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

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. Introduction Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune, inflammatory arthropathy of unknown etiology, characterized by progressive destruction of the affected joints, deformity, disability, and premature death [1]. Genetic and environmental factors have been implicated in the pathogenesis of RA [2]. The inflammatory response in the synovial membrane includes hyperplasia, increased vascularity, and infiltration of inflammatory cells [3]. Various inflammatory cascades ultimately lead to activation of macrophages and fibroblast-like synoviocytes to overproduce proinflammatory cytokines such as IL-1, IL-6, and TNFa [4,5]. Other cytokines, as well as * Correspondence: mhcardiel@hotmail.com Centro de Investigacion Clinica de Morelia, Morelia, Virrey de Mendoza 1998-Int. 522 Col Félix Ireta, Mich 58070, Mexico Full list of author information is available at the end of the article Cardiel et al. Arthritis Research & Therapy 2010, 12:R192 http://arthritis-research.com/content/12/5/R192 © 2010 Cardiel et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. matrix metalloproteinases, are produced that are responsible for cartilage degradation and bone erosion. IL-1 is considered a pivotal cytokine in chronic destructive arthritis; it is a strong activator of chondrocytes, induces cartilage breakdown through upregulation of metalloproteinases, and causes profound suppression of cartilage matrix synthesis. IL-1 is also able to increase receptor activator of NFB ligand expression and thus drive osteoclast formation and activation [6,7], leading to bony erosions. Several murine models have shown the arthritogenic and erosive potency of IL-1. In collageninduced arthritis, a frequently used animal model for RA, TNF was an important contributor to inflammation at the onset of disease, but IL-1 receptor (IL-1R) blockage was highly efficacious in reducing inflammation, both in acute and advanced stages [8]. In antigen-induced arthritis, cartilage damage, erosion progression, and propagation of inflammation are dependent on IL-1 [9,10]. In a recent study of immune complex arthritis, IL-1deficient mice were strongly protected [11]. In a novel transgenic mouse model of adjuvant arthritis, a pure T-cell model, mice deficient in the IL-1R antagonist displayed uncontrolled IL-1 activity and developed spontaneous T-cell-dependent autoimmune arthritis [12]. Overall, the preclinical data strongly support a role for IL-1 in the pathogenesis of synovial inflammation. In RA patients, however, IL-1 antagonists display relatively modest effects, although they are very effective in the treatment of systemic-onset juvenile idiopathic arthritis, of adult-onset Still’s disease, and of several autoinflammatory disorders [13]. The question remains whether these inhibitors were given at doses and intervals that would be able to achieve robust coverage of the IL-1 pathway. We therefore investigated whether use of more continuous blockade of IL-1 could translate into increased efficacy in the treatment of RA. AMG 108 (Amgen Inc., Thousand Oaks, CA, USA) is a fully human IgG2 monoclonal antibody that binds IL-1R type 1 and nonselectively inhibits the activity of both forms of IL-1 (IL-1a and IL-1b). The objective of the present study was to compare the efficacy and safety of three dose levels of AMG 108 with placebo in patients with active RA who were receiving stable methotrexate (MTX) (15 to 25 mg/week). Materials and methods