Expanding the Armamentarium Against Respiratory Viral Infections: DAS181

Abstract

Respiratory viral infections result in significant morbidity and mortality in adults and children globally. Influenza, alone, is responsible for seasonal epidemics resulting in 3–5 million severe infections and 250 000–500 00 deaths per year [1]. Additionally, influenza results in milder infections which significantly reduce productivity among otherwise healthy adults, resulting in approximately $26.7 billion in direct and indirect costs annually [2]. During the recent influenza A(H1N1) pandemic, influenza was associated with a significant increase in hospitalizations, particularly among individuals <65 years of age and those without co-morbidities, as compared with what is seen in interpandemic years [3]. Furthermore, the pandemic was associated with 284 400 (range, 151 700–575 400) excess deaths [4]. Data from randomized, placebo-controlled studies have documented that antiviral therapy with neuraminidase inhibitors (oseltamivir and zanamivir) and M2 inhibitors (amantadine and rimantadine) reduce the duration of illness attributable to influenza, speed clearance of virus from the host, and reduce infectious and noninfectious complications among otherwise healthy ambulatory adults and children [5, 6]. Furthermore, data from several retrospective studies prior to and during the pandemic consistently demonstrated that antiviral therapy, typically with oral oseltamivir, for adults hospitalized with influenza is associated with more rapid improvement in clinical symptoms, return to usual activity, clearance of viral shedding, and reduction in overall mortality; some studies have also shown a shorter duration of hospitalization and reduced progression to pneumonia and critical illness [7]. Unfortunately, development of antiviral resistance has significantly limited our options in the treatment of influenza. Early after the introduction of M2 inhibitors to clinical practice, emergence of resistance during therapy, as the result of mutations in 1 of 5 commonly recognized sites in the M2 gene, occurred frequently. More recently, M2 resistant variants of influenza A(H3N2) emerged and became established within the viruses circulating globally; in addition, the pandemic influenza A(H1N1) virus, which replaced the seasonal influenza A(H1N1) virus worldwide, is resistant to M2 inhibitors [8]. As a result, most guidelines now recommend against the use of M2 inhibitors for the prevention and treatment of influenza [9]. Resistance to the neuraminidase inhibitors may occur as the result of mutations in the neuraminidase gene, the hemagglutinin gene, or both [10]. Group 1 neuraminidases appear to be more susceptible to the development of oseltamivir resistance, as was seen with the global emergence of oseltamivir resistance in the previous seasonal influenza A(H1N1) virus in 2008–2009 [10]. Given our current reliance on neuraminidases for the management of influenza, oseltamivir resistance emerging globally in the background of M2 inhibitor resistance would greatly limit our options for treatment of influenza. As such, antiviral agents with novel mechanisms of action are clearly needed. DAS181 is a novel antiviral that consists of a sialidase from Actinomyces viscosus attached to a respiratory epitheliumanchoring domain that is critical for enhancing the efficacy and prolonging retention within the respiratory tract [11]. The drug cleaves the terminal sialic acid residues from the surface of human respiratory epithelial cells, thereby reducing the binding and, therefore, infectivity of influenza A and B viruses as well as parainfluenza viruses (PIV) [11]. Desialyation occurs rapidly and results in an inhibitory effect that lasts, ex vivo, for at least 2 days [11]. In addition, DAS181 appears to be potent against seasonal influenza A and B viruses, the 2009 pandemic influenza A(H1N1) virus, avian influenza A(H5N1) virus, and PIV types Received 27 August 2012; accepted 31 August 2012; electronically published 8 October 2012. Correspondence: Michael G. Ison, MD, MS, FIDSA, Divisions of Infectious Diseases, 645 N. Michigan Avenue Suite 900, Chicago, Illinois 60611, United States (mgison@ northwestern.edu). The Journal of Infectious Diseases 2012;206:1806–8 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jis623