Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics

Journal of Infectious Diseases, Feb 2015

Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence.

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Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics

JID Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics Eric A. F. Simes John P. DeVincenzo Michael Boeckh Louis Bont James E. Crowe Jr Paul Griffiths Frederick G. Hayden Richard L. Hodinka Rosalind L. Smyth Keith Spencer Steffen Thirstrup Edward E. Walsh Richard J. Whitley Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence. - respiratory syncytial virus; therapeutic strategies; patient populations. Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory tract infection (LRTI) in infants and young children worldwide and can cause LRTI in elderly and immunocompromised patients; it is associated with significant morbidity and mortality in these target populations. No effective licensed therapies are generally available, but existing and emerging pointof-care diagnostics and investigational RSV-specific antiviral inhibitors offer promise of progress. In industrialized countries, RSV receives little publicity and is not widely recognized by the general public. There is a common, mistaken belief among drug developers that RSV is a disease primarily of preterm infants and that the disease is fundamentally different in term infants and older children. Furthermore, the adult market is assumed to be small. This underlines 2 of the fundamental obstacles that have constrained antiviral product development: perception of disease severity and clinical end points. This report summarizes outputs from 2 meetings addressing the challenges in developing RSV therapeutics. BURDEN OF RSV INFECTION Infants and Young Children By the age of 1 year, 60%70% of children have been infected by RSV (2%3% of whom are hospitalized) [1], and almost all children are infected by 2 years [2]. RSV is estimated to cause 33.8 million cases of acute respiratory illness in children <5 years of age globally, resulting in 2.84.3 million hospital admissions and 66 000199 000 deaths in 2005 [3]. Most infected infants experience upper respiratory tract symptoms, but 20%30% will develop LRTI (bronchiolitis and/or pneumonia). Bronchiolitis, also known as RSV-associated acute LRTI, is frequently associated with coinfection with other viral agents, particularly human rhinovirus infections [48]. Signs and symptoms of disease include tachypnea, cough, crackles, and wheezing. Frequently, disease is associated with lethargy, irritability, and poor feeding. Comorbid factors, which increase the risk of severe LRTI, include prematurity, cyanotic or complicated congenital heart disease, chronic lung disease of prematurity, immunodeficiency, and immunosuppressive therapy (at any age for the last 2). Some children, including those otherwise healthy, are at risk for disease progression to respiratory failure, mechanical ventilation, and intensive care unit management. The incubation period ranges from 2 to 8 days, but 46 days is most common. Because 99% of the deaths reported from RSV in 2005 [3] occurred in developing countries, reducing the burden of RSV infections has become a priority of the World Health Organizations new BRaVe (Battle Against Respiratory Viruses) initiative [9]. Ongoing population-based surveillance studies in several emerging countries will provide a platform to more accurately define the global burden of disease in children. Such data are beginning to emerge from Kenya and Malaysia, where lifethreatening disease seems more common than in Europe and North America [10, 11]. Most infections occur between November and April in northern temperate locations [12]. In the United States, RSV is associated with 18% of all respiratory illnesses in children <5 years, 20% of all hospitalizatio (...truncated)


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Eric A. F. Simões, John P. DeVincenzo, Michael Boeckh, Louis Bont, James E. Crowe Jr, Paul Griffiths, Frederick G. Hayden, Richard L. Hodinka, Rosalind L. Smyth, Keith Spencer, Steffen Thirstrup, Edward E. Walsh, Richard J. Whitley. Challenges and Opportunities in Developing Respiratory Syncytial Virus Therapeutics, Journal of Infectious Diseases, 2015, pp. S1-S20, 211/suppl 1, DOI: 10.1093/infdis/jiu828