Two randomised controlled trials (PHOENIX 1 & 2), published in the Lancet, report on the efficacy of the human monoclonal antibody ustekinumab in treating psoriasis. Ustekinumab is directed at interleukins 12 and 23, which have been implicated in the pathophysiology of psoriasis.

PHOENIX 1:
This phase III parallel, double-blind, placebo-controlled study 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. The trial was conducted between December 2005 and September 2007 across 48 sites in the USA, Canada, and Belgium. The safety and efficacy of ustekinumab were assessed over three phases: a placebo-controlled phase (weeks 0–12), a placebo-crossover and active treatment phase (weeks 12–40), and a randomised withdrawal phase (weeks 40–76). Overall, 766 patients with moderate-to-severe psoriasis were randomly allocated 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 and 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. The primary endpoint measure used in the study was the proportion of patients achieving PASI 75 at week 12. Analyses were carried out on an intention to treat basis. All randomised patients were included in the efficacy analysis. The results found (direct from source):

• 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• PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p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.

The authors conclude “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.”
PHOENIX 2:
This phase III, multicentre, double-blind, placebo-controlled study was carried out across 70 sites in Europe and North America between March 2006 and September 2007. The study assessed the efficacy and safety of ustekinumab in psoriasis patients with up to 52 weeks of treatment and assessed response to dosing intensification in partial responders. A total of 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly allocated to treatment with either 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 (defined as patients achieving > or = 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. The primary endpoint measure was the same as that used for PHOENIX 1. Analyses were carried out on an intention to treat basis and all randomised patients were included in the efficacy analysis. PHOENIX 2 found:

• 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.

The authors conclude, “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.”
Both studies were funded by the drug’s manufacturer, Centocor Ltd.

The authors of a related Comment article state that the maintenance of response between injections every three months provides a more convenient regimen than those currently available. They conclude, “Although ustekinumab seems to provide a significant tool for the therapy of moderate to severe psoriasis, many questions remain. What is the long-term safety of ustekinumab in terms of infections and malignancies? Will tachyphylaxis eventually develop after long-term use? Will ustekinumab benefit psoriatic arthritis? Because a third of the patients in these two ustekinumab studies, as well as in most surveys of patients with psoriasis, have psoriatic arthritis, a decision to use any agent for psoriasis should be partly based on whether it also has efficacy for psoriatic arthritis. Hopefully, longer-term studies with ustekinumab and other monoclonal antibodies to interleukins 12 and 23 will answer these questions.”
NHS Choices has also featured an evaluation of the study, and newspaper reports of the study – please see link above.