The toll-like receptor 4 (TLR4) pathway is not likely a relevant target in treating patients with rheumatoid arthritis (RA) who demonstrate an inadequate response to methotrexate therapy, according to research published in the Annals of the Rheumatic Diseases.

Researchers conducted a phase 2, proof-of-concept, randomized, placebo-controlled, double-blind, international, multicenter study of patients with moderate to severe anticitrullinated protein antibody-positive RA who previously demonstrated an inadequate response to methotrexate therapy. The study included adults with active RA ≥6 months who fulfilled the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria.

In total, 250 patients were screened for eligibility and 90 were randomly assigned to receive either placebo (n=29) or 5 mg/kg NI-0101 — a first-in-class humanized monoclonal antibody-blocking TLR4 — every 2 weeks for 12 weeks (n=61). All participants also continued methotrexate therapy. From each group, 57 and 29 patients (from treatment and control group, respectively) completed both the 12-week visit and the follow-up phase through week 24.

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Overall, no major differences were noted between groups in terms of individual disease parameters, although patients in the NI-0101 group had a longer RA duration (8.5 vs 5.4 years) and were younger at the time of diagnosis (45.7 vs 51.2 years). The mean C-reactive protein (CRP) level was also higher in this group at baseline (18.3 mg/L vs 13.4 mg/L).

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Both treatment groups demonstrated similar decreases from baseline to week 12 disease activity scores in 28 joints with CRP, with no significant between-group differences noted. Both Clinical Disease Activity Index and Simplified Disease Activity Index scores decreased approximately 40% from baseline to 12 weeks, and the proportion of patients who achieved good or moderate EULAR responses increased with treatment.

By week 12, 27.6% and 26% of patients in both groups (placebo and NI-0101, respectively) achieved good EULAR responses whereas 55.2% and 53.6%, respectively, achieved EULAR moderate responses. Similarly, no significant between-group differences were noted in ACR responses at week 12, with 55.2% in the placebo group and 58.9% in the treatment group achieving improvement of ≥20% in ACR criteria responses, 20.7% and 14.3% achieving improvement of ≥50% in ACR criteria (ACR50) responses, and 10.3% and 10.7% achieving improvement of ≥70% in ACR criteria responses. A subgroup analysis found no significant effects on stratification by either CRP or FcγRIIa genotype for either disease activity score in 28 joints with CRP or ACR50 response.

A pharmacokinetics profile of NI-0101 showed expected concentrations and elimination consistent with simulations. NI-0101 concentrations were maintained above the targeted threshold of 10,000 ng/mL in a majority of patients. In terms of pharmacodynamics, no significant differences between treatment groups were noted for all evaluated biomarkers.

NI-0101 infusions every 2 weeks demonstrated an acceptable safety and tolerability profile in patients with RA, with similar proportions of treatment-emergent adverse events occurring in both the placebo and treatment groups (51.7% and 52.5%, respectively). The most frequently reported adverse events were infections (13.8% in the placebo group and 11.5% in the NI-0101 group).

“The lack of significant effect of NI-0101 in this well-controlled prospective clinical trial indicates that blocking the TLR4 pathway alone is unlikely to benefit patients with established RA,” the researchers concluded. “The good NI-0101 safety and [pharmacokinetic] profiles support further exploration in other diseases.”

Disclosure: This clinical trial was supported by Novimmune SA. Please see the original reference for a full list of authors’ disclosures.


Monnet E, Choy EH, McInnes I, et al. 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 [published online December 31, 2019]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2019-216487