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Thursday 21 September 2006

Viagra's Enzyme Action May Give Pfizer Schizophrenia Advance

By: Shannon Pettypiece

Viagra has improved sex for millions of men and has generated $12 billion in sales for Pfizer Inc. Now the erection pill is providing the world's biggest drugmaker clues to a new way to fight schizophrenia.

Researchers at Pfizer are using insights into Viagra to design experimental drugs that may improve on Zyprexa, the best- selling schizophrenia remedy from Eli Lilly & Co., with $4.2 billion in sales last year. Viagra causes an erection by turning off an enzyme in the body. Blocking similar chemicals in the brain may silence the hallucinations typical of schizophrenia, the researchers say.

A better schizophrenia drug would be a boon for New York- based Pfizer and the 2.5 million Americans who suffer the debilitating mental disorder. Pfizer's current schizophrenia medicine, Geodon, had only 4 percent of the $15 billion spent worldwide in 2005 for anti-psychotic drugs. Researchers say the new Viagra-like compounds will be developed only if shown in human tests to be safer and more effective than existing drugs.

"We believe this drug is going to be different,'' says Frank Menniti, a scientist at Pfizer's Groton, Connecticut, labs. ``Our job isn't just to make another anti-psychotic. We need to make a better anti-psychotic than what is out there.''

Starting in 1998, company researchers began probing the role that a family of enzymes called phosphodiesterases play in the human body, says Martin Jefson, a Pfizer scientist. Viagra works by inhibiting one of the enzymes in the group. The scientists figured drugs similar to Viagra that block other forms of the enzyme might be useful in other diseases, according to Jefson.

Mapping Enzymes

Within a year and a half, the Pfizer team had mapped the location in the body of all the enzymes, including one in the brain linked to mental illnesses such as schizophrenia and obsessive-compulsive disorder, Menniti says.

In late 1999, a research team at Pfizer's Sandwich, England, labs began making gallons of the schizophrenia-related enzyme from insect cells. With plenty of the enzyme on hand, the scientists tested thousands of chemical compounds during the next four years to see whether any blocked the enzyme's activity in test-tube experiments, says Menniti.

Chemists then adjusted the structure of compounds that showed some action against the enzyme to make a molecule most likely to be safe and effective in humans, Jefson says. By 2003, after researchers had synthesized a batch of chemicals that impeded the brain enzyme, they began testing the compounds' effects in lab animals, he says.

Human trials are probably years away, and there is no certainty that the U.S. Food and Drug Administration will be able to measure the mood enhancements that Pfizer envisions. The agency may not be able to approve drug for that benefit.

Hearing Voices

Schizophrenia, which usually strikes people in their teens to late 20s, causes victims to hear voices, feel frightened and hallucinate, all of which makes leading a normal life impossible, doctors say. As many as one in 100 people in the U.S. may be victims of the disease, according to the National Institute of Mental Health in Bethesda, Maryland.

The most popular drugs, such as Zyprexa, from Indianapolis- based Lilly, and Risperdal from New Brunswick, New Jersey-based Johnson & Johnson, and three other similar drugs including Pfizer's Geodon, allow many with the disease to live symptom- free. Still, some patients don't regularly take their pills, and about 74 percent stop treatment after 18 months, according to a 2005 study in the New England Journal of Medicine.

Patients discontinue the medication because they say it makes them lethargic and withdrawn and can cause weight gain that is annoying and dangerous, as it can lead to diabetes, says Robert Freedman, chairman of the department of psychiatry at the University of Colorado at Denver. Current drugs also don't help patients overcome difficulties in making judgments, which can hinder relationships and employment, Freedman says.

1950s-Era Remedies

There has been little innovation in the way schizophrenia treatments work since the 1950s when the first drugs came on the market that allowed victims to live outside mental hospitals, says Jeffrey Lieberman, chairman of psychiatry at Columbia University College of Physicians and Surgeons in New York and director of the New York State Psychiatric Institute.

The older drugs, and the newer ones like Zyprexa and Risperdal, reduce the activity of dopamine, a chemical in the brain that regulates movement, feelings of pleasure and emotions. Scientists say they believe excessive amounts of dopamine, or brain cells' heightened sensitivity to the chemical, trigger troubling thoughts and feelings.

"With schizophrenia, we just by happenstance stumbled on a treatment 50 years ago that we've just been cloning since and haven't made much further progress,'' says Lieberman, who has worked with Pfizer on unrelated research projects. He says one challenge in treating schizophrenia is that no one knows exactly why some people develop the dopamine-related responses.

Rodent Experiments

Preliminary studies suggest Pfizer's new treatment may provide an advance, the company's scientists say. They point to experiments in lab rodents bred to have traits that mimic antisocial human behavior. These findings show the drug may help patients feel more engaged in their surroundings than do the current treatments. Pfizer's approach, which blocks an enzyme called PDE-10, appears to improve how the animals respond to their environment.

Pfizer won't comment on when it expects to begin human testing.

PDE-10 appears to regulate the two other molecules that control the transmission of electrical signals within cells. Scientists found that by turning off the PDE-10 enzyme they can mute the animals' reactions to a variety of stimulation.

'Very Innovative'

This fits into some scientists' hypothesis that schizophrenia is caused when the brain is unable to filter out background noises, like the humming of the lights or drone of an air conditioner. This flood of stimuli causes the brain to create a story around those noises, leading to hallucinations and paranoia, Pfizer's Jefson says. Drugs that can soften the brain's response to visual and auditory stimulation will probably reduce disease symptoms, he says.

"This is a very innovative and potentially important development strategy because it is not focusing on dopamine,'' Lieberman says. ``It is high-risk and there is no idea if it will work.''

Pfizer is in a race with other drugmakers, including London- based AstraZeneca Plc and Eli Lilly, to produce drugs that sharpen patient awareness and other cognitive skills, says Kate Hohenberg, a health-care analyst at Decision Resources Inc., a market research firm in Waltham, Massachusetts.

Amgen Inc., a biotechnology company based in Thousand Oaks, California, and Memory Pharmaceuticals Corp. are also exploring ways to use the PDE-10 enzyme to treat certain psychological disorders, according to a statement last October by Memory Pharmaceuticals, a Montvale, New Jersey-based company focused on treating psychological conditions.

No FDA Guidelines

Pfizer and its competitors say it may be difficult to prove that drugs like this one are advances over existing pills. That's because the Food and Drug Administration doesn't have guidelines to measure whether a medicine improves a person's judgment, mental awareness or social interactions.

While Pfizer may be able to get a new drug approved that only eliminates hallucinations and other symptoms, company researchers say they want to be able to market a medicine that does more.

"It is very frustrating to have this great unmet need, and the regulatory path is not clear, and there is not much pharma can do about it,'' Hohenberg says.

Mental Judgment

Thomas Laughren, the FDA's head of psychiatric products, says the agency has talked with ``many companies'' developing drugs to determine what data would be required to get approval for a medicine that improves a patient's mental judgment as well as quieting the disease's disturbing symptoms.

"In the beginning, you've got about a one in a hundred chance of making a compound into a medicine,'' Menniti says. ``At this stage in the game, it is probably down to about one in 10. That says nothing about this program. It says something about the process in general.''

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