Discovery of the RNA Interference Therapeutic Imdusiran, a GalNAc‐conjugated siRNA

Short interfering RNAs (siRNAs) have been a transformative therapeutic modality since the approval of the lipid nanoparticle (LNP)-formulated siRNA Onpattro (patisiran) in 2018 for the treatment of transthyretin amyloidosis. Since then, siRNA have been approved against multiple host targets to treat diseases ranging from acute hepatic porphyria to hypercholesterolemia. To date, no siRNA therapeutic against a viral target has yet been approved. Effective antiviral treatment with siRNA will require selection of an appropriate delivery platform and viral RNA targets to provide the maximum benefit. In this chapter, the discovery of imdusiran, an N -acetylgalactosamine-conjugated siRNA against hepatitis B virus (HBV), is described through a process of siRNA delivery platform comparison, HBV target site selection, and siRNA optimization. Preclinical characterization in cell and in vivo mouse models confirmed imdusiran as a potent, pan-genotypic antiviral siRNA therapeutic against HBV. Imdusiran is currently being evaluated for the treatment of chronic HBV infection in Phase 2 clinical trials.