By Randall Osborne

Editor

Like a distant memory or like the memory of where the car keys got placed yesterday Alzheimer's disease had, until recently, all but faded from the public view as an indication worth shoveling money into.

A few years ago, the condition made regular headlines, and figured into what seemed an endless stream of jokes. Former President Ronald Reagan's diagnosis had brought it to the forefront especially, although not in an altogether serious light. Many made sport of the one-time chief executive's befuddlement, as if it were not the result of a medical difficulty, but brought on by garden-variety senility, or "old timers' disease," as it was dubbed by quipsters.

But, before long, the disease seemed to disappear. It remained a major concern for the sons and daughters of afflicted patients, but as a cover story for the newsmagazines and prime positioning in the Sunday supplements, Alzheimer's lost appeal.

That's starting to change again, in a big way.

The shift is happening partly because of the steady trudge by Baby Boomers toward the Alzheimer's age bracket, and partly because of progress made in diagnosis and treatment of the disease progress that came about, hardly by coincidence, in tandem with the collective aging of this key demographic.

Does a crisis loom, as it always seems to? Speakers this summer at the World Alzheimer Congress 2000 in Washington said yes. They predicted more cases of the disease, with a shortage of long-term work-force care.

Four million people in the U.S. today are afflicted. By the year 2050, that number will soar to 14 million, unless a cure or prevention is found. Each Alzheimer's patient eventually requires "total care," either in a facility or at home. Already, at least half of all nursing home residents have Alzheimer's or some other form of dementia.

"It's kind of like prostate cancer," said Tim Anderson, an analyst with Prudential Vector Healthcare. "If you live long enough, you're going to get it. There's a ton of companies that have Alzheimer's drugs," he added but none has proven effective against the disease in late-stage trials, although a few are showing promise.

The disease is regaining its high profile. This time, the jokes are few. On the other hand, declarations like the one made last week by NeoTherapeutics Inc. seem likely to become more common. NeoTherapeutics vowed in a press release to "fast forward" its development of Neotrofin (leteprinim potassium, also known as AIT-082) for Alzheimer's disease, with a one-year, higher-dosage study in patients with moderate forms of the disease.

The company said it was basing its altered effort, including the design of a new trial, on results from three recent trials, and on evidence from a Positron Emission Tomography (PET) imaging study of Neotrofin. Fourteen trials in more than 1,000 patients have shown Neotrofin is safe and well tolerated in elderly subjects and Alzheimer's patients.

NeoTherapeutics said data from a global Phase IIb trial indicated Neotrofin would work better at higher doses, for longer duration, in moderate-stage patients. A study in the U.S. showed 150 mg for 90 days didn't reach the targeted level of efficacy, and confirmed the results of a global study at the low dose. Results from the PET work, to be detailed at a scientific meeting in December, confirmed doses of 500 mg and 1,000 mg had more biological activity.

PET is turning out to be at least adequately effective in finding Alzheimer's early, as a report this month in the Journal of Nuclear Medicine showed. But gauging the success of treatment has proved a major roadblock, Anderson said a roadblock that has turned back companies before they began the trip down that bumpy neurological path.

"It's relatively hard to measure endpoints of trials because you are measuring activity in daily living, for example," Anderson said. "They're subjective measurements. It's not like you can do a blood test or a scan."

Still, treatment-oriented investigations are going on. In the journal Nature this month, Juan Botas, genetics professor at Baylor College of Medicine, reports his research on neuron degeneration in spinocerebellar ataxia type 1, a genetic disease. Oxidative damage in a nerve-cell protein is linked to Alzheimer's, says a University of Pennsylvania study, also published this month, in Science. The protein, alpha-synuclein, is a component of the brain lesions typical of patients with neurodegenerative disease.

A handful of already available drugs seem to help certain Alzheimer's patients, although not much, and the side effects are troublesome. Acetylcholinesterase inhibitors have been approved by the FDA for mild to moderate Alzheimer's disease. These boost the amount of acetylcholine, a substance that transmits nerve impulses, in the brain.

Three such drugs are on the market. The fourth has an approvable letter from the FDA. But all are for mild to moderate disease.

"As you progress from moderate to severe, it's brain atrophy, and the drugs don't seem to work as well," Anderson said. "You no longer have efficacy you just have side effects," including dry mouth and urine retention.

The field is not entirely barren, however.

Memantine, an orally active N-methyl-D-aspartate antagonist, is a potential new drug that became the subject of a deal between Neurobiological Technologies Inc. (NTI), the German firm Merz & Co., and Forest Laboratories Inc., which intends to develop and market the drug.

"It's on the market in Germany, and [Forest is] meeting with the FDA next year to decide if they have enough data to submit for approval," Anderson said. "In four Phase III trials, they've targeted moderate to severe patients. This could be a very promising product."

Anderson said Memantine's different mechanism of action means it could be used with the other therapies because the two arms of treatment would attack the process from different directions.

"The FDA has been stodgy when it comes to approving Alzheimer's drugs," Anderson said. "In the best-case scenario, Memantine could be [on the market] in early 2002."

Meanwhile, NeoTherapeutics, convinced it's onto something, is shifting gears, stopping the 16-country Phase II/III study along with the global and U.S. Phase IIb studies as part of the "fast forward" Neotrofin push.

Elan Corp. plc is testing a potential Alzheimer's drug and vaccine. In July, Elan said in the journal Nature that the same peptide that triggers amyloid plaque deposits in the brain could be part of the drug and vaccine. Immunizing transgenic mice with a 42-amino-acid form of the beta-amyloid peptide (A42), called AN-1792, significantly reduced pre-existing amyloid plaque and inhibited further plaque formation. In another study, prophylactic immunization with AN-1792 prevented the majority of treated mice from developing virtually any amyloid plaque, Elan said.

Elan and Biogen Inc. "are both attacking it in the same area," Anderson said. "Both have patents issued, and both companies say they were there first." Last month, Neurome Inc. teamed its genomics technology with Elan's mouse model of amyloid deposition to perform an analysis of Alzheimer's disease.

Prana Biotechnology Ltd., an Australian firm, has faith in PBT1, undergoing tests in 50 Alzheimer's patients for its ability to bind copper and zinc, metals associated with the brain plaques characteristic of Alzheimer's. Data from the Phase II study will be available in about a year. Last week, Prana disclosed mouse data at the annual meeting of the Society of Neuroscience in New Orleans.

Cephalon Inc. last year entered a deal with the Danish pharmaceutical company H. Lundbeck A/S to develop orally active small-molecule receptor tyrosine kinase inhibitors to promote neuronal survival, for neurodegenerative diseases such as Alzheimer's and Parkinson's. (For years, Cephalon has been working on Alzheimer's. It signed a deal in 1991 with Schering-Plough Corp. to develop protease inhibitors for blocking beta-amyloid from accumulating in plaques. That deal was given up by Schering-Plough in 1997.)

A similar mechanism is the target of Active Pass, a Vancouver, British Columbia-based firm whose platform technology is designed to stop the beta-amyloids from passing through cell membranes, using molecular pumps transporting molecules that regulate ATP-binding cassette transporters.

Targacept Inc., a spin-off from R.J. Reynolds Tobacco Co., said in August it had completed a Phase I trial and is continuing work with Aventis Pharmaceuticals Inc. on TC-2403 for Alzheimer's and Parkinson's. The spin-off grew out of work done on cholinergic receptors by the tobacco firm.

SignalGene Inc., of Montreal, is developing targets for Alzheimer's disease based on its work in identifying susceptibility genes, and this summer disclosed its plan to acquire Nova Molecular Inc., which has been focused on genotyping subjects for proprietary apolipoprotein E variants in relation to the condition.

What does all this mean for investors? Is it too early to jump aboard the Alzheimer's bandwagon too difficult, yet, to begin judging the likes of NTI, NeoTherapeutics, Elan and Cephalon, and et al.? Can the true contenders be sifted from the also-rans, in a neuroscientific field with particularly tough challenges?

"Elan's product is still four or five years away," Anderson said, but it's his favorite of those he has studied. "If this was a small biotech product, and this was its only product, the world would be paying attention."

Anderson said he is "excited" by Elan's potential drugs.

"Would I buy Elan just for its Alzheimer's products? Absolutely not," Anderson said.

Neurology, he said, has "probably the hardest [field of medicine] to make progress in. It hasn't made huge advances, like cardiology. There are many more late-stage cancer drugs."

Alzheimer's simply is not a lucrative space for biotech, Anderson said.

"Collectively, [currently marketed drugs] sell about $350 million in the U.S.," he said. "When I first saw the number, I said, 'This is really wrong,' but it's not. And the drugs don't turn people's lives around. They just make them tolerable."

So, whether it's a good thing socially or not, investors shopping in Alzheimer's won't find much reward in the near term. Firms "continue to look" for treatments and even a cure, Anderson said, "but the world realizes it's an enormously tough disease." *

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