Objectives Anti-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.
Methods Placebo-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.
Results 90 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.
Conclusions We 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.
- rheumatoid arthritis
- DMARDs (biologic)
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Handling editor Josef S Smolen
EHC and IM contributed equally.
Contributors EM, EHC, IMcI, KdG, PJ, GL and CdM participated in the design of the study. EM, KdG, GL and TK participated in data collection. EM, KdG and GL participated in data analysis. EM, EHC, IMcI, KdG, PJ, GL and CdM participated in interpreting the data, in writing and in critically reviewing the manuscript. All authors approved the final version. EHC and IMcI contributed equally to the study design and data interpretation.
Funding Novimmune SA was the sponsor of the study.
Competing interests EM, KdG, GL and CdM were employees and stock options holders of Novimmune SA. PJ was consultant of Novimmune SA. EHC and IMcI were consultants of Novimmune SA: EHC received consultancy fees or grants from UCB, Pfizer, BioCancer, Biogen, Novartis, Roche, Amgen, Chugai, Eli Lilly, Sanofi, Abbvie, Janssen, Gilead and Bristol Myer Squibbs. IMcI received consultancy fees and grants from Celgen, Janssen, Novartis, Beorhinger Ingelheim, Abbvie, Eli Lilly, Bristol Myer Squibbs, GlaxoSmithKline and Pfizer. TK received Investigator fees from Novimmune SA to conduct the study. Novimmune SA and Genentech entered into a collaboration agreement for the development of NI-0101, under this agreement Novimmune SA received funding from Genentech.
Patient consent for publication Not required.
Ethics approval All relevant study documentation and amendments were approved by Independent Ethics Committees. The study was conducted in accordance with the principles set forth in the Declaration of Helsinki, the Guidelines of the International Council for Harmonisation (ICH) on Good Clinical Practice (GCP) Guideline E6 (R2) (EMA/CPMP/ICH/135/95), European Union (EU) Directive 95/46/EC, and other applicable regulatory requirements. Patients provided informed written consent prior to any study procedures.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Individual anonymised participant data, pooled study data, protocol or statistical analysis plan will not be shared unless a specific data sharing agreement is established with Light Chain Bioscience. For inquiries about data sharing, please send request at NIemail@example.com.