Research published in two articles in this week’s The Lancet has demonstrated that moderate-to-severe psoriasis can be effectively treated with the drug ustekinumab. In these PHOENIX trials, the authors have also shown that treatment every 12 weeks maintains efficacy in most people.
As the most common immune-mediated adult skin disease, psoriasis affects nearly 2 to 3% of the population. The condition is characterized by red scaly patches on the skin and joints that mark excessive skin production. It is thought that immune system-produced proteins that mediate inflammatory reactions, called interleukins 12 and 23, are crucial to the physiology of psoriasis. In researching drug treatments, the focus has been on developing agents that block these interleukins, and there have been some promising results. The problem is that these current therapies still lack the convenience, effectiveness, and toleration that is required for long term treatment.
The drug ustekinumab binds to interleukins 12 and 23 to prevent their interaction with their receptors on cell surfaces. An investigation of the efficacy of this treatment, the PHOENIX studies, has been conducted by two research teams. The PHOENIX I trial, led by Dr. Kenneth Gordon (Northwestern University, Feinburg School of Medicine and Evanston Northwestern Healthcare, Evanston, IL, USA), studied 766 patients with moderate-to-severe psoriasis. During randomization, 255 patients were assigned to received ustekinumab 45 mg and 256 patients were assigned to receive a 90 mg dose at weeks 0 and 4 and then every 12 weeks; 255 patients were randomly assigned to take placebo at weeks 0 and 4 and then change to ustekinumab at week 12. If patients who were originally assigned to take ustekinumab achieved at least a 75% improvement in the psoriasis and severity index [PASI 75] at weeks 28 and 40, they were considered to have reached long-term response. These patients were then randomly assigned at week 40 to either maintain ustekinumab or to withdrawal from treatment until they lost response. The trial’s primary focus was to find the percentage of patients who achieved PASI 75 at week 12.
After analyzing the data, the researchers report that 67% (171) of patients who received ustekinumab 45 mg, 66% (170) who received ustekinumab 90 mg, and 3.1% (8) who received placebo reached PASI 75 at week 12. After 40 weeks, 150 patients in the 45 mg group and 172 in the 90 mg group achieved long-term response. At 40 weeks, these 222 patients were randomly assigned so that 162 patients maintained ustekinumab and 160 withdrew. The group that received maintenance treatment better maintained PASI 75 response to at least 1 year.
“Our results suggest that ustekinumab could be an important therapeutic agent for treating patients with psoriasis…The high level of efficacy was generally maintained with dosing every 12 weeks, a schedule that could offer a novel level of convenience for patients and physicians,” conclude the PHONEIX I authors.
The PHOENIX 2, led by Dr. Kim Papp (Probity Medical Research Inc, Waterloo, ON, Canada), studied 1230 patients with moderate-to-severe psoriasis – PASI score greater than or equal to 12 and at least 10% of body surface area involved. Similar to the PHOENIX I trial, 409 patients were randomly assigned to receive ustekinumab 45 mg and 411 patients were assigned to receive 90 mg at weeks 0 and 4 and then every 12 weeks; 410 patients were assigned to placebo.
Those patients who were found to have achieved between PASI 50 and PASI 75 were considered partial responders and were reassigned (randomly) at week 28 to either continue the 12 week dosage cycle or to increase the frequency of dosing to every eight weeks. The primary outcome of this study was the same as for PHONEIX I: the proportion of patients achieving PASI 75 at week 12.
The PHOENIX 2 researchers found that 67% (273) of patients in the 45 mg ustekinumab group, 76% (311) who received the 90 mg dose of ustekinumab 90 mg, and 4% (15) of patients in the placebo group reached PASI 75 at week 12. Of the partial responders at week 28 who were reassigned to receive ustekinumab 90 mg every 8 weeks, 69% achieved PASI 75 – more than two times the 33% of those who maintained the same dose every 12 weeks. No response was noted, however, in the group of partial responders who were changed to ustekinumab 45 mg every eight weeks.
In both PHOENIX trials, the researchers noted similar rates of adverse events ustekinumab and placebo groups.
“Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every eight weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen,” conclude the PHOENIX 2 authors.
An accompanying Comment, written by Dr. Brenda Bartlett and Professor Stephen Tyring (University of Texas Health Science Center, Houston, TX, USA), remarks: “Not only does ustekinumab compare favourably to the best available therapies for psoriasis, the maintenance of response between injections every three months also provides a more convenient regimen than those currently available.”
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)
C L Leonardi et al.
The Lancet(2008). 371[9625]: pp. 1665-1674.
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)
K A Papp et al.
The Lancet(2008). 371[9625]: pp. 1675-1684.
Written by: Peter M Crosta