Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis

Burmester, Gerd R; Weinblatt, Michael E.; McInnes, Iain B.; Porter, Duncan; Барбараш, О. Л.; Vatutin, Mykola; Szombati, István; Esfandiari, Ehsanollah; Sleeman, Matthew A.; Kane, Christopher D.; Cavet, G.; Wang, Bing; Godwood, A.; Magrini, Fabio

doi:10.1136/annrheumdis-2012-202450

Cited by 144 publications

(128 citation statements)

References 39 publications

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“…We show here that CBP30 also inhibits GM-CSF cytokine secretion. Th17 cells secreting additional cytokines have been described as being particularly pathogenic, with GM-CSF in particular implicated in rheumatoid arthritis (35). The observed discrepancy between inhibitory effects of CBP30 on GM-CSF secretion and CSF2 transcription might be explained by minor differences in the experimental time course.…”

Section: Discussionmentioning

confidence: 99%

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Hammitzsch

Tallant

Fedorov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

221

200

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Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.CBP/p300 | bromodomain | epigenetic inhibitors | Th17 | ankylosing spondylitis

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Section: Discussionmentioning

confidence: 99%

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Hammitzsch

Tallant

Fedorov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

221

200

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“…Inhibition of GM-CSFRα and CSF-1R has now been tested for clinical efficacy in RA. In the phase II trial of mavrilimumab (anti-GM-CSFRα), all doses combined of mavrilimumab (n = 158) were associated with a significantly higher proportion of patients achieving a ≥ 1.2-point reduction in DAS28-CRP than placebo (n = 75) at Week 12 (55.7% vs 34.7%, p = 0.003) 21 . It is tempting to conclude that the efficacy of mavrilimumab may partly validate the targeting of macrophages, although the cellular pharmacology of GM-CSF antagonism may be complex because of the effect of this cytokine not only on macrophages but also on neutrophils, eosinophils, and perhaps other cell lineages.…”

Section: Discussionmentioning

confidence: 99%

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

et al. 2015

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Objective.To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy.Methods.In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16.Results.Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527–treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527–treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527–treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE.Conclusion.Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.

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“…Therefore, neutralization/blocking Abs are a useful approach and can easily receive clinical applications. Now, Mavrilimumab, anti-GM-CSF receptor a Ab, is being developed, and a phase II study in subjects with rheumatoid arthritis patients is reported to have significant efficacy and no serious adverse events, including PAP (54). Regarding the fact that neutralization of GM-CSF ameliorated ILD in SKG mice even after the onset of ILD, it can provide a useful therapeutic strategy in CTD-ILD in humans.…”

Section: Discussionmentioning

confidence: 99%

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

Shiomi

Usui

Ishikawa

et al. 2014

The Journal of Immunology

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Interstitial lung disease (ILD) is a common complication and sometimes a prognostic factor of connective tissue diseases (CTDs) in humans. However, suitable animal model of severe CTD-associated ILD (CTD-ILD) has been limited. In this study, we showed that zymosan-treated SKG mice developed not only arthritis but also chronic–progressive ILD with high mortality over several months. The pathological and clinical features of ILD in zymosan-treated SKG mice were similar to that of human severe CTD-ILD. ILD in this mouse was characterized by massive infiltration of Th17 cells, GM-CSF–producing CD4+ T cells, and CD11b+ Gr1+ neutrophils with fibrosis. Naive SKG T cells were skewed to differentiate into GM-CSF–producing cells, and GM-CSF secreted by T cells enhanced IL-6 and IL-1β production by macrophages, which in turn enhanced differentiation of IL-17A– and/or GM-CSF–producing T cells and infiltration of neutrophils into lung. Neutralization of GM-CSF completely blocked the development of this ILD, and the blocking of IL-6 signaling resulted in partial prevention of it, whereas neutralization of IL-17A did not. In contrast, the progression of arthritis was inhibited by the neutralization of GM-CSF and slightly by the neutralization of IL-17A, but not by the blocking of IL-6 signaling. These data suggested zymosan-treated SKG mice could be a useful mouse model of severe CTD-ILD, and GM-CSF, rather than IL-17A or IL-6, contributed to the development of ILD in zymosan-treated SKG mice, indicating that neutralization of GM-CSF would be a useful therapeutic strategy for severe CTD-ILD.

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Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis

Cited by 144 publications

References 39 publications

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy

GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice

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