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J Hepatol. 2016 Sep;65(3):490-8. doi: 10.1016/j.jhep.2016.04.016. Epub 2016 Apr 27.

Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study.

Author information

1
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.
2
Myr GmbH, Weinbergsweg 66, 61348 Bad Homburg, Germany.
3
Clinical Pharmacy, Saarland University, Campus C2 2, 66123 Saarbrücken, Germany.
4
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.
5
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
6
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.
7
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.
8
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.
9
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.

Abstract

BACKGROUND & AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

LAY SUMMARY:

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.

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

PMID:
27132170
DOI:
10.1016/j.jhep.2016.04.016
[Indexed for MEDLINE]

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