title: Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study.
abstract: The therapeutic option for patients with chronic hepatitis delta virus infection (CHD) is limited to interferon alpha with rare curative outcome. Myrcludex B is a first-in-class entry inhibitor inactivating the hepatitis B virus (HBV) and hepatitis D virus (HDV) receptor sodium taurocholate co-transporting polypeptide. We report the interim results of a pilot trial on chronically infected HDV patients treated with myrcludex B, or pegylated interferon alpha (PegIFNα-2a) or their combination.
  
  
  
  Twenty-four patients with CHD infection were equally randomized (1:1:1) to receive myrcludex B, or PegIFNα-2a or their combination. Patients were evaluated for virological and biochemical response and tolerability of the study drugs at weeks 12 and 24.
  
  
  
  Myrcludex B was well tolerated and no serious adverse event occurred. Although hepatitis B surface antigen levels remained unchanged, HDV RNA significantly declined at week 24 in all cohorts. HDV RNA became negative in two patients each in the Myrcludex B and PegIFNα-2a cohorts, and in five patients of the Myrcludex B+PegIFNα-2a cohort. ALT decreased significantly in the Myrcludex B cohort (six of eight patients), and HBV DNA was significantly reduced at week 24 in the Myrcludex B+PegIFNα-2a cohort. Virus kinetic modeling suggested a strong synergistic effect of myrcludex B and PegIFNα-2a on both HDV and HBV.
  
  
  
  Myrcludex B showed a strong effect on HDV RNA serum levels and induced ALT normalization under monotherapy. Synergistic antiviral effects on HDV RNA and HBV DNA in the Myr-IFN cohort indicated a benefit of the combination of entry inhibition with PegIFNα-2a to treat CHD patients.
  
  
  
  Myrcludex B is a new drug to treat hepatitis B and D infection. After 24weeks of treatment with myrcludex B and/or pegylated interferon α-2a, HDV R NA, a relevant marker for hepatitis D infection, decreased in all patients with chronic hepatitis B and D. Two of eight patients which received either myrcludex B or pegylated interferon α-2a, became negative for HDV RNA, and five of seven patients who received both drugs at the same time became negative. The drug was well tolerated.
authors.affiliation: Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, 61/2 Schepkina str., 129110 Moscow, Russia; Centrosoyuz Clinical Hospital, 57 Gilyarovskogo str., Moscow 129110, Russia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Bogomolov
authors.affiliation: Myr GmbH, Weinbergsweg 66, 61348 Bad Homburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Alexandrov
authors.affiliation: Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, 61/2 Schepkina str., 129110 Moscow, Russia; Centrosoyuz Clinical Hospital, 57 Gilyarovskogo str., Moscow 129110, Russia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Voronkova
authors.affiliation: Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, 61/2 Schepkina str., 129110 Moscow, Russia; Centrosoyuz Clinical Hospital, 57 Gilyarovskogo str., Moscow 129110, Russia.
authors.forename: Maria
authors.initials: M
authors.lastname: Macievich
authors.affiliation: Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, 61/2 Schepkina str., 129110 Moscow, Russia; Centrosoyuz Clinical Hospital, 57 Gilyarovskogo str., Moscow 129110, Russia.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Kokina
authors.affiliation: Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, 61/2 Schepkina str., 129110 Moscow, Russia; Centrosoyuz Clinical Hospital, 57 Gilyarovskogo str., Moscow 129110, Russia.
authors.forename: Maria
authors.initials: M
authors.lastname: Petrachenkova
authors.affiliation: Clinical Pharmacy, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
authors.affiliation: German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Florian A
authors.initials: FA
authors.lastname: Lempp
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Wedemeyer
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, E.-Aulhorn-Str. 6, 72076 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, E.-Aulhorn-Str. 6, 72076 Tübingen, Germany; Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany; Department of Pharmacy and Biochemistry, University of 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 Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.affiliation: German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: antje.blank@med.uni-heidelberg.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Blank
authors.affiliation: German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Urban
mesh_terms: D006509:Hepatitis B; D006515:Hepatitis B virus; D003699:Hepatitis D; D003698:Hepatitis Delta Virus; D006801:Humans; D055666:Lipopeptides
chemical_list: D055666:Lipopeptides; C571888:myrcludex-B
keywords: Chronic hepatitis B; Entry inhibitor; Hepatitis B treatment; Hepatitis B virus receptor; Hepatitis D; Hepatitis D treatment; Myrcludex B; SLC10A1); Sodium taurocholate co-transporting polypeptide (NTCP; Virus kinetic modeling