Alzheimer’s disease: pharma’s greatest challenge

pharmafile | April 4, 2014 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  AD, Alzheimer's, Alzheimer’s, Eisai, Lunt, Pfizer, galantamine, karran, priddy 

Like it or not, we are all becoming increasingly prone to a currently incurable and debilitating disease, that places an enormous emotional and financial drain not only on ourselves and our families, but on the state too.

It is estimated that just under one million people in the UK are affected by the clinical outcome known as dementia – of these, 62% (or around half a million) are affected by Alzheimer’s Dementia (AD). 

“The greatest risk factor is age – the older you get, the greater the likelihood you’ll have Alzheimer’s,” says Dr Eric Karran, director of research at the UK’s leading dementia research charity Alzheimer’s Research UK. “Although hard data is hard to obtain, it’s thought that by the age of around 85, there is a 45-50% chance of having Alzheimer’s,” he adds. 

Given the increasingly elderly population not only in the West but also globally, the prevalence of AD can only increase significantly with time. Based on a World Health Organization (WHO) report dated April 2012, an estimated 35.6 million people were living with the condition in 2010. However, that number is projected to double every 20 years – increasing to more than 65 million in 2030, and more than 115 million in 2050.

Unsustainable costs

According to Karran, the rise in the percentage of the world population with dementia can be put down in part to individuals living longer – and thus not dying of other diseases – and also to diminishing birth rates.

The costs of this are significant, in terms of both medicines and social care, as well as the impact on society at large. One great fear, he says, is that the ratio of people providing tax revenue to those needing support will begin to become unsustainable. 

“It’s one of those disasters that’s happening slowly – it’s never going to happen suddenly on any politician’s watch,” he adds. “Unless there’s a co-ordinated effort to tackle this problem, it will start to impact healthcare systems around the world, as there’s only a finite amount of money you can spend on care.”

As far as the UK is concerned, it is estimated that the overall cost of dementia to the economy has already spiralled beyond the cost of cancer and heart disease put together. At present, dementia racks up costs of £23 billion every year, and this is likely to rise to £27 billion by 2018, based on a 2012
report by cross-party think tank the Social Market Foundation. 

As the disease can be debilitating, and people with AD often need round-the-clock care, a large proportion of these costs are borne by the social care sector, as well as by family and friends of AD sufferers.

With this in mind, research commissioned in Europe by big pharma’s Eli Lilly (and published in 2013) shows that family and friends provided in excess of £11,000 worth of informal care a year for people with moderate Alzheimer’s disease, while this figure was over £17,000 in patients with severe AD.

“Informal care is currently unaccounted for when we assess the cost of the disease to society, but can have a huge knock-on effect on our economy,” says Professor Michael Hutton, chief scientific officer for neurodegeneration at Lilly UK. “Not only will families be under great financial pressure but this caring role prevents them from accessing other forms of employment,” Hutton says.

Early intervention, on the other hand, has been shown to reduce the need for institutionalisation by 22%, according to a 2013 report in the Journal of Alzheimer’s Disease, with a potential knock-on effect on care home admissions.

As Hutton notes, even if early intervention and treatment reduced care home admissions by just 10%, this could result in savings of £120 million to the public purse. What is more, he says that those individuals and their families suffering from the disease who collectively shoulder a massive financial burden, could be relieved of an additional financial drain of £125 million. 

And many people are still unaware that Alzheimer’s disease itself can be fatal for patients. Remarkable research published in March found that it may now be the third-most deadly killer in the US. According to the Journal of Neurology study, many more Americans die from the disease than is known. 

The study’s authors believe that as many as half a million people in the US are killed by Alzheimer’s each year – which is about five times more than the 83,494 currently cited on death certificates, the research found.

Many people fail to understand the destruction that results from Alzheimer’s disease; it can be fatal when it impairs parts of the brain that control basic functions like breathing and swallowing.

The findings should increase the urgency to spend more on research into an illness that’s becoming more common as the population ages, according to Bryan James, the study’s lead author and an epidemiologist at Rush University Medical Center in Chicago.

In the US, Alzheimer’s costs the healthcare system more than $200 billion a year to cover the expense of caring for patients with the disease. 

Where are we now?

At present, AD is treated by four medicines, three of which – donepezil (marketed under the name Aricept by its developer Eisai and partner Pfizer), galantamine (originally development in the former Soviet Union in the 1950s) and rivastigmine (sold under the trade name Exelon) act by more or less the same mechanism.

Inhibiting an enzyme in the brain called acetylcholinesterase, they increase the amount of neurotransmitters which affect signals in the brain. Whilst they can improve symptoms, allowing people precious time with their loved ones, their effects are limited. 

The inhibitor currently in use only provides a three-point improvement on the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), which measures aspects of cognition such as obeying commands or remembering words on a scale of zero to 70. 

“It’s modest,” Karran admits. “It works better for some than others, but there’s a short-lived effect and it wears off after six to 12 months.” The other drug used to treat moderate-to-severe AD is memantine, first synthesised by Lilly in 1968 and marketed under a range of brand names. “To be honest, no-one really knows how that works – but it does,” Karran says.

In a nutshell, not only is the extent of medicine currently available for all AD sufferers poor, more importantly, none of the drugs currently available change the course of the disease. “They don’t slow it up; they do nothing for the course of the disease but give a temporary boost in some of the limited brain functions,” he adds. 

“Ultimately, the positive effects wear off; this is mainly because the brain cells, and the neurons on which they act, are being lost because of the disease, so there’s nothing left to work on.” Karran notes that current aims are to try to find drugs that will alter the course of the disease. “We now understand that the pathology in the brain starts a decade before you actually notice the symptoms,” he says.

“[As] the process you are trying to affect is, by that stage, already 10 years old, it’s hardly surprising to see an effect late in the disease process.” Other themes undergoing investigation include new technology which could enable the selection of individuals with the pathology – but no symptoms – who could enter very early trials, with the goal of making drugs more efficacious when the disease is not so far advanced.

Given that asking people to take drugs when they have no symptoms of a particular condition raises ethical questions, and thus significant clinical hurdles, their impact is likely to be incredibly valuable.

Where next?

As the drugs currently available tend to be overwhelmed by the ongoing advance of AD, the current challenge is to find a disease-modifying treatment. One cause for optimism is that our understanding of the neuropathology of AD is growing. 

Over the past 15 years, more than 100 experimental Alzheimer’s drugs have failed in tests, but pharma industry analysts believe that a truly effective drug could be worth around $10 billion in peak annual sales.

There are two main theories on the causes of Alzheimer’s: the first is that the tau protein forms in the brain and creates ‘tangles’, while the second is that the amyloid protein creates a build-up of plaques in the brain.

“We increasingly understand the relationship between the build-up of amyloid plaques and tau tangles in the brain and, despite the high profile failure of clinical trials in this area, research is ongoing,” Hutton says. “Multiple drugs are in development that target the underlying disease process and which are designed to slow or even halt the progression of the disease,” he says. 

Echoing commitments made at the G8 summit at the end of 2013 – which set the challenge of making AD preventable by 2025 – Hutton adds that Lilly is seeking to hit that target. The firm has already invested over £100 million into its Surrey-based UK Research Centre since 2003 which supports around 400 scientists, working mainly in neuroscience.

“But we can’t do it alone,” he says. “There needs to be a strong partnership between academia, biotech, pharmaceuticals and research charities if we are to overcome some of the most challenging medical conditions, such as Alzheimer’s disease.” 

It is exactly such needs which lie behind the creation of the Dementia Consortium, uniting the know-how of two pharma companies, Eisai and Lilly, with Alzheimer’s Research UK and MRC Technology, the UK government’s technology transfer and drug discovery experts.

The Dementia Consortium seeks to reduce the long wait for new dementia treatments by closing the gap between fundamental academic research and the industry’s drug discovery capabilities. Plans are for it to provide funding, resources and expertise to both increase the number of – and capitalise upon – new drug targets emerging from the academic sector that hold promise.

New targets range from de-risking the early, difficult phase of drug discovery, to increasing the flow of new research and plugging the gap as pharma moves out of this area. The consortium’s arrival is nothing if not timely, given the ongoing significant pressure on pharma across the board to deploy the R&D function in areas where decent returns on investment are most likely, adds Karran. 

“Clinical trials [for AD] are so long and expensive, and two Phase III studies on AD, which is what is required to get a licence, will cost half a billion pounds,” he says. Since the beginning of 2014, there have been some promising developments.

In January, the private Swiss biotech AC Immune launched the world’s first trial of an Alzheimer’s vaccine, ACI-35, which is designed to stimulate the body’s immune system to produce antibodies which target the tau protein. 

Whilst in February, under a five-year collaboration co-ordinated by the US government’s National Institutes of Health, pharma companies including GlaxoSmithKline, Merck and Pfizer agreed to invest $230 million to help identify new biological targets for the disease.

And finally in March, Eisai and Biogen Idec joined forces to look for new Alzheimer’s treatments, and said they will develop and commercialise two of the Japanese firm’s clinical candidates for the disease, E2609 and BAN2401. Eisai has also been given the option on a pair of Biogen’s Alzheimer’s candidates, the anti-amyloid beta antibody BIIB037 and an anti-tau monoclonal antibody.

‘There is hope’

Given the support of initiatives such as the Dementia Consortium, the general consensus is that science is on the right track and that – at some point – it will be possible to slow AD down. “There is hope,” says Karran. 

He adds that particularly good genetic data has been gathered from human studies which gives real encouragement that if a suitably safe medicine is developed, it may be possible to significantly delay the onset of AD in the first place. 

“We may get to the point where something similar to a vaccination [exists], where people are vaccinated in their fifties to prevent the onset of AD, or there may be a safe medicine that they take that prevents the onset of the disease,” he says.

Such developments are likely to be far off and require significant groundwork to be carried out – such as testing early medicine – but, theoretically, data suggests that this is by no means unrealistic. What is certain is that we live in an exciting time for Alzheimer’s research and that understanding of the condition is increasing every day, adds Hutton.

“However, we do not underestimate the difficulties in researching in this area,” he says. “The condition is complex and clinical trials are lengthy to allow researchers to adequately assess the impact on a person’s cognitive ability over time.” 

In order to address the huge challenge of meeting the G8 summit’s goal of making Alzheimer’s disease preventable by 2025, he urges governments to pledge to invest more money into the basic and translational research that will increase scientific understanding and lead to treatments and cures for Alzheimer’s.

“Alongside research, structures and systems must be in place to ensure that patients can access the new types of AD medication when they become available, which could be as early as within the next five to 10 years,” he says.

“This is important not just in the high income nations, but also in mid and low income countries that are expected to contribute to much of the growth in the numbers of patients over the next 50 years.”

Living with Alzheimer’s 

At the age of 36, Mark Priddy was diagnosed with early-onset Alzheimer’s, which affects people under the age of 65 and accounts for about 5% of Alzheimer’s disease. With two young daughters, he and his wife Dione were devastated by the news and decided to make the most of their time together, while they could. 

Within a short time, however, Mark’s condition deteriorated and he became a danger to himself and his young girls – needing 24-hour care in a specialist nursing home – and eventually could not walk or talk. Mark died in 2010 aged just 41, two weeks before Dione was due to run the Virgin London Marathon to raise money for Alzheimer’s Research UK. 

“We initially thought Mark was unsettled after a move; he was really unhappy and we didn’t know why,” Dione says. Initially diagnosed with depression, he was put on antidepressants for 18 months prior to his eventual diagnosis in 2005 with early onset Alzheimer’s. 

“Everything took a really long time as nobody was thinking about Alzheimer’s at that age,” Dione says. “People have to realise that this can happen to young people and not just brush it under the carpet as depression, as our doctor did. We didn’t really know enough about the illness and we feel so guilty – if we’d known sooner, he could have had a better quality of life.” 

Once diagnosed, Mark was tried on a range of medication, including Aricept, Reminyl and galantamine, and benefited from the support of an early onset nurse, who tested him for deterioration and monitored the effectiveness of his medication, as well as the chance to attend a specialist home one day a week. 

He was the youngest person in the UK to be diagnosed with the illness, but his widow notes that care in Britain is largely geared to people over the age of 65. As someone who used to play football and run, she says he was restless and did not enjoy standard activities at the home, such as gardening or cooking. 

“However, the staff were wonderful and supportive and kept me informed of any health concerns,” Dione says. One difficulty was that people did not realise her husband was ill, as he looked like a normal, healthy man. “At a Christmas party at his care home, somebody was angry at him as he was unsteady on his feet and they thought he was a drunken relative; it was heartbreaking and I felt so protective,” she says.

Given her own experiences of AD, she emphasises the importance of care and early diagnosis. “Early diagnosis is really important – a lot more is going on now, with leaflets going into doctor’s surgeries to prompt checks, but doctors need to be more aware,” she says. 

“Mark could have been diagnosed a couple of years before, and we had a horrible time during those last years. Early diagnosis would have made a huge difference to all of us.” Dione suggests that anyone with a family member who is diagnosed makes as many special moments as possible. “We fortunately renewed our vows soon before Mark went into care, having a wonderful fun day with all our family and friends,” she says. 

Dione looks forward to – if not to a cure being found – the chance to slow down the onset of Alzheimer’s. “So many people are diagnosed with cancer – it’s awful, but there is hope. When people with AD are diagnosed, they can only be given medication that may slow it down. 

“I’d like to see hope for sufferers, as the worst thing is to know ‘this is it’.”

Susie Lunt