The US FDA has approved Centocor Ortho Biotech's (Johnson & Johnson) biological psoriasis therapy Stelara (ustekinumab), with labelling that directs it be administered only by a healthcare provider, not for self-injection.

Approval was delayed by more than a year owing to BLA amendment extensions in the user fee date and the agency's request for a risk evaluation and mitigation strategy (REMS).

Ustekinumab is indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. The weight-based dosing schedule calls for an initial dose of either 45mg or 90mg (depending upon whether the patient weighs less or more than 100kg), followed by a second dose four weeks later. Maintenance dosing is every 12 weeks.

While the 12-week maintenance schedule gives a Stelara competitive edge over other biological therapies in frequency of dosing, the requirement that the monoclonal antibody be administered under a physician's supervision is a drawback when compared with various self-injectable agents.

Ustekinumab is an antagonist of the cytokines IL-12 and IL-23, which stimulate type 1 T-helper cell responses. The other FDA-approved biologicals for psoriasis include three tumour necrosis factor inhibitors – Amgen/Wyeth's Enbrel (etanercept), Abbott's Humira (adalimumab) and J&J's Remicade (infliximab) – and Astellas's T-cell immunosuppressant Amevive (alefacept). Genentech's T-cell targeted Raptiva (efalizumab) was voluntarily withdrawn from the market in April owing to an increased risk of progressive multifocal leucoencephalopathy.

The maintenance dose for Enbrel is weekly subcutaneous injections, while Humira is given subcutaneously every other week; both are labelled for self-injection. Remicade is administered by intravenous infusion every eight weeks, and Amevive is given weekly by intramuscular injection.

In June 2008, an FDA advisory panel unanimously recommended approval of ustekinumab but voted against labelling the product for self-use based on FDA concerns that allowing patients to self-inject every 12 weeks could prolong the time between follow-up physician visits to assess effectiveness and delay diagnosis and treatment of other clinically significant conditions, including adverse events (scripnews.com, June 20th, 2008).

postmarketing

The panel also deemed Centocor's postmarketing risk management plans insufficient, and many committee members called for creation of a mandatory patient registry to monitor long-term risks of malignancy and infection.

The FDA, however, stopped short of a mandatory patient registry. Centocor said its postmarketing surveillance commitments to evaluate long-term safety and efficacy include data gathered from the following studies:

* Long-term extensions from the two Phase III pivotal trials, PHOENIX 1 and 2, through five years from date of enrolment;

* The Psoriasis Longitudinal Assessment Registry (PSOLAR), a global, multi-centre, open registry of patients involving 450 clinical trial sites in North America, Europe and Asia;

* The Pregnancy Research Initiative, to identify and evaluate pregnant women with psoriasis who were exposed, or not exposed, to ustekinumab during pregnancy; and

* The Nordic Database Initiative, a prospective study of adverse events over the course of at least five years in psoriasis patients in Sweden who are treated with ustekinumab.

* The company said it has already compiled three years of safety data from the ongoing five-year extension studies.

warnings

Approval was based on the PHOENIX 1 and 2 studies, which collectively enrolled about 2,000 patients. In both studies, at least 66% of ustekinumab-treated subjects achieved a 75% or greater improvement from baseline in their Psoriasis Area Severity Index score at week 12, compared with only 3-4% in the placebo groups.

Labelling warns about the occurrence of serious infections and the theoretical risk for particular infections. The biological may increase the risk of malignancy, and safety in patients with a history of or a known malignancy has not been evaluated. The warnings also cite one reported case of reversible posterior leucoencephalopathy syndrome.

The Stelara REMS includes a patient medication guide and healthcare provider communication plan.