Control of Hepatitis\nB Virus with Imdusiran, a Small\nInterfering RNA Therapeutic

Chronic hepatitis B is a global health concern with a\nhigh risk\nof end-stage liver disease. Current standard-of-care agents have low\ncure rates, and new therapies are needed. Small interfering RNAs (siRNAs)\nthat target viral RNAs fulfill a gap not addressed by standard-of-care\nagents and may contribute to a functional cure. Here, we describe\nthe preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic\nsiRNA therapeutic that effectively reduces HBsAg, viral antigens,\nand viral replication in chronic hepatitis B patients and is currently\nin Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based\nsystems, imdusiran possessed pan-genotypic nanomolar potency and retained\nactivity against HBV target site polymorphisms. Imdusiran was active\nagainst nucleos(t)ide analogue- and capsid assembly modulator-resistant\nHBV isolates, and combination with standard-of-care agents was additive.\nIn an HBV adeno-associated virus mouse model, HBsAg was reduced up\nto 3.7 log<sub>10</sub> after a single imdusiran dose, with sustained\nsuppression for 10 weeks. Imdusiran did not intrinsically stimulate\ncytokine release in healthy donor human whole blood, supportive of\nits mechanism of action as a direct acting RNA interference antiviral.\nTaken together, these data support imdusiran in combination treatment\napproaches toward chronic hepatitis B functional cure.