TLR4 ‘not a relevant target’ for RA
medwireNews: Addition of the toll-like receptor (TLR)4-directed monoclonal antibody NI-0101 to methotrexate treatment fails to improve outcomes for patients with rheumatoid arthritis (RA), indicate findings from a phase 2 trial.
The study included 86 participants with anti-citrullinated protein antibody (ACPA)-positive RA and an inadequate response to methotrexate who were randomly assigned to receive 12 weeks of add-on treatment with either NI-0101 administered as a 5 mg/kg infusion every 2 weeks (n=57) or placebo (n=29).
Outlining the rationale behind their trial, Emmanuel Monnet (NovImmune SA, Geneva, Switzerland) and co-investigators explain that immune complexes formed by citrullinated proteins and ACPAs stimulate cellular receptors including TLR4, and “[n]umerous preclinical mechanistic studies have shown the potential role for TLR4 and its ligands in RA.”
However, NI-0101 treatment did not improve any of the efficacy outcomes in the phase 2 study.
Average DAS28-CRP scores improved from 5.9 points at baseline to approximately 4.6 points at 12 weeks among patients given NI-0101, while those in the placebo group experienced a comparable improvement from 5.8 to approximately 4.6 points.
Monnet and team report in the Annals of the Rheumatic Diseases that a similar pattern of results was seen for DAS28-ESR scores, while CDAI and SDAI scores improved by approximately 40% from baseline to week 12 in both groups, with no significant between-group differences.
These findings were “further confirmed by the lack of treatment-associated changes in levels of cytokines downstream from TLR4 and known to be involved in the inflammation characteristic of RA,” they say.
Therefore, “blockage of TLR4 is likely not a relevant target in RA patients with inadequate response to [methotrexate],” write the investigators. Describing their results as “surprising,” they suggest “[i]t is possible that redundancy in TLR signalling may underlie the lack of effect of TLR4 blockade,” because TLR2, TLR5, and TLR7 have also been implicated in RA pathology.
The team reports that NI-0101 had “an acceptable safety and tolerability profile,” with 52.5% of patients receiving the TLR4 inhibitor and 51.7% of those in the placebo group experiencing treatment-emergent adverse events (TEAEs). Infections were the most commonly reported TEAEs, affecting 11.5% and 13.8% of participants in the NI-0101 and placebo arms, respectively.
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