Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial

Landewé, Robert; Houbiers, J. G. A.; Bosch, Filip Van den; Hout, Joanna in't; Verschueren, Patrick; Meijerink, Jan; Hoogen, F.H.J. van den; Masek, Anna; Bruyn, G. A. W.; Wouters, Jacques M.G.W.; Voskuyl, Alexandre E.; Laar, Jacob M van; Bijlsma, Joost A.; Heijde, D.M.F.M. van der; Breedveld, Ferdinand C.; Putte, L.B.A. van de; Miltenburg, A. M. M.; Keyser, Filip De

doi:10.1136/ard.2009.117234

Cited by 11 publications

(9 citation statements)

References 10 publications

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“…Several drugs in development have targeted recently identified pathways7 8; however, not all have shown efficacy 9. Trial designs such as ours will help shorten the development process.…”

Section: Discussionmentioning

confidence: 99%

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

et al. 2012

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Background Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). Objective This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo ( part A). An interim analysis after part A would determine whether the dose-finding part ( part B) would be performed. Methods In part A, eligible methotrexate (MTX)-refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. Results The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. Conclusions This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA.

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“…Several drugs in development have targeted recently identified pathways7 8; however, not all have shown efficacy 9. Trial designs such as ours will help shorten the development process.…”

Section: Discussionmentioning

confidence: 99%

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

et al. 2012

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“…Oral delivery of this peptide led to improved clinical responses and a shift from inflammatory to regulatory cytokine production. By contrast, intranasal delivery of a potential RA autoantigen, human cartilage glycoprotein-39, failed to provide any additional benefit compared to placebo [26]. More recent phase 1 studies in RA patients, and also in diabetic patients, have delivered the tolerising antigen using patient derived APCs.…”

Section: Autoimmune Diseasementioning

confidence: 79%

Antigen-based immunotherapy (AIT) for autoimmune and allergic disease

MacLeod

Anderton

2015

Current Opinion in Pharmacology

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Autoimmune and allergic diseases are major causes of morbidity. Antigen-based immunotherapy (AIT) is immunologically the most satisfying means of specifically targeting only those T cells driving disease, thereby inducing antigen-specific immune tolerance, with the lowest adverse risk profile. AIT is highly effective in rodent models of T cell-driven inflammation and is now in clinical trials. The range of approaches to applying AIT in the clinic prevents a consensus on the molecular basis for this form of tolerance. In particular, there has been a paucity of information on how pre-activated effector and memory T cells respond to AIT. New, advanced murine models of AIT are beginning to deliver such information at the cellular, biochemical, transcriptional and epigenetic levels.

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“…We demonstrated that antigen‐specific T cells themselves express HC gp‐39 in the early phase of arthritis. Intranasal administration of HC gp‐39 was also conducted in human RA, but in Phase II the treatment lacked efficacy when compared with the placebo . We need to further characterize whether human antigen‐specific T cells express HC gp‐39 in the induction phase of RA.…”

Section: Discussionmentioning

confidence: 99%

Antigen-specific over-expression of human cartilage glycoprotein 39 on CD4+CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose-6-phosphate isomerase-induced arthritis

Tanaka

Matsumoto

Inoue

et al. 2014

Clinical and Experimental Immunology

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SummaryHuman cartilage gp-39 (HC gp-39) is a well-known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp-39 in RA are unknown. Therefore, using a glucose-6-phosphate isomerase (GPI)-induced model of arthritis, we investigated these aspects of HC gp-39 in arthritis. The rise in serum HC gp-39 levels was detected on the early phase of GPI-induced arthritis (day 7) and the HC gp-39 mRNA was increased significantly on splenic CD4 cells, T cell proliferation assay and cytokine production from CD4+ T cells using recombinant HC gp-39 was assessed. We found that GPI-specific T cell proliferation and interferon (IFN)-γ or interleukin (IL)-17 production were clearly suppressed by addition of recombinant HC gp-39. Antigen-specific over-expression of HC gp-39 in splenic CD4 + CD25 + FoxP3 + Treg cells occurs in the induction phase of GPIinduced arthritis, and addition of recombinant HC gp-39 suppresses antigen-specific T-cell proliferation and cytokine production, suggesting that HC gp-39 in CD4 + T cells might play a regulatory role in arthritis.

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Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial

Abstract: It was concluded that with the treatment protocol used (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in more clinical improvement than in placebo-treated patients.

Cited by 11 publications

References 10 publications

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

Antigen-based immunotherapy (AIT) for autoimmune and allergic disease

Antigen-specific over-expression of human cartilage glycoprotein 39 on CD4+CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose-6-phosphate isomerase-induced arthritis

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