Toreforant, an orally active histamine H4-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. ThurmondEmail author
Original Research Paper



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 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).


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.


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.


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.


Histamine receptor antagonist Pharmacodynamics Rheumatoid arthritis Biomarkers 



This phase 2 study was sponsored by Janssen Research & Development, LLC. Authors of the paper who were involved in data analysis/interpretation and who made the decision to submit the manuscript for publication are employed by Janssen. Janssen provided funding to a professional medical writer to assist the authors with manuscript preparation and submission.

Author contributions

All authors participated in data analysis and interpretation (DLB, SED, CC, DC, PJD, WB, GSF, and RLT) and manuscript preparation (DLB, SED, CC, DC, PJD, WB, GSF, and RLT). All authors also read and approved the final manuscript for submission (DLB, SED, CC, DC, PJD, WB, GSF, and RLT), and agree to be accountable for all the aspects of the work (DLB, SED, CC, DC, PJD, WB, GSF, and RLT).


This phase 2 study was sponsored by Janssen Research & Development, LLC.

Compliance with ethical standards

Conflict of interest

SE DePrimo, C Calderon, D Chen, PJ Dunford*, W Barchuk*, and RL Thurmond are/were employees of Janssen, a Johnson and Johnson (J&J) Pharmaceutical Company, and own stock in J&J. DL Boyle and GS Firestein have each received research grant funding from Janssen. *These authors were employed by Janssen at the time this study was conducted.

Ethical approval

All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional review board and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained for all individual participants included in the study.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • David L. Boyle
    • 1
  • Samuel E. DePrimo
    • 2
  • Cesar Calderon
    • 3
  • Dion Chen
    • 4
  • Paul J. Dunford
    • 3
  • William Barchuk
    • 3
    • 5
  • Gary S. Firestein
    • 1
  • Robin L. Thurmond
    • 3
    Email author
  1. 1.Division of Rheumatology, Allergy and ImmunologyUC San Diego School of MedicineSan DiegoUSA
  2. 2.Immunology BiomarkersJanssen Research & Development LLCSan DiegoUSA
  3. 3.Immunology Clinical DevelopmentJanssen Research & Development LLCSpring HouseUSA
  4. 4.BiostatisticsJanssen Research & Development LLCSpring HouseUSA
  5. 5.Immunology Clinical DevelopmentEli Lilly and CompanySan DiegoUSA

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