Background/Purpose: Spleen Tyrosine Kinase (SYK) mediates immunoreceptor signaling in a range of hematopoietic cells important for the initiation and progression of inflammatory diseases such as rheumatoid arthritis (RA) and other autoimmune diseases including B lymphocytes, monocytes, macrophages, dendritic cells, and osteoclasts. Cellular data and multiple animal models of disease provide strong preclinical validation for SYK as a therapeutic target in RA. GS-9876 has been identified as a novel, potent and selective SYK inhibitor. Preclinical characterization of GS-9876 utilized in vitro biochemical and cellular assays to assess on-target and off-target pharmacology, and the rat collagen-induced arthritis model to establish in vivo efficacy. Here we describe first-in-human studies of GS-9876 which characterize the pharmacokinetic (PK) profile, safety and tolerability of escalating single- and multiple-doses of GS-9876, as well as the impact of food and acid-reducing agents on GS-9876 PK in healthy subjects.

Methods: Healthy subjects were administered escalating single (2 mg to 50 mg) or multiple (15 mg once daily to 50 mg once daily for 7 days) doses of GS-9876 in the fasted state. PK, safety and tolerability were assessed throughout the study, and reviewed following each dose level, prior to initiation of successive dose escalation cohorts. The impact of food (high-fat breakfast) and a representative acid-reducing agent (omeprazole 20 mg) on GS-9876 PK were assessed using a crossover study design.

Results: Sixty-two subjects received at least one dose of GS-9876. GS-9876 exhibited slightly greater than dose proportional increases in C_max but not area under the curve extrapolated to infinity (AUC_inf) following single doses (2 mg, 5 mg, 15 mg, 30 mg and 50 mg); dose proportional PK was observed following multiple doses (15 mg and 30 mg once daily). The median terminal elimination half-life was consistent following single or multiple doses and ranged from approximately 21 to 28 hours. Accordingly, GS-9876 exposure accumulated approximately 1.9-fold following multiple once daily doses. Administration of GS-9876 with a high-fat meal slightly reduced GS-9876 C_max (13%), but did not affect AUC_inf; administration with omeprazole did not affect GS-9876 C_max or AUC_inf. Intersubject variability in GS-9876 C_max and AUC following multiple doses was <25% (coefficient of variation). No clinically significant changes in vital signs, ECGs and safety laboratory tests were observed. No clinically relevant changes in bleeding time were observed. Mild vomiting in one subject was reported as related to GS-9876. All reported AEs were generally mild and self-limiting. No serious AE or discontinuations were reported.

Conclusion: GS-9876 was safe and well tolerated following single doses up to 50 mg and multiple doses up to 30 mg once daily for 7 days. The long terminal elimination half-life of GS-9876 supports a once daily dosing regimen, and GS-9876 may be administered without regard to food or acid-reducing agents. These data support the ongoing development of GS-9876 in inflammatory diseases.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-in-human-pharmacokinetics-and-safety-of-escalating-single-and-multiple-doses-of-gs-9876-a-novel-oral-syk-inhibitor-in-healthy-subjects/