The Age of Alzheimer's

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In 1907, German physician Alios Alzheimer noted tangles and plaques in the brain tissue biopsy of an elderly patient and first described the disease that would come to bear his name. And while advances have been made in the nearly 100 years since then, widespread education, ease of diagnosis and highly effective medications are still sadly lacking—as is, of course, a cure.
In the US alone, Alzheimer's Disease (AD) afflicts an estimated 4.5 million people, according to the Alzheimer's Association (AA)—that's one in 10 people over the age of 65 and nearly half over 85—causing memory impairment, loss of orientation and changes in personality and behavior. It is the most common form of dementia and the eighth leading cause of death in the US. While available treatments can only slow the rate of decline, the US drug market has grown at a fast pace in recent years (Fig. 1), from $750 million in 2001 to almost $2.2 billion in 2005 (up 20% over 2004). During that time, total US prescriptions increased from 6.2 million to 15.8 million (Fig. 3).

Of the key medications—Aricept, Exelon, Razadyne, Razadyne ER and Namenda—the first four are cholinesterase inhibitors, approved to treat cognitive symptoms of mild to moderate AD. Alzheimer's damages brain cells producing and using acetylcholine—a chemical messenger involved in memory, judgment and other thought processes—and cholinesterase inhibitors slow this breakdown, therefore partially alleviating the loss of functional brain cells. Namenda—a N-methyl-D-aspartate antagonist—shields the brain from glutamate, a neurotransmitter contributing to the death of brain cells in AD patients, and is the only drug currently approved for severe AD.

Aricept from Eisai and Pfizer is the leader with 55% of the market in 2005, according to IMS Health. Approved in 1996, Aricept posted 2005 sales of $1.18 billion, with 8.4 million prescriptions dispensed (or 53% of total scripts). And the brand seems to be holding its ground this year,reporting $330 million in US sales (a 55% share) from January to March, with 2.28 million prescriptions dispensed (54% share).

Forest Pharmaceuticals' Namenda is Aricept's biggest competitor. Since approval in October 2003, Namenda quickly grabbed 23% market share (Fig. 2), with US sales hitting $498 million last year—a whopping 77% increase over 2004. Namenda's fast start was aided by an aggressive professional advertising strategy. In fact, Namenda was the most advertised product in medical/surgical journals in 2004, with an outlay of around $18 million, according to data from PERQ/ HCI. Forest spent about $13 million more on journal ads in 2005.

Next is Exelon from Novartis, with a 10.5% share on US sales of $223 million in 2005—a 4% decrease over the previous year and 5.5% down on 2003's high. Sales for the first quarter of this year were down 3% from the same period in 2005. Cleared for marketing in 70 countries since 1997, Exelon was eventually approved for use in the US in 2000 after safety concerns over high doses during clinical trials.

Razadyne, manufactured by Johnson & Johnson's Ortho-McNeil Neurologics, was approved in 2001 under the name Reminyl, but was renamed in July 2005 after confusion with diabetes medication Amaryl had resulted in two deaths. Having peaked in 2004 with US sales of $247 million (14% market share), Razadyne fell 10% to $224 million last year (10% share) and 2006 sales are on course to decrease at least another 30%. The main reason for the decline, however, is the emergence of the once-daily Razadyne ER. Approved in December 2004 and manufactured under a co-development and licensing agreement with Shire Pharmaceuticals, Razadyne ER is approved in 24 countries, and posted $25 million in US sales in 2005, with 132,000 scripts dispensed. And while Razadyne ER's debut might not be as impressive as Namenda's, sales could triple this year with $17 million posted in the first three months.

Aricept and Namenda's dominance stems in part from the fact that they are often used together. “Physicians have learned how to use these products in combination with each other,” says Kim Lazarus, category business leader, neurology, at market research firm GfK Market Measures. “That is also the reason that the market has grown tremendously in the last few years.” According to GfK research, both brands used to treat all stages of AD, regardless of their indication.

Amongst the cholinesterase inhibitors, Aricept has a large lead. “Studies have generally shown that it does better than some of the other products in terms of efficacy in combination with the side effects,” says Lazarus. “With both Razadyne and Exelon, that fewer people are able to get up to the levels of effective dosage because of the side effects, so it is hard for those drugs to have the efficacy of Aricept.” A Razadyne spokesperson declined comment.

For all brands, dosages are increased gradually to minimize side effects, most commonly nausea, vomiting, loss of appetite and increased bowel movement. Exelon, however, carries a strong warning about potential vomiting and nausea that may be serious enough to lead to weight loss, while two clinical trials completed in 2005 indicated that patients taking Razadyne had higher death rates than those taking a placebo, with 13 drug-treated patients dying from conditions including heart attack and stroke, compared to one death in the placebo group. Razadyne's label now carries a warning and J&J sent a letter to physicians detailing the change.

Overall, the benefits far outweigh the risks. “If you were to take patients off these drugs,” says Lazarus, “you would see a much more precipitate decline in terms of them being able to deal with cognition and activities of daily living.” Medication's value also lowers stress in caregivers and minimizes time and money spent on long-term care. National direct and indirect annual costs of caring for individuals with AD are at least $100 billion, according to estimates used by the AA and National Institute on Aging. The average direct cost of caring for an Alzheimer's patient from diagnosis until death is $174,000, while the average annual cost for nursing home care in the US is $52,200. Businesses suffer through insurance costs and lost productivity by primary caregivers, adding to more than $60 billion per year. The number of patients is expected to more than triple in the next 50 years.

Lazarus speaks to the necessity for increased vigilance surrounding onset and greater education for physicians and consumers. “The sooner you get people on medication,” she says, “the more able you will be to contain some of the issues and slow down the progression.” GfK research shows that over half of caregivers, after receiving the AD diagnosis, realized that the patient has displayed symptoms for over a year.

Kate Hohenberg, an analyst with market research firm Decision Resources, agrees diagnosis is difficult. “Diagnosis is done simply and solely by clinical history,” she states. “Often by the time patients are referred to a neurologist it could be too late for the drugs to really have any kind of an effect.”

Therefore, newer diagnostic tools and more effective drugs are essential. One promising new diagnostic technique centers on AD biomarkers, which could help to identify early stages of the disease and enable more effective treatment. Biomarker Pittsburgh Compound-B, which images the protein fragment beta-amyloi—thought to comprise nerve-killing plaques in the AD brain—is in development by GE Healthcare, and projected to be on the market by 2011. However, the extent of coverage by HMOs for biomarkers and other diagnostic techniques remains to be seen.
Another focus is beta-amyloi vaccines which, given to patients at the onset of symptoms, fight AD using the bodies' own immune mechanism. While Decision Resources does not expect a vaccine to hit the market until after 2015, preliminary efficacy results are promising.

Perhaps the most promising research centers on disease-modifying drugs, especially those targeting beta-amyloi proteins. “It is going to be a revolutionary change,” says Hohenberg. Decision Resources predicts that Neurochem's Alzhemed, currently in Phase III development, will be a $2 billion drug. “It is going to be far more than a symptomatic therapy because its mechanism is targeting the disease itself,” says Hohenberg. “As long as it is tolerable, and it looks as though it is going to be, Alzhemed is going to have a huge market share in the disease stages for which it is approved.” Decision Resources data also predict that Myriad Genetics' Flurizan—a selective beta-amyloi-lowering agent also in Phase III trials—will become a market leader, but to a lesser extent. “Experts are really divided on that drug,” says Hohenberg. “Many still perceive it as a non-steroidal, so it has the specter of cardiovascular risk, and that would be very bad to give to the elderly population.” By 2015, Decision Resources forecasts Alzhemed will secure about 46% of AD sales and Flurizan 13%.

Cholinesterase inhibitors will still be used, however. “You will see more combination therapies,” says Lazarus. “There doesn't seem to be a magic bullet that people are finding because there are many reasons for the loss of memory.”

Hohenberg agrees, believing that these drugs will not “obviate the need for symptomatic therapy.” However, Decision Resources predicts that market share of cholinesterase inhibitors, currently 72%, will fall to 31% by 2015. The main threat to the class, she says, is  generics. “The biggest skeleton in the closet for cholinesterase inhibitors—the biggest bogeyman —is generic competition.”

Generics could arrive by the end of 2010. Eisai currently has a lawsuit against generic manufacturer Teva regarding Teva's application to approve generic Aricept before patent expiration. “That is fairly typical in a hot market like this one where you have billion-dollar drugs,” says Hohenberg. “It is fairly automatic for generic companies like Teva to challenge the patent, it is part of their marketing strategy.” In this case, Hohenberg predicts Eisai's patent will hold up.

The AD market also faces difficulty expanding overseas. In the UK, concerns over cost-effectiveness of cholinesterase inhibitors prompted the National Institute of Health and Clinical Excellence to limit reimbursements to patients with moderate AD. Additionally, only neurologists can prescribe AD medications, and the majority of patients are referred to these specialists only at later disease stages. “There is not very much use of these drugs in the European markets,” said Hohenberg. “But disease-modifying drugs will be well accepted in Europe.”

Despite the launch of such drugs, along with an aging population and better diagnostic techniques, there are still factors limiting growth and impeding treatment. Increased diagnosis could be stalled by limitations in access to neurologists and specialized equipment, while a lack of public awareness regarding early symptoms and a continued stigma surrounding diagnosis could also limit growth as patients and caregivers deny signs and delay treatment.

“More people need to understand this disease state and recognize that there is something that can be done,” says Lazarus. “We are just uncomfortable because we can't yet solve the problem; all we can do is slow down the progression.”

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