FRI0156 A PHASE 1, SINGLE AND MULTIPLE ASCENDING DOSE STUDY OF TAS5315—A NOVEL HIGHLY SELECTIVE INHIBITOR OF BRUTON’S TYROSINE KINASE—IN HEALTHY MALE VOLUNTEERS
Authors: Yuji Kumagai, Yoshiya Tanaka, Mitsuru Murata, Tsutomu Takeuchi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Bruton's tyrosine kinase (BTK) is expressed in the cells of the immune system and osteoclasts, and plays an important role in inflammation and bone resorption<sup>1</sup>. TAS5315 is a novel, highly selective inhibitor of BTK. In animal models, TAS5315 suppressed the inflammation at the joints and significantly suppressed extreme bone destruction, in a dose-dependent manner. It has the potential to become a treatment option in patients with rheumatoid arthritis (RA). <h3>Objectives</h3> To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TAS5315 in healthy male volunteers. <h3>Methods</h3> The single ascending dose (SAD) study, which was the first-in-human study, and the multiple ascending dose (MAD) study were conducted as randomized, double-blind, placebo-controlled and parallel-group comparative studies in a single center. In the SAD study, 70 subjects were enrolled and received 0.01–8 mg of TAS5315 or placebo. In the MAD study, 31 subjects were enrolled and received 1–8 mg of TAS5315 or placebo once daily for 7 days. The allocation ratio (TAS5315: placebo) was 7:3 in the SAD study and 6:2 in the MAD study. The PD of TAS5315 was assessed by measuring the rate of BTK occupancy in peripheral blood mononuclear cells using a fluorescence probe. The expression level of CD203c in peripheral blood basophils treated with anti-IgE antibodies was also measured with a flow cytometer. The SAD and MAD studies were reviewed and approved by the IRB of Kitasato University Hospital. <h3>Results</h3> The observed PK profile of TAS5315 was linear in the dose range of 0.01–8 mg. TAS5315 was rapidly absorbed (median T<sub>max</sub>: 0.5–1.5 hr) and eliminated (mean T<sub>1/2</sub>: 1.00–1.37 hr). The maximum percentage of BTK occupancy by TAS5315 increased dose-dependently at 0.01–2 mg in SAD study. The occupancy rate of BTK peaked at 2 mg and was almost 100% at 2–8 mg, 6 hr after administration and remained almost 80% or higher for up to 24 hr. The expression level of CD203c after basophil activation decreased by 80% at 2–8 mg of TAS5315 6 hr after administration. No changes in the PD biomarkers were observed in the placebo group. The PD response was maintained after the reduction in the drug concentration. In the SAD and MAD studies, the incidence of adverse drug reactions (ADR) in the TAS5315 groups was 6.1% and 13.0%, respectively. Two subjects (8.7%) experienced subcutaneous hemorrhage in MAD study. No other ADR occurred twice in SAD and MAD studies. The severity of all ADR in SAD and MAD studies was mild and they were resolved without any treatment. There were no serious adverse events. None of the ADR showed a tendency towards a dose-dependent increase. The administration of TAS5315 resulted in a decrease in platelet aggregation and prolonged bleeding time. These changes returned to baseline level in the follow up measurement and there were no clinical safety concerns. <h3>Conclusion</h3> TAS5315 was tolerable when administered as repeated doses of up to 8 mg once daily for 7 days. The inhibitory effect of BTK by TAS5315 was demonstrated and this provides the basis for an early Phase II study to evaluate the efficacy of TAS5315 in patients with RA. <h3>Reference</h3> [1] Drug Discov Today. 2014;19,1200-4. <h3>Disclosure of Interests</h3> Yuji Kumagai: None declared, Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics, Mitsuru Murata Consultant for: Taiho Pharmaceutical Co., Ltd., Tsutomu Takeuchi Grant/research support from: Astellas Pharma Inc, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co. Ltd., Novartis Pharma K.K., Grant/research support from: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Grant/research support from: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co.Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., GlaxoSmithKline K.K., UCB Japan Co. Ltd., Consultant for: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Asahi Kasei Medical K.K., AbbVie GK, Daiichi Sankyo Co., Ltd., Bristol Myers Squibb, and Nipponkayaku Co. Ltd., Speakers bureau: Astellas Pharma Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Celltrion Inc., Nipponkayaku Co. Ltd., and UCB Japan, Speakers bureau: AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, Teijin, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma Inc, Diaichi Sankyo Co. Ltd., Eisai Co. Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co. Ltd., Novartis Pharma K.K.