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Open Access Research article

A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis

David A Martin1*, Melvin Churchill2, Luis Felipe Flores-Suarez3, Mario H Cardiel4, Daniel Wallace5, Richard Martin6, Kristine Phillips7, Jeffrey L Kaine8, Hua Dong109, David Salinger1, Erin Stevens1, Chris B Russell1 and James B Chung9

Author Affiliations

1 Amgen Inc, 1201 Amgen Court West, Seattle, WA 98119, USA

2 Arthritis Center of Nebraska, 3901 Pine Lake Road, Lincoln, NE 68516, USA

3 Primary Systemic Vasculitis Clinic, National Institute of Respiratory Diseases, México City, Mexico

4 Clinical Research Center of Morelia, Morelia, Mexico

5 Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

6 Division of Rheumatology, College of Medicine, Michigan State University, 775 Ball Avenue NE, Grand Rapids, MI 49503, USA

7 Scleroderma Program, Division of Rheumatology, School of Medicine, University of Michigan, 7C27 NIB, 300 N Ingalls Street, Ann Arbor, MI 48109, USA

8 Sarasota Arthritis Center, 3500 S Tamiami Trail, Sarasota, FL 34239, USA

9 Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, USA

10 Present address: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA

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Arthritis Research & Therapy 2013, 15:R164  doi:10.1186/ar4347

Published: 25 October 2013

Abstract

Introduction

The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA).

Methods

This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥6/66 swollen and ≥8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics.

Results

Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70.

Conclusions

Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA.

Trial registration

ClinicalTrials.gov, NCT00771030