Abstract 26: Evaluation of the safety, pharmacokinetics and pharmacodynamics of GS-9973, a novel SYK inhibitor, and GS-1101, a novel PI3Kδ inhibitor, when administered alone or in combination in humans.
Authors: Jin Feng , Di Paolo Julie A. , Shao Lixin , Yellin Ori , Hawkins Michael J. , Ramanathan Srinivasan 
Published: August 2014

Abstract
Background: GS-9973 is a selective, reversible, small molecule spleen tyrosine kinase (Syk) inhibitor. GS-1101 is a potent and selective PI3Kδ inhibitor currently in Phase 3 studies. The safety, pharmacokinetics (PK), pharmacodynamics (PD) of GS-9973 given alone or together with GS-1101 were evaluated in healthy subjects.
Methods: GS-9973 and GS-1101 were each given twice-daily (BID) with food for 4 days (Day 4: AM dose only) either alone or together as follows: Cohort 1: 200 mg and 100 mg, respectively; Cohort 2: 600 mg and 100 mg, respectively; Cohort 3: 600 mg and 150 mg, respectively. Along with PK, PD samples were assessed for functional inhibition of ex vivo αIgE-stimulated CD63 expression on basophils. Safety was assessed throughout the study.
Results: Across cohorts, subjects were ≥ 83% white, 100% female, with mean ages of 20 to 57 years. Adverse events (AEs) were generally mild to moderate; one subject discontinued due to Grade 1 ALT/AST elevation during GS-1101 150 mg dosing. Most common AEs were headache and somnolence. GS-9973 exposures were higher with GS-1101 (51% to 64% for AUCtau; 74% to 96% for Ctau; Table 1). Minor changes in GS-1101 exposures were noted. GS-9973 (600 mg) plus GS-1101 (≥ 100 mg) dosing provided near complete inhibition of CD63 expression over the dosing interval, consistent with synergy demonstrated from in vitro studies.
Conclusions: GS-9973 and GS-1101 were generally well tolerated over the dose range evaluated. Coadministration of GS-9973 and GS-1101 provided substantial PD response over the dosing interval; moderately higher GS-9973 exposures and minor changes in GS-1101 exposures were noted. These safety, PD, and PK results support further clinical evaluation of these agents in combination.
Table 1. GS-9973 and GS-1101 PK PK Parameter Mean (% CV) % Geometric Least Squares Means Ratio (90% CI) GS-9973 GS-9973 200 mg (N = 8) GS-9973 200 mg + GS-1101 100 mg (N = 8) Combination vs Alone AUCtau 4150 (48) 6750 (47) 1.64 (1.41, 1.91) Cmax 618 (40) 915 (38) 1.50 (1.24, 1.80) Ctau 201 (66) 379 (62) 1.96 (1.61, 2.38) GS-9973 GS-9973 600 mg (N = 16) GS-9973 600 mg + GS-1101 100/150 mg (N = 14) AUCtau 12700 (69) 16000 (55) 1.51 (1.30, 1.75) Cmax 1570 (60) 1900 (55) 1.38 (1.20, 1.59) Ctau 832 (82) 1120 (72) 1.74 (1.48, 2.03) GS-1101 GS-1101 100 mg (N = 16) GS-1101 100 + GS-9973 200 or 600 mg (N = 16) AUCtau 8070 (22) 9510 (25) 1.17 (1.13, 1.22) Cmax 1660 (18) 1880 (18) 1.13 (1.07, 1.20) Ctau 127 (44) 170 (50) 1.33 (1.20, 1.48) GS-1101 GS-1101 150 mg (N = 7) GS-1101 150 mg + GS-9973 600 mg (N = 6) AUCtau 13800 (15) 15800 (20) 1.11 (1.00, 1.24) Cmax 2680 (11) 2870 (21) 1.06 (0.93, 1.21) Ctau 320 (43) 411 (29) 1.23 (1.03, 1.47) Units for AUCtau: ng*h/ml; Cmax and Ctau: ng/ml; all doses BID
Citation Format: Feng Jin, Julie A. Di Paolo, Lixin Shao, Ori Yellin, Michael J. Hawkins, Srinivasan Ramanathan. Evaluation of the safety, pharmacokinetics and pharmacodynamics of GS-9973, a novel SYK inhibitor, and GS-1101, a novel PI3Kδ inhibitor, when administered alone or in combination in humans. [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 26. doi:10.1158/1538-7445.AM2013-26