The Other Drug for Avian Flu
As things stand, if an Avian Flu pandemic breaks out before a vaccine has been
developed, the first line of defense is Roche’s much-ballyhooed antiviral drug, Tamiflu.
As a second choice, doctors will turn to GlaxoSmithKline’s Relenza, a drug that is more
expensive and harder to obtain.
In the freewheeling drugstores of Hong Kong, pharmacists have seen neither
Tamiflu nor Relenza for several months. The local agents for GSK and Roche no longer
deliver the drugs to private drugstores, pharmacists say. But whereas drugstore managers
expect Tamiflu to soon become available again in local shops, they aren’t holding their
breath for Relenza.
The World Health Organization (WHO) says that oseltamivir and zanamivir –
Tamiflu and Relenza, respectively, by their generic names – have proven effective in
reducing the severity and duration of the seasonal flu. Therefore, the drugs “may
improve the prospects of survival [from avian flu], if administered early,” the agency
says.
Peter Corkingley, a Manila-based WHO spokesman, says it may be a good idea to
stockpile both drugs in order “to have several options, since we don’t know what kind of
virus would a pandemic.” The bird flu virus, also known as H5N1, is still evolving and
has not yet developed into a strain that can transmit from human to human.
Kenneth W. T. Tsang, a specialist in respiratory medicine who is an honorary
professor at both the University of Hong Kong and Hong Kong Polytechnic University,
has a slight preference for Relenza. The possible side effects of Relenza include
bronchospasms, which he says are manageable. But trials have shown that a quarter of
Tamiflu users develop flulike symptoms that could be the source of much confusion
during a pandemic.
Tsang has studied respiratory infections for 15 years and managed patient care in
the West Hong Kong region during the 2003 severe acute respiratory syndrome (SARS)
crisis. Despite his bias toward Relenza, he does not have much confidence in the
effectiveness of either medicine against the H5N1 virus. It’s too virulent, he says. Avian
flu deaths in Vietnam and Thailand have exceeded 60% even after patients received
Tamiflu.
Still, available drugs should be more rigorously tested for their efficacy against
the bird flu, he says. Unlike SARS, which hit medical authorities without warning, the
avian flu is providing much advance notice of its arrival.
Several governments have ordered Relenza, although Tamiflu remains by far their
first choice. Last month, for example, the U.S. Department of Health & Human Services
ordered 16.2 million Tamiflu treatment courses but only 3.95 million Relenza treatment
courses.
WHO prefers Tamiflu to Relenza, partly because Relenza is more expensive and
partly because it believes the GSK drug is unsuitable for people with chronic respiratory
problems such as asthma. Similarly, the Hong Kong government, which has ordered 1.5
million Relenza treatments, believes zanamivir to have “relatively low systemic
bioavailability.”
At issue is the way Relenza is administered. A major difference between Tamiflu
and Relenza is that the former is ingested while the latter is inhaled. Roche packs
Tamiflu in a box containing 10 blisters. A full course of treatment involves taking the 10
pills over five days. GSK similarly sells Relenza as one course of treatment. The
Relenza package contains 20 pills that are to be inhaled over five days with the help of a
device know as the Diskhaler.
The GSK inhaler is the source of controversy. WHO spokesman Cordingley syas
it is too complicated to use. “It is expected to be very difficult to teach people who
cannot read or who are not familiar with such devices,” he says. He adds that the
presence of the inhaler in each box makes stockpiling Relenza difficult. Finally, he says,
the device is costly to produce and prevents GSK from offering volume discounts.
The inventor of Relenza, the Australian company Biota, is suing GSK over its
allegedly poor performance in promoting the antiviral drug. Part of the problem, Biota
says, is that GSK “did not adequately pursue alternative or improved inhalation systems.”
Biota agreed to license Relenza to GSK in 1990 in exchange for a 7% royalty on global
sales of the drug.
Yusuf K. Hamied, the chairman and managing director of Indian generic drug
company Cipla, says there is no need to administer Relenza with a complex device like
the Diskhaler. His company has developed a generic version of Relenza and has applied
to market it in India and the U.S. in conjunction with a lower cost inhaling device.
Cipla will sell its generic zanamivir for the same price as its generic oseltamivir,
Hamied predicts. He expects that the U.S. Food & Drug Administration will approve
generic oseltamivir and zanamivir in the event of a pandemic.
Controversy has dogged Relenza almost since the product was first approved in
1999 as a treatment for seasonal flu. It led the biostatistician Michael Elashoff to leave
FDA. The holder of a Ph.D. in biostatistics from Harvard University, Elashoff was one
of the officials reviewing Relenza’s clinical trials data. He opined that Relenza should
not be approved given that the data he reviewed did not show much effectiveness and that
it has potential side effects such as bronchospasms.
In an interview aired by the Public Broadcasting Service in 2003, Elashoff said
some asthmatic patients who took Relenza later died from severe bronchospasms. He left
FDA, claiming that senior officials relieved him of most of his duties because of his
views on Relenza.
Today, Elashoff does not believe that Relenza will work against the bird flu
either. “Since it had such limited efficacy against regular flu, it would seem unlikely to
have much efficacy against the bird flu,” he tells C&EN. Elashoff now runs his own
biostatistics consultancy.
In the U.K., where GSK is headquartered, Relenza gave rise to a battle in 1999
between the drug company and the National Health Service, the government agency that
funds most hospitals. Then-health minister Frank Dobson instructed doctors not to
prescribe Relenza for the seasonal flu because of its price and the potential risks posed by
side effects. This led Richard Sykes, chairman of what was then Glaxo Wellcome, to
threaten to pull the company out of the U.K. in view of the government’s “antagonistic”
attitude toward the drug industry.
These setbacks early in the commercial life of Relenza are not water under the
bridge as bird flu fears intensify. Until new drugs, or a vaccine, emerge, Relenza is still
one of the only two possible ways to treat H5N1, and demand for Relenza is outstripping
GSK’s ability to meet it.
Relenza had until very recently been a disappointing drug for GSK. According to
the pharmaceutical market consultancy IMS Health, worldwide sales of Relenza, based
on the manufacturer price, were a mere $8.1 million last year.
According to Sarah J. Stuckey, a GSK spokeswoman based in Australia, it takes
more than a year for GSK to fulfill new Relenza orders. “Orders placed now, if in excess
of the available existing installed capacity (due to other health agency pandemic
stockpiling orders), could not be supplied for at least 18 months,” she says.
This suggests that GSK’s ability to supply the drug is declining. Diana Kam, a
spokeswoman for Hong King’s Department of Health, says GSK took five months to
fulfill an order the agency made last September for 1.5 million Relenza treatments.
Roche recently announced that its capacity for Tamiflu will reach 190 million
treatments this year and 400 million in 2007. The company has licensed production of
Tamiflu to other companies and is also working with subcontractors to boost supplies.
By contrast, it is difficult to gauge how much progress GSK is making in boosting
Relenza capacity. The company answered only a few of C&EN’s questions on this
subject numerous inquiries. Stuckey does say GSK is not spending close to $100 million
on expanding production of Relenza. Of this amount, the company recently spent $15
million to boost Relenza output at a plant in Australia.
As to GSK’s current capacity, “we don’t provide specific numbers because the
number changes as we work on increasing capacity,” Stuckey says. She adds that GSK is
“open to voluntary licenses with any companies that can assist in our efforts to supply
Relenza.”
GSK would not provide details on the process it uses to synthesize zanamivir,
though Stuckey insists it is complex. A paper published in 1996 in Drugs of the Future
describes an eight-to-nine-step process. The starting material for Relenza is Nacetylneuraminic acid (NANA), which at present costs $3,000-$4,000 per kg, according
to Cipla’s Hamied. He says he obtains his material from China.
CMS Chemicals, a British specialty chemical manufacturer, recently announced
that it will be producing several tons of NANA in Slovakia, making use of an enzymatic
process developed by Germany’s Julich Research Center. The process was later refined
by CMS and Julich Chiral Solutions, an enzyme developer based near the research center.
CMS says the NANA produced could be used to make Relenza and in nutraceutical
formulations.
Although some research shows that Relenza may be more effective than Tamiflu
against H5N1, GSK is focusing mostly on the development and production of an
effective vaccine. The $100 million or so the company is spending to boost Relenza’s
output pales in comparison to the almost $2 billion it claims to be investing in bird flu
vaccine development. GSK announced late last month that it was initiating clinical trials
of two avian flu vaccines in Europe.
In Hong Kong, respiratory diseases specialist Tsang agrees that R&D efforts
should be applied to developing a vaccine rather than new courses of treatments.
Immunizing humans will allow life to continue more normally in the event of a
pandemic, he says. Furthermore, he adds, H5N1 has shown it can grow resistant to
antiviral drugs.
But the possibility of a pandemic should be kept in perspective, Tsang says.
Since 2003, roughly 100 people worldwide have died of the bird flu. A clearer danger is
posed by the seasonal flu, which according to the Centers for Disease Control &
Prevention, kills about 50,000 per year in the U.S. alone.