Background GLPG0634 is an orally-available, selective Janus kinase 1 (JAK1) inhibitor. Less-selective JAK inhibitors have shown long-term efficacy in treating rheumatoid arthritis (RA) but also dose-limiting side effects. Selective inhibition of JAK1 may combine favorable safety and clinical efficacy profiles with rapid onset of action. GLPG0634 showed encouraging pharmacodynamics, safety and efficacy in early clinical studies treating RA patients for 4 weeks. Longer term Phase 2B studies are ongoing.
Objectives Support GLPG0634 dose selection for Phase 2b studies in RA using exposure-response modeling and simulation.
Methods Population predicted and individual responses to treatment were investigated on the basis of simulated exposures to GLPG0634 and its main metabolite. Non-linear mixed effects E-R models were built to describe the proportion of cells showing phosphorylation of STAT1 following activation with IL-6 in healthy subjects (PD response) and DAS28 improvement from baseline in RA patients treated for 4 weeks (clinical response). The pSTAT1 response over 24-h at steady state and the contribution of the active metabolite to the biomarker response were predicted for a male with bodyweight of 75 kg. The DAS28 E-R model was used to predict the improvement of the clinical response following 12 weeks of GLPG0634 treatment. Simulations of both biomarker and clinical responses were investigated over a 30 to 300 mg daily dose range.
Results The PK of GLPG0634 and its active metabolite were adequately described by an integrated model with two- and one-compartmental disposition, respectively. The observed pSTAT1 response was described by a sigmoidal EMAX model, with EC50 values of 471 ng/mL (1.1 μM) and 1770 ng/mL (4.9 μM) for GLPG0634 and its metabolite, respectively. The steady state inhibition of pSTAT1 was predicted to be between 64.3% (pre-dose) and 91.9% (at Cmax) following treatment with 200 mg GLPG0634 QD with no relevant increase in PD response at higher doses. Biomarker response over the dosing interval correlates with the time profiles of GLPG0634 and its metabolite. While inhibition is maximal at the peak of GLPG0634, the sustained metabolite exposure results in a continued basal inhibition when GLPG0634 exposure declines. The observed DAS28 change from baseline was adequately described by a linear direct response model using the individual predicted metabolite exposure as a predictor of response. The population DAS28 change from baseline was predicted of -2.2 and -2.6 at week 4 and 12 following 200 mg GLPG0634 QD with no improvement in DAS28 response at higher doses.
Conclusions Current modeling and simulation on the basis of early clinical data suggests that the pharmacokinetics of GLPG0634 is dose proportional at doses up to 200 mg QD, in agreement with observed data, and shows that both GLPG0634 and its main metabolite contribute to biomarker response. Simulations of the pSTAT1 and DAS28 dose-response relation suggest that the efficacy is favorable up to a daily dose of 200 mg GLPG0634, with clinical response in the range of that observed with registered compounds. A daily dose range from 50 to 200 mg is currently being tested in the DARWIN Phase 2B program.
Disclosure of Interest : F. Namour Employee of: Galapagos, C. Tasset Employee of: Galapagos, G. van't Klooster Employee of: Galapagos, P. Diderichsen: None declared, E. Cox: None declared