Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic
Emily P. Thi, Xin Ye, Nicholas M. Snead, Amy C. H. Lee, Holly M. Micolochick Steuer, Andrzej Ardzinski, Ingrid Graves, Christine Espiritu, Andrea Cuconati, Cory Abbott, Agnes Jarosz, Xiaowei Teng, Bhavna Paratala, Kevin McClintock, Troy O. Harasym, René Rijnbrand, Angela M. Lam, Michael J. Sofia
Abstract
Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log 10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.