|Systematic (IUPAC) name|
|Synonyms||5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4H-pyran- 2-carboxylic acid|
|PDB ligand ID||ZMR (, )|
|Mol. mass||332.31 g/mol|
|(what is this?)|
Zanamivir INN // is a neuraminidase inhibitor used in the treatment and prophylaxis of influenza caused by influenza A and B viruses. It was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.
Zanamivir is used for the treatment of infections caused by influenza A and influenza B viruses, but in otherwise-healthy individuals, benefits overall appear to be small. It decreases the risk of one's getting symptomatic, but not asymptomatic influenza. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of zanamivir for the prophylaxis and treatment of healthy individuals. As of 2009, no influenza has shown any signs of resistance in the US. Since then, genes expressing resistance to zanamivir were found in Chinese people infected with avian influenza A H7N9 during treatment with zanamivir.
In otherwise-healthy individuals, benefits overall appear to be small. Zanamivir shortens the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. In children with asthma there was no clear effect on the time to first alleviation of symptoms. Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear. There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as bronchitis, middle ear infection and sinusitis. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia or radiologically confirmed pneumonia in adults. The effect on pneumonia in children was also not significant.
Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1% to 12% in those exposed. Prophylaxis trials showed that zanamivir reduced the risk of symptomatic influenza in individuals and households, but there was no evidence of an effect on asymptomatic influenza or on other, influenza-like illnesses. Also there was no evidence of reduction of risk of person-to-person spread of the influenza virus. The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature.
Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms. In 2006 the FDA found that breathing problems (bronchospasm), including deaths, were reported in some patients after the initial approval of Relenza. Most of these patients had asthma or chronic obstructive pulmonary disease. Relenza therefore was not recommended for treatment or prophylaxis of seasonal influenza in individuals with asthma or chronic obstructive pulmonary disease. In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation.
In adults there was no increased risk of reported adverse events in trials. There was little evidence of the possible harms associated with the treatment of children with zanamivir. Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body.
Mechanism of action
Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others. It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.
As of 2009, no influenza had shown any signs of resistance in the US. A meta-analysis from 2011 found that zanamivir resistance had been rarely reported. Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed). In 2013 genes expressing resistance to zanamivir (and oseltamivir) were found in Chinese patients infected with avian influenza A H7N9.
Zanamivir was first synthesised in 1989 by scientists led by Peter Colman and Joseph Varghese at the Australian CSIRO, in collaboration with the Victorian College of Pharmacy,and the Monash University. Zanamivir was the first of the neuraminidase inhibitors. The discovery was initially funded by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design. Its strategy relied on the availability of the structure of influenza neuraminidase by X-ray crystallography. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), a sialic acid analogue, is an inhibitor of neuraminidase. Sialic acid (N-acetyl neuraminic acid, NANA), the substrate of neuraminidase, is itself a mild inhibitor of the enzyme, but the dehydrated derivative DANA, a transition-state analogue, is a better inhibitor.
As Biota was a small company, it did not have the resources to bring zanamivir to market by itself. In 1990, zanamivir patent rights were licensed to Glaxo, now GlaxoSmithKline (GSK). The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of zanamivir.
In 1999, the product was approved for marketing in the US and Europe for treatment of influenza A and B. The FDA advisory committee had recommended by a vote 13 to 4 that it should not be approved, because it lacked efficacy an was no more effective than placebo when the patients were on other drugs such as paracetamol. But the FDA leadership overruled the committee and criticised its reviewer, biostatistician Michael Elashoff. The review of oseltamivir, which was also in approval process at that time, was taken away from him, and reassigned to someone else. In 2006 zanamivir was approved in the US and Europe for prevention of influenza A and B.
Although zanamivir was the first neuraminidase inhibitor to the market, it had only a few months lead over the second entrant, oseltamivir (Tamiflu), with an oral tablet formulation.
According to the CDC, Tamiflu, zanamivir’s main competitor, is not as effective at treating the influenza viruses as zanamivir, especially in H1N1 seasonal flu. In fact, tests showed 99.6% of the tested strains of seasonal H1N1 flu and 0.5% of 2009 pandemic flu were resistant to Tamiflu, while no flu samples, seasonal or pandemic, showed any resistance to zanamivir.
When first marketed in the US in 1999/2000, zanamivir captured only 25% of the influenza antiviral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling zanamivir 3:1. During that season, zanamivir experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of zanamivir, and Tamiflu's dominance increased. More than US$20 million worth of zanamivir sold by Glaxo in the first US season was returned to the company in the next two seasons because its sales to patients were far less than expected.
Biota commenced legal proceedings in 2004 alleging Glaxo's reduced marketing of zanamivir to be a breach of contract. Biota claimed about A$700 million from Glaxo. After Biota spent four years trying to progress its case, and incurring A$50 million in legal costs, the company abandoned the claim in July 2008, recovering only A$20 million, including legal costs following settlement at mediation. Biota had refused an earlier tactical offer from Glaxo of A$75 million plus legal costs.
In August 2006, Germany announced it would buy 1.7 million doses of zanamivir, as part of its preparation strategy against bird flu. "Germany's purchase shows that countries are starting to take a balanced view of influenza preparedness," said Simon Tucker, head of research at Melbourne-based Biota, where zanamivir was originally developed.
In April 2009, many cases of swine flu (H1N1-type virus) were reported in US and Mexico. Zanamivir is one of only two drugs prescribed to treat it. A study published in June 2009 emphasized the urgent need for augmentation of oseltamivir stockpiles, with additional antiviral drugs including zanamivir, based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 swine flu neuraminidase (NA) were to acquire the Tamiflu-resistance (His274Tyr) mutation, which is currently widespread in 99.6% of all tested seasonal H1N1 strains.
In January 2011, GSK announced it would commence phase III trials for intravenous zanamivir in a study that will span 20 countries in the Northern and Southern Hemispheres.
Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the amino acid residues of the catalytic site, so would be potent and specific inhibitors of the enzyme. The GRID software by Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This investigation showed a negatively charged zone occurs in the neuraminidase active site that aligns with the C4 hydroxyl group of DANA. This hydroxyl is, therefore, replaced with a positively charged amino group; the 4-amino DANA was shown to be 100 times better as an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. Glu 119 was also noticed to be at the bottom of a conserved pocket in the active site, just big enough to accommodate a more basic functional, positively charged group, such as a guanidino group, which was also larger than the amino group. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.
- "FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children FDA press release March 29, 2006". FDA.
- Michiels, B; Van Puyenbroeck, K; Verhoeven, V; Vermeire, E; Coenen, S (2013). "The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews.". PLoS ONE 8 (4): e60348. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231.
- "2008-2009 Influenza Season Week 32 ending August 15, 2009". Flu Activity & Surveillance. Centers for Disease Control and Prevention (CDC). August 21, 2009.
- Hu, Y.; Lu, S.; Song, Z.; Wang, W.; Hao, P.; Li, J.; Zhang, X.; Yen, H. L.; Shi, B.; Li, T.; Guan, W.; Xu, L.; Liu, Y.; Wang, S.; Zhang, X.; Tian, D.; Zhu, Z.; He, J.; Huang, K.; Chen, H.; Zheng, L.; Li, X.; Ping, J.; Kang, B.; Xi, X.; Zha, L.; Li, Y.; Zhang, Z.; Peiris, M.; Yuan, Z. (2013). "Association between adverse clinical outcome in human disease caused by novel influenza a H7N9 virus and sustained viral shedding and emergence of antiviral resistance". The Lancet 381 (9885): 2273. doi:10.1016/S0140-6736(13)61125-3.
- Jefferson, T; Jones, MA; Doshi, P; Del Mar, CB; Heneghan, CJ; Hama, R; Thompson, MJ (Jan 18, 2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.". The Cochrane database of systematic reviews 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996. Retrieved 19 April 2014.
- Heneghan, CJ; Onakpoya, I; Thompson, M; Spencer, EA; Jones, M; Jefferson, T (Apr 9, 2014). "Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.". BMJ (Clinical research ed.) 348: g2547. doi:10.1136/bmj.g2547. PMC 3981976. PMID 24811412.
- Heneghan, C. J.; Onakpoya, I.; Thompson, M.; Spencer, E. A.; Jones, M.; Jefferson, T. (9 April 2014). "Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments". BMJ 348 (apr09 2): g2547–g2547. doi:10.1136/bmj.g2547. PMC 3981976. PMID 24811412.
- Wang, K; Shun-Shin, M; Gill, P; Perera, R; Harnden, A (Apr 18, 2012). "Neuraminidase inhibitors for preventing and treating influenza in children (published trials only).". Cochrane database of systematic reviews (Online) 4: CD002744. doi:10.1002/14651858.CD002744.pub4. PMID 22513907.
- Hayden FG (December 2001). "Perspectives on antiviral use during pandemic influenza". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 356 (1416): 1877–84. doi:10.1098/rstb.2001.1007. PMC 1088564. PMID 11779387.
- "FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children". FDA press release.
- "Safe and Appropriate Use of Influenza Drugs". Public Health Advisories (Drugs). U.S. Food and Drug Administration (FDA). April 30, 2009. Archived from the original on 2009-11-04. Retrieved 2009-11-11.
- Freund, B; Gravenstein, S; Elliott, M; Miller, I (Oct 1999). "Zanamivir: a review of clinical safety.". Drug safety : an international journal of medical toxicology and drug experience 21 (4): 267–81. doi:10.2165/00002018-199921040-00003. PMID 10514019.
- Cyranoski D (September 2005). "Threat of pandemic brings flu drug back to life". Nature Medicine 11 (9): 909. doi:10.1038/nm0905-909. PMID 16145557.
- Moscona A (September 2005). "Neuraminidase inhibitors for influenza". The New England Journal of Medicine 353 (13): 1363–73. doi:10.1056/NEJMra050740. PMID 16192481.
- Thorlund, Kristian; Awad, Tahany; Boivin, Guy; Thabane, Lehana (2011). "Systematic review of influenza resistance to the neuraminidase inhibitors". BMC Infectious Diseases 11 (1): 134. doi:10.1186/1471-2334-11-134.
- "Influenza Antiviral Medications: Summary for Clinicians". CDC. Retrieved 21 April 2014.
- Varghese, J. N.; Laver, W. G.; Colman, P. M. (1983). "Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 a resolution". Nature 303 (5912): 35–40. doi:10.1038/303035a0. PMID 6843658.
- Meindl P, Bodo G, Palese P, Schulman J, Tuppy H (April 1974). "Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid". Virology 58 (2): 457–63. doi:10.1016/0042-6822(74)90080-4. PMID 4362431.
- Cohen, D.; Carter, P. (3 June 2010). "WHO and the pandemic flu "conspiracies"". BMJ 340 (jun03 4): c2912–c2912. doi:10.1136/bmj.c2912.
- Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. (2008). "Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants". Nature 453 (7199): 1258–61. doi:10.1038/nature06956. PMID 18480754.
- Garcia-Sosa AT, Sild S, Maran U. (2008). "Design of Multi-Binding-Site Inhibitors, Ligand Efficiency, and Consensus Screening of Avian Influenza H5N1 Wild-Type Neuraminidase and of the Oseltamivir-Resistant H274Y Variant". J. Chem. Inf. Model. 48 (10): 2074–2080. doi:10.1021/ci800242z. PMID 18847186.
- Soundararajan V, Tharakaraman K, Raman R, Raguram S, Sasisekharan V, Sasisekharan R (June 2009). "Extrapolating from sequence--the 2009 H1N1 'swine' influenza virus". Nature Biotechnology 27 (6): 510–3. doi:10.1038/nbt0609-510. PMID 19513050.
- Hirschler, Ben (2011-01-19). "GSK tests intravenous flu drug vs Roche's Tamiflu". Reuters.
- Laver, Graeme (March 2007). "Flu drugs - pathway to discovery". Education in Chemistry. Retrieved 2009-11-11. ISSN 0013-1350
- von Itzstein M, Wu WY, Kok GB, et al. (June 1993). "Rational design of potent sialidase-based inhibitors of influenza virus replication". Nature 363 (6428): 418–23. doi:10.1038/363418a0. PMID 8502295.
- The development of Relenza for treatment of influenza
- Drug Information: Zanamivir Inhalation MedlinePlus drug
- Relenza: Consumer Questions and Answers US Food and Drug Administration (FDA)
- Relenza Biota Holdings
- Relenza web site GlaxoSmithKline