Data from Alex Keen - Curated by EPG Health - Last updated 01 August 2018

Alzheimer’s is a neurodegenerative disease that is the most common cause of dementia, an umbrella term that describes a collection of symptoms that include memory loss, cognitive dysfunction and language problems. Dementia has a varied pathophysiology. Alzheimer’s disease is responsible for about two-thirds of dementia cases, with vascular dementia, frontotemporal dementia and Lewy body disease also prevalent (NICE, 2017).

Forty-six million people live with dementia worldwide. That number is expected to increase to 131 million by 2050, with much of that growth being seen in low- and middle-income countries. The total global cost of dementia is estimated to double to $2 trillion by 2030, illustrating the significant socioeconomic burden and scale of the problem (Prince et al., 2015).

This is exacerbated by the lack of progress in drug development. The last major new drug to come to market for the treatment of Alzheimer’s disease was memantine, an NMDA (N-methyl D-aspartate) antagonist released in 2003 that treats moderate-to-severe Alzheimer’s by reducing glutamate release in the brain. However, studies have shown that the drug only somewhat slows the worsening of symptoms, with a delay in cognitive decline over a period of 6 months only seen in one in 10 patients (PubMed Health, 2017).

None of the current Alzheimer’s treatments cure the disease and have modest efficacy at best. This highlights a real unmet need between current therapies and the large and ever-growing burden of disease, creating a perfect storm that is one of the greatest health challenges facing society today.

We spoke to Professor Craig Ritchie of the University of Edinburgh, someone who is trying to change this. He’s the project co-coordinator for the EPAD (European Prevention of Alzheimer’s Dementia) Consortium, a collaborative venture started 4 years ago with the aim of facilitating meaningful progress in preventative Alzheimer’s therapies.

What is EPAD?

“The challenge that EPAD is trying to address is the complete lack of progress over the last 15 years to develop any new pharmacological interventions for Alzheimer’s disease”, said Prof. Ritchie, “What EPAD is tasked with doing is to create a much better trial environment, to develop a much better understanding of disease before dementia and also to develop a new way of doing clinical trials. We’re not just trying to pick one or two of the problems that we think are relevant for why there have been no new drugs, but deal with all of them in a coordinated and comprehensive way.”

The project focus is on prevention, not cure, encouraging the development of therapies that are able to effectively interfere with the disease process, preventing clinical onset. It is widely accepted that the processes that lead to Alzheimer’s disease start decades before the disease becomes symptomatic (EPAD, 2017).

“What are the biological changes that take place in the brain 30 years before you get dementia and can you target those changes to stop the pathology accumulating?”

A number of initiatives are being taken to help reinvigorate the drug development process, with the ultimate goal of finding a cure for Alzheimer’s.

The adaptive clinical trial

The roots of the adaptive trial design can be traced back to the 1970s, however, they have recently seen a renaissance. As one of the flagship features of EPAD, the adaptive design allows for changes to be made to key components as the trial progresses, unlike in a conventional clinical trial. This has led to their promotion and adoption by many members of the scientific community as a flexible and efficient method to enrich the drug pipeline (Mahajan, 2010).

“There could be a moment, and maybe should be a moment, earlier in the course of the study where you could have known that your drug was never going to work. Or, maybe more optimistically, you could have realised that it was so successful it could move on to the phase III study.”

This means that the trials are continuously evaluated, with drugs exhibiting less than promising results cut short before completion. Likewise, drugs that have encouraging results could be expedited to phase III (Thorland et al., 2018).

“There is a general consensus that they [adaptive trials] are a better way of doing things, at least for phase II studies… as they allow you to make better and quicker decisions about the drug.”

This speeds up the development process. Drugs are evaluated sooner with decisions made earlier leading to reduced failure rates later on as underperformers have already been cut from the study.

The master protocol

Next, investigators designed a master protocol that is followed by all drugs that enter the project. This allows for the trials of different drugs to be run concurrently, with one placebo being shared between all candidate drugs and data being exchanged throughout the trial process to ensure decisions are as well-informed as possible.

“We have a single protocol for the trial, called the master protocol, and each of the drugs that we put into the master protocol writes their own appendix. What that means is that we can run several interventions under the same protocol, so you then have an efficiency by having, for example, three active to one placebo randomised.”

When you consider that classical clinical trials assign half the cohort to the placebo and half to the trial drug, you can see how much more efficient the adaptive protocol could be. Additionally, this means that a greater proportion of candidates receive the trial drug, not placebo, therefore more patients could benefit from their potential therapeutic action.

The readiness cohort

Finally, to address the staggeringly high screen failure rates of test patients, a readiness cohort has been established. This requires suitable research participants to be thoroughly screened, with blood tests, brain scans and cognitive assessments determining the relative risk of Alzheimer’s development and providing in-depth information about each patient.

“The brain changes that take place and lead to dementia almost undoubtedly start in your 40s and 50s. Having that data and having that knowledge about what those brain changes are: how they are related to risk factors, could they be genetic or lifestyle? This creates the backdrop for developing smart intervention.”

When it comes to selecting candidates for a trial, a wealth of information is readily available to investigators to help them choose candidates that have the most appropriate characteristics for their study, allowing them to be selected with much greater precision.

“You have access to the research participant’s amyloid status, you have their genetic status, you have their cognitive status, so when a company comes to us and says ‘we want this particular profile of person for our intervention’ we have them there, they’re on our database. When the trial starts we recruit from the cohort, rather than the general population, so we should get screen failure rates of about 2%, rather than 90%.”

The perpetual nature of the cohort study means that candidates are being continually recruited to replace those participating in trials and to grow the cohort.

“Every time someone comes out of the cohort and into a trial you need to replenish that, so the cohort is always recruiting. The cohort itself is never-ending. The trials themselves are likely to be about 3-years long.”

Collaboration is key

Thirty-eight universities, pharmaceutical companies and other institutions across Europe are partners in the project, reflective of its wide-reach and ambitious aspirations. EPAD itself also works with a number of other international initiatives, such as the Collaboration for Alzheimer’s Prevention, a joint US and European venture that recognises the critical role that cooperation plays in ensuring that knowledge gained is quickly disseminated to help progress the field as a whole. This goes against the traditional protective stance taken by individuals and institutions to maintain their competitive advantage at the expense of overall progress.

“We get together once a quarter. We share data. We share knowledge. We take key challenges. For me, the most exciting thing in the field at the moment is the willingness of investigators and project leaders to really share knowledge, information… and pain. I think the public should be really optimistic that at least we’re working together to try and bring this to a really good conclusion.”

EPAD also operates in conjunction with nine other projects funded by the EU’s Innovative Medicines Initiative (IMI) like EMIF-AD and AETIONOMY, that together form the IMI Alzheimer’s disease platform; there is also close collaboration with the US-based Global Alzheimer’s Platform; and the data collected during from the EPAD project will ultimately be made publicly available so help researchers worldwide progress and succeed (EPAD, 2017).

Where does the money come from?

This collaborative philosophy also helps fund the project. The €64 million funding comes from a public-private partnership between the EU’s IMI (as mentioned earlier) and the 38 partner institutions to spread the cost, but is led by the University of Edinburgh.

“You need public-private partnership to address massive unmet medical needs, as there is in Alzheimer’s.”

This money is only used for setting up and running the cohort study, whereas companies pay for the trial themselves using research participants from the cohort.

Challenges

With the UK having a large stake in the project there’s the very real question of what will happen after Brexit, not just with EPAD project but for collaborative Europe-wide projects as a whole.

“It’s a real and present danger. The IMI funding, which is billions, literally billions across the whole of medicine, will be so much harder for the UK to access post-Brexit. We [The UK] are an incredible beneficiary of the IMI project, and we’re already seeing IMI project leadership, and therefore funding for new projects, being established elsewhere.”

A number of other challenges also exist, most notably the difficulty in encouraging colleagues to believe in the project and its ultimate goal.

“That’s probably the toughest part of my job, trying to get colleagues to buy into the vision.”

“We all have a part to play”

To make meaningful progress in Alzheimer’s research the public need to begin to understand that Alzheimer’s starts to develop in middle-age and that it is preventable.

“I think most of the public would still consider dementia as an inevitable part of aging, it only happens to older people. It would be a very different perception to what I’ve described which is people in mid-life with the beginnings of Alzheimer’s disease.”

“You have to build up a belief system, a grounded belief system, that dementia is preventable. You have to believe that it is possible. I think we’re beginning to do that.”

By changing the public perception of Alzheimer’s and dementia this helps people to understand that the choices you make earlier in your life can have a profound effect on your brain health.

“Working together; the academics, the government, the media, working in a collaborative and coherent way, we will achieve that [successful Alzheimer’s prevention]. There needs to be a grand vision that people can work towards.”

To the future…

Prof. Ritchie is upbeat about what the future holds.

“I’m fairly confident that in 15 to 20 years’ time, someone in their late 50’s or early 60’s will be able to go to a GP and have a series of tests done which will tell them if they have markers of Alzheimer’s pathology, a little like how you get told that you have high cholesterol. They’ll be a conversation with your GP saying ‘… you’ve got an early Alzheimer’s biomarker. You should lose weight, do this or the other. Come back and see me in a few months or so and if we need to we’ll put you on an anti-Alzheimer’s therapy’, like we give out statins today. And in 30 years’ time, you’ll be able to go to [a retail pharmacy shop] and get those medicines.”

The timeline seemed ambitious, however, Prof. Ritchie went on to use statins and HIV as examples.

“If you had said to a cardiologist 40 years ago about preventing stroke or heart attacks that you could go to a local pharmacy and get a statin over the counter, they would have probably said ‘that’s unrealistic, you can’t do that’. As I was growing up in the late 80s and 90s, HIV was apparently going to be an existential threat to civilization, and now people living with HIV are virtually cured to a point where they have essentially normal life expectancy.”

“It has echoes of the ‘man on the moon’ approach. We set our target (no matter how ambitious) and our ingenuity, creativity, leadership and coordination will be able to overcome these challenges.”

The hard work being done by the EPAD team and the related projects worldwide is admirable, generating a wealth of invaluable data that represents a turning point in the development of new Alzheimer’s treatments. Hopefully the successes of the adaptive trial, master protocol, readiness cohort and collaborative philosophy can be used more widely across the whole of medicine to expedite drug discovery.

Further reading

Alzheimer’s Association. Treatment horizons. Alzheimer’s Association. 2018. Available from: http://www.alz.org/research/science/alzheimers_treatment_horizon.asp

Cummings J, Aisen PS, DuBois B, Lutz F, Jack Jr CR, Jones RW, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimer's Research & Therapy. 2016;8:39

Pearce M. How close are we to a disease-modifying treatment for Alzheimer’s? epgonline.org. 2017. Available from: https://www.epgonline.org/global/horizons/disease-modifying-treatment-for-alzheimers.html

References

EPAD. Project Objectives. EPAD. 2017. Available from: http://ep-ad.org/project-objectives/ (accessed June 2018).

Mahajan R, Gupta K. Adaptive design clinical trials: Methodology, challenges and prospect. Indian J Pharmacol. 2010;42:201–207.

NICE. Dementia. NICE. 2017. Available from: https://cks.nice.org.uk/dementia#!backgroundsub:1 (accessed July 2018).

Prince M, Wimo A, Guerchet M, Ali GC, Wu Y, Prina M. World Alzheimer's Report 2015. Alzheimer's Disease International. 2015. Available from: https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf (accessed June 2018).

PubMed Health. Alzheimer's disease: Does memantine help? 2017. Available from: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072540/ (accessed July 2018).

Thorland K, Haggstrom J, Park JJH, Mills EJ. Key design considerations for adaptive clinical trials: a primer for clinicians. BMJ. 2018;360:k698.

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