood concentration of parent HM71224 and above 90 percent of BTK occupancy was achieved at a trough level with 20 mg twice daily MAD. Conclusions HM71224 is being developed as a BTK inhibitor for RA treatment. HM71224 demonstrated well-tolerated safety profile in HVs and desirable PK and PD properties supporting sustained target inhibition. Phase 2 study will be initiated in active RA patients soon. References Bioessays. 2001 May; 23(5):436-46. Nat Rev Immunol. 2002 Dec; 2(12):945-56. Nat Rev Drug Discov. 2003 Jun; 2(6):473-88. Immunol Rev. 2007 Aug; 218:45-64. Immunol Rev. 2009 Mar; 228(1):58-73. Nat Rev Rheumatol. 2009 Jun; 5(6):317-24. Int Rev Immunol. 2012 Apr; 31(2):119-32. Clin Immunol. 2013 Jul; 148(1):66-78. Disclosure of Interest J. Lee Employee of: Hanmi Pharmaceutical Co., Ltd., J. Son Employee of: Hanmi Pharmaceutical Co., Ltd., H. J. Sin Employee of: Hanmi Pharmaceutical Co., Ltd., J. Woo Employee of: Hanmi Pharmaceutical Co., Ltd., S. Hadi: None declared, K. H. Suh Employee of: Hanmi Pharmaceutical Co., Ltd., Y.-M. Lee Employee of: Hanmi Pharmaceutical Co., Ltd., S. Jang Employee of: Hanmi Pharmaceutical Co., Ltd., J.-A. Jung Employee of: Hanmi Pharmaceutical Co., Ltd.