Advertisement

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
  • 3 Downloads

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.

Keywords

Histamine receptor antagonist Pharmacodynamics Rheumatoid arthritis Biomarkers 

Notes

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.

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).

Funding

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.

References

  1. 1.
    Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, Liu WL, et al. International union of basic and clinical pharmacology. XCVIII. Histamine receptors. Pharmacol Rev. 2015;67:601–55.CrossRefGoogle Scholar
  2. 2.
    Zhang M, Venable JD, Thurmond RL. The histamine H4 receptor in autoimmune disease. Expert Opin Investig Drugs. 2006;15:1443–52.CrossRefGoogle Scholar
  3. 3.
    Frewin DB, Cleland LG, Jonsson JR, Robertson PW. Histamine levels in human synovial fluid. J Rheumatol. 1986;13:13–4.Google Scholar
  4. 4.
    Ikawa Y, Suzuki M, Shiono S, Ohki E, Moriya H, Negishi E, et al. Histamine H4 receptor expression in human synovial cells obtained from patients suffering from rheumatoid arthritis. Biol Pharm Bull. 2005;28:2016–8.CrossRefGoogle Scholar
  5. 5.
    Ohki E, Suzuki M, Aoe T, Ikawa Y, Negishi E, Ueno K. Expression of histamine H4 receptor in synovial cells from rheumatoid arthritic patients. Biol Pharm Bull. 2007;30:2217–20.CrossRefGoogle Scholar
  6. 6.
    Cowden JM, Yu F, Banie H, Farahani M, Ling P, Nguyen S, et al. The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis. Ann Rheum Dis. 2014;73:600–8.CrossRefGoogle Scholar
  7. 7.
    Thurmond RL, Greenspan A, Radziszewski W, Xu XL, Miao Y, Chen B, et al. Toreforant, a histamine H4 receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate therapy: results of 2 Phase II studies. J Rheumatol. 2016;43:1637–42.CrossRefGoogle Scholar
  8. 8.
    Kiener HP, Hofbauer R, Tohidast-Akrad M, Walchshofer S, Redlich K, Bitzan P, et al. Tumor necrosis factor alpha promotes the expression of stem cell factor in synovial fibroblasts and their capacity to induce mast cell chemotaxis. Arthritis Rheum. 2000;43:164–74.CrossRefGoogle Scholar
  9. 9.
    Kiener HP, Baghestanian M, Dominkus M, Walchshofer S, Ghannadan M, Willheim M, et al. Expression of the C5a receptor (CD88) on synovial mast cells in patients with rheumatoid arthritis. Arthritis Rheum. 1998;41:233–45.CrossRefGoogle Scholar
  10. 10.
    Mommert S, Gschwandtner M, Koether B, Gutzmer R, Werfel T. Human memory Th17 cells express a functional histamine H4 receptor. Am J Pathol. 2012;180:177–85.CrossRefGoogle Scholar
  11. 11.
    Kirkham BW, Kavanaugh A, Reich K. Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis. Immunology. 2014;141:133–42.CrossRefGoogle Scholar
  12. 12.
    Roeleveld DM, Koenders MI. The role of the Th17 cytokines IL-17 and IL-22 in Rheumatoid Arthritis pathogenesis and developments in cytokine immunotherapy. Cytokine. 2015;74:101–7.CrossRefGoogle Scholar
  13. 13.
    Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015;74:1311–6.CrossRefGoogle Scholar
  14. 14.
    Kavanaugh A, Rosengren S, Lee SJ, Hammaker D, Firestein GS, Kalunian K, et al. Assessment of rituximab’s immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results. Ann Rheum Dis. 2008;67:402–8.CrossRefGoogle Scholar
  15. 15.
    van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Rustenburg F, Baggen JM, Verweij CL, et al. Responsiveness to anti-tumour necrosis factor alpha therapy is related to pre-treatment tissue inflammation levels in rheumatoid arthritis patients. Ann Rheum Dis. 2008;67:563–6.CrossRefGoogle Scholar
  16. 16.
    Li N, Wang JC, Liang TH, Zhu MH, Wang JY, Fu XL, et al. Pathologic finding of increased expression of interleukin-17 in the synovial tissue of rheumatoid arthritis patients. Int J Clin Exp Pathol. 2013;6:1375–9.Google Scholar
  17. 17.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.CrossRefGoogle Scholar
  18. 18.
    Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include 28 joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–8.CrossRefGoogle Scholar
  19. 19.
    Van Riel PLCM, van Gestel AM, Scott DL. EULAR handbook of clinical assessments in rheumatoid arthritis. Alphen Aan Den Rijn, The Netherlands: Van Zuiden Communications B.V. 2000; 40.Google Scholar
  20. 20.
    Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-joint disease activity score (DAS28) and European league against rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009;68:954–60.CrossRefGoogle Scholar
  21. 21.
    Kelly S, Humby F, Filer A, Ng N, Di Cicco M, Hands RE, et al. Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients. Ann Rheum Dis. 2015;74:611–7.CrossRefGoogle Scholar
  22. 22.
    Firestein GS, Paine MM, Littman BH. Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intraarticular corticosteroids. Arthritis Rheum. 1991;34:1094–105.CrossRefGoogle Scholar
  23. 23.
    Firestein GS, Paine MM, Boyle DL. Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arthritis Rheum. 1994;37:193–200.CrossRefGoogle Scholar
  24. 24.
    Boyle DL, Rosengren S, Bugbee W, Kavanaugh A, Firestein GS. Quantitative biomarker analysis of synovial gene expression by real-time PCR. Arthritis Res Ther. 2003;5:R352-60.CrossRefGoogle Scholar
  25. 25.
    Rosengren S, Firestein GS, Boyle DL. Measurement of inflammatory biomarkers in synovial tissue extracts by enzyme-linked immunosorbent assay. Clin Diagn Lab Immunol. 2003;10:1002–10.Google Scholar
  26. 26.
    Han SH, Hur MS, Kim MJ, Kim BM, Kim KW, Kim HR, et al. Preliminary study of histamine H4 receptor expressed on human CD4 + T cells and its immunomodulatory potency in the IL-17 pathway of psoriasis. J Dermatol Sci. 2017;88:29–35.CrossRefGoogle Scholar
  27. 27.
    Thurmond RL, Chen B, Dunford PJ, Greenspan AJ, Karlsson L, La D, et al. Clinical and preclinical characterization of the histamine H4 receptor antagonist JNJ-39758979. J Pharmacol Exp Ther. 2014;349:176–84.CrossRefGoogle Scholar
  28. 28.
    Iwamoto T, Okamoto H, Iikuni N, Takeuchi M, Toyama Y, Tomatsu T, et al. Monocyte chemoattractant protein-4 (MCP-4)/CCL13 is highly expressed in cartilage from patients with rheumatoid arthritis. Rheumatology. 2006;45:421–4.CrossRefGoogle Scholar
  29. 29.
    Doyle MK, Rahman MU, Frederick B, Birbara CA, de Vries D, Toedter G, et al. Effects of subcutaneous and intravenous golimumab on inflammatory biomarkers in patients with rheumatoid arthritis: results of a phase 1, randomized, open-label trial. Rheumatology. 2013;52:1214–9.CrossRefGoogle Scholar
  30. 30.
    Bakker MF, Cavet G, Jacobs JW, Bijlsma JW, Haney DJ, Shen Y, et al. Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis. 2012;71:1692–7.CrossRefGoogle Scholar
  31. 31.
    Buch MH, Boyle DL, Rosengren S, Saleem B, Reece RJ, Rhodes LA, et al. Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study. Ann Rheum Dis. 2009;68:1220–7.CrossRefGoogle Scholar
  32. 32.
    Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol. 2010;184:3336–40.CrossRefGoogle Scholar
  33. 33.
    Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999;42:963–70.CrossRefGoogle Scholar

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

Personalised recommendations