piperidines and Hepatitis-D

Topics: Antiviral Agents; Drug Therapy, Combination; Europe; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis D; Humans; Interferon-alpha; Lipopeptides; Piperidines; Pyridines; Treatment Outcome; Viral Load; Virus Replication

Lonafarnib (Zokinvy™) is an orally active farnesyltransferase inhibitor developed by Eiger BioPharmaceuticals under license from Merck & Co. for the treatment of hepatitis D virus (HDV) infections, and progeria and progeroid laminopathies. The drug was originally discovered by Merck & Co as an investigational drug in oncology. In progeria, lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the nucleus and cellular cytoskeleton. In November 2020, lonafarnib received its first approval in the USA to reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) and for the treatment of processing-deficient progeroid laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation, or homozygous or compound heterozygous ZMPSTE24 mutations) in patients ≥ 12 months of age with a body surface area (BSA) of ≥ 0.39 m

Topics: Antiviral Agents; Enzyme Inhibitors; Farnesyltranstransferase; Hepatitis D; Humans; Piperidines; Progeria; Pyridines

Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection.

Topics: Antiviral Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coinfection; Drug-Related Side Effects and Adverse Reactions; Hepatitis B, Chronic; Hepatitis D; Hepatitis Delta Virus; Humans; Interferon-alpha; Lipopeptides; Nucleic Acids; Piperidines; Polymers; Pyridines; Recurrence; Treatment Outcome

Current treatment of chronic hepatitis D viral infection with interferons is poorly tolerated and effective only in a minority of patients. Despite delta virus causing the most severe form of chronic viral hepatitis, no other treatments are available. After many years of inactivity, there is now hope for new treatment approaches for delta virus and some are likely to enter clinical practice in the near future. Four new treatment approaches are currently being evaluated in phase 2 studies. These involve the hepatocyte entry inhibitor myrcludex B, the farnesyl transferase inhibitor lonafarnib, the nucleic acid inhibitor REP 2139 Ca and pegylated interferon lambda. Results obtained so far are promising, and phase 3 studies are expected shortly. This review summarizes the available data on the efficacy and safety of these new drugs.

Topics: Antiviral Agents; Clinical Trials as Topic; Hepatitis D; Hepatitis Delta Virus; Humans; Interferon-alpha; Interleukins; Lipopeptides; Nucleic Acids; Piperidines; Polyethylene Glycols; Polymers; Pyridines

Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis and is associated with a higher risk of cirrhosis, liver decompensation and liver cancer. Interferon alpha is the only agent that has demonstrated efficacy to date, although response rates are low and it is associated with significant side effects. A better understanding of the relevant molecular virology has resulted in the identification of new candidate targets. Future therapeutic options are rapidly evolving as several new agents have entered clinical development, including the entry inhibitor myrcludex-B, the nucleic acid polymer REP2139-Ca inhibiting HBV surface antigen secretion, the farnesyltransferase inhibitor lonafarnib that targets virus assembly, and a better tolerated interferon-interferon lambda.

Topics: Animals; Antiviral Agents; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Interferon-alpha; Lipopeptides; Liver Cirrhosis; Liver Neoplasms; Mice; Piperidines; Pyridines

Topics: Adult; Chronic Disease; Female; Fibrosis; Global Burden of Disease; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Incidence; Interferon-alpha; Lipopeptides; Liver Diseases; Male; Middle Aged; Piperidines; Prevalence; Pyridines; Risk Factors; Superinfection; Uzbekistan

Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and natural killer cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small-animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis and immune responses and for testing novel HDV therapeutics.

Topics: Adaptive Immunity; Animals; Disease Models, Animal; Drug Therapy, Combination; Genome, Viral; Glycoproteins; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Hepatocytes; Humans; Immunity, Innate; Immunocompetence; Lipopeptides; Mice, Inbred C57BL; Mice, Transgenic; Organic Anion Transporters, Sodium-Dependent; Piperidines; Pyridines; Symporters; Transgenes; Viremia