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The Next Wave of Influenza Drugs Megan L. Shaw* Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, United States ABSTRACT: Options for influenza therapy are currently limited to one class of drug, the neuraminidase inhibitors. Amidst concerns about drug resistance, much effort has been placed on the discovery of new drugs with distinct targets and mechanisms of action, with great success. There are now several candidates in late stage development which include small molecules targeting the three subunits of the viral polymerase complex and monoclonal antibodies targeting the hemagglutinin, as well as hostdirected therapies. The availability of drugs with diverse mechanisms now opens the door to exploring combination therapies for influenza, and the range of administration routes presents more opportunities for treating hospitalized patients.
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APPROVED DRUGS FOR INFLUENZA AND GOALS FOR THE NEXT GENERATION There are two classes of approved drugs for influenza: the neuraminidase inhibitors (NAI) and the M2 ion channel inhibitors or adamantanes. However, because all currently circulating influenza A viruses (IAV) are resistant to the adamantanes, they are no longer used clinically, which means that we are reliant on a single class of drug. NAIs act by preventing release of new virus particles (Figure 1), and of the approved NAIs, oseltamivir is the most widely prescribed owing to its oral bioavailability. Zanamivir is administered via inhalation, while peramivir (which received FDA approval in 2014) is an intravenous drug which is beneficial when treating hospitalized patients. The newest NAI drug, which has only been approved in Japan so far, is laninamivir octanoate, the prodrug of laninamivir. This drug is also delivered via inhalation; however, its distinguishing property is that it has a long half-life, and patients can be effectively treated with a single dose.1 A rapid rise in oseltamivir resistance among H1N1 IAVs prior to 20092 raised alarms about the paucity of influenza drugs in the pipeline, and although oseltamivir resistance is only observed sporadically now,3 these concerns have spurred the development of new drugs. The ideal goals for the next generation of influenza drugs are (i) that they have a different mechanism of action from the NAIs, (ii) that they display a high barrier to resistance, (iii) that they show broad activity against both influenza A and B viruses, (iv) that they are superior to the standard of care (oseltamivir) or act synergistically with oseltamivir, and (v) that they are effective when delivered late in infection (>2 days). While not all of these goals may be met by a single drug, it illustrates what the field is striving for in developing the next influenza drugs. In the following sections, I will summarize the most promising candidates that are in late stage development as influenza therapeutics, including both small molecule drugs and therapeutic monoclonal antibodies.
developed by Janssen Pharmaceuticals. It targets the PB2 subunit of the viral polymerase and acts by preventing the polymerase from binding the 7-methyl GTP cap structures on host pre-mRNAs.4 This process, known as “cap-snatching”, is required for viral transcription, and thus, pimodivir prevents viral gene expression (Figure 1). Pimodivir potently inhibits IAV but is inactive against influenza B virus due to structural differences in the PB2 cap-binding pocket. Importantly, pimodivir has been shown to be effective when delivered up to 4 days postinfection in a mouse model and shows superior efficacy to oseltamivir.5,6 Mutations in PB2 that confer resistance to pimodivir have been identified in vitro, and the variants display up to 250-fold reduced sensitivity to pimodivir but retain sensitivity to NAIs,5 suggesting that a combination therapy may limit their emergence. The latest results from a Phase 2b trial in adults with uncomplicated influenza (NCT02532283) indicate significant reductions in viral load following 7 days of treatment and even greater efficacy when combined with oseltamivir.7 Plans for Phase 3 trials are reported for late 2017. S-033188. S-033188 was discovered by Shionogi & Co., Ltd., and it is now being developed in collaboration with F. Hoffmann-La Roche Ltd. S-033188 is the oral prodrug of S033447 which targets the endonuclease activity of the viral PA polymerase subunit thereby preventing the polymerase from cleaving the pre-mRNA once it has been bound by PB2.8 As such, just like the PB2-inhibitor, it blocks viral transcription and all gene expression (Figure 1). S-033447 is active against both influenza A and B viruses, including viruses bearing oseltamivir resistance mutations. 8 Results from a Phase 3 study (NCT02954354), in which a single dose of S-033188 was compared to placebo or 5 days of oseltamivir treatment, indicate significant reductions in virus titer.9 A similar time to alleviation of symptoms was observed when compared to oseltamivir, but fewer adverse events were reported. Another Phase 3 trial, this time in individuals at high risk for influenzaassociated complications, is in progress (NCT02949011).
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POLYMERASE COMPLEX INHIBITORS Pimodivir. Pimodivir (also known as JNJ63623872 and VX787) was discovered by Vertex Pharmaceuticals and is being © XXXX American Chemical Society
Received: August 31, 2017
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Figure 1. Mode of action of influenza virus antivirals. A schematic of the influenza virus life cycle indicating where each influenza therapeutic exerts its antiviral activity. FDA approved drugs are shown in green; those approved in other countries are in orange, and those in clinical trial are in red.
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Another endonuclease inhibitor that is at an earlier developmental stage (Phase 1) is AL-794 (also known as JNJ64155806), which is being developed by Alios Biopharma Inc. This is an ester prodrug of ALS-033719 that is active against both influenza A and B viruses. Favipiravir. Favipiravir (also known as T-705) is a purine nucleoside analog that displays potent antiviral activity against several RNA viruses by targeting the viral RNA-dependent RNA polymerase.10 It was discovered by Toyama Chemical Co., Ltd. and has received conditional approval in Japan for treating influenza patients in a pandemic setting. In the USA, favipiravir is being developed by the US Department of Defense in collaboration with MediVector, Inc. Favipiravir is ribosylated and phosphorylated intracellularly to form favipiravir-RTP, which is the active form of the drug. This form is recognized by the viral RNA polymerase and misincorporated into nascent RNA as a purine which results in chain termination during RNA synthesis (Figure 1) and can lead to lethal mutagenesis.11 Favipiravir is active against all influenza viruses, and so far, there are no reports of resistant virus isolated from patients treated with favipiravir.12 Combinations of favipiravir and oseltamivir show synergistic antiviral activity, and as a monotherapy, favipiravir is superior to oseltamivir in a mouse model.13 One of the major concerns for favipiravir is potential teratogenicity, and this is the reason behind the conditional approval of the drug in Japan. In the USA, a Phase 3 clinical trial (NCT02008344) to assess the time to resolution of symptoms following favipiravir treatment of adults with uncomplicated influenza has been completed and is awaiting publication of results. At the same time, favipiravir is being investigated for treatment of other infections caused by RNA viruses, such as Ebola.
MONOCLONAL ANTIBODIES FOR INFLUENZA THERAPY
A number of monoclonal antibodies that target the viral hemagglutinin (HA) are currently being investigated as potential influenza therapeutics. These antibodies all bind to the more conserved stalk portion of the HA molecule, and thus, they have broad antiviral activity against several or all IAV subtypes. Those that are in clinical development include MEDI8852 (MedImmune), MHAA4549A (Genentech), VIS410 (Visterra), CT-P27 (Celltrion), CR6261, and CR8020 (both Crucell) (reviewed in Sparrow et al.14). Mechanistically, these HA antibodies work by preventing fusion of the virus with the host cell, and they have also been shown to mediate antibody dependent cell-mediated cytotoxicity in vivo.15 Some, like MEDI8852, have been compared to oseltamivir in preclinical animal studies and have been shown to be superior to, or at least as effective as, oseltamivir depending on the virus subtype.16 A Phase 2 clinical trial (NCT02603952) to evaluate effects of MEDI8852 alone or in combination with oseltamivir has been completed, but the results have yet to be reported while a similar trial for MHAA4549A is in the recruitment phase (NCT02293863). Results from an earlier Phase 2 trial evaluating safety and efficacy of MHAA4549A in an influenza challenge model (NCT01980966) have been published and show that MHAA4549A was well tolerated and significantly reduced viral loads.17 One imagines that if this type of passive immunotherapy is approved for influenza, a cocktail of antibodies targeting both influenza A and B viruses will be the goal, and to this end, Genentech is also developing an antibody targeting influenza B HA, MHAB5553A (currently in B
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Phase 1),18 placing them in a strong position to pursue this option. In addition to the HA antibodies, there is also an antibody targeting the IAV M2 protein that is in clinical trial. TCN032 is being developed by Theraclone Sciences and specifically binds to the conserved ectodomain of M2 which is exposed on the surface of infected cells. In doing so, it prevents virus budding and thus acts via a very different mechanism from the M2 ion channel inhibitors (Figure 1). TCN032 has been evaluated in a Phase 2 study and found to be safe and effective at reducing symptoms and virus shedding when administered 1 day postinfection.19
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CONCLUDING REMARKS Overall, great strides are being made in the development of new influenza drugs. The number of new targets has been expanded dramatically, and this opens the door to the prospect of combination therapies for influenza. Such approaches are now standard for treating HIV and HCV patients, and it has been shown that this helps to limit the emergence of drug resistant virus. Of course, this is mostly a concern with drugs targeting viral proteins, such as NAIs, the polymerase inhibitors, and possible antibody therapies. At the moment, we lack sufficient information to know if resistance may be a problem with any of these new therapies, but those with lower resistance barriers will likely have to be used in combination. The one big advantage of the host-directed therapies is that they generally have a high barrier to resistance, so they too are good candidates for use in an influenza drug cocktail. Of these new drug candidates, the PA inhibitors, favipiravir, and the hosttargeting therapies provide the broadest antiviral spectrum (i.e., influenza A and B) which is another major goal as influenza B is the predominant virus in some seasons. Again, those drugs that have IAV-specificity may have to be paired with a more broader-acting inhibitor. Finally, we have seen a surge in the development of antibodies for passive immune therapy, which until recently was not considered for influenza. In comparison to small molecules, antibodies are costly to manufacture and have to be administered intravenously, so for these reasons, they will likely be more appropriate for treating severely ill patients who are hospitalized with influenza. In summary, from a position of only having one class of drug, we are poised to have multiple options available for the treatment of influenza, including therapies that may be better suited to either outpatients or hospitalized patients.
HOST-DIRECTED INFLUENZA ANTIVIRALS
Fludase (DAS181). Fludase, or DAS181, is a recombinant protein designed to remove sialic acid from respiratory epithelium and thereby prevent attachment of influenza virus (Figure 1) or other viruses that use sialic acid as a receptor. Fludase is being developed by Ansun Biopharma for the treatment of influenza and is currently in Phase 2 clinical trials. The protein, which is delivered via inhalation, consists of a heparin binding sequence that anchors the protein on respiratory epithelial cells and a sialidase derived from Actinomyces viscosus which cleaves sialic acid linkages from surrounding glycans.20 Fludase has been shown to be effective against both influenza A and B viruses and protects mice from a lethal influenza challenge when administered either as prophylaxis or up to 48 h postinfection. Results of a Phase 2 trial reported in 2012 indicate that the drug is well tolerated and significantly reduces viral load and viral shedding when administered over 3 days.21 One of the major concerns for using a protein therapy is the development of antibodies which would prohibit subsequent use of the drug. Neutralizing antibodies to Fludase have been observed, particularly when the drug is given for longer periods; thus, this may limit the use of Fludase in settings other than a once off treatment.22 Nitazoxanide. Nitazoxanide, also known as Alinia, is an example of a repurposed drug. It was originally approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum and is now being developed by Romark for treatment of influenza. Nitazoxanide is a thiazolide compound that is metabolized into its active form, tizoxanide. These drugs have antiviral activity against several different viruses, indicating that they act on a cellular function.23 For influenza virus, it has been shown that tizoxanide prevents correct maturation of the HA protein by blocking trafficking between the endoplasmic reticulum and Golgi.24 In doing so, glycosylation of HA is also affected, and ultimately, this prevents assembly of new virus particles (Figure 1). Nitazoxanide is effective against both influenza A and B viruses and has been shown to act synergistically with oseltamivir.25 One of the advantages of a repurposed drug is that there is already a great deal of experience with using it in humans; thus, trials of nitazoxanide for influenza have been able to progress fairly rapidly. Results from a Phase 2b/3 study indicate that treatment with nitazoxanide (600 mg twice daily for 5 days) provides a faster time to resolution of symptoms than a placebo control.26 Phase 3 studies that compare nitazoxanide to oseltamivir, as well as nitazoxanide/oseltamivir combinations, are awaiting publication of results (NCT01610245)
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AUTHOR INFORMATION
Corresponding Author
*Tel: 212-241-8931. E-mail:
[email protected]. ORCID
Megan L. Shaw: 0000-0002-1267-0891 Notes
The author declares no competing financial interest.
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REFERENCES
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