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Prostitutes, Gene Flaw Spur Pfizer Hunt for AIDS Drug (Update2)

By Andrea Gerlin

March 1 (Bloomberg) -- In 1996, scientists solved a mystery surrounding certain gay men who were immune to AIDS. This year, Pfizer Inc. will sell the first drug based on that discovery.

The U.S. and European researchers, writing in several science journals, said a small group of Caucasian gay men carry a gene mutation that provides natural protection against HIV, the virus that causes AIDS. This week, culminating an 11-year race among three drugmakers, Pfizer released successful studies of a new pill specifically designed to mimic the gene defect.

``We still remember reading those papers and thinking, `God, we should do something with this',' says Pino Ciaramella, a scientist at Pfizer's laboratories in the U.K. seacoast town of Sandwich, where the drug was created.

Regulators in the U.S. and Europe have accelerated reviews of the drug, called maraviroc, based on clinical trials showing that, when combined with other medicines, the pill is more effective than existing therapies in treating AIDS patients. The new drug may gain regulatory approval this year and generate more than $300 million in sales by 2011 for New York-based Pfizer, the world's largest drugmaker. It also may arm doctors with a new weapon against forms of the virus that are resistant to current drugs.

Ciaramella, 38, says he and his colleagues were spurred into action because the reports involving gay men were followed three months later by another study reinforcing the notion that some people can inherit immunity to HIV. In that research, Canadian and Kenyan investigators reported that 60 prostitutes in Nairobi didn't become infected after being repeatedly exposed to the virus over 10 years.

HIV Hooks

As a result of the studies, scientists realized that HIV carries out its damage by first hooking onto a spike called a receptor that juts out from the surface of white blood cells, much as a key enters a lock. The gay men of European descent, the scientists found, were shielded from HIV infections by inheriting a defective version of the cell receptor, called CCR5.

Pfizer scientists say this critical finding led them to believe they might be able to create a drug against the virus that worked by binding to the CCR5 receptor, thereby blocking the doorway HIV uses to infect cells.

``The whole thing was started by noticing this genetic defect,' says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.

Other drug companies, including GlaxoSmithKline Plc, based in London, and Schering-Plough Corp. of Kenilworth, New Jersey, also began chasing after their own CCR5-blockers when the gene defect discovery was reported in 1996. Glaxo terminated its project in 2005 when its drug proved to be toxic to the livers of test patients.

Schering-Plough Setback

Schering-Plough's candidate suffered a setback in 2006 after five patients in one study developed cancer. The company expects to begin a larger trial of the drug later this year after an independent monitoring board ruled there wasn't enough evidence to determine the drug caused the cancers, says spokesman Robert Consalvo.

``It's why competition is good,' says David Roblin, Pfizer's head of clinical research and development at the Sandwich site. ``It's lucky it was us' that succeeded.

Shares of Pfizer fell 37 cents to $24.59 at 9:54 a.m. in New York Stock Exchange composite trading. The stock has dropped about 4.8 percent this year.

Maraviroc, when used in combination with other drugs, more effectively suppressed blood levels of the virus than the standard three-drug HIV therapy in current use, according to data Pfizer presented at an AIDS research meeting in Los Angeles on Feb. 27.

No Admittance

Ciaramella, a biochemist, had only arrived at Pfizer a few months before the 1996 studies were published. ``It was one of my first projects,' he says.

He and his colleagues at the Sandwich lab, where five of the company's current 20 top-selling medicines, including Viagra, were discovered, spent five months in 1997 testing 500,000 chemicals to see whether any interacted with the CCR5 receptor.

After finding the chemical with the most promise, the team spent the next two years modifying it. Using robots in a laboratory outfitted to limit the risk of accidental infection, they tinkered with the drug candidate, manipulating its structure to produce more than 1,100 different versions.

By 2000, their research had led to two compounds, maraviroc and another, called UK-436488. The chemicals were structurally identical except a nitrogen bond in the center of the molecules projected outwards in one and inwards in the other.

The Prototype

That difference meant UK-436488 was also 1,000 times less active than maraviroc, says Tony Wood, 41, head of discovery chemistry at the lab. ``You can make very small changes and lose activity altogether,' he says.

That year, Wood and his colleagues synthesized a prototype drug that in test-tube experiments tightly bound to the CCR5 hook and also appeared unlikely to cause side effects.

``What really made maraviroc stand out was that it was a compound that seemed to balance all the properties we were looking for better than the others,' Wood says. ``It was very potent.'

In the next year, Pfizer tested maraviroc in lab animals including rodents. It was first administered to people in 2001 and, after positive initial results, trials aimed at gaining regulatory approval began at 250 centers in 16 countries in 2004.

Blood Tests

Marketing clearance this year would mean that it took about a decade for maraviroc to go from the laboratory to the market. That's less than the average time of 14.2 years, according to research by Joseph A. DeMasi of the Tufts Center for the Study of Drug Development in Boston.

``That's faster than most,' said Annette Doherty, a Pfizer senior vice president and director of the Sandwich lab.

The U.S. Food and Drug Administration says it will review Pfizer's application on April 24 and may make its decision in June. The European Medicines Agency may rule on the drug later this year.

One drawback for the drug is that it only works in patients in which HIV uses CCR5 to pierce cells -- estimated to be about half the people infected. The virus can use another similar receptor to enter cells of other patients. The drugmaker plans to sell maraviroc only to those patients identified in blood tests as having active CCR5 receptors, company spokesman Joel W. Morris says.

The cost of that test may be as high as $1,000 in the U.S., says Bob Huff, editorial director of New York-based Treatment Action Group, an advocacy group. Pfizer hasn't set a price for maraviroc. Analysts estimate Pfizer will charge about $5,000 a year for the drug.


Maraviroc may be especially valuable in treating patients for whom existing drugs don't work anymore. Doctors now estimate that as many as 65,000 people with HIV in the U.S. are resistant to all three major classes of medications and in worsening health.

Blocking the receptor may lead to unintended effects, including the possibility that the virus may eventually find a way into cells through another receptor, say Huff and Fauci. Humans have numerous such receptors, which is why some people can function normally without a working version of CCR5.

``It's a theoretical risk,' says Fauci, ``but it's not so far-fetched either.'

To contact the reporter on this story: Andrea Gerlin in London

Last Updated: March 1, 2007

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