© 2004 New England Journal of Medicine

Current and emerging Alzheimer Disease treatment options hinge on the hypothesis that amyloid β (Aβ), created by the sequential cleavage of amyloid precursor protein (APP), is the culprit behind neurodegeneration and associated cognitive and behavioral abnormalities. This could occur through multiple pathways. (Reprinted with permission from N Engl J Med, 351:56, 2004.)

Neuroscience has made impressive strides since 1936 Nobel laureates Henry Hallett Dale and Otto Loewi first showed that chemicals transmit signals between nerve cells. Yet decades later, scientists have only begun to tap potential therapeutic treatments that target brain and nervous system disorders.

Enormous demand exists for medicines, vaccines, and devices that not only alleviate neurological or psychiatric symptoms, as many current treatments do, but also stem the progression of these debilitating conditions. Statistics from the World Health Organization underscore the unmet need: As many as 50...


Few neurological diseases have created as much buzz in the pharmaceutical world as AD, and it's not hard to see why. "It's a hot area because the population is aging, and so this is going to be a tremendous driver for the pharmaceutical companies and the market in general," says Andrea S. Witt, an analyst with Decision Resources.

The market for AD treatments will easily double over 10 years, swelling from $1 billion in 2002 to $2.7 billion by 2012, Witt predicts. A third of that growth will come from treatments that are currently in the pipeline, she says.

AD typically strikes after the age of 60, and the risk for the disease rises as people age. Considering global demographics, clinicians anticipate an explosion of new cases. By 2050, one of every five people around the globe will be 60 or older; by 2150, a third of the world's population will be part of the demographic, says Global Action on Aging, an international grassroots citizens' group.

Because AD alters the lives of people across all socioeconomic and ethnic backgrounds, it commands greater notice than certain other diseases. President Ronald Reagan's death in June after at least a decade-long struggle with AD focused attention on the problem and reignited calls to expand funding for embryonic stem cell research.

AD treatments may one day look a lot like those for AIDS. If current drug innovations pan out, a combination of drugs, a "cocktail," could be a better way to treat the memory-robbing illness than any single medication alone, says Dr. Jacobo E. Mintzer, professor of psychiatry and neurology and co-director of Alzheimer research and clinical programs at the Medical University of South Carolina in Charleston. "If each one has a very small effect," he says, "the overall effect will be substantial."

Current pharmaceutical treatments cannot cure AD but may help control or reduce symptoms. The cholinesterase inhibitors, which include Aricept (donepezil), Exelon (rivastigmine), and Reminyl (galantamine), work by slowing the breakdown of acetylcholine. These drugs help stem cognitive decline in at least half of the patients who take them, according to the Alzheimer's Association, a research and support organization.

Last October, the US Food and Drug Administration (FDA) approved Namenda (memantine), made by Forest Laboratories, Jersey City, NJ. The first drug in its class, Namenda is believed to work by protecting brain cells from excess glutamate, which may contribute to memory loss when it reaches toxic levels. "It's by no means a silver bullet, but at least it's something; it's driving money into the market," says Hohenberg.

Pharmaceutical companies are testing more than two-dozen experimental treatments, according to survey data compiled by PhRMA. Analysts and researchers say a number of those efforts look promising.

Much of the excitement is reserved for Montreal-based Neurochem's Alzhemed, a drug that seeks to prevent the sticky buildup of beta-amyloid plaque in the brain, the hallmark of AD. In June, Neurochem announced a Phase III trial of the drug involving roughly 950 patients with mild-to-moderate AD living in the United States and Canada.

Prana Biotechnology of Melbourne, Australia, has another promising drug, Clioquinol (PBT-1), which works by scavenging copper and zinc and preventing plaque formation. Results of a small Phase II trial, published in the December 2003 issue of the Archives of Neurology,1 showed that the drug was able to slow the decline of cognitive function in patients with moderate-to-severe AD. Observers are watching intently to see whether further studies uphold the drug's safety. Clioquinol, first introduced decades ago as a diarrhea medication, caused nerve damage and blindness in thousands of people, particularly Japanese; the oral form of the drug eventually was pulled from the market.

Axonyx in Reno, Nev., primarily focuses on developing Phenserine, another cholinesterase inhibitor. Unlike its predecessors, this Phase III drug packs a dual punch, inhibiting both the breakdown of acetylcholine and the toxic accumulations of beta-amyloid protein.

Scientists also are working on vaccines to clear plaques from the brain, but analysts suspect it could take years for these efforts to succeed. "We're not going to find the magic bullet," says Mintzer. Rather, he's betting that each new discovery will bolster a cocktail approach, and patients will one day rely on a combination of drugs to improve their symptoms and slow their mental decline.

Meanwhile, some success stories in recent years for conditions other than AD include:


The selective serotonin reuptake inhibitors (SSRIs), a class that includes the popular antidepressants Zoloft, Prozac, and Paxil, are the workhorses in depression therapy. First approved in the late 1980s and early 1990s, their combined US sales reached $4.5 billion last year, according to Atlanta-based health information provider NDCHealth.

While SSRIs currently dominate the market, watch for a novel twist on depression treatment. DOV Pharmaceutical of Hackensack, NJ, has done early testing of a new class of medications, called triple reuptake inhibitors, which have been shown to be safe, effective, and well tolerated. "That is very interesting because it may offer enhanced tolerability over existing drugs," Hohenberg says. DOV recently granted Merck & Co. exclusive worldwide rights to develop and market its two compounds for depression therapy.


Pfizer may have a winner with Lyrica (pregabalin), a successor to the company's top-selling epilepsy drug, Neurontin (gabapentin). Last month, the FDA granted the company conditional approval to market the drug as a treatment for nerve pain and seizures. The FDA rejected Pfizer's request, however, to label Lyrica for use in treating generalized anxiety disorder.


Sanofi-Sythelabo's Ambien (zolpidem) currently dominates the sleep-aid market. But don't write off Estorra (eszopiclone), made by Sepracor of Marlborough, Mass., which gained tentative FDA approval in March, or San Diego-based Neurocrine Biosciences' Indiplon, currently in late-stage trials. With Ambien's patent set to expire in 2006, newcomers may be poised to grab market share.

Indiplon is a top contender for blockbuster status, meaning it could generate more than $1 billion in annual sales, because Neurocrine has the marketing and sales prowess of Pfizer behind it, says Patrick Rajan, a research analyst with Frost & Sullivan. Overall, Rajan forecasts a doubling of the $1.8 billion insomnia market by 2010.


After years of faint hope for patients with multiple sclerosis (MS), the past decade has proven to be a watershed for innovation. Three interferon-based drugs for patients with the relapsing forms of MS have become available since 1993: Avonex (interferon beta-1a), Betaseron (interferon beta-1b), and Rebif (interferon beta-1a). For patients with progressive and worsening MS, an immune-system suppressor, Novantrone (mitox-antrone), gained approval in 2000. The FDA also approved Copaxone (glatiramer acetate), a synthetic peptide copolymer that mimics myelin basic protein.

Top sellers Avonex and Betaseron had combined sales of roughly $1 billion in 2003. Robert P. Lisak, professor and chairman of neurology at Wayne State University School of Medicine in Detroit and a member of the National Multiple Sclerosis Society's medical advisory board, anticipates that more studies will test MS drug combinations to determine which pairings may be most effective. "In 10 years, I think we'll have new and better combination therapies for MS," he predicts.

Antegren (natalizumab) is an experimental monoclonal antibody given monthly by intravenous infusion. In May, Biogen Idec and Elan filed for FDA approval based on first-year data from two-year trials of the drug alone and in combination with Biogen's Avonex.


Like AD, Parkinson disease is both chronic and progressive. Roughly a dozen-and-a-half experimental treatments are in the pipeline. In July, Teva Pharmaceutical Industries received an "Approvable" letter from the FDA for Agilect (rasagiline), a once-daily drug for treating patients with early symptoms of Parkinson disease and for patients with moderate to advanced Parkinson's who are taking levodopa. Teva must work with the FDA to meet additional requirements before receiving final approval to market the drug.


In 1996, the FDA approved intravenous tissue plasminogen activator (tPA) for treating ischemic stroke within the first three hours after the start of symptoms. The clot-busting drug can ameliorate the effects of stroke and reduce permanent disability, a significant advancement for a medical emergency that was once virtually untreatable. Drugs aimed at poststroke brain damage are more elusive, however. Drug makers churned out neuroprotective agents aimed at restoring lost brain function, but those drugs were ineffective or produced deleterious side effects. "For a long time, stroke was the graveyard of drug development," says Hohenberg.

Despite previous failures, the prevalence of stroke and the dearth of effective treatments keep research efforts aglow. Cero-vive (NXY-059), an intravenous treatment for acute ischemic stroke, is now in Phase III trials. AstraZeneca has exclusive marketing rights in a pact with Renovis of South San Francisco, which makes Cerovive.

The pressing need for new drugs to treat stroke, as well as other neurological and psychiatric conditions will keep researchers searching for effective treatments. "The neurosciences is the last frontier of biomedical research, lagging behind areas like cardiovascular by 15 years or more," says Jayme Zage, a director at Sg2, a research and consulting firm in Evanston, Ill. "As basic science begins to unlock the doors of what drives neurological function, we will develop an understanding of the causes of many diseases that currently elude us and will see an increase in drug targets."

Karen Pallarito kpallarito@the-scientist.com

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Seeking FDA approval, two neurological device makers get very different receptions

For privately held Concentric Medical of Mountain View, Calif., nearly a decade of development paid off in August when the US Food and Drug Administration (FDA) approved its novel device for clearing blood clots from the brains of stroke patients.

Cyberonics, a NASDAQ-traded company in Houston, was not so fortunate. Just days before Concentric got the nod, the FDA rejected Cyberonics' application to market a vagus nerve stimulation (VNS) system to treat depression. The implantable device, which is already FDA-approved for epilepsy, delivers electrical impulses to the vagus nerve in the neck. The electric signals, which are transmitted to the brain, are delivered at regular intervals. The FDA's move came as a surprise, considering that its own neurological devices panel voted 5-2 in June to recommend approving the device for treating depression.

"We are shocked and bewildered by FDA's decision to ignore its expert Advisory Panel's recommendation," Cyberonics board chairman and CEO Robert P. "Skip" Cummins said in a prepared statement issued in the wake of the setback. "In the end, the FDA felt there were some shortcomings in the data that [were] presented," says Chad Simmer, a senior research analyst with Miller Johnson Steichen Kinnard, a Minneapolis-based investment firm.

Hoping to quell the FDA's safety and effectiveness concerns, Cyberonics submitted an amendment in late September containing two-year safety and effectiveness data and analyses for more than 240 patients. That supplemented its original application, which included one-year data and analyses for 460 patients. The company also provided revised labeling for patients and physicians and delivered a formal response to the FDA's letter rejecting the device for treating depression.

Also in late September, the FDA gave Cyberonics permission to study the device for depression in 100 patients. It's a small exemption that clears the way for the company to use VNS in patients with life-threatening depression while the company pursues marketing approval for the device.

Cyberonics' stock plunged 40% to $14.29 per share on news of the FDA's refusal, off a 52-week high of $40.07 on June 17. Meanwhile, Advanced Neuro-modulation Systems of Plano, Texas, made overtures to buy out the company, but Cyberonics ultimately rejected the move. The company's bid boosted Cyberonics' shares by 23%, closing at $23.23 on Sept. 15.

Cyberonics' experience contrasts sharply with Concentric's recent regulatory success. The FDA okayed Concentric's Merci Retrieval System after reviewing patient data from a 25-site clinical study that involved 141 patients who arrived in the hospital too late for the clot-busting drug therapy used to treat ischemic stroke.

The corkscrew-like device, used for mechanical embolus removal in cerebral ischemia (MERCI), is inserted through the femoral artery in the groin and threaded up to the carotid artery in the neck. The device gives physicians a tool to grab and remove brain clots instead of dissolving them with drugs.

"I certainly envision a whole lot of scenarios where it would be better than a thrombolitic," says Dr. Michael A. Sloan, associate professor of neurological sciences and neurosurgery at Rush Presbyterian-St. Luke's Medical Center in Chicago.

From the start, the two device makers faced differing burdens of proof based on the nature of the medical conditions the devices were designed to treat, suggests Jayme Zage, a director at Evanston, Ill.-based Sg2, a research and consulting firm. Ischemic stroke is a defined event, and removing the clot quickly restores blood flow. By contrast, a diagnosis of depression is much more arbitrary, as no molecular markers or diagnostic tests can demonstrate a particular type of depression. "That makes clinical trials difficult," notes Zage.

Still, when there's data to substantiate a treatment, manufacturers need to make sure that information is getting analyzed the way they want it to be. "One of the lessons learned is just, from a company perspective, to continue to work with the FDA throughout the clinical trial process," Zage says. "They really want to work with the companies," she says of the FDA. "They're not the bad guys."

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