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Open Access Highly Accessed Research article

A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to IL-1R, in patients with rheumatoid arthritis

Mario H Cardiel1*, Paul P Tak2, William Bensen3, Francis X Burch4, Sarka Forejtova5, Janusz E Badurski6, Tarundeep Kakkar7, Terry Bevirt8, Liyun Ni9, Ellen McCroskery10, Angelika Jahreis10 and Debra J Zack10

Author Affiliations

1 Centro de Investigacion Clinica de Morelia, Morelia, Virrey de Mendoza 1998-Int. 522 Col Félix Ireta, Mich 58070, Mexico

2 Department of Clinical Immunology/Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands

3 St Joseph's Hospital, McMaster University, 25 Charlton Avenue East, Hamilton, ON, L8N 1Y2, Canada

4 San Antonio Center for Clinical Research, 8527 Village Drive, San Antonio, TX 78217, USA

5 Revmatologicky ustav, Na Slupi 4, Praha 128 50, Czech Republic

6 Centrum Osteoporozy i Chorób Kostno-Stawowych, Waryńskiego 6/2, 15-461 Białystok, Poland

7 Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA

8 Global Development Operations, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA

9 Global Biostats and Epidemiology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA

10 Global Development, General Medicine and Inflammation Therapeutic Area, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA

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Arthritis Research & Therapy 2010, 12:R192  doi:10.1186/ar3163

Published: 15 October 2010

Abstract

Introduction

Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week).

Methods

Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient-reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108.

Results

Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose-dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C-reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups.

Conclusions

This large double-blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community.

Trial Registration

ClinicalTrials.gov NCT00293826