Abstract 32: Single and multiple dose-ranging evaluation of safety, pharmacokinetics, and pharmacodynamics of GS-9973, a novel pSYK inhibitor.
Authors: Srini Ramanathan, Julie A. DiPaolo, Tom Doan, Dan Burge
Journal: Cancer Research (2013)

Abstract Background: GS-9973 is a selective, reversible, ATP-competitive small molecule spleen tyrosine kinase (Syk) inhibitor that blocks BCR-mediated activation/ proliferation, Fc receptor signaling/ function, and inhibits immune complex-mediated inflammatory cytokine production, including TNFα. The safety, pharmacokinetics (PK), and pharmacodynamics (PD) of GS-9973 were evaluated in a double-blind, single/multiple ascending dose study. Methods: In sequential cohorts (n=8 active, 2 placebo), subjects (fasted) received GS-9973 (25 mg to 1200 mg) as a single dose (Part A) or multiple twice-daily doses for 7 days (Part B). Along with PK, PD sampling Parts A and B assessed functional inhibition of ex vivo αIgE-stimulated CD63 expression on basophils. Safety and tolerability were assessed throughout the study, with dose-escalation gated by pre-specified stopping criteria. PK-PD was evaluated using GS-9973 concentrations vs CD63 inhibition. Results: Across dose cohorts, subjects were ≥ 60% white, ≥ 50% male, with mean age of 28 to 37 years. Adverse events (AEs) were generally mild to moderate, with no AE-driven study drug discontinuations noted. GS-9973 exposures (Table 1) reached a plateau at ≥ 600 mg BID (due to solubility-limited absorption), provided &amp;gt; 90% CD63 inhibition at peak levels, and &amp;gt; 60% inhibition over the dosing interval, due to 10-14 hr plasma half-life. PK-PD analyses indicated a sigmoidal exposure-response relationship, with EC50 of ∼ 400-450 ng/ml and hill slope &amp;gt; 1. Single and Multiple dose PK of GS-9973 Part A Single Dose (mg) AUCinf (ng.h/ml) Cmax (ng/ml) 25 231 (80) 42.3 (76) 75 413 (98) 67.8 (84) 200 4250 (64) 534 (56) 600 5960 (90) 779 (70) 1200 9740 (111) 1060 (101) Part B Multiple Dose (mg) AUCtau Cmax Ctrough T1/2 (hr) 25 356 (65) 57.8 (68) 11.9 (65) 8.7 (7.7, 9.5) 75 1880 (48) 273 (52) 79.2 (64) 8.9 (6.9, 10.8) 200 7650 (57) 1050 (59) 380 (63) 10.0 (8.4, 14.9) 600 21500 (64) 2960 (61) 1240 (66) 15.4 (12.8, 19.7) 900 23900 (62) 2810 (58) 1470 (67) 13.5 (11.7, 16.9) 1200 26800 (77) 3430 (77) 1470 (80) 13.9 (9.8, 16.4) Values presented as mean (%CV) except for T1/2 (median (Q1,Q3)); Part B: Cmax, Ctrough units ng/ml; AUCtau: ng.h/ml Conclusions: GS-9973 was generally well tolerated over a 48-fold dose range. GS-9973 exposures plateaued ≥ 600 mg and provided robust exposure-dependent PD activity over the dosing interval. The overall safety, PK, and PD profile of GS-9973 support further clinical evaluation of doses with strong PD activity. Citation Format: Srini Ramanathan, Julie A. DiPaolo, Tom Doan, Dan Burge. Single and multiple dose-ranging evaluation of safety, pharmacokinetics, and pharmacodynamics of GS-9973, a novel pSYK inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 32. doi:10.1158/1538-7445.AM2013-32