Elsevier

The Lancet

Volume 371, Issue 9625, 17–23 May 2008, Pages 1665-1674
The Lancet

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Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)

https://doi.org/10.1016/S0140-6736(08)60725-4Get rights and content

Summary

Background

Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis.

Methods

In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969.

Findings

All randomised patients were included in the efficacy analysis. 171 (67·1%) patients receiving ustekinumab 45 mg, 170 (66·4%) receiving ustekinumab 90 mg, and eight (3·1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63·9%, 95% CI 57·8–70·1, p<0·0001 for 45 mg and 63·3%, 57·1–69·4, p<0·0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0·0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54·5%) of the 510 patients receiving ustekinumab and 123 (48·2%) of the 255 receiving placebo. Serious adverse events occurred in six (1·2%) of 510 patients receiving ustekinumab and in two (0·8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase.

Interpretation

Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients.

Funding

Centocor Inc.

Introduction

Psoriasis is a chronic immune-mediated inflammatory disease of the skin that significantly impairs patients' physical and mental functioning and wellbeing.1 The condition affects about 2–3% of the population worldwide.2 Characterisation of the immunopathophysiological basis of psoriasis has led to the development of novel therapeutic agents that selectively target aberrant immune responses putatively involved in psoriasis, including agents that target leucocyte function-associated antigen-3, CD11a, and tumour necrosis factor α.3 However, currently available therapeutic options have left substantial unmet need for treatments that are convenient, effective, and well tolerated, especially for long-term treatment.4

Interleukins 12 and 23 have an important role in the pathophysiology of psoriasis. Genetic polymorphisms in the genes that encode the shared p40 subunit of these cytokines (interleukin 12B), and one of the interleukin-23 receptor subunits, have been linked to psoriasis.5 Furthermore, an uncommon variant of the interleukin-23 receptor subunit that confers protection against Crohn's disease6 has also been shown to confer protection against psoriasis.7 The p40 subunit of interleukins 12 and 23 is overexpressed in psoriasis plaques,8 and preclinical studies implicate p40-containing cytokines in the pathogenesis of psoriasis.9 Many current therapies used in the treatment of psoriasis modulate levels of interleukins 12 and 23, which are speculated to contribute to their efficacy,10 and agents that specifically target these cytokines improved psoriasis in early clinical trials.11, 12

Ustekinumab (CNTO 1275, Centocor Inc, Malvern, PA, USA) is a human monoclonal antibody that binds to the shared p40 protein subunit of human interleukins 12 and 23 with high affinity and specificity (unpublished data), thereby preventing interaction with their cell surface IL12Rβ1 receptor. A phase II trial showed improvements in psoriasis that were dependent on dose and exposure after ustekinumab was given once or weekly for 4 weeks, with clinical effects that were sustained for many weeks.11 The phase III PHOENIX 1 study, together with PHOENIX 2,13 examined the safety and efficacy of ustekinumab compared with placebo for 12 weeks in patients with moderate-to-severe plaque psoriasis and also used a randomised withdrawal design to assess the safety and efficacy of long-term ustekinumab treatment for up to 76 weeks.

Section snippets

Patients

This phase III, double-blind, placebo-controlled, multicentre trial was done between December, 2005, and September, 2007, at 48 sites in the USA, Canada, and Belgium. Eligible patients were at least 18 years old, had a diagnosis of plaque psoriasis for at least 6 months, were candidates for phototherapy or systemic therapy, had a baseline psoriasis area and severity index (PASI) score of 12 or higher, and had at least 10% body surface area involvement. Patients were to have no history or

Results

The trial profile is shown in figure 2. Baseline demographic and clinical characteristics were much the same across treatment groups (table 1) and among patients re-randomised at week 40 (data not shown). About two-thirds of patients in each group were men. On average, patients had a 20-year history of psoriasis and about a quarter of their body surface area affected by psoriasis. Over 90% of patients had used topical treatments previously, and at least 50% each had previously used conventional

Discussion

Our findings, together with the results of the PHOENIX 2 study,13 suggest that ustekinumab, administered at 45 mg or 90 mg every 12 weeks, is efficacious for the treatment of mild-to-moderate psoriasis. Our results also lend support to the notion that interleukins 12 and 23 have a role in the immunopathophysiology of psoriasis.11, 12 These cytokines participate in immune function through activation of natural killer cells and CD4+ T-cell differentiation. Interleukin 12 induces differentiation

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