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Zanamivir

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Zanamivir
Clinical data
Pronunciation/zəˈnæmɪvɪər/
Trade namesRelenza
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: B1
Routes of
administration		Inhalation, IV
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability2% (oral)
Protein binding<10%
MetabolismNegligible
Elimination half-life2.5–5.1 hours
ExcretionRenal
Identifiers
  • (2R,3R,4S)-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1R,2R)-1,2,3-trihydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.218.632 Edit this at Wikidata
Chemical and physical data
FormulaC12H20N4O7
Molar mass332.313 g·mol−1
3D model (JSmol)
  • O=C(O)C=1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](/N=C(\N)N)C=1
  • InChI=1S/C12H20N4O7/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16)/t5-,6+,8+,9+,10+/m0/s1 checkY
  • Key:ARAIBEBZBOPLMB-UFGQHTETSA-N checkY
  (verify)

Zanamivir is a medication used to treat and prevent influenza caused by influenza A and B viruses. It is a neuraminidase inhibitor and 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.[1] 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.

Medical uses

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.[2] As of 2009, no influenza had shown any signs of resistance in the US.[3] Since then, genes expressing resistance to zanamivir were found in Chinese people infected with avian influenza A H7N9 during treatment with zanamivir.[4]

Treatment

In otherwise-healthy individuals, benefits overall appear to be small.[2] 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.[5] Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear.[2] There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as bronchitis, middle ear infection, and sinusitis.[5][6] 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.[7]

Prevention

Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1% to 12% in those exposed.[2] 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.[5] The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature.[8]

Resistance

As of 2009, no influenza had shown any signs of resistance in the US.[3] A meta-analysis from 2011 found that zanamivir resistance had been rarely reported.[9] Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed).[10] In 2013 genes expressing resistance to zanamivir (and oseltamivir) were found in Chinese patients infected with avian influenza A H7N9.[4]

Adverse effects

Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms.[11] In 2006 the Food and Drug Administration (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.[12] In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease.[13] 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.[14]

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.[5] Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body.[15]

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.[16] 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.

The bioavailability of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and oropharynx, where up to 15% of the dose is absorbed and excreted in urine.[17]

History

Zanamivir was first made in 1989 by scientists led by Peter Colman[18][19] and Joseph Varghese[20] 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.[21]

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 that is just big enough to accommodate the larger, but more basic guanidine functional group.[22] Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.[23]

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 and 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.[24] In 2006 zanamivir was approved in the US and Europe for prevention of influenza A and B.[1]

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 capsule formulation.

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.[16]

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.[25]

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.[26]

References

  1. ^ a b "FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children FDA press release March 29, 2006". FDA.
  2. ^ a b c d 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. Bibcode:2013PLoSO...860348M. doi:10.1371/journal.pone.0060348. PMC 3614893. PMID 23565231.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b "2008-2009 Influenza Season Week 32 ending August 15, 2009". Flu Activity & Surveillance. Centers for Disease Control and Prevention (CDC). August 21, 2009.
  4. ^ a b 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): 2273–2279. doi:10.1016/S0140-6736(13)61125-3. PMID 23726392.
  5. ^ a b c d Jefferson, T; Jones, MA; Doshi, P; Del Mar, CB; Hama, R; Thompson, MJ; Spencer, EA; Onakpoya, I; Mahtani, KR; Nunan, D; Howick, J; Heneghan, CJ (10 April 2014). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children" (PDF). The Cochrane Database of Systematic Reviews. 4 (4): CD008965. doi:10.1002/14651858.CD008965.pub4. PMC 6464969. PMID 24718923.
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  12. ^ "FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children". FDA press release.
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  20. ^ "Archived copy". Archived from the original on October 5, 2013. Retrieved October 2, 2013.{{cite web}}: CS1 maint: archived copy as title (link)
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  24. ^ Cohen, D.; Carter, P. (3 June 2010). "WHO and the pandemic flu "conspiracies"". BMJ. 340 (jun03 4): c2912. doi:10.1136/bmj.c2912. PMID 20525679.
  25. ^ 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.
  26. ^ Hirschler, Ben (2011-01-19). "GSK tests intravenous flu drug vs Roche's Tamiflu". Reuters.
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