Toreforant, an orally active histamine H-receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate: mechanism of action results from a phase 2, multicenter, randomized, double-blind, placebo-controlled synovial biopsy study.
David L Boyle, Samuel E DePrimo, Cesar Calderon, Dion Chen, Paul J Dunford, William Barchuk, Gary S Firestein, Robin L Thurmond
Author Information
David L Boyle: Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Samuel E DePrimo: Immunology Biomarkers, Janssen Research & Development LLC, San Diego, CA, USA.
Cesar Calderon: Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA.
Dion Chen: Biostatistics, Janssen Research & Development LLC, Spring House, PA, USA.
Paul J Dunford: Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA.
William Barchuk: Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA.
Gary S Firestein: Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Robin L Thurmond: Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA. RThurmon@its.jnj.com.
OBJECTIVE/DESIGN: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant. PATIENTS/TREATMENT: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52). METHODS: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics. RESULTS: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected. CONCLUSIONS: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.
