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Signalling change

Researchers are starting to focus on alternative targets in the search for a cure for AD

A green traffic lightThe brain represents the most complex machine in the known universe — it possesses over 100 billion neurons, each with up to 100 trillion synaptic connections. This natural supercomputer enables humankind to think, remember, feel and learn via the seamless neurotransmission of electrical and chemical signals between neurons. This forms the basis of our memories, thoughts, skills, abilities and behaviour.

In turn, memory and cognition are essential in shaping and maintaining our unique sense of personal identity. It would be impossible to imagine a truly fulfilling life without these key brain functions — we would cease being who we are, and yet, this is the exact dreaded scenario faced by millions of individuals living with Alzheimer's disease (AD) worldwide.

Dementia is defined as the clinically diagnosed loss of memory and other intellectual functions that are serious enough to interfere with daily life. AD represents the most common type of dementia in the elderly, accounting for 60-80 per cent of all cases. The latest global estimate of AD prevalence revealed that 26.6 million people were living with the disease in 2006; researchers forecast that this figure will rise steadily to more than 100 million by 2050, when 1 in 85 individuals will be living with AD due to rapidly ageing populations and longer life expectancy in most countries.

AD is a major contributor to the global burden of chronic disease and disability in the elderly. Although advancing age is an important risk factor for AD, this condition is not a normal part of ageing. The Centers for Disease Control and Prevention (CDC) reported in June 2008 that the disease has surpassed diabetes as the sixth-leading cause of death in the US.

AD progressively damages and kills brain cells. Production of key neurotransmitters is gradually lowered, which disrupts normal neuronal signalling to the point where patients lose their personality and are no longer able to live on their own, plus they require a high degree of help to perform everyday tasks. On average, most people with AD die within eight years of diagnosis, although that period could be as short as one year or as long as 20 years.

Although the causes of AD are not fully understood, the brains of patients display two major disease features that were first described by the German neurologist, Dr Alois Alzheimer, in 1906. These hallmarks encompass neuritic or amyloid plaques comprising toxic, extracellular amyloid-beta (Aß) protein deposits, and neurofibrillary tangles made up of abnormally twisted, intracellular fibres of tau protein.

As scientists continue to unravel the AD puzzle, a cure still seems out of reach due to the fact that dead nerve cells cannot be regenerated.

Addressing the underlying cause
For a century, existing therapeutic options for AD have been limited to the treatment of disease symptoms. This covers the management of cognitive symptoms with conventional drugs such as the cholinesterase inhibitors donepezil, rivastigmine, galantamine plus tacrine (least popular drug due to an inconvenient regimen and associated serious adverse events, including possible liver damage) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, or the control of behavioural symptoms with standard antipsychotics, antidepressants or anxiolytics. However, these drugs can help to modestly improve such cognitive and behavioural symptoms or temporarily slow down their progression in some people, depending on the stage of disease.

In order to discover and develop treatments that delay, halt or even reverse the progression of AD, researchers and players within the pharmaceutical industry are attempting to address the underlying cause and pathology of AD. Given the sobering worldwide prevalence of AD and the projected increase of disease burden in the future, any product that successfully alters the course of the disease would easily become the next 'blockbuster' billion-dollar drug. Consequently, virtually every major pharmaceutical and biotech company is racing to develop such a disease-modifying drug.

Scientists are still arguing whether or not amyloid plaques and neurofibrillary tangles do actually cause AD or are these merely the simple by-products of disease. Supporters of the amyloid theory have held the upper hand for many years, which saw Aß being the most popular target for drug development in AD. However, a growing number of amyloid-targeting drugs have failed to deliver robust efficacy results from clinical trials. This includes the antibody bapineuzumab and the vaccine ACC 001, which were both co-developed by Wyeth and Elan Corporation; mediocre phase II trial results were reported for bapineuzumab, while phase II trials of ACC 001 were voluntarily suspended due to a patient being hospitalised with skin lesions. Similarly, Myriad Genetics has also reported disappointing efficacy data for tarenflurbil from a phase III (ActEarliAD) trial. Another once-promising anti-amyloid drug, tramiprosate, was also abandoned by Bellus Health due to inconclusive phase III study findings.

Faced with such setbacks, the validity of the amyloid hypothesis has been called into question — has too much scientific effort and financial resource been invested in the validation of amyloid-based compounds at the expense of other potentially useful targets? Additionally, some studies have found that even when amyloid was eliminated from the brain, some patients still have dementia.

Alternative targets
Although targeting amyloid is still practical, the growing body of evidence indicates that it may not be the only avenue towards attaining a cure for AD.

Nonetheless, researchers are starting to focus on alternative targets, ie tau protein resulting in formation of neurofibrillary tangles. TauRx Therapeutics is developing methylthioninium chloride (in phase II trials), which could hold the key to a first-generation tau protein inhibitor that may delay the progress of AD for as long as 19 months. TauRx researchers have found that abnormal polymerisation and aggregation of tau protein within neurons was directly linked to dementia, irrespective of Aß load. In contrast, amyloid plaques are considered more a feature of normal ageing and are poorly correlated with dementia. The validity of the tau aggregation hypothesis has been confirmed by tau-transgenic animal models, which indicate that tau aggregation alone was sufficient to produce a cognitive deficit, and blockade of tau aggregation reverses this effect. Thus, TauRx and its allies believe that inhibition of tau proteins could offer a feasible disease-modifying strategy of halting and preventing the formation and spread of neurofibrillary tangles throughout the brain.

Additionally, Allon Therapeutics has also presented encouraging phase II trial data for its anti-tau drug AL 208. In the small trial of patients with mild cognitive impairment at risk of AD, AL 108 improved some aspects of short-term memory. Another non-amyloid drug yielding promising results is Medivation's dimebolin, which is an antihistamine used in Russia. Dimebolin delayed progression of AD in a large phase III trial. Overall, this represents the first-ever time that clinical results from anti-tau drugs have been available. While findings for such drugs are not yet definitive, they do indicate that further evaluation in larger trials are warranted, which could produce more definitive results.

Despite disappointing clinical outcomes for several drugs, most scientists and industry executives view the glass as half full.

To put things into perspective, 20 years ago there were no compounds for AD therapy, but currently there are at least 30 drugs in clinical development. With many potential targets still to explore, it would be prudent to investigate all the options to increase the chances of discovering that elusive cure for AD.

The Author
Written by Darrell Ng of Adis International - Wolters Kluwer Health - using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Camille Scot-Smith on +44 (0)20 7981 0733

24th November 2008

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