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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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Zanamivir In The Prevention Of Influenza Among Healthy Adults
From Journal of Family Practice, 10/1/99 by Douglas J. Bower

Clinical question How effective is orally inhaled zanamivir in the prevention of influenza in healthy adults?

Background Although vaccination is the preferred method of prevention for influenza, chemoprophylaxis is an important adjunct in specific situations. Amantadine and ramantadine are currently used for this purpose, but they are only effective against influenza A, not influenza B. Zanamivir, a neuraminidase inhibitor, is in a new class of antiviral medications shown effective in the treatment of influenza A and B. This study addressed the efficacy of zanamivir as a chemoprophylaxis agent for influenza.

Population studied A total of 1107 healthy adults, mainly students and community volunteers aged 18 to 69 years (mean = 29 years), were recruited from the midwestern university communities of Ann Arbor, Michigan, and Columbia, Missouri, before the 1997-1998 influenza season. Exclusion criteria included any chronic condition that increased the risk of complications due to influenza, pregnancy, lactating women, and any respiratory illness present at the onset of treatment. The 14% who were vaccinated before randomization were not excluded.

Study design and validity In this double-blind randomized placebo-controlled trial, subjects received either 10 mg orally inhaled zanamivir once daily or an identical placebo at the beginning of the influenza season. During the 4-week trial, participants rated and recorded any symptoms twice a day and obtained daily temperatures. Each week they returned to the study center, and culture for virus isolation was obtained for any respiratory symptoms. On day 35, serum viral serology was obtained and compared with serum collected during enrollment. In both groups compliance was high, and the dropout rate was low. After randomization, all analyses were done on an intention-to-treat basis. This study was well designed to demonstrate the effectiveness of zanamivir in preventing clinically relevant influenza in a healthy adult population.

Outcomes measured The percentage of laboratory-confirmed clinical influenza, laboratory-confirmed influenza with fever, all febrile illnesses, and influenza infection without illness were compared between the treatment and control groups. Laboratory confirmation of infection required a rise in titer or isolation by culture. Clinical illness was defined as 2 or more symptoms, including cough, headache, sore throat, myalgia, feverishness, or a temperature of at least 37.8 [degrees] C on 3 or more successive diary entries. Laboratory-confirmed influenza with fever required recording a fever on only one occasion.

Results Orally inhaled zanamivir once a day was 67% effective in preventing laboratory confirmed clinical influenza (95% confidence interval [CI], 39% - 83%; P [is less than] .001; number needed to treat [NNT] = 25), and 84% at preventing laboratory-confirmed influenza with fever (95% CI, 55% - 94%; P = .001; NNT = 36). All influenza infections were prevented with a lower efficacy of 31% (95% CI, 4% - 50%; P = .03; NNT = 25). Side effects and number of withdrawals from the study because of adverse events were the same in both the treatment and placebo groups. Unfortunately, only influenza type A isolates were identified. No type B influenza was identified at either site.

Recommendations for clinical practice Zanamivir is not currently clinically available; however, this is a well-done clinical study showing convincing evidence that when orally inhaled, zanamivir is efficacious in preventing influenza type A. Its efficacy is at a level comparable with estimates for amantadine and rimantadine in studies with a similar design and is at least as well tolerated. Although theoretically promising, the potential for demonstrating the efficacy of zanamivir in preventing influenza B could not be assessed, because there was no circulating influenza B virus detected at the time of the study. Since this study included only healthy younger adults, we cannot generalize the efficacy and safety to the elderly or other high-risk populations in whom chemoprophylaxis is most often needed.

Monto AS, Robinson DP, Herlocher ML, Hinson JM, Elliott M J, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999; 282:31-5.

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