As reported in Drug & Market Development Newsletter as recently as January 2000, Alzheimer's disease (AD) continues to be an affliction for which an effective therapy has been hard to pin down. Still, with some four million Americans (and as many as 14 million, including milder forms) suffering from AD, and with the cost of providing treatment and daily care to patients reaching $90-120 billion per year, researchers continue to strive for the key target for treatment or prevention.

Beta-amyloid deposits, neuritic plaques, and neurofibrillary tangles are most strongly linked to AD, especially as prospective targets for future therapy. Decreased amounts of acetylcholine are also a characteristic of AD. What follows is an update on current research in AD.

The significance of genetic links to AD, including apolipoprotein E4 (ApoE4), deserves special attention for the clues they will provide toward prevention and treatment of AD. ApoE4 has already been used in trials to determine subsets of patients likely to respond to particular drugs in development.

Beta-Amyloid

Beta-amyloid is an insoluble polypeptide with adverse effects thought to result from free radicals that cause oxidative stress and lead to neuronal damage. Among the theories for addressing AD is to use free radical scavenging agents to limit the damage caused by free radicals created through beta-amyloid.

Compounds of this type include idebenone (Takeda Chemical Industries; Osaka, Japan), which is both a free radical scavenger and a stimulant of certain nerve growth factors. Early studies indicated that idebenone may have value in the treatment of mild dementia, but although licensees Glaxo Wellcome (Middlesex, UK) and American Home Products (Madison, NJ) launched the drug in several countries, it has been withdrawn in Japan and Phase III trials have been discontinued.

Sue Griffin of the Geriatric Research, Education, and Clinical Center at the McClellan Veterans Affairs Medical Center (North Little Rock, AR) and the Geriatric Department at the University of Arkansas for Medical Sciences (Little Rock, AR) recently noted research that examined factors that stress or injure neurons. According to Griffin, stress increases the synthesis and translation of beta-amyloid precursor protein, which in turn leads to increased secretion of amyloidogenic fragments. Furthermore, this process prompts microglia to create interleukin-1, which drives further beta-amyloid precursor protein production, activates astrocytes, and induces expression of S-100beta, which promotes the growth of neurites. Griffin reports that vitamin E can inhibit microglia activity and thus production of interleukin-1.

In the January 7, 2000, Nature researchers from Harvard Medical School (Boston, MA) and BioDesign Research Group (Saitama, Japan) revealed that they have uncovered a novel mechanism by which cells die involving the endoplasmic reticulum (ER) and caspase-12. Importantly, the collaborative work also establishes a direct connection between caspase-12 and AD, providing a significant new lead toward potential treatments for the disease. Junying Yuan and colleagues focused their research on clarifying the specific function of caspase-12. Surprisingly, they found that the caspase was located in the ER, which is also where the beta-amyloid precursor resides. In theory, a caspase-12 inhibitor could potentially prevent beta-amyloid-induced apoptosis, a major factor in AD-related neurodegeneration.

Neuritic Plaque

The development of neuritic plaque is also, in part, associated with inflammation. Therefore, anti-inflammatory drugs may lead to a new therapeutic venue. Some studies have linked a decreased risk of AD among users of NSAIDs (non-steroidal anti-inflammatory drugs), but there have as yet been few randomized trials to test this. Adverse gastrointestinal effects are hallmark of some anti-inflammatory drugs, which would be problematic for elderly patients, but there are now trials underway testing the possible role of the less toxic cyclooxygenase-2 (COX-2) inhibitors in AD patients and people at risk for AD.

Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors include physostigmine (Synapton®; Forest Laboratories; New York, NY), tacrine (Cognex®; Parke-Davis; Morris Plains, NJ), donepezil (Aricept®, Pfizer/Eisai; New York, NY/Tokyo, Japan), metrifonate (Bayer; Leverkusen, Germany), and rivastigmine (Exelon®; Novartis; Basel, Switzerland). These compounds increase the concentration of acetylcholine and the duration of its action in synapses by inhibiting the acetylcholinesterase enzyme.

Tacrine, the first cholinesterase inhibitor to receive FDA approval for use in patients with AD, nonetheless provides only modest improvements in cognition, has a lower bioavailability than rivastigmine and donepezil, and it has a worse side-effect profile. In Phase II and III trials, donepezil significantly improved cognition and reduced the severity of the disease when compared with placebo. Unlike tacrine, donepezil is not hepatotoxic and is more tolerable. Rivastigmine matches or exceeds its peers in the improvement experienced by patients, but requires a longer period of titration than donepezil before a therapeutic dose is attained.

On March 1, 2000, Sanochemia Pharmazeutika AG (Vienna, Austria) announced the first European registration of its acetylcholinase inhibitor, Reminyl (galantamine; formerly known as SPH-1286). The approval came from Sweden; Reminyl will now be submitted through the EU Mutual Recognition Procedure to gain marketing approval throughout Europe.

NeuroSearch (Ballerup, Denmark) recently selected NS2330 for clinical development. NS2330 increases the activity of dopamine and noradrenaline through an uptake inhibition mechanism that also increases the release of acetylcholine in areas of the brain involved in cognitive function. Since the function of all three neurotransmitters is affected in AD, NeuroSearch expects that NS2330 will have a greater therapeutic effect on patients suffering from AD than compounds that solely increase acetylcholine function. Phase I trials have been completed, and the FDA has granted NeuroSearch approval to commence Phase II trials.

Other compounds being tested include xanomeline (Novo Nordisk/Eli Lilly; Bagsvaerd, Denmark/Indianapolis, IN), besperidine (Hoechst Marion Roussel; Frankfurt, Germany), and talsaclidine (Boehringer Ingelheim/Pharmacia & Upjohn; Ingelheim, Germany/Peapack, NJ).

Other Mechanisms

Some studies have suggested that estrogen replacement therapy may significantly delay the onset of AD in women and lower their risk of developing it at all. Several small trials found that estrogen treatment improved cognition. Estrogen's ability to act both as an antioxidant and as an anti-inflammatory may explain this risk reduction, but estrogen also boosts acetylcholine, may promote growth and survival of neurons, and may reduce the creation of beta-amyloid by affecting its precursor protein. Additional studies, however, will be required to prove any connection between estrogen therapy and the risk of AD in women.

In the second quarter of 2000, Toyama Chemical (Tokyo, Japan) expects to begin Phase II trials in Britain of T-588, and may also shortly begin tests of the drug in the US. In collaboration with New York University (New York, NY), Toyama found that T-588 demonstrated an ability to protect nerve cells in the brain.

Fujisawa Pharmaceutical Co.'s (Osaka, Japan) FK-960 is in Phase II clinical trials in Japan and in the United States. FK-960 is a cognitive enhancer believed to have a new mechanism of action.

Other Research

In an article published in Behavioural Brain Research (March 2000; 108(2):145-155) Minoru Onozuka and his team at the Gifu University School of Medicine (Gifu, Japan) reported that chewing helps prevent memory loss as people age. Onozuka et al. believe chewing stimulates the brain and helps memory retention, but they aren't sure of the mechanism. Their study involved mice genetically altered to develop the signs of human aging. Mice whose teeth were extracted--to prevent chewing--did not perform as well on memory tests as did mice with teeth. In addition, Onozuka's team studied the brain activity of humans during the process of chewing and found that jaw movements increased signals in the hippocampus.

Researchers at the Sanders-Brown Center on Aging at the University of Kentucky (Lexington, KY) have found that reducing food intake may help protect the brain against age-related disorders like AD. In a study published in the January 1999 Annals of Neurology, Mark P. Mattson, Ph.D., et al. found they could reduce the effects of induced brain injuries in rats by maintaining the animals on reduced diets. Studies of calorie intake and neurodegenerative diseases in humans have not yet been conducted, but some correlations have previously been made linking lower caloric intake and lower incidences of AD for people in Japan and China compared with people in the US and Canada.

Neurobiological Technologies, Inc. (Richmond, CA) announced in February 2000 that its corporate collaborator, Merz & Co. GmbH (Frankfurt, Germany) reported significant positive results from a US Phase III trial of memantine, a non-competitive NMDA antagonist, in patients with advanced AD.

In the December 2, 1999, issue of Nature (402:533-537, 1999), researchers from Pharmacia & Upjohn (Kalamazoo, MI and Stockholm, Sweden) reported they have successfully isolated the gene widely believed to trigger the development of AD. The gene, aspartyl protease (Asp2), causes the production of beta-amyloid peptide, the main component of amyloid plaques.

A Selection of Ongoing Clinical Trials in AD

Source: D&MD.

Upcoming Conferences

World Alzheimer Congress 2000

Washington, DC

July 9-18, 2000

Organized by the Alzheimer's Association

The 6th Symposium, Neurodegenerative Disorders: Common Molecular Mechanisms

Tobago, West Indies

April 8-14, 2000

Organized by the International Brain Research Organization

Sixth International Stockholm/Springfield Symposium on Advances in Alzheimer's Therapy

Stockholm, Sweden

April 5-8, 2000

Organized by Southern Illinois School of Medicine's Department of Continuing Medical Education, Geneva University Hospitals' Department of Geriatrics, and the Karolinska Institute's Department of Clinical Neuroscience and Family Medicine

52nd Annual Meeting of the American Academy of Neurology

San Diego, CA

April 29-May 6, 2000

Organized by the American Academy of Neurology

This article was written by Lynn M. Savage, Managing Editor of D&MD Newsletter. Questions and comments are welcome at lsavage@drugandmarket.com.

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