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Title: Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B
Authors: Edward Gane
Man Fung Yuen
Dong Joon Kim
Henry Lik Yuen Chan
Bernadette Surujbally
Vedran Pavlovic
Sudip Das
Miriam Triyatni
Remi Kazma
Joseph F. Grippo
Simon Buatois
Annabelle Lemenuel-Diot
Ben Fillippo Krippendorff
Henrik Mueller
Yuchen Zhang
Hyung Joon Kim
Apinya Leerapun
Tien Huey Lim
Young Suk Lim
Tawesak Tanwandee
Won Kim
Wendy Cheng
Tsung Hui Hu
Cynthia Wat
Siriraj Hospital
Chang Gung Memorial Hospital
Prince of Wales Hospital Hong Kong
F. Hoffmann-La Roche AG
College of Medicine
The University of Hong Kong
University of Ulsan College of Medicine
Hallym University, College of Medicine
Middlemore Hospital, Auckland
Roche Products Limited UK
Chiang Mai University
Seoul National University College of Medicine
Roche Innovation Center
Roche Innovation Center Shanghai
Linear Clinical Research
Auckland Clinical Studies
Keywords: Medicine
Issue Date: 1-Oct-2021
Citation: Hepatology. Vol.74, No.4 (2021), 1795-1808
Abstract: 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 log10 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.
ISSN: 15273350
Appears in Collections:Scopus 2021

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