Toll-like receptor agonists for nonresponders to HCV treatment: Hope versus promise?

▪ Through immunomodulation, Toll-like receptor (TLR) agonists are able to decrease hepatitis viral load. It is not clear if TLR agonists will be potent enough to compete against the current hepatitis C standard of care. ▪ Two drugs were shown to have unfavorable outcomes in toxicology studies. ANA975 demonstrated intense immune activation in toxicology study, which led to the discontinuation of this compound and of isatoribine. ▪ IMO-2125 development is on hold secondary to atypical lymphocytic proliferation in rodents. ANA773 and GS-9620 are in Phase I of development. ▪ Thymosin α-1 mechanism of action involves TLR9. Even if commercialized in some countries, not clear if it is useful in the context of the current standard of care. CPG 10101 developments are on hold, awaiting the era of the direct-acting agents.