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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

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Abstract

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.

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Data availability

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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.

Funding

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

Author information

Author notes

  1. William Barchuk

    Present address: Immunology Clinical Development, Eli Lilly and Company, San Diego, CA, USA

Authors and Affiliations

  1. Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine, La Jolla, San Diego, CA, USA

    David L. Boyle & Gary S. Firestein

  2. Immunology Biomarkers, Janssen Research & Development LLC, San Diego, CA, USA

    Samuel E. DePrimo

  3. Immunology Clinical Development, Janssen Research & Development LLC, Spring House, PA, USA

    Cesar Calderon, Paul J. Dunford, William Barchuk & Robin L. Thurmond

  4. Biostatistics, Janssen Research & Development LLC, Spring House, PA, USA

    Dion Chen

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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).

Corresponding author

Correspondence to Robin L. Thurmond.

Ethics declarations

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.

Additional information

Responsible Editor: Bernhard Gibbs.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The authors would like to thank Wendy Cordier, BS of Janssen Research & Development, LLC, for assistance with the study protocol, sample collection, and laboratory analysis processes; Francisco Leon, MD PhD, formerly of Janssen, for contributions to the initial study design concept; Bruno Rachwal of Janssen Research & Development, LLC for assistance with programming and data management; and Michelle L Perate, MS, a professional medical writer funded by Janssen, for assistance with manuscript preparation and submission.

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Boyle, D.L., DePrimo, S.E., Calderon, C. et al. 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. Inflamm. Res. 68, 261–274 (2019). https://doi.org/10.1007/s00011-019-01218-y

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