Background/Purpose: A potential role for IL-17 in rheumatoid arthritis (RA) has been supported by data from clinical studies of inhibitors of the IL-17A ligand. To evaluate efficacy and safety of brodalumab (AMG 827), a human monoclonal antibody inhibitor of the IL-17 Receptor, in subjects with RA.

Methods: Subjects with RA who had an inadequate response to methotrexate (ie, continuing RA symptoms) and were biologic-naïve were randomized 1:1:1:1 to receive brodalumab (70, 140, or 210 mg) or placebo subcutaneously at day 1 and weeks 1, 2, 4, 6, 8, and 10 (Q2WK). Primary endpoint was proportion of subjects achieving an American College of Rheumatology (ACR) 50 response at week 12. Secondary endpoints included proportion with ACR 20 and 70 at week 12 and Disease Activity Score 28 joint (DAS28) at week 12. Safety was assessed by monitoring adverse events (AEs). Analyses were based on intent to treat using non-responder imputation.

Results: Two hundred fifty-two subjects were randomized; 189 to brodalumab and 63 to placebo. Two hundred forty-two subjects (183 [97%] AMG 827; 59 [94%] placebo) completed the study (defined as 16 weeks of study evaluations). Demographics and baseline characteristics were generally balanced among treatment groups. The majority (> 75%) of subjects were female and white. In subjects treated with brodalumab and placebo, respectively, mean (SD) age was 50.6 (11.5) years and 53.3 (10.3) years, mean weight was 72.8 (15.1) kg and 74.8 (16.5) kg, mean duration of RA was 8.1 (7.9) years and 7.5 (6.9) years, mean Disease Activity Score 28 joint (DAS28) was 6.5 (0.8) and 6.4 (0.8), and mean C-reactive protein (CRP) was 12.8 (12.1) mg/L and 14.6 (17.6) mg/L.

ACR 50 at week 12 occurred in 16% (70 mg), 16% (140 mg), 10% (210 mg), and 13% (placebo; all non-significant vs placebo) of subjects. Differences in ACR 20 and 70 were non-significant (p > 0.05) for any treatment group as compared with placebo. Mean (SD) change from baseline in DAS28 at week 12 was -1.4 (1.3) , ‑1.3 (1.2) , -1.3 (1.2) , and -1.3 (1.2) for the 70 mg, 140 mg, 210 mg and placebo groups, respectively. The p-values for DAS28 at week 12 in brodalumab treatment groups compared with placebo were all non-significant (p > 0.05). Mean (SD) percent CRP change was 97.5 (345.4), 50.7 (168.7) , 45.1 (159.3) , and 33.5 (170.3) for the 70 mg, 140 mg, 210 mg and placebo groups, respectively. No differences in efficacy outcomes for subgroup analyses based on sex, age, weight, or region were observed. Incidences of all AEs, including serious AEs (SAEs), were similar across treatment groups. A total of 7 subjects reported SAEs during the study (2 in the placebo group and 5 in the brodalumab groups), none of which was treatment related. There was 1 death (cardiopulmonary failure) ~1 week after last dose in the 140 mg group.

Conclusion: There was no evidence of meaningful clinical efficacy or change in CRP with brodalumab treatment in subjects with RA who had an inadequate response to methotrexate. Short-term treatment was well tolerated across a dose range of 70 to 210 mg and these analyses did not suggest any safety risks with brodalumab administration. These preliminary results do not support further evaluation of brodalumab as a treatment for RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-randomized-double-blind-placebo-controlled-multiple-dose-study-to-evaluate-the-safety-tolerability-and-efficacy-of-brodalumab-amg-827-in-subjects-with-rheumatoid-arthritis-and-an-inadequate-r/