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Frontiers in Microbiology www frontiersin org 1 June 2019 Volume 10 Article 1327 REVIEW published 19 June 2019 doi 10 3389 fmicb 2019 01327 Edited by Daniel Roberto Perez University of Georgia United States Reviewed by Luis Martinez Sobrido University of Rochester United States Hana Maria Dobrovolny Texas Christian University United States Correspondence Victor H Leyva Grado victor leyva grado mssm edu Specialty section This article was submitted to Virology a section of the journal Frontiers in Microbiology Received 04 March 2019 Accepted 28 May 2019 Published 19 June 2019 Citation Behzadi MA and Leyva Grado VH 2019 Overview of Current Therapeutics and Novel Candidates Against Influenza Respiratory Syncytial Virus and Middle East Respiratory Syndrome Coronavirus Infections Front Microbiol 10 1327 doi 10 3389 fmicb 2019 01327 Overview of Current Therapeutics and Novel Candidates Against Influenza Respiratory Syncytial Virus and Middle East Respiratory Syndrome Coronavirus Infections Mohammad Amin Behzadi and Victor H Leyva Grado Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY United States Emergence and re emergence of respiratory virus infections represent a significant threat to global public health as they occur seasonally and less frequently such as in the case of influenza virus as pandemic infections Some of these viruses have been in the human population for centuries and others had recently emerged as a public health problem Influenza viruses have been affecting the human population for a long time now however their ability to rapidly evolve through antigenic drift and antigenic shift causes the emergence of new strains A recent example of these events is the avian origin H7N9 influenza virus outbreak currently undergoing in China Human H7N9 influenza viruses are resistant to amantadines and some strains are also resistant to neuraminidase inhibitors greatly limiting the options for treatment Respiratory syncytial virus RSV may cause a lower respiratory tract infection characterized by bronchiolitis and pneumonia mainly in children and the elderly Infection with RSV can cause severe disease and even death imposing a severe burden for pediatric and geriatric health systems worldwide Treatment for RSV is mainly supportive since the only approved therapy a monoclonal antibody is recommended for prophylactic use in high risk patients The Middle East respiratory syndrome coronavirus MERS CoV is a newly emerging respiratory virus The virus was first recognized in 2012 and it is associated with a lower respiratory tract disease that is more severe in patients with comorbidities No licensed vaccines or antivirals have been yet approved for the treatment of MERS CoV in humans It is clear that the discovery and development of novel antivirals that can be used alone or in combination with existing therapies to treat these important respiratory viral infections are critical In this review we will describe some of the novel therapeutics currently under development for the treatment of these infections Keywords antiviral influenza respiratory syncytial virus MERS coronavirus novel therapeutic agents INTRODUCTION Respiratory viral infections are of global public health concern because they are the most common cause of symptomatic disease leading to a heavy economic burden due to an increased number of sick days Borchardt and Rolston 2012 Kim et al 2017 In addition respiratory diseases are one of the most common causes of mortality in developing countries Ferkol and Schraufnagel 2014 Behzadi and Leyva Grado Novel Therapeutics for Respiratory Virus Infections Frontiers in Microbiology www frontiersin org 2 June 2019 Volume 10 Article 1327 Among the two leading causes of respiratory virus infection are influenza A and B viruses and the respiratory syncytial virus RSV Amarelle et al 2017 Heylen et al 2017 Yip et al 2018 Most cases are observed in infants and children although the elderly and the immunocompromised are also at high risk of getting infected and develop severe disease Jorquera and Tripp 2017 While influenza viruses and RSV circulate seasonally between beginning of fall and early spring the increased numbers of avian influenza H7N9 in China including highly pathogenic HP strains of the virus the continued outbreaks of the HP avian influenza HPAI H5N1 viruses novel variants of seasonal influenza viruses H3N2var and the emergence of the Middle East respiratory syndrome coronavirus MERS CoV highlight the serious and important need for developing novel more effective antiviral therapies Zumla et al 2016 International Society for Influenza and other Respiratory Viral Diseases 2018 This review article focuses on therapies currently under development for treatment of influenza RSV and MERS CoV infections We will briefly review drugs that have been approved by the United States Federal Drug Administration FDA and then drugs that are in clinical trials Figure 1 When available the clinical trial identifier is included INFLUENZA VIRUS Influenza virus is a negative sense segmented RNA virus that presents a substantial burden to human health Despite the availability of successful vaccines and antivirals infection with seasonal influenza viruses is still the cause of 3 5 million cases of severe illnesses and up to 300 650 thousand deaths worldwide World Health Organization 2017 In the US alone it is estimated that seasonal influenza affects up to 9 million people a year resulting in 12 000 56 000 deaths annually Centers for Disease Control and Prevention 2018c The economic burden is estimated to be in the tens of billions of dollars Putri et al 2018 In addition pandemic influenza outbreaks emerge at unpredictable intervals causing increased morbidity mortality and a negative economic impact Erbelding et al 2018 Currently Federal Drug Administration Approved Anti influenza Antivirals Briefly these drugs can be divided in three groups the M2 ion channel blockers the neuraminidase inhibitors NAIs and the virus polymerase inhibitors Amantadine and rimantadine are adamantane derivatives that inhibit viral replication by blocking the proton conductivity of the M2 ion channel preventing delivery of the virus ribonucleoprotein in the cytoplasm Schnell and Chou 2008 Ison 2017 These compounds are specific for influenza A viruses since the M2 protein of influenza B viruses is structurally different Wang et al 2009 Pielak and Chou 2011 In recent past seasons surveillance studies reported high levels of resistance 99 to adamantanes among circulating influenza A H3N2 and influenza A H1N1 pdm09 viruses and the centers for disease A B C FIGURE 1 Mechanisms of action of different antivirals A diagram of the virus life cycle of A influenza virus B respiratory syncytial virus and C Middle East respiratory syndrome coronavirus indicating where each therapeutic exerts its antiviral activity Drugs approved by the FDA are shown in bold Behzadi and Leyva Grado Novel Therapeutics for Respiratory Virus Infections Frontiers in Microbiology www frontiersin org 3 June 2019 Volume 10 Article 1327 control and prevention CDC does not recommend these compounds for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses Centers for Disease Control and Prevention 2018a Development of NAI started in the early 1970s with derivatives of 2 deoxy 2 3 dehydro N acetylneuraminic acid Palese et al 1970 although it was not until 1999 that the first NAI was approved for use in humans Chaudhuri et al 2018 The NAI binds to the neuraminidase of the virus and prevents its cleavage thus inhibiting the release of new virus particles Ison 2017 NAIs currently approved by the FDA include oseltamivir zanamivir and peramivir Oseltamivir acid is a pro drug indicated for oral administration Once in the gastrointestinal tract the pro dug is rapidly cleaved to the active metabolite oseltamivir carboxylate Kim et al 2017 Due to poor oral bioavailability zanamivir is approved for inhalation delivery with intravenous administration only available by compassionate use Ison 2017 Shaw 2017 Peramivir also has poor oral bioavailability therefore it has been approved for intravenous administration only Because the drug reaches high concentrations in plasma and respiratory tissues it has been approved as a single dose infusion One of the inherit problems of these drugs is that in order to be effective treatment should start within 48 h post exposure Antiviral resistance to oseltamivir zanamivir and peramivir is very low in currently circulating influenza virus strains although this can change because several clusters of oseltamivir resistance have been detected in Japan Australia and China Takashita et al 2015 Alame et al 2016 Koszalka et al 2017 Also known as S 033188 baloxavir marboxil Xofluza is a pro drug that is hydrolyzed in vivo to S 033447 the active form that selectively inhibits cap dependent endonuclease preventing the initiation of mRNA synthesis of the influenza virus Takashita et al 2018 This is a potent small molecule that shows activity against several influenza A viruses including oseltamivir resistant viruses as well as B viruses Noshi et al 2018 Preclinical studies demonstrated that treated mice infected with influenza virus were protected from clinical signs and mortality even in a delay of treatment approach treatment started 4 days post infection Furthermore a subtherapeutic dose of baloxavir in combination with oseltamivir also protected mice from infection and mortality Fukao et al 2018 In addition studies in mice infected with avian influenza viruses such as H5N1 or H7N9 also demonstrated protection after oral administration with baloxavir Uehara et al 2016 A clinical study NCT02954354 aimed to compare the efficacy of baloxavir with a placebo or oseltamivir in healthy patients infected with influenza demonstrated that the drug was well tolerated and was associated with a significant reduction in viral load compared to the oseltamivir group Time of alleviation of symptoms was similar to oseltamivir The currently undergoing clinical program for this drug includes phase 3 clinical trials to determine safety pharmacokinetics and efficacy in healthy pediatric participants aged less than 1 year NCT03653364 or in pediatric patients with influenza like symptoms NCT03629184 and a study to assess efficacy and safety of baloxavir in combination with standard of care neuraminidase inhibitor in hospitalized participants with severe influenza NCT03684044 These studies are currently recruiting and expected to be concluded in spring 2020 In Japan baloxavir has been approved for the treatment of adult and infant patients infected with influenza while in the US the drug has just been approved by the FDA for the treatment of acute uncomplicated influenza in people aged 12 years and older Food and Drug Administration 2018 The emergence of resistant variants to polymerase inhibitors has been observed and it is conferred by an I38T mutation in the PA polymerase Jones et al 2018 In the same study a novel mutation conferring resistance E23K was also observed Both mutations have been encountered during clinical trials for baloxavir Hayden et al 2018 Promising Drug Candidates in the Pipeline Given the inherit limitations of these currently approved compounds and the potential risk for the arising of antiviral resistance there is still an urgent need for developing new anti influenza drugs These novel drugs should have some ideally all of the following characteristics effective when delivered late in infection low propensity for developing antiviral resistance broad activity influenza A and B improved effectiveness compared to the standard of care and can be easily administered in uncomplicated as well as complicated cases of influenza Koszalka et al 2017 Shaw 2017 Next we will summarize the most advanced phase 2 and 3 clinical trials promising drug candidates VIRAL TARGETING CANDIDATES Antibodies New and more efficient technologies for the production of monoclonal antibodies mAbs have stimulated the development of novel mAbs based therapies for influenza and other infectious diseases Jin et al 2017 A number of broadly neutralizing mAbs targeting the conserved stalk region of the influenza virus hemagglutinin HA molecule are currently under development In addition a non neutralizing mAb targeting the virus matrix protein is also in clinical trials CR6261 and CR8020 CR6261 is directed against a highly conserved helical region in the membrane proximal stalk of hemagglutinin In vitro studies on this class of mAbs demonstrated neutralization activity across a broad spectrum of influenza A subtypes CR6261 is protective in mice against lethal doses of H1N1 and H5N1 viruses Koudstaal et al 2009 A challenge study successfully demonstrated both therapeutic and prophylactic efficacy in the ferret model against a lethal dose of an H5N1 virus Friesen et al 2010 A clinical trial phase 2 NCT02371668 aimed to determine if the CR6261 reduces flu disease in people treated with this drug versus a placebo has concluded but results are still not available CR8020 targets an immunosubdominant relatively conserved membrane proximal stalk region of hemagglutinin The mAb is active against group 2 Behzadi and Leyva Grado Novel Therapeutics for Respiratory Virus Infections Frontiers in Microbiology www frontiersin org 4 June 2019 Volume 10 Article 1327 influenza viruses and has been shown to have neutralization activity against H3 H7 and H10 subtypes both in vitro and in vivo Ekiert et al 2011 A phase 2a trial to evaluate the protective efficacy and safety of CR8020 in an influenza challenge model was completed in 2014 NCT01938352 Unfortunately a recent study showed that CR8020 targets a region of the HA stalk that is prone to escape therefore escape mutants are likely to arise Tharakaraman et al 2014 CT P27 This product contains two distinct but complementary mAbs that have shown broad efficacy in vitro and in vivo against different group 1 and group 2 influenza viruses A phase 2a clinical trial NCT02071914 was conducted to evaluate the efficacy and safety of CT P27 in an influenza challenge model The study concluded in July 2014 however no results were reported Currently recruiting a phase 2b clinical trial NCT03511066 is aimed to evaluate the efficacy and safety of the mAbs combo in comparison to placebo in subjects with acute uncomplicated influenza A infection MEDI8852 This is a potent broadly neutralizing investigational human IgG1 mAb targeting a highly conserved stalk region of the HA protein MEDI8852 has been reported to effectively neutralize all known influenza A HA subtypes Kallewaard et al 2016 Preclinical studies in animal models have shown efficacy in protecting against H5N1 influenza virus lethal challenges when used alone or in combination with oseltamivir Paules et al 2017 A phase 2a study NCT02603952 to evaluate the safety of MEDI8852 in adults with acute uncomplicated influenza was recently concluded and results demonstrated an acceptable safety profile in this group of patients In 2016 MEDI8852 received Fast Track designation by the FDA that allows the drug an expedite development and review Ali et al 2018 MHAA4549A This is a human monoclonal IgG1 antibody containing a VH 3 30 59 heavy chain paired with a V 1 15 light chain McBride et al 2017 MHAA4549A targets a highly conserved epitope on the stalk region of HA and is capable of neutralizing all tested seasonal human influenza A strains Nakamura et al 2013 Two mechanisms of action have been described for this mAb one by binding the HA to avid virus infectivity and two by antibody dependent cell mediated cytotoxicity to increase killing of infected cells McBride et al 2017 Preclinical studies demonstrated efficacy in the mouse model against a diverse group of influenza viruses including group 1 and group 2 strains even when administered 72 h post infection In addition synergism was observed when administered with oseltamivir at 48 h post infection Finally studies in ferrets demonstrated protection against an H5N1 HPAI virus challenge Nakamura et al 2013 A few clinical trials have been conducted to evaluate safety pharmacokinetics and efficacy of MHAA4549A alone or in combination with oseltamivir Lim et al 2016 McBride et al 2017 Deng et al 2018 Results established that the mAb is well tolerated with a half life similar to other human antibodies 23 days but with a nonlinear nasal pharmacokinetics McBride et al 2017 Deng et al 2018 Furthermore treatment significantly reduced viral loads McBride et al 2017 The most recent clinical trial NCT02293863 aimed to investigate the safety and clinical activity of a single intravenous IV dose of MHAA4549A in adult participants hospitalized with severe influenza A in combination with oseltamivir was recently concluded and results indicated no advantage on any of the primary clinical outcomes evaluated when compared with the standard of care Furthermore no significant differences were observed in any of the virologic outcomes evaluated including viral shedding or peak of virus load Virus Polymerase Inhibitors Pimodivir This is a novel non nucleoside polymerase inhibitor that targets the PB2 subunit of influenza A viruses Targeting the PB2 avoids docking of the 7 methyl GTP cap structure thus preventing viral RNA synthesis Clark et al 2014 Boyd et al 2015 The early activity of pimovidir in the cell cycle has shown to improve cell viability compared to oseltamivir Byrn et al 2015 Furthermore it is active against a diverse group of influenza A viruses including the H1N1pdm H5N1 and H7N9 Byrn et al 2015 Preclinical studies in mice demonstrated protection against a lethal challenge even when given 4 days post infection with H1N1pdm or H5N1 viruses Byrn et al 2015 Further studies also showed protection against a lethal challenge using an H3N2 virus Smee et al 2016 Studies using pimodivir and oseltamivir suggest a potential benefit for a combination therapy Trevejo et al 2018 A phase 2b clinical study NCT02342249 treatment with pimodivir significantly decreased viral load over 7 days versus placebo in adult patients with acute uncomplicated seasonal influenza A Recently pimodivir has received FDA Fast Track designation due to its potential to address an unmet medical need in those who develop influenza A infection complications A phase 3 clinical trial NCT03381196 aimed to evaluate the efficacy and safety of pimodivir in combination with oseltamivir in adults at risk of developing complications is currently recruiting patients and it is expected to be concluded in October 2019 Favipiravir Formerly known as T 705 this substituted pyrazinecarboxamide derivative is an inhibitor of the influenza virus polymerase As a purine nucleoside analog favipiravir directly inhibits the activity of the RNA dependent RNA polymerase Furuta et al 2005 and it has broad spectrum activity against all influenza subtypes including those resistant to neuraminidase and M2 inhibitors Furuta et al 2017 Preclinical studies demonstrated the broad antiviral spectrum of this compound against different human and avian influenza A and B viruses including avian influenza viruses H5N1 and H7N9 Sidwell et al 2007 Watanabe et al 2013 where it has shown protection and reduction of virus titers in the infected mice Furthermore mice treated with favipiravir had a better outcome Behzadi and Leyva Grado Novel Therapeutics for Respiratory Virus Infections Frontiers in Microbiology www frontiersin org 5 June 2019 Volume 10 Article 1327 after an H7N9 infection compared to mice treated with neuraminidase inhibitors Watanabe et al 2013 Combination therapy studies found that this drug works synergistically with neuraminidase inhibitors to improve lung virus titers body weight loss and survival in mice infected with a pandemic H1N1 influenza virus Tarbet et al 2012 or with an avian influenza virus H5N1 Smee et al