The Biologic Stelara (Ustekinumab): Recently Approved for Plaque Psoriasis Therapy in the US

Psoriasis is an inflammatory skin disorder associated with raised, scaly, and itchy plaques that affects approximately 125 million people worldwide. The size of the plaques can range from very small localized patches to covering a large percentage of the body surface area. Biologics, such as anti-TNF agents, are a class of drugs that are reserved for more severe, and treatment refractory manifestations of psoriasis. To be considered a biologic, a drug must have a biological source as opposed to being a synthetic chemical. The biologic Stelara (Ustekinumab) is an antibody that neutralizes inflammatory cytokines and was approved in late September of this year by the FDA for the treatment of moderate to severe plaque psoriasis.

Stelara, a product of Centocor, is a fully human antibody that is raised against the p40 subunit shared by both interleukin-12 (IL-12) and interleukin-23 (IL-23). These cytokines are thought to drive inflammation in the skin and promote hyper-proliferation of keratinocytes in psoriatic lesions. Overgrowth of keratinocytes alters the skin differentiation program, leading to raised plaques and scaling of the skin. These deformations often occur on top of the knees, outside of elbows, on the scalp, and on the trunk. It is no surprise that psoriasis patients may feel self conscious about the appearance of the plaques and depression is a frequently occurring comorbidity.

Two concurrent phase III trials were published in the journal Lancet last year, assessing both the efficacy and safety of Stelara (Ustekinumab). Both trials demonstrated Stelara could significantly improve plaque psoriasis symptoms within 12 weeks. Stelara treatment led to at least a 75% improvement in the psoriasis area and severity index score (PASI-75) in 66.7% and 75.7% of patients treated with 45 mg and 90 mg injections, respectively, by week 12 in the PHOENIX II trial. This is in sharp contrast to the 3.7% of placebo treated patients that achieved the trials primary outcome of PASI-75, which again is a 75% improvement in the psoriasis area and severity index score.

In both phase III studies, no statistically significant adverse events were observed with Stelara treatment in comparison to placebo. This is not without worry however. In genetic mouse models, knockout of the Stelara target IL-12 sensitizes mice to UV induced skin carcinogenesis. However, both clinical trials demonstrated no difference in the cancer rates between the placebo and Stelara treatment groups that could be linked solely to Stelara. The manufacturer does still suggest the use of caution in patients with prior cancer episodes. Caution is also recommended in patients with tuberculosis, as neutralizing immuno-modulating cytokines may worsen the infection.

The dosing schedule of Stelara is more convenient for psoriasis patients than the anti-TNF biologics. Stelara only needs to be injected 5-6 times per year, while Remicade, Enbrel, and Humira require more frequent dosing. The PHOENIX II trial demonstrated that high and more frequent dosing may be used safely in patients that do not respond well to initial Stelara therapy. The authors suggested several parameters, such as weight, resistance to other treatments, and severity of psoriasis, influence the response to Stelara.

Stelara was recently reported to be more effective in treating psoriasis than the widely used anti-TNF agent Enbrel at the 17^th meeting of the European Academy of Dermatology and Venereology. The use of Stelara in other conditions such as psoriatic arthritis and crohn's disease is also currently being investigated in clinical trials. However, FDA approval for use in the aforementioned indications has yet to be granted.

References:

Leonardi, CL. et al. Lancet. 2008; 371: 1665-74

Meeran, SM. et al. Molec Cancer Ther. 2006; 5(4): 825-832

Papp, KA. et al. Lancet. 2008; 371: 1675-84

Tracey, D. et al. Pharmacol Ther. 2008; 117(2): p. 244-79

Trial Watch: Novel biologic for psoriasis shows superiority over current best-seller. 2008. Nature Reviews Drug Discovery. 7 (11):880-881