P.M Diderichsen, F. Namour, E. Cox, C. Tasset, G. van ’t Klooster
Quantitative Solutions bv, Galapagos SASU, Galapagos nv
Objectives: GLPG0634 is an orally-available, selective (JAK1) inhibitor and has shown encouraging pharmacodynamics, safety and efficacy in early clinical studies treating RA patients for 4 weeks. The purpose of analysis was to support GLPG0634 dose selection for Phase 2b studies in RA.
Methods: Non-linear mixed effects models were built for plasma pharmacokinetics (PK) of both GLPG0634 and its main metabolite , for the pSTAT1 response in healthy subjects (biomarker) and DAS28 improvement from baseline in RA patients treated for 4 weeks (clinical response). Model-predicted responses for both steady-state pSTAT1 and DAS28 (12 weeks) as well as the contribution of the active metabolite to the biomarker response were investigated for a GLPG0634 dose range of 30-300 mg/day.
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. 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. Simulations indicated that 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 an indirect response model using the metabolite exposure as a predictor of response. The DAS28 change from baseline was predicted to be -2.2 and -2.6 at week 4 and 12 following 200 mg GLPG0634 QD with no substantial improvement in DAS28 response at higher doses.
Conclusions: This analysis of early clinical data suggests that (1) the pharmacokinetics of GLPG0634 is dose proportional at doses up to 200 mg QD, (2) both GLPG0634 and its main metabolite contribute to pSTAT1 biomarker response, and (3) clinical efficacy (DAS28) increases with the dose up to a daily dose of 200 mg GLPG0634, with clinical response in the range of that observed with JAK inhibitors.
Reference: PAGE 23 () Abstr 3280 [www.page-meeting.org/?abstract=3280]
Poster: Drug/Disease modeling - Other topics