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
| Autor: | Mark C. Genovese, Andrew Greenspan, Tingting Ge, Stanley M. Belkowski, Carl L. Manthey, Xiaoyu David Yan, Carol F. Franks, Tara Masterson, Elizabeth C. Hsia, Robin L. Thurmond, Caly Chien |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male medicine.medical_specialty medicine.medical_treatment Immunology Administration Oral Pharmacology Placebo Gastroenterology Risk Assessment Severity of Illness Index Drug Administration Schedule Arthritis Rheumatoid Rheumatology Pharmacokinetics Double-Blind Method Internal medicine medicine Clinical endpoint Immunology and Allergy Humans Disease-modifying antirheumatic drug Adverse effect Active metabolite Dose-Response Relationship Drug business.industry Macrophage Colony-Stimulating Factor Drugs Investigational Middle Aged medicine.disease Treatment Outcome Pharmacodynamics Rheumatoid arthritis Antirheumatic Agents Drug Therapy Combination Female Patient Safety business Follow-Up Studies |
| Zdroj: | The Journal of rheumatology. 42(10) |
| ISSN: | 0315-162X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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