LISBON – Validation of the interleukin-17 cytokine family in psoriasis pathophysiology has gotten a boost from positive, phase II clinical trials involving two novel biologic agents.
The double-blind, placebo-controlled, phase II studies documented rapid and marked improvement in patients who had moderate to severe plaque psoriasis and were treated with secukinumab or AMG 827.
Dr. Kim A. Papp
Roughly 80% of patients who were randomized to the maximum dose of either biologic experienced at least a PASI 75 (that is, improvement of 75% as measured by the Psoriasis Area and Severity Index) at 12 weeks. Those are efficacy rates in excess of the improvement obtainable with the earlier-generation biologics that targeted tumor necrosis factor–alpha, according to Dr. Kim A. Papp, who presented the data on both drugs at the annual congress of the European Academy of Dermatology and Venereology.
"This is a very robust, profound response suggesting that we’re really getting to the fundamentals of what’s driving psoriasis," Dr. Papp said.
Secukinumab is the agent further along in the developmental pipeline. A phase III clinical trial is already underway on the strength of three phase II studies presented at the congress.
Secukinumab is a fully human monoclonal antibody targeting IL-17A, a key member of the IL-17 cytokine family. The sequence of pathophysiologic events in psoriasis, as understood today, is that IL-23 induces activated Th17 cells, which in lesional skin express IL-17, in turn eliciting the production of proinflammatory cytokines by keratinocytes and keratinocyte hyperproliferation. IL-17A is one of several types of IL-17 that bind to the IL-17 receptor.
In contrast, AMG 827 is a human monoclonal antibody that blocks the IL-17 receptor itself, explained Dr. Papp, director of research at Probity Medical Research Inc. in Waterloo, Ont.
Secukinumab: Study 1
Dr. Papp presented the results of two of the three phase II studies of secukinumab. One study randomized 125 patients to subcutaneous secukinumab of 150 mg, 75 mg, or 25 mg once monthly for 3 months; to a single 25-mg dose; or to placebo.
The primary end point (PASI 75 response rate at 12 weeks) was 81%, 57%, 19%, 3%, and 9%, respectively. PASI 90 (that is, an improvement of 90% on the PASI) response rates were 52%, 19%, 8%, 0%, and 5%, respectively. Investigator Global Assessment scores of clear or almost clear at 12 weeks were achieved in 48% of patients in the 150-mg group and in 33% of those who received 75 mg, which were significantly better ratings than the 0%-12% rates in the other study arms.
Secukinumab: Study 2
The second secukinumab phase II study that was presented by Dr. Papp examined possible intravenous induction doses. The 100 participants were randomized to 3 mg/kg given on day 1; to 10 mg/kg on day 1; to 10 mg/kg on days 1, 15, and 29; or to placebo. The PASI 75 rates at 12 weeks were 40%, 75%, 83%, and 10%, respectively. The PASI 90 response rates were 10%, 54%, 76%, and 0%.
Secukinumab: Study 3
Dr. Phoebe A. Rich presented the third secukinumab phase II trial, which aimed to find the best dosing regimen. The study included 404 patients at 63 centers in seven countries who were randomized 1:2:2:1 to subcutaneous placebo; to a single 150-mg dose at week 0; to 150 mg at weeks 0, 4, and 8; or to 150 mg at weeks 0, 1, 2, and 4.
The treatment arm with dosing at weeks 0, 1, 2 and 4 was the winner, with a PASI 75 response rate of 55% at week 12, compared with 42% with dosing at weeks 0, 4, and 8; 11% for a single dose; and 2% with placebo. The corresponding PASI 90 rates were 32%, 17%, 3%, and 2%, added Dr. Phoebe of the Oregon Dermatology and Research Center, Portland.
None of these relatively brief trials suggested any safety signals. The side effect pattern was basically the same as in the placebo arms, according to the investigators.
AMG 827
Dr. Papp also presented the first phase II, randomized, double-blind trial of AMG 827. It involved 198 patients who were randomized to subcutaneous AMG 827 at 280 mg monthly; to 70, 140, or 210 mg every 2 weeks; or to placebo. The primary end point was the PASI 75 response rate at week 12. It was highest (83%) in patients who received 210 mg every 2 weeks.
Interestingly, nearly all of the PASI 75 responders were also PASI 90 responders. The PASI 90 and PASI 100 response rates in the group taking 210 mg every 2 weeks were 75% and 63%, respectively. Again, as for secukinumab, the safety profile was unremarkable.