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Myrcludex B: Preclinical and Clinical Development

 

Blank, A., Markert, C., Hohmann, N., Carls, A., Mikus, G., Lehr, T., Alexandrov, A., Haag, M., Schwab, M., Urban, S. and Haefeli, W.E., 2016. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. Journal of hepatology65(3), pp.483-489.

 

Li, W. and Urban, S., 2016. Entry of hepatitis B and hepatitis D virus into hepatocytes: Basic insights and clinical implications. Journal of hepatology64(1), pp.S32-S40.

 

Bogomolov, P., Alexandrov, A., Voronkova, N., Macievich, M., Kokina, K., Petrachenkova, M., Lehr, T., Lempp, F.A., Wedemeyer, H., Haag, M. and Schwab, M., 2016. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study. Journal of hepatology65(3), pp.490-498.

 

Slijepcevic, D., Kaufman, C., Wichers, C.G., Gilglioni, E.H., Lempp, F.A., Duijst, S., de Waart, D.R., Oude Elferink, R.P., Mier, W., Stieger, B. and Beuers, U., 2015. Impaired uptake of conjugated bile acids and hepatitis b virus pres1‐binding in na+‐taurocholate cotransporting polypeptide knockout mice. Hepatology62(1), pp.207-219.

 

Cole, P., 2015. MYRCLUDEX-B Viral entry inhibitor Treatment of hepatitis B virus (HBV) and HDV infection. Drugs of the future, 40(7), pp.433-436.

 

Bogomolov, P., Voronkova, N., Allweiss, L., Dandri, M., Schwab, M., Lempp, F.A., Haag, M., Wedemeyer, H., Alexandrov, A. and Urban, S., 2014. A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B. Hepatology60(6), pp.1279A-1280A.

 

Allweiss, L., Volz, T., Giersch, K., Petersen, J., Lohse, A.W., Lütgehetmann, M. and Dandri, M., 2014. Proliferation of hepatitis B virus infected human hepatocytes in humanized mice treated with the entry inhibitor Myrcludex-B induces strong cccDNA reduction and maintenance of cccDNA-free hepatocytes. Zeitschrift für Gastroenterologie52(01), p.P_5_36.

 

Oehler, N., Volz, T., Bhadra, O.D., Kah, J., Allweiss, L., Giersch, K., Bierwolf, J., Riecken, K., Pollok, J.M., Lohse, A.W. and Fehse, B., 2014. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology60(5), pp.1483-1493.

 

Ni, Y., Lempp, F.A., Mehrle, S., Nkongolo, S., Kaufman, C., Fälth, M., Stindt, J., Königer, C., Nassal, M., Kubitz, R. and Sültmann, H., 2014. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology146(4), pp.1070-1083.

 

Volz, T., Allweiss, L., ḾBarek, M.B., Warlich, M., Lohse, A.W., Pollok, J.M., Alexandrov, A., Urban, S., Petersen, J., Lütgehetmann, M. and Dandri, M., 2013. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. Journal of hepatology58(5), pp.861-867.

 

Schieck, A., Schulze, A., Gähler, C., Müller, T., Haberkorn, U., Alexandrov, A., Urban, S. and Mier, W., 2013. Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts. Hepatology58(1), pp.43-53.

 

Lütgehetmann, M., Volz, T., Allweiss, L., Helbig, M., Alexandrov, A., Lohse, A.W., Petersen, J., Urban, S. and Dandri, M., 2012. The entry inhibitor Myrcludex-B efficiently blocks viral spreading in vivo in human liver chimeric uPA/SCID mice previously infected with hepatitis B virus. Zeitschrift für Gastroenterologie50(01), p.P4_37.

 

Lütgehetmann, M., Mancke, L.V., Volz, T., Helbig, M., Allweiss, L., Bornscheuer, T., Pollok, J.M., Lohse, A.W., Petersen, J., Urban, S. and Dandri, M., 2012. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology55(3), pp.685-694.

 

Schulze, A., Schieck, A., Gähler, C., Meier, A., Müller, T., Alexandrov, A., Mier, W. and Urban, S., 2010. Preclinical studies on Myrcludex B, a novel Hepatitis B virus (HBV)-envelope protein derived entry inhibitor. Zeitschrift für Gastroenterologie48(01), p.P4_43.

 

 

Recent Review Articles Featuring Myrcludex B

 

General Reviews

 

Lempp, F.A., Ni, Y. and Urban, S., 2016. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nature Reviews Gastroenterology & Hepatology13(10), pp.580-589.

 

Kaufmann, S.H., Dorhoi, A., Hotchkiss, R.S. and Bartenschlager, R., 2018. Host-directed therapies for bacterial and viral infections. Nature Reviews Drug Discovery17(1), p.35.

 

Slijepcevic, D. and van de Graaf, S.F., 2017. Bile Acid Uptake Transporters as Targets for Therapy. Digestive Diseases35(3), pp.251-258.

 

Takeyama, Y. and Sakisaka, S., 2017. Bile Acids and Viral Hepatitis and Hepatocellular Carcinoma. Bile Acids in Gastroenterology, pp.157-168.

 

Urban, S., Bartenschlager, R., Kubitz, R. and Zoulim, F., 2014. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology147(1), pp.48-64.

 

Lempp, F.A. and Urban, S., 2014. Inhibitors of hepatitis B virus attachment and entry. Intervirology57(3-4), pp.151-157.

 

 

Myrcludex B in Hepatitis D

 

Lempp, F.A. and Urban, S., 2017. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen. Viruses9(7), p.172.

 

Soriano, V., Sherman, K.E. and Barreiro, P., 2017. Hepatitis delta and HIV infection. AIDS31(7), pp.875-884.

 

Rizzetto, M., 2017. Investigational drugs in development for hepatitis D. Expert opinion on investigational drugs, 26(9), pp.999-1005.

 

Elazar, M. and Glenn, J.S., 2017. Emerging concepts for the treatment of hepatitis delta. Current Opinion in Virology24, pp.55-59.

 

Yurdaydin, C., 2017. Recent advances in managing hepatitis D. F1000Research6.

 

Paraná, R., Schinoni, M.I. and de Souza Campos, M., 2017. Hepatitis D Virus. Human Virology in Latin America, pp.361-374.

 

 

Myrcludex B in Hepatitis B

 

Schinazi, R.F. and Asselah, T., 2017. From HCV To HBV Cure. Liver International37(S1), pp.73-80.

 

Lok, A.S., Zoulim, F., Dusheiko, G. and Ghany, M.G., 2017. Hepatitis B cure: From discovery to regulatory approval. Journal of hepatology67(4), pp.847-861.

 

Tang, L., Zhao, Q., Wu, S., Cheng, J., Chang, J. and Guo, J.T., 2017. The current status and future directions of hepatitis B antiviral drug discovery. Expert opinion on drug discovery12(1), pp.5-15.

 

Soriano, V., Barreiro, P., Benitez, L., Peña, J.M. and de Mendoza, C., 2017. New antivirals for the treatment of chronic hepatitis B. Expert Opinion on Investigational Drugs, (just-accepted).

 

Dawood, A., Basit, S.A., Jayaraj, M. and Gish, R.G., 2017. Drugs in Development for Hepatitis B. Drugs77(12), pp.1263-1280.

 

Arends, J.E., Lieveld, F.I., Ahmad, S. and Ustianowski, A., 2017. New Viral and Immunological Targets for Hepatitis B Treatment and Cure: A Review. Infectious diseases and therapy6(4), pp.461-476.

 

Serigado, J.M., Izzy, M. and Kalia, H., 2017. Novel therapies and potential therapeutic targets in the management of chronic hepatitis B. European journal of gastroenterology & hepatology29(9), pp.987-993.

 

Allweiss, L., Volz, T., Giersch, K., Kah, J., Raffa, G., Petersen, J., Lohse, A.W., Beninati, C., Pollicino, T., Urban, S. and Lütgehetmann, M., 2017. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo. Gut, pp.gutjnl-2016.

 

Anikhindi, S.A., Kumar, A., Sharma, P., Singla, V., Bansal, N. and Arora, A., 2017. Ideal cure for Hepatitis B infection: The target is in sight. Journal of Clinical and Experimental Hepatology.

 

Alonso, S., Guerra, A.R., Carreira, L., Ferrer, J.Á., Gutiérrez, M.L. and Fernandez-Rodriguez, C.M., 2017. Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon?. BMC gastroenterology17(1), p.168.

 

Nassal, M., 2017. Chronic hepatitis B: divide and conquer?. Gut, pp.gutjnl-2017.

 

Defresne, F. and Sokal, E., 2017. Chronic hepatitis B in children: therapeutic challenges and perspectives. Journal of gastroenterology and hepatology32(2), pp.368-371.

 

Peters, M.G. and Locarnini, S., 2017. New Direct-Acting Antiviral Agents and Immunomodulators for Hepatitis B Virus Infection. Gastroenterology & hepatology13(6), p.348.

 

Lewandowska, M. and Piekarska, A., 2017. New directions in hepatitis B therapy research. Clinical and experimental hepatology3(3), p.119.

 

Verrier, E.R., Schuster, C. and Baumert, T.F., 2017. Advancing hepatitis B virus entry inhibitors. Journal of hepatology66(4), pp.677-679.

 

 

Research Articles

 

Blank, A., Eidam, A., Haag, M., Hohmann, N., Burhenne, J., Schwab, M., van de Graaf, S.F., Meyer, M.R., Maurer, H.H., Meier, K. and Weiss, J., 2017. The NTCP‐inhibitor myrcludex B: Effects on bile acid disposition and tenofovir pharmacokinetics. Clinical Pharmacology & Therapeutics.

 

Blank, A., Meier, K., Urban, S., Haefeli, W.E. and Weiss, J., 2017. Drug-drug interaction potential of the hepatitis B and hepatitis D virus entry inhibitor myrcludex B assessed in vitro. Antiviral therapy.

 

Donkers, J.M., Zehnder, B., van Westen, G.J., Kwakkenbos, M.J., IJzerman, A.P., Elferink, R.P.O., Beuers, U., Urban, S. and van de Graaf, S.F., 2017. Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Scientific Reports7(1), p.15307.

 

Uhl, P., Helm, F., Hofhaus, G., Brings, S., Kaufman, C., Leotta, K., Urban, S., Haberkorn, U., Mier, W. and Fricker, G., 2016. A liposomal formulation for the oral application of the investigational hepatitis B drug Myrcludex B. European Journal of Pharmaceutics and Biopharmaceutics103, pp.159-166.

 

Kremsdorf, D. and Strick-Marchand, H., 2017. Modeling hepatitis virus infections and treatment strategies in humanized mice. Current opinion in virology25, pp.119-125.

 

Giersch, K., Bhadra, O.D., Volz, T., Allweiss, L., Riecken, K., Fehse, B., Lohse, A.W., Petersen, J., Sureau, C., Urban, S. and Dandri, M., 2017. Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo. Gut, pp.gutjnl-2017.

 

Appelman, M.D., Chakraborty, A., Protzer, U., McKeating, J.A. and van de Graaf, S.F., 2017. N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) Determines Its Trafficking and Stability and Is Required for Hepatitis B Virus Infection. PloS one12(1), p.e0170419.

 

Donkers, J., Zehnder, B., van Westen, G., IJzerman, A., Kwakkenbos, M., Urban, S., Elferink, R.O. and van de Graaf, S., 2017. SAT-174-Reduced hepatitis B and D viral entry using novel clinically-applied inhibitors of the sodium taurocholate co-transporting polypeptide. Journal of Hepatology66(1), pp.S696-S697.

 

Slijepcevic, D., Roscam Abbing, R.L., Katafuchi, T., Blank, A., Donkers, J.M., van Hoppe, S., de Waart, D., Tolenaars, D., van der Meer, J.H., Wildenberg, M. and Beuers, U., 2017. Hepatic uptake of conjugated bile acids is mediated by both NTCP and OATPs and modulated by intestinal sensing of plasma bile acid levels in mice. Hepatology.