Zanamivir

Zanamivir (INN) (pronounced /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.

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Development

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.

The strategy relied on the availability of the crystal structure of influenza neuraminidase which was achieved by x-ray crystallography. 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.^[1] 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.^[2]

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.

Limitations

Whilst zanamivir proved to be a potent and effective inhibitor of influenza neuraminidase and 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.

A further limitation concerns the poor oral bioavailability of zanamivir. This meant that oral dosing was impossible, limiting dosing to the parenteral routes. 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 tamiflu that can be taken orally, yet does cause some severe side effects, potentially lethal, and showing more and more signs of viral resistance.

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. ^[3]

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 is of the opinion that Glaxo's reduced marketing of Relenza is a breach of contract, a charge Glaxo denies. Legal proceedings are ongoing.

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).

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