Elsevier

The Lancet

Volume 371, Issue 9625, 17–23 May 2008, Pages 1675-1684
The Lancet

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Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)

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Summary

Background

Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.

Methods

In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score ≥12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving ≥50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437.

Findings

All randomised patients were included in the efficacy analysis. 273 (66·7%) patients receiving ustekinumab 45 mg, 311 (75·7%) receiving ustekinumab 90 mg, and 15 (3·7%) receiving placebo achieved the primary endpoint (difference in response rate 63·1%, 95% CI 58·2–68·0, p<0·0001 for the 45 mg group vs placebo and 72·0%, 67·5–76·5, p<0·0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68·8%] vs 11 [33·3%]; difference in response rate 35·4%, 95% CI 12·7–58·1, p=0·004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53·1%) patients in the 45 mg group, 197 (47·9%) in the 90 mg group, and 204 (49·8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2·0%) patients in the 45 mg group, five (1·2%) in the 90 mg group, and eight (2·0%) in the placebo group.

Interpretation

Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

Funding

Centocor Inc.

Introduction

Psoriasis is the most common immune-mediated skin disease,1, 2 with an estimated prevalence of 2–3%.3, 4 Interleukins 12 and 23 have been postulated to have a central role in psoriasis pathophysiology, and agents that block these cytokines have shown promise as therapeutic agents for the treatment of psoriasis and psoriatic arthritis.5, 6, 7, 8

Ustekinumab (CNTO 1275; Centocor Inc, Malvern, PA, USA) is a human monoclonal antibody that binds to the shared p40 subunit of interleukins 12 and 23, blocking signalling of their cognate receptors. Preclinical studies link the immune response generated by the p40 family of cytokines to psoriasis pathogenesis,9, 10 and in early clinical studies, high levels of clinical response have been seen in patients with psoriasis after treatment with ustekinumab.5, 11, 12 Although most patients achieve a clinically meaningful response,13 a subpopulation achieves only partial response. Whether residual skin disease in these partial responders is mediated by immune pathways distinct from those mediated by interleukins 12 and 23, or whether this subgroup simply requires greater exposure to ustekinumab, has not been determined.

To confirm clinical studies suggesting therapeutic potential for ustekinumab, the phase III PHOENIX 2 trial, along with PHOENIX 1,7 was designed to assess the efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis with up to 52 weeks of treatment. Additionally, PHOENIX 2 assessed whether dosing intensification would improve skin response rates in patients who partially responded to initial treatment.

Section snippets

Patients

This phase III, multicentre, double-blind, placebo-controlled trial was done at 70 sites in Europe and North America (Austria, Canada, France, Germany, Switzerland, UK, USA) between March, 2006, and September, 2007. Patients aged 18 years or older were eligible to participate if they had a diagnosis of plaque psoriasis for 6 months or longer, a baseline psoriasis area and severity index (PASI) score of 12 or higher, at least 10% body surface area involvement, and were candidates for

Results

Figure 2 shows the trial profile. Treatment groups were well balanced with regard to demographic and baseline characteristics (table 1). The mean duration of psoriasis was about 20 years, and the extent of body surface area involvement was about 25%. Most patients had used conventional systemic or biological agents to treat their psoriasis. 43 (3·5%) patients with latent tuberculosis received isoniazid during the study (table 1).

Significantly more patients in both ustekinumab groups achieved

Discussion

The results of this large phase III study, together with those of the PHOENIX 1 study,7 indicate that treatment with ustekinumab 45 mg or 90 mg results in rapid, significant improvements in patients with moderate-to-severe psoriasis. These data also lend support to the notion that interleukins 12 and 23 have a key role in the immunopathophysiology of psoriasis. Results were consistent in both trials—which together assessed almost 2000 patients—in terms of kinetics and magnitude of clinical

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