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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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Effects of Zanamivir on the Course of Influenza
From American Family Physician, 2/1/00 by Jeffrey T. Kirchner

Zanamivir represents a new class of antiviral agents known as neuraminidase inhibitors. In vitro and in vivo studies have demonstrated that zanamivir exerts activity against influenza virus types A and B. Monto and colleagues evaluated the clinical efficacy and safety of zanamivir in a double-blind randomized, placebo-controlled trial.

The multicenter study included 1,256 patients who were at least 13 years of age (mean age: 34, 35 and 36 years in each treatment group) and had symptoms of influenza for 48 hours or less. Symptoms of influenza included fever plus at least two of the following symptoms: cough, sore throat, myalgias and headache. Influenza was confirmed by laboratory tests in 722 (57.5 percent) of the patients. The study included 158 high-risk patients, such as those over the age of 65 and those with chronic cardiovascular, respiratory, metabolic or endocrine disease.

Patients were randomized into four treatment groups: 10 mg of zanamivir by oral inhalation and 6.4 mg by nasal spray, administered twice daily (419 patients); 10 mg of zanamivir by oral inhalation and 6.4 mg by nasal spray, administered four times daily (415 patients); twice-daily administration of placebo by both routes, and four-times-daily administration of placebo by both routes. The placebo groups included 422 patients. Patients took the medication for five days. The first dose was given at the initial clinic visit, when patients received instructions on administering their therapy. Study participants were also given dextromethorphan and acetaminophen but were told to use these drugs only if it was absolutely necessary.

Patients kept a record of oral temperature and severity of symptoms for 10 days. Symptoms were rated on a scale of zero to 5, with a score of 5 corresponding to the severest symptoms. They also noted any sleep disturbances, the level of their ability to perform daily functions and their overall health status.

Analysis of the data revealed that zanamivir reduced by one day the median number of days that clinically significant symptoms were present. Overall, symptoms were present for six days in the patients receiving zanamivir compared with seven days in those receiving placebo. The duration of illness was decreased by 1.0 to 1.5 days in patients who began taking zanamivir within 30 hours of the onset of symptoms. Symptoms were alleviated in a median of 5.5 days among the patients who began receiving twice-daily zanamivir within 30 hours of the onset of symptoms. In the four-times-daily group, symptoms subsided in a median of 5.0 days. In the placebo group, symptoms subsided in 6.5 days. No statistically significant difference in duration of illness was found between the two zanamivir-treatment groups. Among the high- risk patients with laboratory-confirmed influenza, zanamivir reduced the duration of symptoms by 2.75 days in the twice-daily treatment group and by 3 days in the four-times-daily treatment group.

The most common adverse events were nasal symptoms, headaches, bronchitis and gastrointestinal upset. The incidence of these adverse events ranged from 1 to 4 percent in the zanamivir treatment groups. A comparable incidence of adverse events was observed in the placebo group.

The authors conclude that zanamivir is a safe and effective treatment for influenza virus types A and B. The benefits seem to be greatest when the illness is most severe and when antiviral therapy is initiated early in the course in high-risk patients. Thus far, viral resistance to the drug has not been observed.

Monto AS, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis August 1999;180:254-61.

editor's note: Zanamivir (Relenza) was labeled for the treatment of influenza without complications by the U.S. Food and Drug Administration in July 1999. Additional data and clinical experience will further elucidate the effectiveness of this agent in the treatment of influenza.

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