Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

• DOI: 10.3899/jrheum.141580
• Publication Date: 2015-08-02T00:30:01Z
• Authors: Mark C. Genovese; Elizabeth Hsia; Stanley M. Belkowski; Caly Chien; Tara Masterson; Robin L. Thurmond; Carl L. Manthey; Xiaoyu (David) Yan; Tingting Ge; Carol Franks; Andrew Greenspan
• Keywords: Clinical endpoint; Pharmacodynamics; Rheumatoid factor

Objective. To assess the efficacy and safety of JNJ-40346527, a selective inhibitor colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy. Methods. In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients RA had disease activity [≥ 6 swollen/≥ tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] DMARD therapy for months. The primary endpoint was change from baseline at 12 28-joint Disease Activity Score CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses also performed, assessed 16. Results. Ninety-five treated (63 32 placebo); 8 discontinued treatment (6 2 placebo) Mean improvements DAS28-CRP 1.15 1.42 (p = 0.30); thus, statistically significant difference not observed endpoint. Pharmacokinetic exposure its metabolites above projected concentration needed pharmacologic activity, effective target engagement proof demonstrated by increased levels CSF-1 decreased CD16+ monocytes JNJ-40346527–treated, but placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527–treated 16 (50.0%) placebo-treated reported 1 adverse event (AE); (1.6%) 3 (9.4%) serious AE. Conclusion. Although adequate peripheral evident, DMARD-refractory RA. ClinicalTrials.gov identifier: NCT01597739 . EudraCT Number: 2011-004529-28.