Zanamivir

Zanamivir

drugbox
IUPAC_name = 5-acetamido-4-guanidino-6-(1,2,3-trihydroxypropyl)-
5,6-dihydro-4"H"-pyran-2-carboxylic acid


CAS_number = 139110-80-8
ATC_prefix = J05
ATC_suffix = AH01
ATC_supplemental =
PubChem = 60855
DrugBank = APRD00378
C=12 | H=20 | N=4 | O=7
molecular_weight = 332.31 g/mol
bioavailability = 2% (oral)
protein_bound = <10%
metabolism = Negligible
elimination_half-life = 2.5–5.1 hours
excretion = Renal
pregnancy_category = B1 (Au)
legal_status = S4 (Au), POM (UK), ℞-only (U.S.)
routes_of_administration = Inhalation

Zanamivir (INN) (pronEng|zəˈnæmɨvɪr) is a neuraminidase inhibitor used in the treatment of and prophylaxis of both Influenzavirus A and Influenzavirus B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza. Relenza is the only type of Zanamivir.

Development

Introduction

Relenza, discovered in 1989, a neuraminidase inhibitor medication designed to treat Influenza virus A, responsible for both the common ‘seasonal flu’ and notable influenza pandemics such as the Spanish flu (1918) and Influenza virus B which does not cause pandemics. Relenza is the commercial name and only type of Zanamivir, and was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline

Relenza was developed by a team of scientists at the Victorian College of Pharmacy at Monash University. The team was led by scientist, Mark von Itzstein in association with the CSIRO. Relenza was discovered as a part of the Australian biotechnology company Biota's project to develop antiviral agents via rational drug design.

Influenza A and B cause illness, however Influenza A is seen as a much more pathogenic virus. Between 1990 to 2000, nine significant outbreaks of influenza A caused many deaths in England and Wales, compared to just four outbreaks of influenza B [ref needed] .

Background

The word “flu” is short for influenza. The flu is a virus which targets the bodies respiratory cells and damages the lining of the respiratory tract, leading to swelling and becoming inflammation of the tract. Influenza spreads rapidly by replicating itself inside the host cell, producing hundreds of copies of the virus in a short period. In approximately an hour the virus can destroy the host cell and propel its replications out into the body to find new host cells. For some people, the flu and its complications can be very serious, even fatal.

Relenza is a part of a range of neuraminidase inhibitor medications. This medication was designed to attack the infected host cells, preventing the virus from spreading throughout other cells in the body and thus reducing the amount of time the virus can survive.

Influenza A

Influenza A, the seasonal flu, is the common infection which usually outbreaks in the winter months. Typically, the flu is caused when viral particles are transferred between people (Doctors of MedicineNet, 2003). Common symptoms include fever, cough, headache, fatigue, body aches, and sore throat. These symptoms may last longer than those of a cold, sometimes for weeks (Morb Mortal Wkly Rep. 2007).

The most common way to catch the flu is directly from another person. Coughing and sneezing send droplets containing these viral particles from the mouth and nose into the air. If these flu-infected droplets are inhaled by another person, that person may become infected. Another way in which the flu may be caught is by touching something an infected person has transferred these pathogens onto, by sneezing or coughing on the object and a non infected person then touching it.

The reason influenza spreads so rapidly is because a person may be contagious yet show no symptom and thus not know they are infected with the virus and unaware they are spreading it. A person can be contagious for about a week.

Influenza B

Influenza B has a more complicated presence than Influenza A. In 2008 there were two distinct lineages of influenza B that caused disease (Victoria and Yamagata lineage). These two genetically distinct lineages have caused disease for approximately a dozen years. In any year either the Victoria or the Yamagata lineage may predominate in a particular geographical area.

Progression of Relenza

In 1990 licensing of zanamivir was sold to Glaxo, which is now known as GlaxoSmithKline (GSK). In 1999, the product was approved for marketing in the US and subsequently has been registered by GSK in a total of 70 countries. (GlaxoSmithKline News release, 2006)Tamiflu, Relenza’s main competitor, was proven in 2006 to not be as effective at treating the Influenza viruses as Relenza. As a result in August 2006 Germany announced that it would buy 1.7 million doses of Relenza 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," says Simon Tucker, head of research at Melbourne-based Biota, where Relenza was originally developed (David Cyranoski, 2005).

Zanamivir was discovered in 1989 by scientists led by Mark von Itzstein at the Victorian College of Pharmacy, Monash University in collaboration with the CSIRO. The discovery was funded initially by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design.

Computational chemistry techniques to probe the active site of the enzyme in an attempt to design structurally modified derivatives of DANA that would bind tightly to the amino acids in the catalytic site and so prove to be potent and specific inhibitors of the enzyme. They used the software program GRID to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This showed that there was a negatively charged zone in the neuraminidase active site that aligned with the C4 hydroxyl group of DANA. We therefore replaced this hydroxyl with a positively charged amino group; the 4-amino DANA (3) was 100 times better an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. They then noticed that Glu 119 was at the bottom of a conserved pocket in the active site, which was just big enough to accommodate a more basic functional positively charged group, such as a guanidino group, that was also larger than the amino group.(Professor Graeme Laver,2007)

The strategy relied on the availability of the crystal structure of influenza neuraminidase which was achieved by x-ray crystallography.*Created from a knowledge of the crystal structure of a human flu virus neuraminidase, subtype N2.* It was known as far back as 1974 that 2-deoxy-2,3-didehydro-"N"-acetylneuraminic acid (DANA), a sialic acid analogue, was an inhibitor of neuraminidase.Meindl P, Bodo G, Palese P, Schulman J, Tuppy H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-"N"-acetylneuraminic acid. Virology 1974;58(2):457-463. PMID 4362431] Using the crystal structure of neuraminidase and DANA as a starting point, the researchers employed a computer-aided process to attempt to design a molecule which was a better fit for (and therefore inhibited) the active site of neuraminidase. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.von Itzstein M, Wu W-Y, Kok GB, Pegg MS, Dyason JC, Jin B, et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 1993;363(6428):418-423. PMID 8502295] "Sialic acid (N-acetyl neuraminic acid, NANA, 1), the substrate of neuraminidase, is itself a mild inhibitor of the enzyme but the dehydrated derivative, deoxy-dehydro-N-acetyl neuraminic acid, DANA (2), the transition state analogue, is a better inhibitor(Professor Graeme Laver,2007)."In 1990, zanamivir was licensed to Glaxo (now GlaxoSmithKline) for exclusive worldwide development and marketing. In 1999, the product was approved for marketing in the US and subsequently has been registered by GSK in a total of 70 countries.

Relenza jumped back into the spotlight after glowing reports in August of its relative effectiveness compared to Tamiflu. In August Germany announced it would buy 1.7 million doses of Relenza as part of its bird flu preparedness strategy. "Germany's purchase shows that countries are starting to take a balanced view of influenza preparedness," says Simon Tucker, head of research at Melbourne-based Biota, which developed Relenza.(David Cyranoski, 2005)

Limitations

(this section is poorly written)Whilst zanamivir proved to be a potent and effective inhibitor of influenza neuraminidase "by binding to the active site of the virus' neuraminidase protein, rendering the virus unable to escape its host cell and infect others(David Cyranoski, 2005)." It is also an inhibitor of influenza virus replication "in vitro" and "in vivo", this didn't necessarily translate into a successful clinical treatment for influenza. In clinical trials it was found that zanamivir was able to reduce the time to symptom resolution by 1.5 days provided therapy was started within 48 hours of the onset of symptoms.

Relenza is a safe and effective treatment for influenza, but they need to be given early after the first symptoms appear. Six to 12 hours is ideal. In most countries the drugs can only be obtained with a doctor's prescription, and usually the time taken to get a prescription renders them ineffective(Professor Graeme Laver,2007)

A further limitation concerns the poor oral bioavailability of zanamivir. This meant that oral dosing was impossible, limiting dosing to the parenteral routes (limited its usage when treating the elderly because it may induce bronchospasm (F.G. Hayden, 2001)) Zanamivir, therefore, is administered by inhalation - a route that was chosen for patient compliance with therapy. But this route of administration is not acceptable to many in the community.

Zanamivir is specific to the influenza virus, has not been known to cause toxic effects, and does not spread around through the body's systemic circulation. It also shows no signs of viral resistance. It is, however, because of the lack of reports and evidence on its toxicity that the FDA does not license it for use in children under 7 years of age.

Most patients prefer taking an oral dosage over inhalation, zanamivir never attained a high popularity, as opposed to oseltamivir that can be taken orally.

The FDA has issued a Public Health Advisory warning that it has received reports of respiratory problems following inhalation of Relenza by patients with underlying asthma or chronic obstructive pulmonary disease. The Relenza package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. http://www.fda.gov/cder/drug/advisory/influenza.htm FDA Advisory: Safe and appropriate use of Influenza drugs]

Bulk orders of Tamiflu from the UK, France and other countries to cover 20% or more of their population are pushing Roche's production capacity to the limit. But Relenza, which was the first neuraminidase inhibitor on the market, claims only one percent of the growing flu drug market. The drug has suffered from lackadaisical marketing efforts, according to a lawsuit that Biota, which gets a percentage of sales, is bringing against GlaxoSmithKline(David Cyranoski, 2005).

Relenza has also been unpopular in part because it must be breathed in with an inhaler. GlaxoSmithKline is considering repackaging Relenza as a shot or nebulizer to increase sales(David Cyranoski, 2005).

Relenza is at least as effective as Tamiflu and has fewer side effects, including nausea and headaches, according to an article published 13 August (Lancet 366, 533−534; 2005). The report, based on data compiled from the companies' clinical trials and from subsequent studies, also says there is no evidence of resistance to Relenza, compared with resistance levels of up to 18% in those taking Tamiflu (Lancet 364, 759−765; 2004). The researchers recommend stockpiling both.(David Cyranoski, 2005)

Commercial difficulties

Biota, being only a small company, was not able to bring the drug to market by itself. Consequently, it was licensed to Glaxo (now GlaxoSmithKline) to complete development and to market internationally as "Relenza", delivered via Glaxo's proprietary Diskhaler inhalation device. The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of Relenza.

A combination of factors has resulted in the limited commercial success of zanamivir (Relenza). The relatively small effect on the timecourse of influenza symptoms, the inhalation dosage form, a less-than-ideal device, and high expense make it a difficult product to market well. And 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 much preferred by patients and physicians.

When first marketed in the USA in 1999/00, Relenza captured only 25% of the influenza anti-viral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling Relenza 3:1. During that season, Relenza experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of Relenza, and Tamiflu's dominance increased. More than US$20m worth of Relenza sold by Glaxo in the first US season was returned to the company in the next two seasons because Relenza's actual sales to patients were far less than expected, highlighting the fact that the results of the first season were even worse than first thought.

Biota commenced legal proceedings in 2004 alleging that Glaxo's reduced marketing of Relenza was a breach of contract, a charge Glaxo denied. Biota claimed approximately $700m AUD from Glaxo. After Biota spent four years trying to progress its case, and incurring $50m in legal costs, the company abandoned the claim in July 2008, recovering only $20m AUD including legal costs following settlement at mediation. Embarrassingly for Biota's management, it transpired that Biota had refused an earlier tactical offer from Glaxo of $75m AUD plus legal costs.

Developments from zanamivir

Zanamivir was the first of the neuraminidase inhibitors. Despite the limited commercial success of this drug, the work and strategies employed in the development of zanamivir were important first-steps in the development of further members of this class including oseltamivir and the candidate drug RWJ-270201 (Phase I trials).

As a proven anti-influenza drug target, luponeuraminidase continues to be attractive for the development of new inhibitors. The crystal structure of H5N1 avian influenza neuraminidase (PDB code: 2HTY) [13] provides the three-dimensional structural information and opportunity for finding new inhibitors in this regard because the existing inhibitors, such as oseltamivir and zanamivir, were developed based on different structures of neuraminidase, such as subtypes N9, N2, and type B genus of influenza virus [14] , [15] and [16] . Recently, the reported oseltamivir-resistance H5N1 virus neuraminidase still retaining susceptibility to zanamivir [11] indicates that the structure of zanamivir has some more advantages than oseltamivir in binding to the active pocket of H5N1 neuraminidase.(Qi-Shi Du, Shu-Qing Wang and Kuo-Chen Chou, 2007)

References

F.G. Hayden, Perspectives on antiviral use during pandemic influenza, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 356 (2001), pp. 1877–1884.

Qi-Shi Du, Shu-Qing Wang and Kuo-Chen Chou, Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus, Biochemical and Biophysical Research Communications, Volume 362, Issue 2, Pages 525-531, 19 October 2007

David Cyranoski,Threat of pandemic brings flu drug back to life,Nature Medicine, Volume 11, doi:10.103831, pages 905-909, August 2005

Professor Graeme Laver,Flu drugs - pathway to discovery, Education in Chemistry, March 2007

External links

* [http://www.omedon.co.uk/influenza/ The development of Relenza for treatment of influenza]
* [http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500004.html Medlineplus drug information for zanamivir]
* [http://www.fda.gov/cder/news/relenza/default.htm FDA information page for Relenza]
* [http://www.biota.com.au/?page=1021002&subpage=1021104 Relenza Biota Holdings]


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