Nonclinical safety profile for DCR-AUD GalNAc-conjugated siRNA: Subchronic versus chronic findings in mouse and non-human primate.

Alcohol Use Disorder (AUD) is a chronic condition characterized by compulsive alcohol use and impaired control. DCR-AUD is a novel N-acetylgalactosamine-conjugated short interfering RNA (GalNAc-siRNA) therapeutic agent designed to selectively inhibit the expression of alcohol dehydrogenase 2 (ALDH2) enzyme in liver. The ALDH2 mRNA target sequence is conserved across mice, nonhuman primates (NHPs), and humans. A comprehensive nonclinical safety program was performed in mice and NHPs, including repeat-dose subchronic and chronic toxicology studies (dosing up to 300 mg/kg per dose), genotoxicity testing, and safety pharmacology studies. DCR-AUD administered by subcutaneous injection was pharmacologically active in both mice and NHPs with > 90% reduction of ALDH2 transcripts in liver, the primary target organ. Histopathology and clinical pathology changes observed were consistent with siRNA uptake and accumulation and were considered nonadverse. Although minor differences in pathology findings were observed between subchronic and chronic toxicology studies, they were not degenerative and lacked functional correlates. No genotoxicity or safety pharmacology signals of concern were identified. DCR-AUD produced robust, selective hepatic ALDH2 knockdown in relevant nonclinical species with a favorable nonadverse safety profile, supporting progression to first-in-human studies. These findings and literature are discussed in the context of optimizing nonclinical safety programs for GalNAc-conjugated siRNAs.