The online version of this article (doi:10.1186/ar3430) contains supplementary material, which is available to authorized users.
At the time the study was performed, SB Cohen was a consultant for Amgen Inc, Genentech, Biogen-IDEC, Merck, Sanofi-Aventis, Proctor and Gamble, Pfizer, Centocor, Scios, Bristol Meyers Squibb, and Wyeth-Ayerst; S Proudman was a consultant for Amgen Inc, Actelion, Pfizer, and Glaxo-Smith-Klein; A Kivitz, F Burch, and D Burstein were consultants for Amgen Inc; and J Donohue was a consultant for Amgen Inc, Genentech, and Bristol Myers Squibb. Y-N Sun, C Banfield, MS Vincent, L Ni, and DJ Zack are employees of Amgen Inc.
Y-N Sun, C Banfield, MS Vincent, L Ni, and DJ Zack made substantial contributions to the study concept or design. SB Cohen, S Proudman, AJ Kivitz, FX Burch, JP Donohue, and D Burstein assisted with the acquisition of the data. Y-N Sun and L Ni performed data analysis. All authors assisted with interpretation of the data, helped to draft and revise the manuscript for intellectual content, and approved the final manuscript before submission to the journal.
AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee.
In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score.
In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively).
The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed.
This study is registered with ClinicalTrials.gov with the identifier NCT00110942.
Additional file 1: dGEMRIC imaging, analysis and results. (DOC 401 KB)13075_2010_3223_MOESM1_ESM.DOC
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Cooper C: Osteoarthritis and related disorders: epidemiology. Rheumatology. Edited by: Klippel JH, Dieppe PA. 1998, London: Mosby, 2: 8.2.1-8
Samuels J, Krasnokutsky S, Abramson SB: Osteoarthritis: a tale of three tissues. Bull NYU Hosp Jt Dis. 2008, 66: 244-250. PubMed
LeGrand A, Fermor B, Fink C, Pisetsky DS, Weinberg JB, Vail TP, Guilak F: Interleukin-1, tumor necrosis factor alpha, and interleukin-17 synergistically up-regulate nitric oxide and prostaglandin E2 production in explants of human osteoarthritic knee menisci. Arthritis Rheum. 2001, 44: 2078-2083. 10.1002/1529-0131(200109)44:9<2078::AID-ART358>3.0.CO;2-J. CrossRefPubMed
Richette P, Francois M, Vicaut E, Fitting C, Bardin T, Corvol M, Savouret JF, Rannou F: A high interleukin 1 receptor antagonist/IL-1beta ratio occurs naturally in knee osteoarthritis. J Rheumatol. 2008, 35: 1650-1654. PubMed
Caron JP, Fernandes JC, Martel-Pelletier J, Tardif G, Mineau F, Geng C, Pelletier JP: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression. Arthritis Rheum. 1996, 39: 1535-1544. 10.1002/art.1780390914. CrossRefPubMed
Fernandes J, Tardif G, Martel-Pelletier J, Lascau-Coman V, Dupuis M, Moldovan F, Sheppard M, Krishnan BR, Pelletier JP: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Am J Pathol. 1999, 154: 1159-1169. 10.1016/S0002-9440(10)65368-0. PubMedCentralCrossRefPubMed
Fernandes JC, Martel-Pelletier J, Pelletier JP: The role of cytokines in osteoarthritis pathophysiology. Biorheology. 2002, 39: 237-246. PubMed
Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P: Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol. 2005, 32: 1317-1323. PubMed
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, et al: Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee: Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986, 29: 1039-1049. 10.1002/art.1780290816. CrossRefPubMed
Pelletier JP, DiBattista JA, Roughley P, McCollum R, Martel-Pelletier J: Cytokines and inflammation in cartilage degradation. Rheum Dis Clin North Am. 1993, 19: 545-568. PubMed
Yang KG, Raijmakers NJ, van Arkel ER, Caron JJ, Rijk PC, Willems WJ, Zijl JA, Verbout AJ, Dhert WJ, Saris DB: Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthritis Cartilage. 2008, 16: 498-505. 10.1016/j.joca.2007.07.008. CrossRef
Chevalier X, Goupille P, Beaulieu AD, Burch FX, Bensen WG, Conrozier T, Loeuille D, Kivitz AJ, Silver D, Appleton BE: Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2009, 61: 344-352. 10.1002/art.24096. CrossRefPubMed
- A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee
Stanley B Cohen
Alan J Kivitz
Francis X Burch
John P Donohue
Michael S Vincent
Debra J Zack
- BioMed Central
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