May 7, 2007

Institute zeroes in on Alzheimer's

Scientists at the Roskamp Institute are running a clinical trial for Nilvadipine, a drug that shows promise in treating the disease.

By DAVID GULLIVER

At St. James Hospital in Dublin, Ireland, a nurse is checking the blood pressure of a 62-year-old man. Later, a tech will use a hand-held scanner to measure blood flow in his middle cerebral artery.

The patient has never met Michael Mullan, nor Fiona Crawford. But some 4,150 miles away, they could hardly be happier about his test results.

They show that the man, whose identity is confidential, is showing no adverse reactions to a drug that might be a promising treatment for Alzheimer's disease.

That is good news for Mullan and Crawford, directors of the Roskamp Institute on Whitfield Avenue in southern Manatee County, they are running a clinical trial of Nilvadipine, a drug widely used abroad but not approved in the United States.

The drug is intended to lower blood pressure. But in studies on mice, Roskamp researchers found it also reduced the level of a protein in the brain believed to be at the heart of Alzheimer's.

The Ireland trial just completed its second phase, a safety study, and the 20 patients taking the drug showed almost no ill effects, paving the way for a broader study.

The clinical trial is the institute's highest-profile project, but its two dozen scientists also work in fields including drug addiction and head injury.

With even more promising treatments deep in its labs, the little nonprofit academic center is becoming more and more a biotechnology start-up.

Birth of the institute

The institute was born in 1997, but its origins date back another 40 years.

Bob Roskamp was a high school physics teacher. His older brother, diagnosed with schizophrenia, killed himself.

Roskamp tells the story with understatement: "Obviously, it catches your attention in a big way."

The loss of his brother prompted him to give up teaching and work on opening homes for developmentally disabled adults. He later moved into developing housing communities for seniors.

He began selling his companies -- including his Freedom Group to American Retirement Group for $23 million in cash and $14.9 million in stock -- leaving him with a question: "What do we do with these surplus dollars?"

The answer is in the logo of the institute bearing his name: "Curing Diseases of the Mind."

Roskamp and his wife, Diane, are among the pioneers of a style of philanthropy, now more widely followed, of carefully aiming resources at one target and tracking performance.

"Instead of spreading it thinly throughout the world, we would 'rifle-shot' it, and have a lot more fun with it," he said.

Roskamp historically has given the institute about one-third of its operating budget, the rest coming through grants and contracts.

But as federal money has been diverted elsewhere, and the institute's work has grown more complex, Roskamp has had to pick up more of the tab. He gave just over $1 million in 2005, but $4.6 million this year, he said.

His involvement began with funding a lab at the University of South Florida, then a teaching position eventually filled by Mullan.

In 2003, the institute left the university amid personnel and bureaucratic disputes and moved into the former Bausch & Lomb building in southern Manatee County. Roskamp said university overhead was too expensive, and that scientists can work faster in the independent setting.

"You bring your entrepreneurial hat to this kind of research," he said. "We're results-oriented people."

The scientists appreciate not having to wait for grants and approvals.

"We have the funding from Bob and Diane that allow us to move forward very quickly when we make a new discovery," Crawford said. "We are really free to focus on the research."

Paddling mice

Most Alzheimer's researchers now focus on a protein known as beta-amyloid that forms when a chemical process goes awry. The protein clumps together outside neurons, eventually killing those memory cells.

Mullan and Crawford were part of a team that in 1991 published papers establishing a link between a human gene, on chromosome 21, and early onset of the disease in patients in their 40s and 50s.

A year later, after they came to the United States, they published a paper looking at another genetic link to early-onset Alzheimer's.

The research made beta-amyloid a prime suspect in Alzheimer's, and stopping its buildup a potential cure.

Roskamp researchers look for existing drugs and new compounds with that effect. Nilvadipine showed enough promise to test it on lab mice engineered to have Alzheimer's.

At 10 months, with the disease in full bloom, some mice got the drug while others got a placebo. Later, they scanned the mice's brains for blood flow.

In the color-coded pictures, the brighter the image, the better the blood flow. The mice getting Nilvadipine scan largely red and orange.

The control animals scan mostly blue-green.

Mullan points to a chart with results of a more traditional test, tracking a mouse's effort to paddle its way out of a mouse-sized swimming pool.

The mice repeat the test, day after day. Normal mice figure it out and eventually swim a shorter route to the exit.

Mice with Alzheimer's disease never figure it out, actually taking longer and longer routes.

"But if you give them Nivaldipine, they go from here to here; they do better," Mullan said, pointing at the figures. "And if you give Nilvadipine to a normal mouse, they do best of all."

"The drug appears to slow or stop the production of beta-amyloid," Mullan said. As the brain grudgingly yields the mysteries of its architecture, Roskamp's scientists are exploring how those diseases of the mind may be related by more than just words.

'Blocking that burst'

In 2002 the institute teamed with the Department of Veterans Affairs to look at memory skills in people who had received traumatic brain injuries.

They found that people who had a gene linked to Alzheimer's disease recovered less memory function than those without it, even when they had comparable injuries and demographics.

Further research has shown that when the brain suffers such an injury, there is a burst of amyloid production. One theory is that the brain produces the protein as a defense mechanism, but it sometimes overreacts and makes matters worse.

"Blocking that burst appears to be at least one way to try and improve outcomes after head injury," said Crawford, lead author of the 2002 article.

Last year the Department of Defense approved a $1.5 million grant to the institute to expand that research. It is a particularly urgent matter for the military: Improved body armor is helping soldiers survive explosions -- but with little understood head injuries.

"People can have brain injury even if they didn't suffer any loss of consciousness, weeks and months of being in the vicinity of an explosive attack," Crawford said.

For now, that grant is hung up in final reviews.

"We have yet to see dime one," Roskamp said -- but even that $1.5 million pales in comparison with the costs of the Nilvadipine study.

That cuts to the heart of the dilemma scientists face. They might get a moderately effective drug to market quickly, or try to discover the "silver bullet," which could take many years and exponentially more money.

Roskamp is preparing the foundation to do both.

Just a question of when

To Mullan, the question is not whether there will be treatments for Alzheimer's.

"It's the question of when we're going to get them there," he said.

It is a question of how effective they will be. Mullan cited three drugs far along in the pipeline, all targeted at reducing amyloid. "They're not going to be blockbusting, perfect drugs by any means, but I think at least two of them will be approved for Alzheimer's this year."

Nilvadipine most likely would be like them -- useful but not the cure-all. But it offers some advantages.

Developing a new drug from scratch is a much worse bet, Mullan said. Count on 10 to 12 years for development, testing and approvals, with a high failure rate.

"Sometimes they fail spectacularly," he said, citing Vioxx, a promising drug with unforeseen and deadly side effects.

Nilvadipine, in use for more than a decade, already has a track record for safety. It could help patients while allowing the institute time to find the silver bullet.

By mid-year, the institute hopes to continue the Ireland trial with a double-blind study, meaning neither patients nor doctors know who gets Nilvadipine and who gets a placebo until they conclude. That study, which would involve about 200 people, could cost $20 million, Roskamp said.

Should the drug prove effective, Nilvadipine's manufacturer could profit -- but so would the institute. Because it holds rights to the drug's newly indicated use, the institute would receive royalty payments, Roskamp said.

The institute has set up a for-profit subsidiary, Roskamp Research LLC, which holds its patents. Roskamp structured it to allow outside backers to support studies, provide the subsidiary with a return on its investment, and guarantee most of the revenue goes to his institute.

"We don't want to give it to a pharma company, and say here, go make a lot of money off of it," Roskamp said.

Compounds back in the institute's labs could provide better returns -- and better treatments.

© Sarasota Herald-Tribune

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