molnupiravir and Influenza--Human

Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.

Topics: Amides; Antibodies, Neutralizing; Antiviral Agents; Cytidine; Dibenzothiepins; Drug Resistance, Viral; Humans; Hydroxylamines; Influenza, Human; Morpholines; Neuraminidase; Oxazines; Pyrazines; Pyridines; Pyridones; Ribonucleosides; RNA-Dependent RNA Polymerase; Thiepins; Triazines; Virus Replication

Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Birds; Clinical Trials as Topic; Coronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytidine; Drug Development; Drug Industry; Europe; Humans; Hydroxylamines; Indoles; Influenza, Human; Leucine; Orthomyxoviridae; Pandemics; Pyrrolidinones; Severe Acute Respiratory Syndrome; Strategic Stockpile; United States

Topics: Animals; Antiviral Agents; Cytidine; Disease Models, Animal; Drug Resistance, Viral; Humans; Hydroxylamines; Influenza, Human; Macaca; Ribonucleosides

Seasonal influenza viruses cause major morbidity and mortality worldwide, threatening in particular older adults and the immunocompromised. Two classes of influenza therapeutics dominate current disease management, but both are compromised by pre-existing or rapidly emerging viral resistance. We have recently reported a novel ribonucleoside analog clinical candidate, EIDD-2801, that combines potent antiviral efficacy in ferrets and human airway epithelium cultures with a high barrier against viral escape. In this study, we established fundamental EIDD-2801 efficacy paradigms against pandemic and seasonal influenza A virus (IAV) strains in ferrets that can be used to inform exposure targets and treatment regimens. Based on reduction of shed virus titers, alleviation of clinical signs, and lowered virus burden in upper and lower respiratory tract tissues, lowest efficacious oral dose concentrations of EIDD-2801, given twice daily, were 2.3 and 7 mg/kg of body weight against seasonal and pandemic IAVs, respectively. The latest opportunity for initiation of efficacious treatment was 36 hours after infection of ferrets. Administered in 12-hour intervals, three 7 mg/kg doses of EIDD-2801 were sufficient for maximal therapeutic benefit against a pandemic IAV and significantly shortened the time to resolution of clinical signs. Ferrets infected with pandemic IAV and treated following the minimally efficacious EIDD-2801 regimen demonstrated significantly less shed virus and inflammatory cellular infiltrates in nasal lavages, but mounted a robust humoral antiviral response after recovery that was indistinguishable from that of vehicle-treated animals. These results provide an experimental basis in a human disease-relevant influenza animal model for clinical testing of EIDD-2801.

Topics: Animals; Antiviral Agents; Cytidine; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Resistance, Viral; Ferrets; HEK293 Cells; Humans; Hydroxylamines; Influenza A virus; Influenza, Human; Madin Darby Canine Kidney Cells; Mutation; Ribonucleosides