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Clinical Study of Single‐Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B
Author(s) -
Gane Edward,
Yuen ManFung,
Kim Dong Joon,
Chan Henry LikYuen,
Surujbally Bernadette,
Pavlovic Vedran,
Das Sudip,
Triyatni Miriam,
Kazma Remi,
Grippo Joseph F.,
Buatois Simon,
LemenuelDiot Annabelle,
Krippendorff BenFillippo,
Mueller Henrik,
Zhang Yuchen,
Kim Hyung Joon,
Leerapun Apinya,
Lim Tien Huey,
Lim YoungSuk,
Tanwandee Tawesak,
Kim Won,
Cheng Wendy,
Hu TsungHui,
Wat Cynthia
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31920
Subject(s) - medicine , placebo , hbsag , pharmacokinetics , hbeag , gastroenterology , pharmacodynamics , adverse effect , regimen , hepatitis b , hepatitis b virus , pharmacology , immunology , virus , pathology , alternative medicine
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.