New
biologic therapies focused primarily on
cytokine pathways, some targeting T cell-mediated immune responses, are being developed for the treatment of
psoriasis.
Siplizumab is a humanized anti-CD2
monoclonal antibody that interferes with costimulation necessary for T cell activation and proliferation. We assessed the
biological activity, serum concentrations, and pharmacodynamic effects of
siplizumab in patients with plaque
psoriasis. Two multicenter, phase II randomized, double-blind, placebo-controlled studies were conducted: one study randomized 124 patients to one of two intravenous (IV) doses (0.012 and 0.04 mg/kg) of
siplizumab, given every 2 weeks x 8 doses; the other study randomized 420 patients to one of three subcutaneous (SC) dose regimens of
siplizumab given weekly (5 mg for 12 weeks, 5 mg for 6 weeks, and 7 mg for 4 weeks) or placebo for 12 weeks. Adults with plaque
psoriasis involving > or =10% of the body surface area and who were not receiving
psoriasis therapy were eligible. Treatment with
siplizumab resulted in reductions in
psoriasis severity, but most of the effects were not statistically significant compared with placebo. Statistically significant differences among IV
siplizumab-treated and placebo groups were observed at study day 28, with greater
psoriasis area and severity index (PASI) score reductions from baseline in the
siplizumab groups. The difference in PASI50 response rates between the 0.04 mg/kg
siplizumab and placebo groups was also statistically significant at day 28. A trend toward clinical improvement was observed in SC
siplizumab-treated groups. Significant reductions in circulating absolute lymphocyte counts and CD2+ (CD3+, CD8+, and CD16+/56+), but not CD2- (CD19+ and CD14+), lymphocyte populations were observed. These changes were not accompanied by concomitant reductions in infiltrating CD3+ lymphocytes in psoriatic lesions, epidermal thickness, or
keratin 16 (K16) and
intercellular adhesion molecule (ICAM) expression. The effect of
siplizumab did not differentially affect CD45RO+ and CD45RA+ lymphocytes. Low or undetectable mean trough serum concentrations of
siplizumab following IV or SC treatment were observed. Pharmacokinetic data coupled with higher-than-expected placebo clinical response rates may partly explain
siplizumab's marginal clinical activity. Higher doses of
siplizumab may be required to detect significant improvements in
psoriasis; however, further development of this agent was not planned.