By Munna Choudhury, PhD
Almost 47 million people live with dementia worldwide and it is one of the key causes of disability later in life beating cancer, cardiovascular disease and strokes. This number is likely to double by 2030 and almost triple by 2050 (1). There are many different types of dementia, the most common being Alzheimer’s disease, which accounts for ca 60% of all diagnosed cases (1).
There has been a notable failure to develop drugs to cure Alzheimer’s or even significantly delay its progression despite £billions being spent by pharma companies on drug development. It is believed by some that drug treatments will work better if the disease is caught early and before irreversible damage is done to nerve cells. This has turned attention to medical devices and diagnostics and how these might help in early diagnosis through biomarkers and cognitive testing, and in helping to care for patients in various stages of the disease. This presents opportunities for medical device companies to play their part in confronting this enormous healthcare problem. In this white paper we review the current challenges that Alzheimer’s presents, discuss the current treatment options and then look ahead to how devices might play their part in its management.
Dementia is caused by a group of diseases that affect the brain, progressively reducing a person’s ability to understand, remember, communicate and function in daily life. Consequently, dementia victims become increasingly dependent on care provided by others, most of which comes from family and friends (informal care). Victims are also high users of health care and formal social care, including residential and nursing homes.
There are many types of dementia, the most common being Alzheimer’s disease which accounts for about 60% of all diagnosed cases. It progresses in 3 stages: from mild to moderate to severe and exhibits three primary clinical features. Other types of dementia include vascular (affecting ca 17% of those diagnosed) and mixed dementia (affecting 10%).
Although old age is the single biggest risk for dementia, Alzheimer’s is not a normal part of ageing and can affect people as young as their forties. There are about half a million individuals in the United States with early-onset dementia. Research has pinpointed disruptions in specific memory networks in Alzheimer’s patients, such as those involving the posteromedial cortex and medial temporal lobe that appear distinct from normal ageing (2).
HOW BIG IS THE PROBLEM?
Today, almost 47M people live with dementia worldwide. This number is likely to double by 2030 and almost triple by 2050 to reach 131M people (1).
In the UK, dementia affects almost 850,000 people with 60,000 deaths occurring each year. It costs the UK ca £26B annually, equating to ca £32,000 per person with dementia. Prevalence in UK will increase in line with population ageing and reach over 1M by 2025 and almost 2M by 2050. This is the worst-case scenario assuming no public health interventions and that changes are driven by an ageing population alone (2). To put this number into perspective, 1 in 3 people born in the UK this year will develop dementia according to the Alzheimer’s Research Society (1,3).
DEMENTIA IS COMPLEX
Dementia is one of the key causes of disability later in life, beating cancer, cardiovascular disease and strokes. It is vital to find both medical cures but also other interventions that may provide a more realistic opportunity to maintain cognitive function, and potentially reduce the risk of cognitive decline later in life. This is particularly crucial in the absence of any drugs to prevent, slow or arrest dementia.
Given the huge scale of the problem, as a country, we have spent less on dementia research than on these other conditions. Why is that the case? Part of the problem is the complexity of Alzheimer’s and our lack of understanding of the disease pathway. Alzheimer’s is only verified after death when we look at brain biopsies. But we still do not know what actually causes the disease and how we can treat the underlying cause.
HOW IS IT CAUSED?
Multiple hypotheses for the disease mechanism have been proposed; the most cited being the beta-amyloid plaque theory which states that toxic plaque develops in the brain due to infection. The plaque destroys nerve cell connections causing the nerve cells to die. This results in memory loss and decline of cognitive function. Other theories discuss tau protein tangles and the APOE4 risk gene linked to amyloid deposits in the brain (4).
However, from a medical perspective, there is still a lot of work to do. Despite huge efforts from science and industry, Alzheimer’s is extremely complex. A comparison to oncology highlights why: in cancer, you need a medicine to kill cells; in Alzheimer’s you need a medicine to keep cells alive. This is no easy feat.
But even though Alzheimer’s is still incurable, we need to recognise that it is not untreatable. Recent years have seen increasing recognition of the problem exemplified by the launch of the Dementia Challenge in 2012 which aims to increase the rate of dementia diagnoses in UK. Only 42% of the UK population has been diagnosed – this is very low. This figure is even worse for developing countries where a large proportion of the population go undiagnosed. Indeed, one of the greatest challenges facing our society today is providing early and accurate diagnoses together with medical treatment and social care.
There are currently four FDA-approved medications for treating Alzheimer symptoms: these are all cholinesterase inhibitors or NMDA blockers. They target the effects of beta amyloid plaque build-up in the brain and temporarily help memory and thinking problems in about half of the people who take them but have shown limited efficacy.
Scientists now know that toxic plaque forms at least 20 years before any symptoms have appeared, so in reality, treatment occurs after the disease has already advanced. Also, even whilst on the drug, the disease still progresses. Hence the drugs relieve symptoms but ultimately do nothing to slow disease progression. The drugs are not ground-breaking (1). The market for treating the symptoms is estimated at $3B and expected to grow significantly if a disease modifying treatment enters the space (5).
In the absence of such a “wonder” drug, there has been much discussion about how GPs should maximise the use of current treatments (6). Donepezil, the most commonly prescribed drug for early stage Alzheimer’s, has been shown to slow disease progression in moderate to severe stages too. Donepezil may therefore help many more patients than previously thought. Furthermore, the cost of Donepezil is low, and could potentially keep patients out of expensive care homes. However, doctors are only prescribing Donepezil for patients with mild to moderate Alzheimer’s and often stopping medication too early. Therefore, better clinical guidance regarding the optimal use of established treatments might temper some of the growing demand for residential and nursing care and result in huge savings for the NHS.
Pharmaceutical companies are developing targeted novel therapies to modify disease processes that impact one or more of the many wide-ranging brain changes associated with dementia. These changes offer potential “targets” for new drugs to prevent, slow progression or even stop the condition. This unmet medical need represents a huge market opportunity for pharma; at least $20B and has been a key driver for the billions of dollars spent on R&D efforts. However, no truly novel Alzheimer’s drug has entered the market since 2003 (7). Over this period, 99.6% of all Alzheimer’s drugs to enter clinical trials failed to win approval (7). So, while a “cure” or prevention remains the goal, we need to fill the gap now.
The most recent high profile failure of Eli Lilly’s experimental monoclonal antibody, Solanzumab (Sola), wiped more than $10B off the company’s market value. Sola was thought to be the first drug that might delay onset of dementia in Alzheimer’s patients by dissolving beta-amyloid plaque if taken in very early stages. But its failure now undermines the most widely accepted amyloid theory and has had negative repercussions for Biogen who is also developing drugs based on the amyloid theory (5% wiped off its market cap) (8).
SO WHY DO WE STILL TRY?
Despite the disappointments, drug makers have persevered, attracted by the economics of an ageing population and the rich financial rewards if they succeed. There are 10 new drugs for Alzheimer’s currently being tested in late-stage trials – six target beta amyloid, including medicines from Biogen, Roche, Johnson & Johnson, Lilly, AstraZeneca and Merck and Co in the USA.
Less charitable observers argue the potential profits on offer are so large — some estimate as much as $13B a year for a single drug — that Big Pharma is happy to back trials even if evidence is thin. Many feel it is still too early to give up on the hypothesis, including Lilly, which has a further six Alzheimer’s medicines in its pipeline, most of which target amyloid.
Many experts believe that the disease complexities and multiple hypotheses for its cause will result in inconsistencies and controversies which will mean that we will not find a cure “any time soon”. Therefore, we must refocus industry efforts on prevention strategies and technologies for better diagnoses and disease management. These must be tackled in conjunction with, not in isolation with, finding therapeutic cures.
Recent exciting developments on the treatment side include the interactions between vascular disease and memory loss which suggest that at least some aspects of Alzheimer’s may be modifiable through diet and exercise. Dimebon, a drug that improves mitochondrial function, has yielded promising results and is in final stages of testing. In addition, therapeutic strategies which target the brain’s own ability to repair itself – for example, by delivering nerve growth factor through viral vectors – are in clinical trials. Until we have a cure, however, it is vital to focus on improving the quality of life of people with Alzheimer’s. We believe this should begin with earlier diagnoses and a refocus of dementia research and clinical activity on prevention through targeting modifiable risk factors.
PREVENTION & BETTER DIAGNOSES
Many now believe that potential AD victims should be treated long before they develop any symptoms, just like people without heart problems are prescribed cholesterol lowering statins.
“If research and development continue to follow Lilly’s conventional approach of reducing amyloid plaque, which is only one of several hypothetical causes of Alzheimer’s, there is every unfortunate chance of failure until we can diagnose the disease both early enough and accurately. Without a diagnostic, companies developing an Alzheimer’s treatment are almost guaranteed to spend more and lose more in the end”. Steve Brozak, President of WBB Securities LLC (9).
Unlike age and genetics, certain health and lifestyle factors associated with Alzheimer’s risk may be controlled. Scientists are exploring prevention strategies to determine whether or not exercise, diet, and “brain games” can help delay or prevent Alzheimer’s and age-related cognitive decline. They are also investigating how certain medical conditions, such as high cholesterol, high blood pressure, and diabetes, influence risk for cognitive impairment.
So far, studies have not demonstrated that, over the long term, health or lifestyle factors can prevent or slow Alzheimer’s disease or age-related cognitive decline. Similarly, clinical trial results do not support the use of any particular medication or dietary supplement to prevent these conditions. However, promising research in these areas is underway. The NIA supports more than 30 clinical trials, including many that are investigating possible ways to prevent or delay Alzheimer’s disease or age-related cognitive decline. Observational studies have associated factors such as physical activity, blood pressure, and diabetes control with changes in risk. More research is needed to determine whether these factors can in fact directly help prevent Alzheimer’s or cognitive decline.
Brain training games are now being deemed as one way to delay the onset of dementia by encouraging the brain to process information more quickly over time and stay “alert”. Two large studies have been conducted: The Active Study which has been monitoring 2,800 patients over a 10 -year period found that those who played a specially designed video game nearly halved their risk of developing Alzheimer’s and other forms of dementia. This game was subsequently acquired by Posit Science (US company), which sells an updated version called Double Decision as part of its BrainHQ suite.
“Much like with physical exercise, when you exercise your brain in specific ways, you can make it stronger” – Henry Mahncke, Chief Executive, Posit Science.
But this sector is not well received as there are many brain training games that have not been subjected to the same rigorous testing that drugs and medical devices must undergo. The sector has probably been held back by dubious products making claims that are not backed up by scientific research. Lumos labs claimed that its Lumosity brain-training game helped users to perform better at work and could even alleviate symptoms of Alzheimer’s. The US Fair Trade Commission said Lumosity “simply did not have the science to back up its ads”. We believe that the best way to improve this image is by creating more stringent regulations akin to FDA approval.
Akili Interactive, a start-up founded by Boston-based Pure Tech, is also developing mobile video games to treat neurological conditions. It has secured funding from the VC arms of Amgen and Merck. Akili’s main product, Project Evo, aims to train the brains of children with ADHD and will conduct proper clinical trials and seek regulatory approval. If companies such as Akili, Pear and Posit can provide data that proves their products work, they could be part of a flourishing new industry.
The global market for cognitive assessment and training is worth $2.4B, according to the research company, MM, and is expected to triple to $7.5B by 2020 (10). In contrast, the global market for Alzheimer’s treatment will more than double in value from $4.9B in 2013 to reach an estimated $13.3B by 2023, representing a CAGR of 10.50%, according to research and consulting firm GlobalData. This means we are saying that brain games will be worth almost half the treatment market!!
Researchers at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London have shown that their online brain training package can not only improve memory and reasoning skills – but also how well older people carry out everyday tasks such as navigating public transport, shopping, cooking and managing personal finances.
Previous research has shown some promise for brain training in improving memory, although these small-scale studies have been inconclusive. This new research involving almost 7,000 adults aged over 50 is funded by Alzheimer’s Society. It is the largest randomised control trial to-date of an online brain training package and also the first to evaluate the impact of computerised brain training on how well people can perform their daily activities.
Dr Anne Corbett from the Wolfson Centre for Age-Related Diseases at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said: “The impact of a brain training package such as this one could be extremely significant for older adults who are looking for a way to proactively maintain their cognitive health as they age.” The online package could be accessible to large numbers of people, which could also have considerable benefits for public health across the UK.
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, says: “Online brain training is rapidly growing into a multi-million- pound industry and studies like this are vital to help us understand what these games can and cannot do. While this study wasn’t long enough to test whether the brain training package can prevent cognitive decline or dementia, we’re excited to see that it can have a positive impact on how well older people perform essential everyday tasks.”
Diagnosis is a painstaking process where physicians must first rule out all other cognitive disorders by asking questions, testing coordination and evaluating reflexes before arriving at a diagnosis of Alzheimer’s. We still lack a definitive diagnostic tool. This is a missing key that would enable many more researchers to approach the disease from varied vantage points. Part of the problem is that historically, diagnostics have not been lucrative or profitable. They are low-revenue-producing products vs. drugs that generate high revenue. But having a diagnostic is crucial in because it could enable researchers to identify early stages of the disease, providing insight into disease origin and progression.
A better pricing strategy may offer greater incentive for private investment in newer technological approaches which could herald a new era in diagnostics. In Alzheimer’s where there are no good therapeutic options, a diagnostic could enhance the ability to develop a cure or an intervention that could transform a mortal disease into a chronic one. Early detection also supports the view that treatment is most effective at the prodromal stage, i.e. before signs of the disease appear.
A new iPad-based assessment called CogniSense, which has been validated on 3,500 patients, has been launched by Quest Diagnostics.
It is targeted towards primary care physicians as an objective tool to understand patients with cognitive impairment. The tool has been used over the 12 months with an accountable care organization called Primary Partner Care in New York City.
“They have done it on more than 656 patients so far, and within their patient community they were initially able to identify only 17 percent of people with cognitive impairment. After using the tool, the same primary care physicians are able to identify more than 40 percent of patients with cognitive impairment”.
“One in every ten patients over the age of 65 have some form of dementia, and it rapidly advances to one in two over the age of 85. It’s important that our primary care physicians are able to identify the onset of impairment within the patient community that they serve.” Dr Karthik Kuppusamy (11).
Today, advanced technology is making diagnosis less invasive and can help detect disease earlier. By using a combination of biomarkers, genetic tests and new brain scans, we are inching very close to predicting not only who will develop Alzheimer’s but the exact age when they may start developing symptoms. This offers huge opportunities for conducting prevention trials. Of course, it also brings a whole host of ethical challenges, since our diagnostic and predictive abilities are advancing far faster than our ability to prevent AD and cure it with medication.
“It’s time for technology to step in – and to do for Alzheimer’s what it has done for shopping, sharing, investing, and so many other facets of 21st century life. If we truly want technology to improve lives, it’s time to disrupt Alzheimer’s. There is a growing consensus among Alzheimer’s experts – as well as those with Alzheimer’s, their caregivers, nurses, care providers, etc. – that technology can transform care”. Andrew Wright, Otsuka America Pharmaceutical, VP Digital Platform (12).
Yet this potential is unrealised. One of the greatest barriers to unlocking this partnership between tech and the AD community is a lack of true understanding. Tech experts do not sufficiently understand what the disease is and what problems they can solve for patients and caregivers; and the AD community hasn’t sufficiently explained what it needs. We need to bridge this gap.
With a growing disease, as cruel to patients and the people around them as Alzheimer’s, we can neither wait nor fixate on a single-minded approach to attacking this disease. The wrong approach would be to develop only therapeutics or only diagnostics. We must do both. There is an urgency to develop better drugs. There must be an equally intense urgency to develop precise diagnostics. To be successful we must do both.
TECHNOLOGY IN THE NHS
The NHS is using technology to help dementia sufferers manage symptoms at home for longer. The NHS is teaming up with leading technology companies in a series of nationwide trials to study how connected devices that allow patients to monitor themselves at home may benefit older patients and those suffering from dementia, diabetes and mental illness. The projects are part of the first wave of NHS Innovation ‘Test Beds’. They will provide individuals and their carers’ with sensors and wearable technology devices to monitor their health at home. It will allow patients to remain in contact with care professionals and share clinical data as well as increase social contact, track lost patients and help with medication compliance. By reducing the face-to-face contact time, patients with chronic conditions can be more independent and reduce the demand on NHS resources. Digital healthcare company, Intelesant, has been announced as one of the partners in a new £5.2M NHS Test Bed trial. It is providing the use of Howz, an app developed for older people living alone.
NHS chief executive Simon Stevens says technology will be at the forefront of health gains: “Over the next decade major health gains won’t just come from a few ‘miracle cures’, but also from combining diverse breakthroughs in fields such as biosensors, medtech and drug discovery, mobile communications, and computing.”
- Alzheimer’s is a devastating disease that impacts both suffers and carers alike.
- Alzheimer’s is placing an increasing burden on health care systems, and its prevalence is forecast to grow as populations age in the developed world.
- Despite many attempts by pharma companies to find a cure, there is currently no drug available that will do more than temporarily slow its progression. Worse than this, currently there are no drugs that show any more than early promise in the pipeline.
- Some believe that if Alzheimer’s is caught early and before significant damage has been done to nerve cells, there is more chance of restoring function and alleviating symptoms.
- It is believed by the author that medical devices can help to manage Alzheimer’s, by providing early diagnosis and potentially treatments that help maintain cognitive function. Opportunities include identifying biomarkers for the disease and using sophisticated testing of cognitive function. ‘Brain training’ is also being investigated as a means for keeping the brain ‘alert’ and staving off the symptoms for as long as possible.
- Medical devices and technology could also be used for monitoring and helping to care for Alzheimer’s patients. This would enable them to maintain a level of independence, while at the same time reducing the resources needed for their care.
- There is clearly a societal need for medical devices to play their part in addressing the Alzheimer’s epidemic and with this comes opportunities for investing in new technology development and seeing commercial returns for those that are successful in bringing new products to the market.
- Alzheimer’s Research UK, Office of Health Economics Report, “The trajectory of dementia in the UK – making a difference,” 9th June 2014
- “Dementia risk factors explained by Public Health England,” 5th April 2016.
- ” Alzheimer’s may be caused by haywire immune system eating brain connections,” www.science.org , 31st March 2016.
- mktonchart.com, 17th October 2016.
- The Telegraph, “Six pence drug could keep Alzheimer’s patients out of care homes,” 27 October 2015.
- Cummings et al. Alzheimer’s Research and Therapy, 2014.
- “Alzheimer’s drug failure deals blow to US drugmaker Eli Lilly,” Financial Times, 23rd November 2016.
- “After Lilly Bombs, Could Alzheimer’s Become Healthcare’s Trumpshot?” www.forbes.com Pharma and Healthcare, 30th November 2016.
- “Brain training healthcare digital games target dementia” – Financial Times Special Report, November 29th, 2016.
- “The Industry perspective on Alzheimer’s Disease” – AAIC 2016.
- Digital Health Summit – “Disrupt Alzheimer’s: Tech Solutions Needed,” 18th December 2015.