ArticlesComparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials
Introduction
Psoriasis is a common chronic inflammatory skin disease, characterised by red, scaly plaques arising from complex gene–environment interactions.1, 2 Clinical manifestations of skin lesions and coexisting comorbidities have a major effect on social relationships, mental health, and work-related activities.3, 4, 5, 6 Human genome studies uncovered psoriasis-associated polymorphisms in many immune-related genes, reinforcing the importance of deregulated cytokine networks in the cause and pathophysiology of psoriasis.7, 8, 9, 10 Hence, attempts to identify and target specific cytokine pathways to reduce inflammation and resolve lesions have gained momentum over the past decades.11, 12, 13, 14, 15, 16
Although first-generation cytokine antagonists targeting tumour necrosis factor (TNF)α-dependent pathways produced favourable responses,13, 14, 15 higher levels of efficacy in a greater proportion of patients with psoriasis have recently been shown in trials with antibodies targeting interleukin-12/23, interleukin-17A, or interleukin-17 receptor (IL-17RA) subunit.12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Building on phase 126 and phase 2 ixekizumab dose-finding and open-label extension results,19, 27 we report the first 12 weeks of two studies comparing two different dose schedules of ixekizumab (a high-affinity anti-interleukin-17A antibody) with placebo and a European Medicines Agency (EMA) and US Food and Drug Administration (FDA)-approved and effective TNF-blocker, etanercept, in the treatment of plaque psoriasis over 12 weeks.
Section snippets
Study design and participants
In these two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible participants were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by clinician-rated measure of static physician global assessment (sPGA) score of 3 or more, and a psoriasis area
Results
Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (50 mg twice weekly; n=358), or one injection of 80 mg ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347), and between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386).
Overall, patients were well balanced on
Discussion
We report results from two phase 3 studies of more than 2500 patients to extend the rapidly evolving body of evidence implicating interleukin 17A as a cytokine integral to the pathogenesis of psoriasis (panel). Here, ixekizumab, which neutralises interleukin 17A, had greater efficacy than placebo and etanercept, a widely used FDA-approved and EMA-approved biological drug targeting TNFα, with respect to coprimary and all major secondary endpoints. Clinically meaningful responses (PASI 75) by
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