Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study

Abstract

ObjectivesAnti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes.MethodsPlacebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported.Results90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101.ConclusionsWe demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

“…Although the TLR-pathway is more oriented on the inflammatory response in skeletal muscle [ 151 ], many downstream proteins have broad cellular function, especially MAPK, which plays an important role in cellular proliferation [ 152 ]. From the TLR inhibitors listed as putative stabilizing agents, NI-0101 was used in RA in a Phase II clinical trial and did not show any improvement in the disease parameters [ 153 ]. Therefore, it may be less interesting to focus on this antibody.…”

Immunosuppressive agents for rheumatoid arthritis: a systematic review of clinical trials and their current development stage

“…In a phase II trial in ACPA (Anti-Citrullinated Protein Antibody) positive patients, there was no significant difference in RA clinical outcomes. 32 …”

Soluble CD14 Induces Pro-inflammatory Cytokines in Rheumatoid Arthritis Fibroblast-Like Synovial Cells via Toll-Like Receptor 4

“…TLR-4 inhibitor therapy for RA is considered one further promising candidate [ 33 ], and several TLR-4 inhibitors have demonstrated some therapeutic effect in vitro and in vivo [ 34 ]. In fact, an anti-TLR-4 monoclonal antibody has now advanced to a phase II clinical trial [ 35 ]. Further understanding of endogenous TLR-4 ligands in RA pathogenesis will be essential for appropriate and effective use these of new therapeutic agents.…”