Antiviral Research 167 (2019) 45–67 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference T ∗ John H. Beigela, , Hannah H. Namb, Peter L. Adamsc, Amy Kraffta, William L. Inced, Samer S. El-Kamaryd, Amy C. Simse a National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA bNorthwestern University, Feinberg School of Medicine, Chicago, IL, USA c Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA d Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S Food and Drug Administration, Silver Spring, MD, USA e Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA ARTICLE INFO ABSTRACT Keywords: The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv- Influenza AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on Respiratory syncytial virus therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including Coronavirus MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several Antiviral therapy influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, Host-directed therapeutics pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies in- cluding nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting. 1. Background promoting the prevention, detection, treatment, and control of influ- enza and other respiratory virus diseases. The Antiviral Group is a Influenza and other acute respiratory viral diseases are of major special interest group of isirv (isirv-AVG) with specific objectives to global public health importance. Lower respiratory tract infections have promote the understanding and development of antivirals against re- been estimated to cause over 4 million deaths a year (range 3.6–4.4 spiratory viruses, and to collate and provide up to date information on million), of which approximately 40% are caused by respiratory viruses the emergence of antiviral resistance to the established therapeutics. It (Global Burden of Disease Collaborators, 2018). The emergence of high also aims to provide information on the evaluation of resistance to new morbidity viruses such as severe acute respiratory syndrome cor- therapies under development. To communicate advances in preclinical onavirus (SARS-CoV) in 2004, influenza A(H5N1) in 2005, Middle East and clinical development of potent novel antivirals five previous con- respiratory syndrome corona virus (MERS-CoV) in 2012, and influenza ferences have been organized by the isirv-AVG. A(H7N9) in 2013, as well as discovery of novel viral pathogens such as The isirv-AVG held its 6th Conference in Rockville, MD, from 13–15 human metapneumovirus in 2001 and human bocavirus in 2005 have November 2018. The three-day program was focused on therapeutics highlighted the importance of international collaboration on re- towards influenza, respiratory syncytial virus, (RSV) and other re- spiratory virus research for their prevention and control. The Interna- spiratory viruses. Topics included ongoing and recently completed tional Society for Influenza and other Respiratory Viruses Diseases clinical trials, new pre-clinical developments in therapeutics and vac- (isirv) is an independent international scientific professional society cines, regulatory considerations, and study design issues. The aim of ∗ Corresponding author. National Institute of Allergy and Infectious Diseases (NIAID), 5601 Fishers Lane, Room 7E60, MSC 9826, Rockville, MD, 20892-9826, USA. E-mail address: [email protected] (J.H. Beigel). https://doi.org/10.1016/j.antiviral.2019.04.006 Received 29 March 2019; Accepted 6 April 2019 Available online 08 April 2019 0166-3542/ Published by Elsevier B.V. J.H. Beigel, et al. Antiviral Research 167 (2019) 45–67 this conference report is to summarize the presentations given at this gram-negative bacteria endotoxin, lipopolysaccharide (LPS). TLR4 has meeting. been implicated in the pathology associated with other infections as well as tissue damage caused by non-infectious insults. The TLR4 sig- 2. Opening lecture - perspectives on advancing respiratory virus naling pathway is activated by LPS binding initially to CD14, which therapeutics transfers the LPS to a non-covalently associated TLR4 co-receptor, MD2. LPS binding to MD2 leads to TLR4 dimerization and activation. The Robert Johnson, BARDA, Washington, DC, USA. Vogel laboratory previously showed that TLR4-null mice were highly The Biomedical Advanced Research and Development Authority resistant to infection by the mouse-adapted influenza A/PR/8/ (BARDA) partners and invests in a diverse portfolio of researchers and 34(H1N1) [PR8] strain (Shirey et al., 2013), providing the rationale companies, fostering innovation and bolstering America's preparedness that blocking TLR4 signaling might be protective against influenza in- against bioterrorism threats. These partnerships have resulted in 42 fection. Eritoran, a structural analog of LPS, functions as a TLR4 an- U.S. Food & Drug Administration (FDA) approvals, licenses or clear- tagonist by binding to MD2, thereby preventing the interaction of LPS ances for 38 unique products. BARDA plans to advance respiratory virus with MD2. Eritoran was demonstrated to have therapeutic benefit in the therapeutics by focusing on three topics: improving diagnostic testing, context of protection against acute lung injury in experimental murine pursuing host-directed therapeutics, and improving the identification and cotton rat models of influenza infection. Administration of eritoran and treatment of sepsis. once daily for 5 consecutive days to wild-type mice starting 2 days after For any outbreak, the faster the identification, the faster and more PR8 infection resulted in highly significant protection against lethality robust the response. BARDA is supporting work to improve diagnostics and improved lung pathology. Moreover, a significant degree of sur- with the goal of recognizing illness before any symptoms develop. This vival was observed even when eritoran was administered to PR8-in- may include wearable diagnostics or biosensors. The high mortality fected mice starting as late as day 6 post-infection. Protection against associated with human infections with novel coronaviruses MERS-CoV influenza infection was confirmed using other TLR4 antagonists in- and SARS-CoV and avian influenza strains (influenza A(H5N1) and cluding an anti-TLR4-specific antibody, TLR4 cell-permeable decoy A(H7N9)) have raised questions about the possible role of a dysregu- peptides, a structural analog antagonist (FP7), and the small molecule lated immune response, a so called “cytokine storm”, in the patho- TLR4 antagonist, TAK242 (Perrin-Cocon et al., 2017; Piao et al., 2015). genesis of severe respiratory disease. As some patients may not respond Eritoran was also protective in cotton rats (Sigmodon hispidus) infected to typical anti-pathogen therapeutics (e.g. antivirals), BARDA is pur- with non-adapted human influenza A and B strains. suing therapeutics which target the host in order to modify the im- Since influenza is not known to express any TLR4 PAMPs, it was mune/host response. More work needs to be done to identify these host hypothesized that TLR4-activating damage-associated molecular pat- targets and develop therapeutics towards the dysregulated immune terns (DAMPs) were elicited during infection (Patel et al., 2018). In- response. The field also needs better diagnostics to guide treatment as fection of mice or cotton rats with influenza causes the release of over-suppression of the immune response can be just as dangerous as HMGB1, a host-derived protein that has been shown to be a TLR4 over-stimulation. agonist and is released from dying cells. The administration of eritoran Sepsis is one of the most urgent and costly systemic health threats blocks release of HMGB1 and blunts influenza-induced cytokine in- and is a common pathway for mortality associated with novel patho- duction which, in turn, results in improved lung function, reversal of gens. The current approach is to develop better diagnostics to identify edema, and reduced viral titer. Moreover, administration of an HMGB1 and treat sepsis early, and understand the immune profile (activation small molecule antagonist provides the same degree of protection to versus suppression) in this disease. BARDA's Division of Research, PR8-infected mice as eritoran. Innovation, and Ventures (DRIVe) is establishing unique public-private The development