Clinical Study of Single‐Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B

BACKGROUND AND AIMS: RO7062931 is an N‐acetylgalactosamine (GalNAc)‐conjugated single‐stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two‐part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed. APPROACH AND RESULTS: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1‐4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3‐5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self‐limiting injection site reactions and influenza‐like illness. Supradose‐proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose‐dependent and time‐dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log(10) IU/mL) independent of HBeAg status. CONCLUSIONS: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose‐proportional exposure at doses of 3.0‐4.0 mg/kg was indicative of partial saturation of the ASGPR‐mediated liver uptake system. Dose‐dependent declines in HBsAg demonstrated target engagement with RO7062931.