title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From 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.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.affiliation: From 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hsia
authors.affiliation: From 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.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Belkowski
authors.affiliation: From 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.
authors.forename: Caly
authors.initials: C
authors.lastname: Chien
authors.affiliation: From 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.
authors.forename: Tara
authors.initials: T
authors.lastname: Masterson
authors.affiliation: From 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.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.affiliation: From 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.
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.affiliation: From 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.
authors.forename: Xiaoyu David
authors.initials: XD
authors.lastname: Yan
authors.affiliation: From 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.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ge
authors.affiliation: From 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.
authors.forename: Carol
authors.initials: C
authors.lastname: Franks
authors.affiliation: From 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. AGreensp@its.jnj.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Greenspan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D015507:Drugs, Investigational; D016173:Macrophage Colony-Stimulating Factor
keywords: COLONY-STIMULATING FACTOR-1; EFFICACY; RHEUMATOID ARTHRITIS; SAFETY