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Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active
Mark C Genovese1, Elizabeth Hsia1, Stanley M Belkowski1
1From the Division of Rheumatology, Stanford University, Palo Alto; Immunology, and Biostatistics, Janssen Research and Development LLC, La Jolla, California; Immunology, Janssen Research and Development, LLC, Spring House; Medical Affairs, Janssen Scientific Affairs LLC, Horsham, Pennsylvania; Quantitative Sciences, Janssen Research and Development LLC, Titusville, New Jersey, USA.M.C. Genovese, MD, Division of Rheumatology, Stanford University; E. Hsia, MD; S.M. Belkowski, PhD, Immunology, Janssen Research and Development LLC; C. Chien, PhD, Quantitative Sciences, Janssen Research and Development LLC; T. Masterson, MS; R.L. Thurmond, PhD; C.L. Manthey, PhD, Immunology, Janssen Research and Development LLC; X. Yan, PhD, Quantitative Sciences, Janssen Research and Development LLC; T. Ge, PhD, Biostatistics, Janssen Research and Development LLC; C. Franks, BS, Immunology, Janssen Research and Development LLC; A. Greenspan, MD, Medical Affairs, Janssen Scientific Affairs LLC.
Objective:
To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and 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) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16.
Results:
Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE.
Conclusion:
Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.
