PMID- 34037271
OWN - NLM
STAT- MEDLINE
DCOM- 20220110
LR  - 20220731
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 74
IP  - 4
DP  - 2021 Oct
TI  - Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers 
      and Patients With Chronic Hepatitis B.
PG  - 1795-1808
LID - 10.1002/hep.31920 [doi]
AB  - 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.
CI  - (c) 2021 Roche Products Ltd. Hepatology published by Wiley Periodicals LLC on 
      behalf of American Association for the Study of Liver Diseases.
FAU - Gane, Edward
AU  - Gane E
AD  - Auckland Clinical Studies, Auckland, New Zealand.
FAU - Yuen, Man-Fung
AU  - Yuen MF
AD  - Queen Mary Hospital, The University of Hong Kong, Hong Kong.
FAU - Kim, Dong Joon
AU  - Kim DJ
AD  - Hallym University College of Medicine, Chuncheon, South Korea.
FAU - Chan, Henry Lik-Yuen
AU  - Chan HL
AD  - Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
FAU - Surujbally, Bernadette
AU  - Surujbally B
AD  - Roche Innovation Centre, Welwyn Garden City, United Kingdom.
FAU - Pavlovic, Vedran
AU  - Pavlovic V
AD  - Roche Innovation Centre, Welwyn Garden City, United Kingdom.
FAU - Das, Sudip
AU  - Das S
AD  - Roche Innovation Centre, Welwyn Garden City, United Kingdom.
FAU - Triyatni, Miriam
AU  - Triyatni M
AD  - Roche Innovation Centre, Basel, Switzerland.
FAU - Kazma, Remi
AU  - Kazma R
AD  - Roche Innovation Centre, Basel, Switzerland.
FAU - Grippo, Joseph F
AU  - Grippo JF
AD  - Roche Innovation Centre, New York, NY, USA.
FAU - Buatois, Simon
AU  - Buatois S
AD  - Roche Innovation Centre, Basel, Switzerland.
FAU - Lemenuel-Diot, Annabelle
AU  - Lemenuel-Diot A
AD  - Roche Innovation Centre, Basel, Switzerland.
FAU - Krippendorff, Ben-Fillippo
AU  - Krippendorff BF
AD  - Roche Innovation Centre, Basel, Switzerland.
FAU - Mueller, Henrik
AU  - Mueller H
AD  - Roche Innovation Centre, Basel, Switzerland.
FAU - Zhang, Yuchen
AU  - Zhang Y
AD  - Roche Innovation Centre, Shanghai, China.
FAU - Kim, Hyung Joon
AU  - Kim HJ
AD  - Department of Internal Medicine, The Institute of Evidence-based Clinical 
      Medicine, College of Medicine, Chung-Ang University, Seoul, South Korea.
FAU - Leerapun, Apinya
AU  - Leerapun A
AD  - Division of Gastroenterology, Department of Internal Medicine, Faculty of 
      Medicine, Chiang Mai University, Chiang Mai, Thailand.
FAU - Lim, Tien Huey
AU  - Lim TH
AD  - Middlemore Hospital, Auckland, New Zealand.
FAU - Lim, Young-Suk
AU  - Lim YS
AUID- ORCID: 0000-0002-1544-577X
AD  - Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
FAU - Tanwandee, Tawesak
AU  - Tanwandee T
AD  - Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 
      Bangkok, Thailand.
FAU - Kim, Won
AU  - Kim W
AUID- ORCID: 0000-0002-2926-1007
AD  - Seoul National University College of Medicine, Seoul Metropolitan Government 
      Seoul National University Boramae Medical Center, Seoul, South Korea.
FAU - Cheng, Wendy
AU  - Cheng W
AD  - Linear Clinical Research, Perth, Australia.
FAU - Hu, Tsung-Hui
AU  - Hu TH
AD  - Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
FAU - Wat, Cynthia
AU  - Wat C
AD  - Roche Innovation Centre, Welwyn Garden City, United Kingdom.
LA  - eng
SI  - ClinicalTrials.gov/NCT03038113
PT  - Adaptive Clinical Trial
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210825
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Asialoglycoprotein Receptor)
RN  - 0 (Hepatitis B Surface Antigens)
RN  - 0 (Oligonucleotides)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Viral)
RN  - 0 (RO7062931)
RN  - 0 (locked nucleic acid)
RN  - KM15WK8O5T (Acetylgalactosamine)
SB  - IM
CIN - Hepatology. 2022 Jan;75(1):230-231. PMID: 34387887
CIN - Hepatology. 2022 Apr;75(4):1050-1051. PMID: 34396570
MH  - Acetylgalactosamine/analogs & derivatives/*therapeutic use
MH  - Adult
MH  - Asialoglycoprotein Receptor
MH  - Female
MH  - Healthy Volunteers
MH  - Hepatitis B Surface Antigens/blood
MH  - Hepatitis B virus/genetics
MH  - Hepatitis B, Chronic/blood/*drug therapy
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Oligonucleotides/genetics/*therapeutic use
MH  - Oligonucleotides, Antisense/genetics/*therapeutic use
MH  - RNA, Viral/genetics
MH  - Sustained Virologic Response
PMC - PMC9291828
EDAT- 2021/05/27 06:00
MHDA- 2022/01/11 06:00
PMCR- 2022/07/18
CRDT- 2021/05/26 09:05
PHST- 2021/04/15 00:00 [revised]
PHST- 2020/12/23 00:00 [received]
PHST- 2021/05/17 00:00 [accepted]
PHST- 2021/05/27 06:00 [pubmed]
PHST- 2022/01/11 06:00 [medline]
PHST- 2021/05/26 09:05 [entrez]
PHST- 2022/07/18 00:00 [pmc-release]
AID - HEP31920 [pii]
AID - 10.1002/hep.31920 [doi]
PST - ppublish
SO  - Hepatology. 2021 Oct;74(4):1795-1808. doi: 10.1002/hep.31920. Epub 2021 Aug 25.