Targeting Interleukin

Brodalumab

Brodalumab is a fully human IgG2 anti-IL-17RA monoclonal antibody [Papp et al. 2012b]. Clinical results with this agent in RA were recently reported. In a randomized, double-blind, dose-escalation study, 40 patients with moderate to severe RA were randomized in a 3:1 ratio to receive brodalumab or placebo [Churchill et al. 2012]. Brodalumab was administered at 50, 140, or 210 mg subcutaneously every 2 weeks for six doses or at 420 or 700 mg intravenously every 4 weeks for two doses. The primary endpoint was safety. Overall, treatment-related AEs were reported in 23% of patients in the brodalumab groups (with leukocytosis the most common; 7%) and in 30% of patients in the placebo group (with headache the most common; 20%). At the doses administered, brodalumab occupied IL-17RA on circulating leukocytes and inhibited IL-17- mediated signaling. ACR response rates were an exploratory endpoint in this phase IB study. At week 13, the ACR20 rates were 37% with brodalumab and 22% with placebo.

Brodalumab was subsequently evaluated in a randomized, double-blind, placebo-controlled phase II trial [Pavelka et al. 2012]. A total of 252 patients with active RA despite methotrexate treatment who were biologic na?ve were randomized to receive brodalumab 70, 140, or 210 mg subcutaneously or placebo at weeks 0, 1, 2, 4, 6, 8, and 10. The primary endpoint was ACR50 at week 12, which was achieved by 10–16% of patients in the brodalumab groups compared with 13% of those in the placebo group. Mean changes from baseline in DAS28 also did not differ significantly between brodalumab and placebo groups. AEs were similar across treatment arms. The study investigators concluded that there was no evidence of meaningful clinical efficacy, and therefore these preliminary results are not supportive of further evaluation of this agent in RA. As for ixekizumab, no trials in RA are ongoing and development is currently focused on psoriasis and psoriatic arthritis.

Although at least two of the drugs targeting IL-17 pathways described above continue to be developed for treatment of RA, all three drugs have demonstrated efficacy in psoriasis [Leonardi et al. 2012; Papp et al. 2012a, 2012b; Rich et al. 2012].