Anti-IL-17 Agents Show Efficacy in Psoriasis

Emma Hitt, PhD

April 05, 2012

April 5, 2012 — Ixekizumab and brodalumab, 2 humanized monoclonal antibodies that target the interleukin 17 (IL-17) cytokine pathway, significantly improved symptoms of psoriasis relative to placebo, according to the findings of two 12-week, phase 2 studies.

Both studies were published in the March 29 issue of the New England Journal of Medicine. Craig Leonardi, MD, from the Department of Dermatology, Saint Louis University School of Medicine, Missouri, and colleagues led the study on ixekizumab, and Kim A. Papp, MD, PhD, from Probity Medical Research, Waterloo, Ontario, Canada, and colleagues led the study on brodalumab.

According to the researchers, the IL-17 cytokine family and associated receptors may be involved in the pathology of psoriasis. The IL-17 cytokine family consists of 6 cytokines (IL-17A - IL-17F) and 5 receptors (IL-17RA - IL-17RE).

Ixekizumab (LY2439821) is a humanized immunoglobulin G4 monoclonal antibody that neutralizes the IL-17 cytokine. In contrast, brodalumab (AMG 827) is a human, monoclonal antibody that binds to the human IL-17RA receptor with high affinity and blocks the biologic activity of IL-17A, IL-17F, IL-17A/F heterodimer, and IL-17E (IL-25).

In 1 study, ixekizumab was evaluated in patients with chronic moderate-to-severe plaque psoriasis. A total of 142 patients were randomly assigned to receive subcutaneous injections of doses ranging from 10 to 150 mg of ixekizumab or placebo every 2 weeks for 16 weeks.

At 12 weeks, significantly more patients receiving ixekizumab showed a reduction in the psoriasis area-and-severity index (PASI) score by at least 75% (P < .001 for each comparison with placebo except for the lowest 10-mg dose).

Likewise, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%; P < .001 for both comparisons).

Differences were noted beginning at 1 week and were sustained through 20 weeks. Treatment with ixekizumab appeared to be well-tolerated.

The other study, evaluating brodalumab, demonstrated a similar benefit. At week 12, among 198 patients who underwent randomization, the mean percentage improvements in the PASI score ranged from 45.0% to 86.3% for those receiving brodalumab in doses ranging from 70 to 280 mg compared with only 16.0% among those receiving placebo (P < .001 for all comparisons with placebo).

"An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons)," the authors write.

Again, treatment was well-tolerated, with the most commonly reported adverse events in the combined brodalumab groups being nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%).

Anti-IL-17 May Prove More Tolerable Than Tumor Necrosis Factor Agents

In a related editorial, Ari Waisman, PhD, from the Institute for Molecular Medicine at the University Medical Center of the Johannes-Gutenberg University of Mainz, Germany, noted that both trials showed a "marked improvement" with these agents, but "a 12-week follow-up period is too short to assess the safety of treatments targeting interleukin-17."

Dr. Waisman also notes that, with respect to a mechanism of action, "[t]he most likely scenario is that targeting interleukin-17 signaling also affects interleukin-22, since the two need to work in concert for full-blown disease to develop."

According to Dr. Waisman, treatment with antibodies targeting IL-17 or its receptor should be more specific than with anti–tumor necrosis factor agents, and may be expected to result in fewer adverse effects.

The study of ixekizumab was funded by Eli Lilly, and the study of brodalumab was funded by Amgen. Each study included researchers employed by the corresponding company. Dr. Leonardi and Dr. Papp have disclosed that they have each received financial support from Amgen, Eli Lilly, and other commercial entities. Dr. Waisman reports financial relationships with Teva, Phenex, and GlaxoSmithKline. Full disclosures are available on the journal's Web site.

N Engl J Med. 2012;366:1181-1189, 1190-1199, 1251-1252. Leonardi abstract, Papp abstract, Editorial extract

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