TLR4 Blockade May Not Treat RA With Inadequate Response to MTX

Periarticular bone erosions are a diagnostic feature of RA and are detected using radiographic imaging.1,6 They result from progressive periarticular osteoporosis resulting from an imbalance between bone resorption and inadequate bone formation at the joint margins.7 On imaging, they appear as breaks in the cortical bone accompanied by loss of subchondral trabecular bone and bone marrow edema.1,6 Although bone erosions occur in healthy people or patients with other joint diseases, they are more severe in patients with RA.6 Bone erosions arise early in the course of RA (within a few weeks to a few months of onset in some patients).1,7 They most often affect metacarpophalangeal joints and predict more severe disease.1,7 Approximately 63% of patients with RA have erosions at diagnosis.1 Seropositivity and smoking increase the risk for bone erosions.1 Evidence suggests DMARDs and the nuclear factor-kB ligand inhibitor denosumab can prevent progression of bone erosions, but no treatment appears to repair erosions.1,2,7
Investigators sought to determine whether blocking the toll-like receptor 4 pathway alone does or does not improve disease parameters in patients with rheumatoid arthritis, a human immune-mediated inflammatory disease.

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.

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