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Pathophysiology


only anti-IL-17 agent currently approved for the treatment of psoriasis. The monoclonal antibody, administered by subcutaneous injection, is available in the US and has received first-of-its-kind marketing approval in the EU as a first-line systemic treatment for adult patients with moderate to severe plaque psoriasis. Regulatory approval was in part based on the results from four pivotal randomised Phase III trials involving more than 2000 patients who were candidates for systemic therapy.31,32 In the FIXTURE, ERASURE, FEATURE and JUNCTURE trials, patients treated with secukinumab achieved greater clinical response at all the doses tested than placebo, as measured by the Psoriasis Area and Severity Index (PASI), at 12 weeks. In all four studies, the biologic agent was generally well tolerated; nasopharyngitis, headache, diarrhoea and upper respiratory tract infections were the most frequently observed adverse events.33–35


In addition, the FIXTURE trial showed secukinumab to be superior to the anti-TNF agent, etanercept at all assessed timepoints up to 52 weeks.33


released from the extension study of FIXTURE and ERASURE revealed sustained reductions of 75% in PASI (PASI 75) in 88% (and over 70% PASI90, that is clear or almost clear skin) of patients receiving treatment with the 300mg dose of secukinumab for two years. The antibody also presented a favourable long-term safety profile.36


In a


head-to-head Phase III study, designated CLEAR, IL-17A inhibition with secukinumab was superior to dual IL-12 and -23 inhibition with ustekinumab in clearing skin lesions of moderate-to- severe severity over a period of 16 weeks, which translated into meaningful improvements in health-related quality of life measures.37


These studies point to a


safe prolonged use of secukinumab as monotherapy in patients with psoriasis.


6


Experimental IL-17 agents Considering the clinical success of secukinumab in moderate-to-severe cases, it is expected that additional IL-17-based therapeutic strategies will follow. Two additional agents targeting specifically IL-17 are at advanced stages of evaluation (Table 1). Ixekizumab, a humanised mAb, which also inhibits the IL-17 antibody, induced significant PASI 75 responses at 12 weeks, compared with


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In UNCOVER-1, high levels of response were maintained through 60 weeks of treatment. The incidence and severity of adverse events were similar among patients treated with ixekizumab across all three studies and comparable to those observed for etanercept in UNCOVER-2 and -3. The most frequently reported adverse events were nasopharyngitis and mild injection site reactions.39


placebo or active comparator etanercept, in an active Phase III clinical programme (UNCOVER) evaluating patients with moderate and severe forms of the disease.38


The second agent, brodalumab, binds and inhibits IL-17RA, neutralising simultaneously IL-17A, -17C, -17F and -17E. Phase II evaluation of the agent has been completed and significant improvements in PASI scores were observed at all doses tested versus placebo at 12 weeks.40


Preliminary data Data recently


from three ongoing Phase III trials of brodalumab (AMAGINE-1, -2 and -3) confirmed these results and also showed significant improvements from baseline in disease severity with brodalumab, at the highest dose, compared to ustekinumab. As in the Phase II trial, nasopharyngitis, upper respiratory tract infections and arthralgia were among the


“The use of biologics targeting specific immune mediators has improved outcomes for psoriasis”


most frequent adverse events reported in the brodalumab-treated group.41–43 However, rare and unproven suicidal ideation and behaviour events with brodalumab have recently raised concerns about potential labelling restrictions.44 Other IL-17 targeting agents at earlier stages of development may be added to the psoriasis armamentarium in the future (Table 1). MSB0010841, an anti-IL17A/F Nanobody, and the dual TNF-a/IL-17A inhibitor, COVA322, are currently being evaluated in moderate- to-severe chronic plaque psoriasis. COVA322 yielded encouraging results in a preclinical primate model of collagen- induced arthritis.45


Conclusions The use of biologics targeting specific


immune mediators has improved outcomes for several disorders of the immune system, including psoriasis, and provides a viable option to conventional non-biologic agents in the management of symptoms in the long term. Biologics targeting TNF and the IL-12/IL-23 axis are now well established in the treatment of moderate-to-severe psoriasis. IL-17 cytokine inhibition is a relevant therapeutic strategy for psoriasis and may potentially show beneficial effects on cardiovascular disease and other pathologies linked to psoriasis, as well as in patients with other autoimmune diseases.


As we learn more about the complex regulatory and functional mechanisms of the IL-17 pathway, highly specific targeted strategies associated with favourable long-term efficacy and safety profiles have been developed in the context of inflammatory autoimmune diseases, ultimately improving patient adherence and care. ●


References 1. Stern RS et al. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Invest Dermatol Symp Proc 2004;9:136–9.


2. Griffiths CE et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol 2007;156(2):258–62.


3. Brandrup F et al. Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution. Acta Derm Venereol 1982;62:229–36.


4. Nestle F, Kaplan D, Barker J. Psoriasis. N Engl J Med 2009;361:496–509.


5. Martin D et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol 2013;133(1):17–26.


6. Reich K et al. Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis. Exp Dermatol 2015;24(7):529–35.


7. Lowes MA, Suàrez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol 2014;32:227–55.


8. Veal DC et al. Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus. Am J Hum Genet 2002;71:554–64.


9. Trembath RC et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum Mol Genet 1997;6:813–20.


10. Newcomb DC et al. A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and


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