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Alzheimer’s disease: the search for a cure

To ensure the successful discovery and development of new dementia therapies, key gaps in the field need to be addressed

Alzheimer’s is the most common cause of dementia. It is a devastating condition, which affects nearly one million people in the UK today, and we don’t yet have a drug that stops or even slows Alzheimer’s disease.

Where are we now?

The current COVID-19 pandemic has highlighted the vulnerability of people living with dementia and the disproportionate impact the virus has had on those with dementia signals that more needs to be done to protect people affected by the condition.

There has been limited progress in the development of new treatments for dementia- causing diseases and Alzheimer’s disease and other dementias remain a significant unmet clinical need. As the UK’s leading research charity, Alzheimer’s Research UK is committed to funding research to address the many drug discovery challenges.

To ensure the successful discovery and development of new dementia therapies, key gaps in the field need to be addressed by bringing together experts and partners from academia and industry, clinical research and charity organisations. We do this through a range of initiatives, including the Dementia Consortium and the Alzheimer’s Research UK Drug Discovery Alliance.

This multisector approach will accelerate our understanding of the underlying disease mechanisms that cause dementia, helping to identify and validate novel drug targets and demonstrate proof of concept in early clinical trials. Ultimately, our aim is to accelerate the progression of dementia drug discovery and to increase the success of longer and more expensive later phase clinical trials.

We are expecting to see the outcomes of an FDA priority review of the potential Alzheimer’s drug, aducanumab, this year. This will determine whether this drug is licensed in the US, but for the UK we will have to wait longer and see whether there is sufficient evidence that aducanumab is safe and clinically effective to receive regulatory approval.

While this would be such a positive step forward for people with dementia and for our field, aducanumab will not be a panacea.

Any new licensed drug would still need to be judged to be cost-effective by the National Institute of Care and Excellence (NICE). And, as many of the experimental drugs in late-stage clinical trials are thought to be most effective for people at the earliest stages of Alzheimer’s, a new diagnostic pathway would need to be developed so that the people most likely to benefit could be identified and treated early enough to delay the progression of this devastating disease.

We need to fast-track new treatments

As of last year, there are over 100 treatments in clinical trials for Alzheimer’s disease. A quarter are in phase 3 trials, and more agents are in earlier phase 2 trials and phase 1 trials.

Over the past two decades, Alzheimer’s drug discovery has largely focused on targeting the hallmark amyloid protein. As in cancer, multiple drugs tackling different harmful processes involved in the disease are likely to be most effective at slowing or stopping Alzheimer’s progression.

Not all of the drugs entering clinical trials will go on to benefit patients, so we are increasing the probability of successfully delivering a disease- modifying treatment by targeting disease processes other than the build-up of the hallmark Alzheimer’s proteins, amyloid and tau.

How does Alzheimer’s Research UK plan to change this?

One challenge is that the biology underpinning the diseases that cause dementia is complex and difficult to study. It is therefore critical that we continue to fund and facilitate innovative research to understand disease mechanisms. The immune response in the brain is one area that is increasingly receiving attention. It is also an area where new treatments may arise. For example, new start-up companies, like AstronauTx, are looking to develop new medicines designed to reset the behaviour of astrocytes, crucial support cells in the brain that normally help brain cells to function properly, but that can change and contribute to the damage in Alzheimer’s disease.

AstronauTX was spun out of the Alzheimer’s Research UK Drug Discovery Alliance, which houses scientists in state-of-the-art facilities. These Institutes are at the centre of multiple collaborations with industry and universities – bringing together expertise from across the UK and around the world.

Increasing the likelihood of finding successful treatments

While the Alzheimer’s Research UK Drug Discovery Alliance is home to our own in-house drug discovery experts, the Alzheimer’s Research UK Dementia Consortium provides opportunities for academic scientists to collaborate with external industry partners from the start of projects.

By collaborating with industry throughout a project, projects funded through the Consortium are increasing capacity in dementia drug discovery and developing a pipeline of potential new drug targets and therapeutic molecules for dementia.

It’s a bold approach designed to increase the likelihood of finding successful treatments that can transform lives. The Dementia Consortium funds research into novel targets and treatments for dementia including Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, plus Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease.

The initiative involves seven world-leading pharmaceutical companies and two partner contract research organisations. The companies, Abbvie, Astex Pharmaceuticals, Eisai, Johnson & Johnson, Lilly, MSD and Takeda, Evotec and Charles River, participate in research projects alongside academic scientists.

Its collaborative nature means the partners in the Consortium share the cost and risk of early-stage dementia drug discovery. The most successful projects will validate strong genetic targets and will include licensing opportunities for leading drug target development.

Take advantage of new technologies

It is likely that any new therapeutic treatment will need to be given to patients as early as possible. We now know that the diseases that cause dementia start in the brain decades before clinical symptoms begin to show. Yet currently we can only diagnose someone when symptoms such as memory loss become apparent, which means we are currently diagnosing people too late to intervene effectively.

Advances in technology are providing huge opportunities to intervene decades earlier, when these diseases first start to take hold. That’s where the Early Detection of Neurodegenerative diseases (EDoN) initiative comes in.

This ambitious project is pulling together a wealth of information from a huge number of studies that will ultimately allow us to develop and test a digital device designed to pick up subtle clues of disease in people who don’t yet have any obvious symptoms of dementia.

Identifying the very earliest changes in these diseases would transform research efforts today, giving us the best chance of treating or preventing these diseases before the symptoms of dementia start to get in the way of life.

So, what next?

The impact of COVID-19 has seen a loss in charities’ research income and reduced funding for universities, with basic and translational research equally at risk and early career researchers particularly impacted.

Industry partnerships and collaborations will be increasingly important to help sustain critical translational research programmes in dementia, to maintain capacity and infrastructure, retain high quality researchers and ensure the UK remains an attractive investment opportunity.

In a world still affected by COVID-19, the UK government must now deliver on its commitment to double funding for life-changing dementia research, made in 2019 as part of its manifesto pledge. We cannot risk losing a generation of researchers and, with them, the progress that has been made across the field.

To learn more about the petition, visit https:// www.alzheimersresearchuk.org/campaigns/ dementia-research-at-risk-petition/

James Connell is Head of Translational Science at Alzheimer’s Research UK

20th May 2021

James Connell is Head of Translational Science at Alzheimer’s Research UK

20th May 2021

From: Research

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