A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee

Abstract

IntroductionAMG 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.MethodsIn 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.ResultsIn 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).ConclusionsThe 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.Trial RegistrationThis study is registered with ClinicalTrials.gov with the identifier NCT00110942.

Detailed Mechanistic Analysis of Gevokizumab, an Allosteric Anti–IL-1βAntibody with Differential Receptor-Modulating Properties

“…These include recombinant IL-1Ra (Furst, 2004), an IL-1 binding protein based on the soluble receptors (McDermott, 2009), an anti-IL-1RI antibody that blocks IL-1b binding (Cohen et al, 2011), and an anti-IL-1b antibody that competitively blocks interaction with both IL-1RI and IL-1RII (Church and McDermott, 2009;Lachmann et al, 2009). We propose that a therapeutic agent that reduces IL-1b signaling but does not interfere with IL-1Ra or block IL-1b binding to IL-1RII or the soluble forms of the IL-1 receptors will work in concert with the natural regulatory mechanisms to efficiently regulate and clear IL-1b.…”

Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-IgTM) molecule that specifically and potently neutralizes both IL-1α and IL-1β

“…The format and composition of this molecule was inspired by a series of studies demonstrating the feasibility of human and murine DVD-Ig generation, 40,48 the relevance of inhibition of both mouse IL-1a and IL-1b in reducing OA progression and pain, 41 42 and improvement attributes desired in a therapeutic entity based on OA clinical trial data from other IL-1 inhibitors. [37][38][39] The human antibody variable domains necessary to construct a human DVD-Ig with drug-like properties were identified, and were synthesized and characterized to allow the generation of several anti-IL-1a and IL-1b pilot DVD-Igs. A single human mAb to IL-1a (X3) was identified and characterized, and a humanized mAb to IL-1b (SK48-E26) was generated, characterized, and affinity matured using yeast surface display technology.…”

“…AMG 108, a IL-1R1-targeted human IgG2 monoclonal antibody (mAb), was evaluated intravenously (IV) and subcutaneously (SC) in patients with knee OA. 37 AMG-108-dosed patients showed statistically insignificant improvements in pain, although numerically greater improvements were observed. Anakinra (a recombinant form of native IL-1Ra) was evaluated in an intra-articular study in patients with painful knee OA 38 and with symptomatic OA of the knee.…”

Terapias Celulares y Productos de Ingeniería de Tejidos para el Tratamiento de Lesiones Condrales de Rodilla

“…Entre ellos, se destacan proteínas recombinantes humanas que se encuentran en diferentes fases de estudios clínicos. En estudios fase II se encuentran la proteína morfogenética ósea-7 (BMP-7) para aplicación intraarticular (Hunter et al, 2010;Zhang et al, 2016); el anticuerpo monoclonal anti-IL-1a e IL-1b para administración subcutánea o intravenosa denominado AMG 108, (Cohen et al, 2011), el factor de crecimiento de los fibroblastos-18 (FGF-18) para aplicación intraarticular (Dahlberg et al, 2016). En estudio clínico fase III se encuentra el tanezumab, anticuerpo monoclonal anti-factor de crecimiento neuronal (NGF) para administración subcutánea o intravenosa (Chen et al, 2016;Reichert 2017).…”