Molecular structure of zanamivir
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Zanamivir

Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza®. more...

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Development

Zanamivir was discovered in 1989 by scientists at the Australian biotechnology company Biota Holdings, working in conjunction with the CSIRO and the Victorian College of Pharmacy. The development was part of Biota's ongoing program to develop antiviral agents through rational drug design. An outline of the successful rational design strategy used was published in a paper in Nature (von Itzstein et al., 1993).

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 (Meindl et al., 1974). 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 better fitted (and therefore inhibited) the active site of neuraminidase. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.

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 even this route of administration is not acceptable to many in the community.

A troubled commercial venture

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, and some would say cumbersome, 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 formulation much preferred by patients. Faced with this competition, GSK effectively abandoned the product.

Read more at Wikipedia.org


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NICE to rule on influenza flu drug zanamivir - News - Statistical Data Included
From British Medical Journal, 10/9/99 by Gavin Yamey

The British pharmaceutical industry will start to move out of Britain if the government makes the environment antagonistic to its interests, Sir Richard Sykes, chairman of GlaxoWellcome, predicted on Monday.

Sir Richard's comments, on BBC Radio 4's Today programme, came after it was reported that the National Institute for Clinical Excellence (NICE) was about to recommend to the health secretary, Frank Dobson, that GlaxoWellcome's new influenza drug zanamivir (Relenza), should not be available on the NHS.

Sir Richard said that his company was not threatening to pull out of Britain, but he warned: "If [the government] continues to make the environment antagonistic to this industry then obviously it will start to move elsewhere. It is something which needs to be taken into consideration." He added that although 94% of his company's business was abroad, about 50% of its research work was conducted in Britain.

His remarks suggest that there will be a savage straggle between the new institute and the industry whenever the institute tries to restrict the introduction of a new drug.

The institute, which is undertaking a full eight month assessment of zanamivir, set up a special rapid assessment committee, chaired by its chief executive, Andrew Dillon, to produce preliminary guidance on the drug before a possible autumn or winter flu epidemic. The committee met twice in September and invited representatives from GlaxoWellcome to attend its second meeting.

Under the institute's rules, the manufacturer of any drug that is being assessed has the right to appeal to the institute's board, before any interim guidance is submitted to the secretary of state. GlaxoWellcome has just done so.

The crux of the argument over zanamivir hinges on whether trials have proved that the drug is effective in high risk patients, such as elderly people, or those with chronic respiratory disease. In its appeal, GlaxoWellcome has presented the institute with a new pooled analysis of its data, claiming that they show that the drug does benefit high risk patients.

Sir Richard, moreover, told the Today programme that the drug had been tested in 6000 patients. Only a small proportion of that number had come from high risk groups, because it was hard to enrol people from such groups into trials, but the numbers enrolled had been sufficient.

But Dr Robert Pearson, the company's associate medical director, said at a press conference in September: "We can't make any claims for its use in high risk groups" (11 September, p 659).

Professor Rory Collins of the Clinical Trials Services Unit in Oxford commented that "ideally trials should be done in as wide a range of patients as possible. Part of the rationale, on the part of the drug companies, for not recruiting elderly patients is that their side effect profile may be worse. There's also a tendency to try and exclude people with other diseases, with the fear that comorbidity will show up as a side effect."

COPYRIGHT 1999 British Medical Association
COPYRIGHT 2000 Gale Group

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