Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study

Rich, Phoebe; Sigurgeirsson, Bárður; Thaçi, Diamant; Ortonne, Jean‐Paul; Paul, C.; Schopf, R. E.; Morita, Akimichi; Roseau, K.; Harfst, E.; Guettner, A.; Macháček, Matthias; Papavassilis, Charis

doi:10.1111/bjd.12112

Cited by 148 publications

(186 citation statements)

References 27 publications

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“…Suppression of Th17 signature gene expression and IL-17A production in primary cells from psoriatic patients Recent clinical trials have established that IL-17A is a critical factor in the pathogenesis of human psoriasis (3,38,39). Given our findings described earlier showing that inhibition of RORgt modulates cutaneous inflammation in mouse models, we next tested our RORgt inverse agonists in clinical samples obtained from psoriatic patients.…”

Section: Tmp778 Attenuates Imq-induced Skin Inflammationmentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

130

123

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IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

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Section: Tmp778 Attenuates Imq-induced Skin Inflammationmentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

130

123

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“…Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL‐17A, has been shown to have a significant efficacy in the treatment of moderate‐to‐severe psoriasis11, 12, 13, 14 and psoriatic arthritis,15, 16, 17 showing a rapid onset of action and sustained responses with a favorable safety profile. Secukinumab has been approved for the treatment of multiple indications, such as moderate‐to‐severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis in USA and Europe 15, 17, 18.…”

Section: Introductionmentioning

confidence: 99%

Secukinumab improves psoriasis symptoms in patients with inadequate response to cyclosporine A: A prospective study to evaluate direct switch

Ohtsuki

Morita

Igarashi

et al. 2017

The Journal of Dermatology

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There are limited data on the safety and efficacy of switching to secukinumab from cyclosporine A (CyA) in patients with psoriasis. The purpose of the present study was to assess the efficacy and safety of secukinumab for 16 weeks after direct switching from CyA in patients with moderate‐to‐severe psoriasis. In this multicenter, open‐label, phase IV study, 34 patients with moderate‐to‐severe psoriasis and inadequate response to CyA received secukinumab 300 mg s.c. at baseline and weeks 1, 2, 3, 4, 8 and 12. The primary end‐point was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. The efficacy of secukinumab treatment was evaluated up to week 16, and adverse events (AE) were monitored during the study. The primary end‐point of the PASI 75 response at week 16 was achieved by 82.4% (n = 28) of patients receiving secukinumab. Early improvements were observed with secukinumab, with PASI 50 response of 41.2% at week 2 and PASI 75 response of 44.1% at week 4. AE were observed in 70.6% (n = 24) of patients, and there were no serious AE or deaths reported in the entire study period. Secukinumab showed a favorable safety profile consistent with previous data with no new or unexpected safety signals. The results of the present study show that secukinumab is effective in patients with psoriasis enabling a smooth and safe direct switch from CyA to biological therapy.

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“…Secukinumab has been shown to be clinically effective (1,2) with a rapid, strong and sustained efficacy and a favourable safety profile in patients with moderate-to-severe plaque psoriasis (3)(4)(5). Secukinumab is administered by subcutaneous injection, which is typical for the most recent antibody therapies.…”

Section: Introductionmentioning

confidence: 99%

Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion

Dragatin

Polus

Bodenlenz

et al. 2015

Experimental Dermatology

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Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study

Abstract: Secukinumab shows efficacy for induction and maintenance treatment of moderate-to-severe plaque psoriasis.

Cited by 148 publications

References 27 publications

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Secukinumab improves psoriasis symptoms in patients with inadequate response to cyclosporine A: A prospective study to evaluate direct switch

Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion

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