title: First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B.
abstract: Myrcludex B is a first-in-class compound, which blocks entry of hepatitis B and D virus into hepatocytes in vitro and in animal models. Based on the required preclinical data we aimed to translate this compound into the first application in humans.
  
  
  
  Single ascending doses of myrcludex B, a 47 amino acid peptide, were administered up to 20mg intravenously and 10mg subcutaneously in a prospective open first-in-human, phase I clinical trial to 36 healthy volunteers. Safety, tolerability and plasma concentrations of myrcludex B were assessed and a pharmacokinetic model was derived.
  
  
  
  Myrcludex B was well tolerated and no serious or relevant AEs representing off-target effects, and no immunogenic effects were observed up to the highest applied dose of 20mg (intravenously). Myrcludex B showed dose-dependent pharmacokinetics, best described by a 2-compartment target-mediated drug disposition model. Bioavailability of the subcutaneous application was large (85%). Interindividual variability was moderate. The pharmacokinetic model suggested that subcutaneous doses of 10mg and above reach a target saturation of over 80% for at least 15h.
  
  
  
  Myrcludex B showed excellent tolerability up to high doses. Pharmacologic properties followed a 2-compartment target-mediated drug disposition model. These findings are vital for planning of further multiple dose efficacy trials in patients.
  
  
  
  After showing antiviral activity in cell culture and animal models, myrcludex B, a new drug intended for the treatment of hepatitis B and D, has been administered the first time in humans. Healthy volunteers received the drug intravenously and subcutaneously up to high doses (20mg). The drug was well tolerated and the characteristics of the drug determining its way in the human body could be described. These results will allow testing myrcludex B in hepatitis B and D patients.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. Electronic address: antje.blank@med.uni-heidelberg.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Blank
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hohmann
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Carls
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.affiliation: Clinical Pharmacy, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.affiliation: Myr GmbH, Weinbergsweg 66, 61348 Bad Homburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Alexandrov
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany; University of Tübingen, Tübingen, Germany; German Center for Infection Research (DZIF), Tübingen Partner Site, Tübingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Haag
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, Germany; University of Tübingen, Tübingen, Germany; German Center for Infection Research (DZIF), Tübingen Partner Site, Tübingen, Germany; Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Urban
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000998:Antiviral Agents; D006509:Hepatitis B; D006515:Hepatitis B virus; D003698:Hepatitis Delta Virus; D006801:Humans; D055666:Lipopeptides; D011446:Prospective Studies
chemical_list: D000998:Antiviral Agents; D055666:Lipopeptides; C571888:myrcludex-B
keywords: Chronic hepatitis B; Clinical phase I study; Hepatitis B treatment; Hepatitis D treatment; Myrcludex B; Pharmacokinetics; Virus entry inhibitor