Source: The Scientist
Date: 25 October 2004

The Ailing Brain: A Pressing Need for New Treatments

Research in Alzheimer disease abounds, but the pipeline also looks
promising for other neurological and psychiatric conditions

By Karen Pallarito

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 million people worldwide have epilepsy, 37 million live with dementia, 5.5 million die each year of stroke, and 121 million have depression. Demand will likely grow as the population ages, people live longer, and treatments for these conditions improve.

The current market for neurological and psychiatric treatments, at roughly $80 billion for the Group of Seven industrialized nations, could climb to $120 billion in five to 10 years, predicts Kate Hohenberg, therapeutic area director at Decision Resources, a Waltham, Mass.-based pharmaceutical research and advisory firm. The projected figure reflects growth of some existing drugs and the introduction of new therapies. Analysts anticipate some impressive winners, even blockbusters, among today's experimental treatments.

The neurology pipeline isn't as dense as that for infectious disease or cancer. Of the roughly 1,100 drugs currently in human clinical testing, more than 170 are for neurological conditions, according to the Pharmaceutical Research and Manufacturers of America (PhRMA). That figure includes sleep aids but excludes antidepressants. Neurology's totals include 44 medicines under development for acute and chronic pain, 28 for brain tumors, 26 for Alzheimer disease (AD), and 18 for Parkinson disease; these are the most prolific categories.

If innovations in neurological care are lagging compared with other branches of medicine, it's partly because neurologists aren't as well-organized or generously funded as their peers, says Michael A. Sloan, associate professor of neurological sciences and neurosurgery at Rush Presbyterian-St. Luke's Medical Center in Chicago, and member of the American Academy of Neurology's Therapeutics and Technology Assessment Committee. "Cardiologists are probably 10 to 15 years ahead of us in terms of their sophistication," he says.

Neuroscientists also must overcome significant hurdles to move drugs from bench to bedside, Sloan says. What works in the lab may not work in humans. Developing treatments that effectively penetrate the blood-brain barrier is one of the trickier aspects. "Modeling is more difficult in general," he says. Also, finding appropriate treatments for less common neurological conditions becomes all the more challenging, he says. More common conditions, such as AD, tend to get the lion's share of attention.

ALZHEIMER "COCKTAILS" 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 build-up 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:

DEPRESSION 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.

EPILEPSY/NEUROPATHIC PAIN 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.

INSOMNIA 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.

MULTIPLE SCLEROSIS 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 (mitoxantrone), 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.

PARKINSON DISEASE 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.

STROKE 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. Cerovive (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 (

1. C.W. Ritchie et al., "Metal-protein attenuation with iodochlorhydroxyquin (Clioquinol) targeting A beta amyloid deposition and toxicity in AD: a pilot Phase 2 clinical trial," Arch Neurol, 60:1685-91, 2003.
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Parkinson's disease: resources
Alzheimer's disease: resources
Healthier, happier and longer life?
World's Oldest Supercentenarians
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