TLR4 blockade in rheumatoid arthritis disappoints in phase II trial

Blocking the toll-like receptor (TLR) 4 pathway with NI-0101, a first-in-class humanized monoclonal antibody, has failed to improve disease parameters in rheumatoid arthritis (RA) in a phase II trial.

The trial randomized 90 ACPA-positive RA patients with inadequate response to methotrexate to receive either NI-0101 (5 mg/kg every 2 weeks; n=61) or placebo (n=29) for 12 weeks. Of these, 86 completed the study.

Researchers evaluated treatment effect on the following measures: 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. They conducted subgroup analyses defined by biomarkers and reported safety.

Efficacy endpoints did not significantly differ between the active and placebo treatment groups. In subgroup analyses that used baseline parameters as covariants, no patient population particularly benefitted from NI-0101.

The incidence of treatment-emergent adverse events was similar in the two treatment groups, recorded in 51.7 percent of patients on placebo and in 52.5 percent of those on NI-0101.

The present data show that blocking the TLR4 pathway alone does not produce improvements in RA, according to the researchers. Broader and/or earlier inhibitory approaches may be needed for successful targeting of innate immune pathways in RA.