Unlocking the puzzle

After decades of painstaking research in the field, is the scientific community any closer to finding a cure for dementia? Linda Belardi reports.

In the past decade progress in the clinical development of disease modifying treatments for dementia has been disappointing. Previous trials of new drugs have not shown benefit in patients and promising results in the lab or in animal testing have failed to translate when replicated in large-scale human trials. 

A Russian drug Dimebon, trialled by the most experienced and senior researchers in the world showed spectacular results in an early phase trial but a replication study conducted in the US last year did not show any benefit compared to the placebo.

Professor Henry Brodaty, director of the Dementia Collaborative Research Centre at the University of NSW says Dimebon may yet prove to be a new addition for treatment if a third international trial is successful. However, if this trial is also negative then it could well be fatal for this drug, he says.

Anti-amyloid therapies have also failed to demonstrate a benefit over the placebo so far and in one trial fared slightly worse than the control group.

Following a series of clinical setbacks, commercial interest is reportedly cooling amongst the major pharmaceutical companies, as the threshold of industry skepticism is quite high.

To date, the huge financial investment in pharmaceutical research has not reaped any rewards and some drug companies may be reviewing their long-term involvement in future Alzheimer's disease drug testing.

However, from setback emerges innovation. In June last year, in what was an unprecedented step for the industry, a dozen competing international pharmaceutical companies agreed to join forces and share data on thousands of Alzheimer's patients in the hope of igniting a breakthrough.

The public database includes information from 4000 Alzheimer's disease patients from past clinical trials and will allow clinicians and brain researchers to study the files for clues on how to speed the discovery for new drugs.

Some of the world's pharmaceutical giants including Pfizer, GlaxoSmithKline and AstraZeneca are involved in the project alongside patient advocacy groups, national health institutes and government regulators. The initiative is called the Coalition Against Major Diseases and is based in the US.

Certainly a morale boost is needed as both industry and the broader scientific community have become increasingly frustrated over the failure in the past decade to reach a clinical breakthrough.

Despite hundreds of drug trials, dementia and its most common condition, Alzheimer's disease is without effective medical treatment to slow down or the delay the progression of the disease.

"We desperately need the science to deliver better therapies for the dementias, which are still virtually inhabiting a therapeutic vacuum," says Michael Woodward, director of aged care at Austin Health Hospital and one of Australia's leading clinicians and dementia researchers.

"It is disappointing that after two or three decades of the same drugs we still don't have another drug of any significance on the market.

"Most of the trials that have tested the drugs have come back negative or the drugs have turned out to have an unacceptable toxicity. So while the theory has all been good getting them through the research hoops has been more difficult and that's a big problem. It's disappointing," he says.

At a recent conference in Barcelona of movers and shakers in the research field Woodward noted that enthusiasm for the availability of new treatments was waning.

"Over the past 25 years, I've personally carried out 40 or 50 trials of new compounds and very few of them have shown any promise. We're still stuck with the same four drugs we've had for a long time," he says.

There are currently four approved medications on the market; Aricept, Exelon, Reminyl and Ebixa. However, all have modest benefits and treat the symptoms not the underlying cause of the disease.

However, Woodward says that current medications need to be better used by patients and his research has suggested that existing treatments are not being utilized for enough people or for long enough.

"There's a bit of therapeutic apathy or nihilism by some specialists who don't want to even start these drugs. In most conditions patients are also looking for the drugs to stop the condition but that's not the case with Alzheimer's disease. Current treatments work to slow down the progression of the disease.

"It's hard to get people interested in a drug when they are not seeing much benefit but they are achieving a benefit. Slowing the rate of functional decline is still important," says Woodward.

Understanding the science

While the recent decade of clinical failures has been disappointing, it appears the ambition for a quick cure for Alzheimer's disease without first having a complete understanding of the disease has been misplaced.

Professor Ashley Bush from University of Melbourne's Mental Health Research Institute says the science underlying many of the failed clinical trials has been based on guesswork.

"In the past there have been a lot of stabs in the dark and it hasn't got us very far. The greatest challenge is remaining patient with the science and not trying to leap too far too fast," he says.

Drug therapies based on an improved understanding of the disease at a cellular level will accelerate the clinical development of new drugs.

"It is possible to unravel the biochemistry of the disease with enough patience and enough research," says Bush.

Australia has also been able to do more pioneering work in dementia research per man than the US by supporting cutting edge research and building its research infrastructure, he says.

Compared with other chronic diseases, dementia is still a young field of research and trails progress in cancer and cardiovascular disease by 20 years.

Researchers have only just begun to scratch the surface in terms of understanding the underlying science of the disease and scientists have yet to answer one of the condition's most fundamental questions - what causes the condition.

Professor Juergen Goetz from the University of Sydney's Brain and Mind Institute says dementia is a highly complex condition and current initiatives which target Alzheimer's disease will not eradicate other forms of dementia.

The effectiveness of treatments targeting a single pathology will be limited and it is still unclear whether Alzheimer's disease is one disease with a single cause or multiple conditions with shared symptoms.

"There is an increasing awareness that this disease is complex and overlaps pathologically with Parkinson's disease. In the future we will most likely see combinatorial treatment, like with AIDS you need cocktails to tackle the disease," says Goetz.

The shift from treatment to early diagnosis

Where clinical trials have failed to achieve a breakthrough in the past, it may also be the case that current drug therapies have been not been intervening early enough to demonstrate any clinical benefits to patients.

"The ambition over the next 20 to 30 years is to come up with a drug treatment that is as useful for Alzheimer's disease as anti-cholesterol drugs are for heart disease," says Bush.

"Once a person has had a heart attack you can't really treat them with disease modifying drugs. It's too late. So the idea is to go in as early as possible to stop the disease from progressing."

New drugs are therefore being developed to target Alzheimer's disease at its earliest stages, even before the clinical symptoms appear.

Through early diagnosis techniques, such as PET brain scans and diagnostic testing, treatment can be used to effectively target those most at risk, in order to postpone or delay the rate of degeneration.

While a cure may be the holy grail it is, at best, decades away and delaying the progression of the disease through early detection is our best hope, he says.

In March, Bush was awarded a $4 million National Health and Medical Research Council (NHMRC) fellowship to further develop a comprehensive set of biological markers that can be used to diagnose and monitor the progression of the disease.

Acknowledging this important evolution in scientific thinking, the clinical diagnostic criteria for Alzheimer's disease were revised in the US in April to include a greater focus on early diagnosis and biological testing of the condition.

The updated guidelines from the American National Institute on Ageing outline the earliest preclinical stages of dementia and address the use of neuroimaging and diagnostic testing techniques.

The tyranny of distance: Australian researchers competing overseas

While Australia may have the intellectual man-power and a growing research infrastructure, Australia's small pharmaceutical industry is a distinct disadvantage and poses a glass ceiling of sorts for researchers wanting to test and trial their new drugs on a large scale.

Bush says Australia's small pharmaceutical industry is a considerable disadvantage and forces local researchers to compete abroad for the attention of the big drug companies.

While Australia does punch above its weight in terms of attracting international commercial investment, local researchers in the US and Europe by comparison have their drugs more readily trialled, he says.

"We actually have to road show these ideas, turn up to international meetings and persuade the big drug companies that what we've got is worth paying attention to."

The promising Australian drug PBT2, developed by Bush and his colleagues in partnership with Melbourne-based Prana Technology, is currently ready for final stage testing which requires significant financial investment.

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