title: Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial.
abstract: miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes.
  
  
  
  In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49.
  
  
  
  Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4·42 (IQR 3·23-5·00) and 5·07 (4·19-5·35) log10IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5' UTR of the HCV genome.
  
  
  
  This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks.
  
  
  
  Regulus Therapeutics, Inc.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Meike H
authors.initials: MH
authors.lastname: van der Ree
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: J Marleen
authors.initials: JM
authors.lastname: de Vree
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: Stelma
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Sophie
authors.initials: S
authors.lastname: Willemse
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Internal Medicine, Division of Infectious Diseases, Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van der Valk
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Onze Lieve Vrouwe Gasthuis, Oosterpark, Amsterdam, Netherlands.
authors.forename: Svend
authors.initials: S
authors.lastname: Rietdijk
authors.affiliation: Department of Medical Microbiology, Clinical Virology Laboratory, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Molenkamp
authors.affiliation: Department of Medical Microbiology, Clinical Virology Laboratory, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Janke
authors.initials: J
authors.lastname: Schinkel
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Ad C
authors.initials: AC
authors.lastname: van Nuenen
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: PRA Health Sciences, Zuidlaren, the Netherlands.
authors.forename: Salah
authors.initials: S
authors.lastname: Hadi
authors.affiliation: PRA Health Sciences, Zuidlaren, the Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: Harbers
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: van der Veer
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Grundy
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Pavlicek
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Blem
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Huang
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Grint
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Neben
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Gibson
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.w.reesink@amc.uva.nl.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D000116:Acetylgalactosamine; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D009841:Oligonucleotides; D019562:Viral Load / Q000187:drug effects
chemical_list: D035683:MicroRNAs; D009841:Oligonucleotides; D000116:Acetylgalactosamine