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Halted in its tracks

Developmental treatments for Alzheimer's disease could help to prevent its progression
Alzheimer's disease is the most common form of dementia. Initially characterised by short-term memory loss (amnesia), it becomes more pronounced with disease progression. As the disease manifests, other areas of cognitive function, such as language, recognition and decision-making, become impaired. Death usually results within seven to 10 years of disease onset.

The cause of Alzheimer's remains unclear. Its pathology involves the deposition of B-amyloid protein, in the form of plaques, outside nerve cells and on the walls of small blood vessels within the brain, and the formation of neurofibrillary tangles inside the nerve cell bodies, due to the aggregation of abnormally phosphorylated tau protein.

What's available
Patients with Alzheimer's disease exhibit decreased levels of the neurotransmitter, acetylcholine. The majority of available therapies indicated for mild-to-moderate Alzheimer's are acetylcholinesterase inhibitors. These include tacrine, donepezil, rivastigmine and galantamine.

Acetylcholinesterase inhibitors preserve acetylcholine levels by inhibiting the neurotransmitter's natural breakdown. It is currently understood, however, that the decreased acetylcholine levels exhibited by patients are the result of the neuronal damage caused by the disease itself. Acetylcholinesterase inhibitors may, thus, alleviate symptoms, but do not slow the progression of disease.

New research
Some novel treatment advances for the condition were showcased at the 10th International Conference on Alzheimer's Disease and Related Disorders (ICAD), held in Madrid, Spain in July 2006 - the largest gathering of Alzheimer's disease researchers in history.

Among the new prospects was FPF 1070, Ebewe Pharmaceuticals` peptidergic drug, which has been launched in Austria, Germany, China and Russia for treating of mild-to-moderate Alzheimer's. It has been shown to accelerate neural growth and survival of cholinergic neurons.

Results presented at ICAD 2006 by researchers from Euroespes Biomedical Centre, in Spain, and Ebewe Pharma, demonstrated that FPF 1070 has beneficial effects that are still apparent three months after the cessation of therapy, suggesting that the drug is effective in slowing the progression of the disease.

Tramiprosate is a B-amyloid inhibitor that is currently in phase III development with Neurochem. Tramiprosate interacts with the binding site of soluble B-amyloid and prevents it from aggregating into insoluble plaques.

Data presented at ICAD 2006 showed tramiprosate halts B-amyloid-induced neuronal cell death in rats. Results from phase II clinical trials indicate that it may prevent disease progression, particularly in patients with mild illness.

Link with diabetes
There is evidence of a link between diabetes mellitus and Alzheimer's disease. Advanced glycation end products (AGEs) are sugar-related toxins that are elevated in patients with diabetes mellitus and are also present in the brains of patients with Alzheimer's disease.

Pioglitazone and rosiglitazone are thiazolidinediones, and currently prescribed for the treatment of Type II diabetes. However, preliminary studies have shown that these agents may modulate glucose metabolism and inflammation within the central nervous system of patients with Alzheimer's.

Two phase III studies are underway currently with GlaxoSmithKline (REFLECT 2 and 3), investigating the efficacy of rosiglitazone adjunctive to acetylcholin-esterase inhibitors in patients with mild-to-moderate Alzheimer's disease.

Results presented at ICAD 2006 showed that 24 weeks of rosiglitazone 8 mg/day significantly improved Clinician Interview-Based Impression of Change-Plus (CIBIC-plus) scores and scores on the irritability/lability domain of the Neuropsychiatric Inventory (NPI) scale in 511 patients with mild-to-moderate Alzheimer's.

Voyager Pharmaceuticals is currently developing leuprorelin, a luteinising-hormone-lowering drug, which may be an effective adjunctive to acetylcholinesterase inhibitors in female patients with mild-to-moderate Alzheimer's, according to results revealed at ICAD 2006.

The results, which were from a subgroup analysis of data from the ALADDIN I study, showed that over 48 weeks of treatment, leuprorelin was associated with trends towards significant improvements in scores on the Alzheimer's Disease Assessment Scale (ADAS) cognitive subscale and the Alzheimer's Disease Cooperative Study-Clinical Global Impressions (ADCS-CGI) scale.

Researchers at Voyager Pharmaceuticals announced that women treated with the drug were able to maintain their memory and their ability to do things like dress themselves.

NMDA receptor antagonists
Neramexane is an NMDA receptor antagonist being developed by Merz Pharma and Forest Laboratories to treat moderate-to-severe Alzheimer's disease.

Its efficacy is thought to be due to the regulation of glutamate activity within the brain; it's in phase III development, but results so far have been equivocal.

A 24-week, multicentre study, showed that neramexane significantly improved Activities of Daily Living compared with placebo in patients with moderate-to-severe illness, and there was a significant difference in the Severe Impairment Battery in favour of neramexane at week 12, though not at the 24-week endpoint.

Another large study conducted in patients suffering with moderate-to-severe Alzheimer's disease showed that six weeks of treatment with neramexane adjunctive to acetylcholinesterase inhibitors was no more effective than acetylcholinesterase inhibitors alone.

These findings were noted with regard to Severe Impairment Battery, Alzheimer's Disease Cooperative Study, CIBIC-plus scores, Activities of Daily Living Inventory or caregiver input scores.

Memantine is also an NMDA receptor antagonist, developed by Merz Pharma, and is currently the only drug available for those patients with moderate-to-severe Alzheimer's disease.

A study published in the New England Journal of Medicine in April 2003, revealed that after 28 weeks of treatment with memantine, significant improvements were seen in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia scores, Severe Impairment Battery scores and Functional Assessment Staging Test scores in patients with moderate-to-severe illness.

Researchers from Merz Pharma and the New York University School of Medicine, said that memantine had become the first drug to slow the progression of the disease among severely ill Alzheimer's patients.

Studies in rats have shown that memantine inhibits the formation of tau tangles, findings which were supported by clinical results presented at ICAD 2006 by researchers from the Department of Public Health/Geriatrics in Uppsala, Sweden.

They showed that levels of abnormally phosphorylated tau protein were significantly reduced following one year of treatment with memantine.

Total tau levels and B-amyloid levels were not significantly affected, however.

The Author
The author is Steve McMillan of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008

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