Target Analysis - Toll-like receptors
Drugs inhibiting Toll-like receptors
As well as TLR agonists there are also a number of antagonists in development for various indications. Systemic lupus erythamatosus (SLE) is an autoimmune disorder in which it is thought that an immune complex of autoantibodies and protein-bound DNA interacts with dendritic cells and subsequently leads to the activation of intracellular TLR9. Current therapies for SLE are general immunosuppressants which can of course lead to a host of unwanted and potentially dangerous side-effects. TLR-targeted therapies may thus represent a more specific approach. Dynavax Technologies’ TLR7/9 antagonist, IRS-954, has already shown early signs of efficacy; in a murine model of lupus, it reduced serum levels of nucleic acid-specific antibodies and decreased proteinurea, glomerularnephritis and end-organ damage, producing an overall survival benefit.
A more advanced TLR antagonist is Eisai’s eritoran tetrasodium, which targets TLR4 and has reached Phase III trials for the treatment of sepsis and septic shock. In Phase I trials it proved its ability to dose-dependently inhibit TNF-α production, although the results from Phase II trials were not outstanding - 28-day all-cause mortality rates in 293 patients with severe sepsis were 26.9 and 32% on 105mg eritoran tetrasodium every 6 days and 45mg every 6 days, respectively, compared with 33.3% on placebo. However, the trial in question was not sized to show significance, so it remains to be seen how the drug will perform in the largerscale Phase III trial.
