Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: GLPG0634 is an orally-available, selective Janus kinase 1 (JAK1) inhibitor. 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. Here the contribution of exposure-response (E-R) modelling and simulation to support GLPG0634 dose selection for Phase 2B studies is presented
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 (JAK1 activity, PD response) and DAS28 improvement from baseline in RA patients treated for 4 weeks (clinical response). Continuous covariates were evaluated in the models as a power function while binary covariates were tested as factors. 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 and 1770 ng/mL 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 inhibition correlated with the long lasting metabolite exposure. 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 to be -2.2 and -2.6 at week 4 and 12 following 200 mg GLPG0634 QD with no further improvement in DAS28 response at higher doses. No covariates were included in the models of biomarker or clinical response
Conclusion: Current modeling and simulation on the basis of early clinical data support that both GLPG0634 and its main metabolite contribute to JAK1 inhibition, as reflected in pSTAT1 biomarker response. Simulations of the pharmacodynamics (pSTAT1) and efficacy (DAS28) show a dose-related response with a maximum efficacy achieved at a daily dose of 200 mg GLPG0634. No further gain is obtained at higher doses. The overall clinical response is in the range of that observed with registered biological DMARDS. A daily dose range from 50 to 200 mg is currently being tested in the DARWIN Phase 2B program
Disclosure:
F. Namour,
GALAPAGOS,
3;
C. Tasset,
GALAPAGOS,
3;
B. Vayssièrre,
GALAPAGOS,
3;
G. van ‘t Klooster,
GALAPAGOS,
3;
P. Diderichsen,
QUANTITATIVE SOLUTIONS,
3;
E. Cox,
QUANTITATIVE SOLUTIONS,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dose-selection-of-glpg0634-a-selective-jak1-inhibitor-for-rheumatoid-arthritis-phase-2b-studies-pkpd-and-exposure-das28-modeling-approach/