Background HM71224 is an orally active, highly selective, and irreversible Bruton's tyrosine kinase (Btk) inhibitor showing a strong efficacy in mice and rat collagen induced arthritis models. Btk plays a crucial role in B cell development and activation through the B cell receptor (BCR) and represents a new target for autoimmune diseases [1–5]. Therefore, HM71224 may provide a new clinical option to treat patients with active rheumatoid arthritis (RA).
Objectives To evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effect of HM71224 following single ascending doses (SAD) and multiple ascending doses (MAD) in healthy adult male volunteers (HVs).
Methods The first in human study NCT01765478 consisted of three parts; a randomized, double-blind, placebo-controlled, 3 period SAD part with alternating panels (10-200 mg), a randomized, open label, 2-way, crossover food effect part (60 mg), and a randomized, double-blind, placebo-controlled, MAD part (10-120 mg for 14 days). Adverse events (AEs) were monitored throughout the study. Serum samples were collected to measure HM71224/metabolites concentration and detect inhibition of %CD63 activation.
Results To date, HM71224 was generally well tolerated. No serious AEs were reported in this first in human study. Expected gastro-intestinal (GI) symptoms were observed, but were all mild. Two drug-related AEs were reported in the SAD part at 20 mg dosing and in the MAD part at 80 mg dosing. However, no drug-related AEs were reported in the food effect part at 60 mg dosing. Following single ascending administration of HM71224, exposure (Cmax and AUC0–t) increased approximately dose-proportionally. Half-life was approximately 6 hours, and Tmax was about 1.5 hours. Compared fed condition with fasted condition at 60 mg administration of HM71224, no food effects were observed on PK profiles. The value of Cmax and AUC0–t and day1 and day 14 PK profiles indicated that minimal accumulation of HM71224 exposure was observed after multiple ascending dosing of HM71224. Inhibition of the percentage of activated basophils, in an ex-vivo basophil CD63 activation test, showed a decrease in anti-FCɛRI stimulated basophil activation (both number of activated cells and extent of activation) consistent with the downstream activity of BTK.
Conclusions HM71224 is being developed as a Btk inhibitor for RA. HM71224 demonstrated a 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.
Nature Reviews Immunology 2002;2, 354-363
Nature Reviews Immunology 2003;3, 317-330
Nature Reviews Immunology 2005;5, 284-295
Immunological Reviews 2009;228, 58-73
Nature Reviews Rheumatology 2009;5, 433-441
Disclosure of Interest : Y.-K. Yoon Employee of: Hanmi Pharmaceutical, S. Hadi Paid instructor for: PRA International, T. Iersel Employee of: PRA International, H. J. Sin Employee of: Hanmi Pharmaceutical, K. O. Lee Employee of: Hanmi Pharmaceutical, J. Lee Employee of: Hanmi Pharmaceutical, J. Y. Song Employee of: Hanmi Pharmaceutical, S. Jang Employee of: Hanmi Pharmaceutical, Y.-M. Lee Employee of: Hanmi Pharmaceutical, J. Kang Employee of: Hanmi Pharmaceutical, K. H. Suh Employee of: Hanmi Pharmaceutical, J. Son Employee of: Hanmi Pharmaceutical
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