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Nonclinical Studies Investigating Mechanisms of Hepatotoxicity for GalNAc-siRNA Conjugates

We presented nonclinical data on the safety profile and mechanisms of hepatotoxicity for GalNAc-siRNA conjugates at the TIDES 2017 meeting in San Diego, California.


When administered at toxicological doses, certain GalNAc-siRNA conjugates are associated with hepatoxicity, as observed through the development candidate (DC) selection process. However, results from rodent studies showed that blocking the antisense strand of the siRNA from loading into the RNA-induced silencing complex (RISC), without altering the chemical modification content or pattern of the siRNA, mitigated hepatotoxicity with no effect on liver exposure. Further, administration of a Reversir oligonucleotide, designed to rapidly reverse target gene silencing effects by binding to the complementary RISC-bound antisense strand of an siRNA, also mitigated hepatotoxicity without reducing liver exposure or RISC loading. These nonclinical results suggest that sequence-specific off-target effects, not chemical modifications, are a major driver of hepatotoxicity for some GalNAc-siRNA conjugates.

Importantly, the DC selection process enables us to screen out GalNAc-siRNA conjugates associated with hepatotoxicity in nonclinical studies, and it is an integral part of identifying optimal RNAi candidates for clinical development. We will continue to approach this process with scientific rigor as we strive to provide patients with important new therapeutic options.