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25th February 2009
“Subcutaneous ustekinumab▼ (Stelara®) administered every twelve weeks was more effective than placebo for the treatment of moderate to severe psoriasis. This dosing frequency appears to maintain efficacy for at least a year in most patients. The authors of the PHOENIX 2 study suggest that an intensification of the dose regimen to once every 8 weeks for those patients receiving ustekinumab 90mg may elicit a full response in patients who only partially respond to the initial regimen. “
Action
NICE guidance is already available for the use of infliximab, adalimumab, etanercept and efalizumab for severe to very severe psoriasis. Therefore, local decision making bodies will need to consider the potential place of ustekinumab in therapy (given a lack of published evidence comparing this agent with other biologics) and plan for the proposed NICE guidance anticipated in September 2009.
What is the background to this?
Ustekinumab is a human monoclonal antibody that has just been launched for the management of moderate to severe plaque psoriasis in adults. Psoriasis is an immune-mediated inflammatory skin disease which affects about 2 to 3% of the population worldwide. Ustekinumab targets the interleukins 12 and 23 which play an important role in the pathophysiology of psoriasis. Further information on psoriasis is available from the skin section of NPC.
In line with other biologics, ustekinumab is indicated for patients who have failed to respond to, have contra-indications to or are intolerant of other systemic therapies such as ciclosporin, methotrexate and PUVA. The dose is 45mg given via subcutaneous injection at weeks 0 and 4 and then every 12 weeks. Prescribers should consider discontinuing treatment in patients who have not responded up to 28 weeks of treatment. A higher dose is recommended for patients weighing more than 100kg. The product is available as a sterile solution which needs to be stored in a refrigerator. Each single-use vial costs £2,147.
The phase III PHOENIX studies were designed to assess the efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis with up to 52 weeks of treatment
What do these studies claim?
The primary outcome for both studies was the proportion of patients achieving a 75% reduction in the Psoriasis Area Severity Index (PASI) at week 12. NICE guidance for other biologics suggests that this is a suitable measure of treatment response.
The findings of these two studies suggest that ustekinumab could provide a new highly effective therapy for the treatment of moderate-to-severe psoriasis and that efficacy can be maintained with a dosing schedule of 45mg–90mg every 12 weeks. A dosing flexibility of up to 90mg every 8 weeks might be required for a sub-group of patients who have treatment-resistant disease.
In the Phoenix 1 study 67.1% of patients receiving ustekinumab 45mg, 66.4% of patients receiving ustekinumab 90mg and 3.1% of those administered placebo reached the primary endpoint. Compared to placebo, the difference for ustekinumab 45mg was 63.9% (95% confidence interval [CI] 57.8 to 70.1) and for 90mg, 63.3% (95% CI 57.1 to 69.4), P<0.0001 for both doses versus placebo.
In Phoenix 2 the primary endpoint was reached in 66.7% of the 45mg ustekinumab patients, 75.7% of 90mg patients and 3.7% of placebo patients. Compared to placebo, the difference for ustekinumab 45mg was 63.1% (95% CI 58.2 to 68.0) and for 90mg, 72.0% (95% CI 67.5 to 76.5), P<0.0001 for both doses versus placebo.
How does this relate to other studies?
A NICE technology appraisal of ustekinumab is anticipated in September 2009. NICE guidance is already available for infliximab, adalimumab, etanercept and efalizumab for psoriasis.
As these were placebo-controlled studies, they tell us little about the potential place of ustekinumab in therapy. A head-to-head phase III trial with etanercept (n=903) has been completed but so far has only been presented at a conference. According to company press releases, ustekinumab appears to be more effective than etanercept twice weekly. At week 12, 68% and 74% of the ustekinumab 45mg and 90mg patients, respectively, reached the primary endpoint of PASI 75 compared to 57% of the etanercept patients (P=0.012 for 45mg and P<0.001 for 90mg versus etanercept).
Trials for other indications, including psoriatic arthritis and Crohn’s disease are completed or on-going.
So what?
Ustekinumab is efficacious in the treatment of moderate to severe psoriasis compared to placebo, but data against other biologics is required. It may have a practical advantage in that it is given every 12 weeks by subcutaneous injection, whilst other biologics are given more frequently or, in the case of infliximab, administered by intravenous infusion.
Information on rare adverse events is lacking and careful monitoring will be required to identify any long term adverse effects.
Study details
PHOENIX 1
Design: phase III, parallel, double-blind, randomised, placebo-controlled trial.
Patients: 766 adults with moderate to severe psoriasis. 51% had received prior therapy with other biologic agents.
Intervention: ustekinumab 45mg (n=255) or 90mg (n=256) at weeks 0 and 4 and then every 12 weeks.
Comparison: placebo (n=255).
Placebo patients were crossed over to ustekinumab at week 12.
Patients who achieved at least a 75% improvement at weeks 28 and 40 were re-randomised to maintenance ustekinumab or withdrawn from treatment until they had lost 50% of their PASI improvement, at which point they were re-treated.
Outcome: primary endpoint was proportion of patients reaching PASI 75 at week 12.
For results see table below.
Placebo patients who crossed over to ustekinumab achieved similar response rates to those treated with ustekinumab from the start.
PASI 75 response rates were maintained for at least a year in patients who received maintenance ustekinumab compared with those withdrawn from therapy (P<0.0001).
Patients receiving ustekinumab showed improvements in various secondary outcomes including the proportion of patients with a Physician’s Global Assessment score of cleared or minimal at week12 and in the change from baseline to week12 in the patient-scored Dermatology Life Quality Index (DLQI).
Adverse events: during the placebo-controlled phase, 54.5% of ustekinumab patients and 48.2% of placebo patients reported adverse events. Serious adverse events occurred in 1.2% and 0.8% of patients, respectively. Infections were reported by a similar number of patients in each group. Two cutaneous cancers were reported during the trial period week40–76 in the ustekinumab maintenance group, but there is no suggestion of a causal relationship with the drug. A low number of injection site reactions were seen. At the end of week 76, 5.1% of 746 patients with evaluable samples had developed antibodies to ustekinumab. The relevance of this is not known.
Sponsorship: Centocor Inc
PHOENIX 2
Design: phase III, double-blind, randomised, placebo-controlled trial.
Patients: 1,230 adults with moderate to severe psoriasis. 38% had received prior therapy with other biologic agents.
Intervention: ustekinumab 45mg (n=409) or 90mg (n=411) at weeks 0 and 4 and then every 12 weeks.
Comparison: placebo (n=410).
Placebo patients were crossed over to ustekinumab at week 12.
Partial responders were re-randomised at week 28 to either continued dosing at 12 weekly intervals or dosing every 8 weeks.
Outcome: primary endpoint was proportion of patients reaching PASI 75 at week 12.
For results see table below.
Partial responders who received 90mg 8 weekly appeared to do better than those randomised to 90mg 12 weekly (difference 35.4%, 95% CI 12.7 to 58.1, P=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45mg.
Physician’s Global Assessment and patient-scored Dermatology Life Quality Index (DLQI) scores also improved in patients who received ustekinumab.
Adverse events: during the placebo-controlled phase, 53.1% (45mg) and 47.9% (90mg) of ustekinumab patients and 49.8% of placebo patients reported adverse events. Serious adverse events occurred in 2.0%, 1.2% and 2.0% of patients, respectively. Infections were reported by a similar number of patients in each group. A low number of injection site reactions were seen. At the end of week 52, 5.4% of 1,202 patients with evaluable samples had developed antibodies to ustekinumab.
Sponsorship: Centocor Inc
Table – summary of primary endpoint data for the PHOENIX studies
| PHOENIX 1 | PHOENIX 2 | |||||
| ustekinumab 45mg | ustekinumab 90mg | placebo | ustekinumab 45mg | ustekinumab 90mg | placebo | |
| Number of patients | 255 | 256 | 255 | 409 | 411 | 410 |
| Primary endpoint:
% of patients achieving PASI 75 at week 12 |
67.1% | 66.4% | 3.1% | 66.7% | 75.7% | 3.7% |
| Difference between ustekinumab and placebo (95% CI) | 63.9%
(57.8 to 70.1)* |
63.3%
(57.1 to 69.4)* |
63.1%
(58.2 to 68.0)* |
72.0%
(67.5 to 76.5)* |
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* P<0.0001
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