Pavel Bogomolov1, Alexander Alexandrov2, Natalia Voronkova1, Maria Macievich1, Ksenia Kokina1, Maria Petrachenkova1, Thorsten Lehr3, Florian A Lempp4, Heiner Wedemeyer5, Mathias Haag6, Matthias Schwab7, Walter E Haefeli8, Antje Blank9, Stephan Urban4. 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 withmyrcludex 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.
RCT Entities:
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 HDVpatients 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.
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