Background/Purpose:   The cytokine IL-17A is an innate inflammatory cytokine implicated in the pathogenesis of several human autoimmune diseases including rheumatoid arthritis (RA).  Brodalumab is a human, immunoglobulin G2 (IgG2) monoclonal antibody that binds with high affinity to human IL 17RA and blocks the biological activity of IL 17A, IL-17F, IL-17A/F heterodimers, and IL-25.  Increased levels of IL-17A have been detected in the synovial fluid of patients with RA and furthermore, blockade of IL-17A signaling can inhibit osteoclast formation induced by culture media of RA synovial tissues.  The aim of this study was to evaluate safety, pharmacokinetics, and preliminary efficacy of brodalumab in subjects with moderate to severe RA.

Methods:   This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with a moderate to severe RA (>6/66 swollen and >8/68 tender joints).  Subjects were randomized 3:1 to receive multiple doses of brodalumab (50mg, 140mg or 210mg subcutaneously every two weeks for 6 doses, or 420mg or 700mg intravenously every 4 weeks for two doses) or placebo.  The primary endpoint was safety and tolerability of brodalumab,  including incidence of adverse events (AEs).  Multiple dose pharmacokinetics was a secondary endpoint.  Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics.  Assessments were performed up to end of study on day 127.

Results:   40 subjects were randomized and received at least one dose; there was one dropout on day 85 due to worsening RA (placebo).  Treatment with brodalumab resulted in receptor occupancy by brodalumab on circulating leukocytes and inhibition of IL-17 receptor signaling.  Dose-dependent increases in the magnitude and duration of mean receptor occupancy were observed.  Treatment-related AEs were reported by 3 (30.0%) of 10 placebo subjects and 7 (23.0%) of 30 brodalumab subjects.  The most common treatment-related adverse event was headache (20%) for placebo subjects and leukocytosis (7%) for brodalumab subjects. Serious AEs occurred in 2 subjects during the study [complicated migraine (placebo) and non-cardiac chest pain (brodalumab, 420 mg IV)]; neither was considered by the investigator related to investigational product.  On day 85 (week 13) ACR20 was achieved by 11 (36.7%) of 30 subjects receiving brodalumab and 2 (22.0%) of 9 subjects receiving placebo. Few ACR50 or ACR70 responses were observed in either active or placebo group at day 85.

Conclusion:   This small ascending dose phase 1b study demonstrates that multiple dose administration of brodalumab was tolerated in subjects with active RA.  Conclusions about efficacy cannot be reached given the study design.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-ib-multiple-ascending-dose-study-evaluating-safety-pharmacokinetics-and-early-clinical-response-of-brodalumab-amg-827-a-human-anti-interleukin-17-receptor-il-17r-antibody-in-rheum/