~ Scientist's Theory on Diseases of Aging Being Put to Test

Milwaukee Journal Sentinel, 09-20-05

MADISON, Wis. - Craig Atwood thinks he knows why most of us will get old and die. And it's all about sex.

The maverick University of Wisconsin-Madison researcher is convinced that's the secret of why cancer cells might spread through our organs, why our hearts someday might fail and why our brains might be short-circuited by Alzheimer's disease.

His theory soon will be tested in two large, yearlong clinical trials of a novel Alzheimer's drug, according to a company founded by the doctor who developed the theory with Atwood. The Food and Drug Administration has approved the trials, the company said in documents filed this month.

Voyager Pharmaceutical plans an initial public stock offering to raise as much as $129 million to help fund the trials and to advance its research on using its drug to treat prostate cancer and brain cancer. It has enlisted Tommy G. Thompson, the former Wisconsin governor and former secretary of the U.S. Department of Health and Human Services, to serve on the company's board of directors.

In their paper published last year in the journal Gerontology, Atwood and co-author Richard Bowen titled the idea "Living and Dying for Sex." Simply stated, they say hormones that regulate sexual reproduction early in life can act in a harmful manner later in life, generally when people reach their 40s. That happens because in an attempt to maintain reproduction, the hormones futilely stimulate cells in the body to divide, resulting in cell damage and disease.

Beginning later this year, a total of 1,100 people with mild to moderate Alzheimer's disease will be enrolled in the two trials, which will be a major test of the theory's validity.

"That's going to be the proof," said Donald Ingram, a scientist with the National Institute on Aging, part of the part National Institutes of Health.

Out of the mainstream "No one has come up with anything that contradicts this idea, that reproduction and longevity are coupled," Atwood said in an interview.

But the idea remains far out of the mainstream, said Ingram, who is not a part of the research.

"It's like a little tributary trying to find its way to the sea," he said.

Still, the theory is based on some sound scientific ideas, Ingram said. He noted that humankind has defeated a lot of the environmental forces, such as germs and poor nutrition, that used to kill people earlier in life.

"We are not evolved to live such long lives," Ingram said. "There is no genetic program to keep us staying vital past a certain age."

The scientific concept of hormonal wear and tear, which the theory taps into, has been around for years, Ingram added.

Aubrey de Grey, a biomedical gerontologist at the University of Cambridge in England, said of the theory: "It is consistent with what we know, and therefore, it's well worthy of further detailed investigation."

The theory's main weakness is that it says only that reproductive hormones have some effect on aging, not specifically how much, said de Grey, who is not associated with Bowen and Atwood.

Equally out of the mainstream is their view of what causes Alzheimer's disease. Even the company Bowen co-founded acknowledges that its theory has not gained the wide acceptance of the prevailing view: that the disorder is caused by the buildup of beta-amyloid protein in the brain. Much of Alzheimer's research focuses on preventing beta-amyloid from forming or clearing it from the brain.

Voyager Pharmaceutical's drug works in a completely different way, by reducing the levels of sex hormones that Atwood and Bowen think are causing damage to brain cells.

In public documents, the company released unpublished data from smaller clinical trials it conducted, suggesting that its drug might stabilize Alzheimer's patients.

The results are promising, but questions remain, said William Thies, vice president of medical and scientific affairs at the Alzheimer's Association.

With plans to enroll 1,100 patients, the trials will be among the largest Phase 3 Alzheimer's drug trials when they begin this year, he said. Phase 3 trials are large, double-blind trials designed to prove the effectiveness of a therapy. In general, successful Phase 3 trials are needed before a drug can be approved.

It's also likely to be expensive, as much as $300 million, he said.

"If they prove this does stabilize Alzheimer's disease, they will have done a wonderful thing," Thies said. "If not, they will have spent a lot of money."

Piero Antuono, an Alzheimer's specialist at the Medical College of Wisconsin, said the earlier trial results, although involving only a small number of patients, seem to show a significant benefit.

The current line of Alzheimer's drugs affects levels of certain neurotransmitters, chemicals made in brain cells that can facilitate memory. And those drugs have only a modest effect.

"Hormones are a totally different class of drugs than we've seen before," said Antuono, a professor of neurology.

At the same time, Voyager is looking into the treatment of other diseases, including prostate cancer, brain cancer, amyotrophic lateral sclerosis (Lou Gehrig's disease) and disorders that occur in infants who are born prematurely, according to a document filed Sept. 9 with the Securities and Exchange Commission.

For Atwood, an assistant professor of medicine at the University of Wisconsin, the Alzheimer's trials represent the culmination of several years of work developing a controversial - some say revolutionary - theory of why people age.

He has lectured on the theory but made few converts. Atwood and Bowen, who also serves as chairman and chief scientific officer of Voyager Pharmaceutical, which is based in Raleigh, N.C., have sent manuscripts to prominent scientific journals such as Nature and Science, only to have them rejected.

Even the University of Wisconsin, which recruited Atwood and where he has worked for two years, has yet to promote his work, although Atwood's laboratory program at the university and the VA Hospital in Madison has about 10 people who work on various aspects of the theory.

"We've become very frustrated," said Atwood, who owns stock in Voyager and is a company consultant. "We thought people would sit up and notice."

However, with the FDA's approval of the Phase 3 Alzheimer's trials, they now are getting the attention of researchers.

Atwood said Bowen stumbled upon the idea several years ago when a prostate cancer patient who also had Alzheimer's saw his Alzheimer's symptoms become stabilized after he started taking the drug leuprolide acetate, which has been used for more than 20 years to treat conditions such as prostate cancer, endometriosis and precocious puberty.

For Alzheimer's, their theory works something like this:

Adult brain cells generally do not divide and replicate. However, when those cells continually are stimulated to divide by certain sex hormones, it can result in damage to those cells, leading to Alzheimer's disease.

The main culprit, according to Atwood and Voyager Pharmaceutical, is luteinizing hormone, a substance made in the pituitary gland that helps regulate production of testosterone and estrogen. Research suggests that levels of luteinizing hormone go up significantly later in life.

In addition to stimulating brain cells to abnormally divide, luteinizing hormone might promote the process that leads to production of beta-amyloid in the brain. Leuprolide acetate dramatically lowers levels of luteinizing hormone. The drug also brings down testosterone and estrogen.

In its earlier clinical trials, Voyager used an injectable form of leuprolide acetate. Since then it has developed an implantable form of the drug, called Memryte, that provides sustained, long-term release of the drug.

The Phase 3 clinical trials will use Memryte along with some existing drugs that provide modest benefits in treating the symptoms, but not the cause, of Alzheimer's.

One trial with as many as 550 patients will take place in the United States, Canada and South America. The other trial also will enroll 550 patients and will take place mainly in Europe. The University of Wisconsin, which took part in the Phase 2 trial, could be a site for the next phase as well.


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