August 6, 2024

expert reaction to perspective article considering challenges for the new Alzheimer’s drugs at a population level

A perspective article published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association looks at challenges for new Alzheimer’s drugs.

Prof Tara Spires-Jones, FMedSci; President of the British Neuroscience Association, Group Leader in the UK Dementia Research Institute, and Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said:

“This perspective paper from Walsh and colleagues quite rightly points out that there are challenges with the new Alzheimer’s drugs that are coming onto the world market.  While new immunotherapies remove toxic amyloid from the brain and do slow disease progression, the treatments come with substantial risks and will be difficult to implement for many reasons as outlined in the article.  The good news is scientific research is working and even if they are not perfect, we finally have proof that Alzheimer’s disease can be slowed down.  These drugs do slow disease progression and future work will no doubt make more effective, safer treatments.”

Jen Keen, Head of Policy at Alzheimer’s Society, said:

“Dementia is the UK’s biggest killer and the greatest health and social care challenge that we face in this country. 

“This research highlights potential barriers surrounding new treatments for Alzheimer’s disease if approved, and we must be honest about the challenges we face. Confirming eligibility for new treatment requires specific diagnostic tests and, currently, a third of people living with dementia in the UK don’t get a diagnosis at all. We need to see investment into diagnostic infrastructure and workforce to ensure that people who are eligible for new treatments can access them when they’re most effective, which appears to be in the early stages of Alzheimer’s.

“Meanwhile, regulators will scrutinise the evidence around these treatments and Alzheimer’s Society awaits decisions from the MHRA and NICE on both lecanemab and donanemab. 

“These treatments are not a cure and they aren’t for everyone living with Alzheimer’s disease – they are a part of the puzzle. But improving dementia diagnosis can help us prepare for new treatments whilst also benefiting many more people living with dementia. Early diagnosis gives people access to existing treatments that can improve outcomes and reduce admissions to hospitals and care homes. This has obvious benefits for individuals and for the health and social care system as a whole.

“Despite the issues raised in this research, we remain at an important and exciting moment for dementia. Scientists are learning more all the time about Alzheimer’s disease and our ability to slow it down. There are currently 164 active clinical trials for Alzheimer’s disease and we expect more treatments to be submitted for regulatory approval in the future.

“More people receiving an early and accurate diagnosis is going to be vital in the future both for identifying people who are most likely to benefit from new Alzheimer’s treatments, and for getting existing treatment and support to more people.”

Prof Dag Aarsland, Professor of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London (KCL), said:

“Walsh et al provide a thoughtful description of the challenges linked to the possible introduction of the new disease-modifying therapies for Alzheimer’s disease. While I agree that there are indeed challenges both at the clinical, societal and healthcare levels, we should not forget the opportunities and the breakthrough that after decades of very costly negative trials we finally have unequivocal evidence that it is possible to reduce the disease progression. There are no generally established criteria for what constitutes a “clinically significant effect”. While the 25-37% reduced rate of decline reported does not fulfil the authors own requirement, it is within criteria stated by others (July 23, 2019 issue 93 (4) e322-e333 https://doi.org/10.1212/WNL.0000000000007831). The authors ask for long-term data, and to some extent this was addressed by the presentation of open-label extension data presented at the recent AAIC meeting in Philadelphia. I missed a more detailed discussion about the opportunity to identify subgroups with enhanced effect and reduced risks. While clinicians in the US, China, Japan and Israel now have the opportunity to discuss and in some cases prescribe disease-modifying drugs to their patients with AD, this is not possible in Europe. I hope this will soon be possible in the UK.”

Dr Mark Dallas, Associate Professor in Cellular Neuroscience, University of Reading, said:

“Few in the research community ever believed that the recent amyloid-targeting medicines would be the ultimate solution to Alzheimer’s disease. This article highlights the limitations of these recent amyloid therapies, particularly when considering their broader clinical use within the wider dementia community. It underscores the urgent need for alternative strategies to improve the lives of those living with dementia. Ongoing fundamental research is making significant strides, in developing non-amyloid targeting drugs that will diversify the available treatment options for managing Alzheimer’s disease. While some individuals may benefit from amyloid-targeting medicines, a broader array of disease-modifying treatments is essential to address the diverse needs of those living with Alzheimer’s.”

Prof Sir John Hardy, Professor of Neuroscience and Group Leader at the UK Dementia Research Institute, University College London (UCL), said:

“I respectfully disagree with the shorthand implication taken from this publication by the Cambridge group that amyloid immunotherapy drugs will not have value in Alzheimer’s treatment. Indeed, the article itself is more nuanced. Dr Brayne’s long-term campaign, with which I agree, has been for better public health measures to reduce dementia incidence.  These anti-amyloid antibodies have beneficial effects in carefully screened patients with early Alzheimer’s disease. As the article notes, an effect of the licensing of these agents will be to improve diagnostic and clinical procedures so that earlier and more accurate diagnoses of Alzheimer’s disease are made so that the correct dementia patients for Alzheimer’s treatment are identified.  We do not yet know whether longer-term treatment will continue to cause treated and placebo curves to diverge: no doubt such data is being gathered now, but we now have disease modifying therapy and it would be unfortunate if those in the UK who would benefit from this therapy had to fly to the US to receive it.”

Prof Paresh Malhotra, Professor of Clinical Neurology, Imperial College London, said:

“This review paper addresses many important issues relating to the recently developed amyloid-clearing drugs for Alzheimer’s disease- lecanemab and donanemab. It summarises available evidence and focuses particularly on the relatively small absolute effects of the drugs, their side effects,  and the low likelihood that they will have a large effect on Alzheimer’s Disease burden at a population level. The authors rightly stress the importance of ensuring that, in the event of these drugs being approved in a particular country, due attention is given to the provision of balanced information as well as shared decision making between patients, families and healthcare practitioners. The authors note that the licensing of these medications is newsworthy and contentious. This applies to the recent European Medicines Agency to refuse marketing authorisation to lecanemab and will no doubt also apply to the upcoming decision of the Medicines & Healthcare products Regulatory Agency in the UK, whether authorisation is given or refused. Over twenty years ago, similar arguments took place over the newly developed interferon treatments for Multiple Sclerosis. The authors are absolutely right to stress the importance of minimising hype and undue claims of efficacy, but it is also important to recognise that these drugs are the first to have clinical effects which appear to relate to a key mechanism of disease progression, and their introduction may accelerate treatment development and transform clinical services for Alzheimer’s Disease, the most common cause of dementia worldwide.”

Dr Tom Russ, Reader in Old Age Psychiatry and honorary Consultant Psychiatrist, University of Edinburgh, said:

“I welcome this very sensible appraisal from the team at Cambridge Public Health. They succinctly and accurately summarise the science that – while these drugs do affect the level of amyloid detectable in the brain – they have very little observable effect on the person and are associated with significant risks. I appreciated their use of the word ‘hyperbole’ which sums up much of the discussion we have seen about these medications. Dementia – including Alzheimer dementia, the most common type – is a terrible condition, but the very modest benefits seen in these medications (even over an extended period as in the data recently presented at AAIC) do not outweigh the risks. This risk-benefit analysis even trumps the huge financial costs associated with treating one person, let alone the costs of service redesign which would be necessary across most of the NHS in order to deliver these medicines.

“If Lecanemab were to be licensed in the UK – which now seems by no means certain – only a minority of people would be eligible for but and they would have to come to a healthcare setting twice a month to receive it. This would mean they would see a clinical team twice a month and receive – at the very least – informal support from them. We should be providing enhanced support to everyone who has a diagnosis of dementia so that everyone is seen twice a month – otherwise the inequality between people receiving Lecanemab (if it is licensed) and those who aren’t would be unacceptable.

“We also need broad research, focusing on population health and risk reduction, social science and care research, as well as the continued search for a cure. However, all this research should empower people with lived experience of dementia (people with a diagnosis, their family, friends, and supporters) to engage in research on an equal footing with the ‘professional’ researchers and make truly co-produced research much more common.

“There needs to be a revolution in dementia research, care, and support, and we remain optimistic that our new government in Westminster will have the clear sight needed to provide the necessary funding and reform.”

‘Considering challenges for the new Alzheimer’s drugs: Clinical, population, and health system perspectives’ by Sebastian Walsh et al. was published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association at 12:00 UK time on Tuesday 6 August 2024.

DOI: 10.1002/alz.14108

Declared interests

Prof Paresh Malhotra: I have received research funding from NIHR, MRC, Dementia Platforms UK, Alzheimer’s Research UK, British Heart Foundation, FIFA and Alzheimer’s Society. I am lead for an NIHR-funded trial with drug/placebo provided by Takeda Pharmaceuticals. I sit on the Alzheimer’s Society Research Strategy Council, am an Associate Member of the UK DRI, and am the National Specialty Lead for Dementia and Neurodegeneration in the NIHR Research Delivery Network. I sit on two NHS England policy working groups looking at diagnostic pathways and delivery issues relating to disease-modifying therapies for Alzheimer’s Disease.

Dr Tom Russ: “I am a Reader in Old Age Psychiatry at the University of Edinburgh and an honorary Consultant Psychiatrist in NHS Lothian. I am Clinical Research Champion of the NHS Research Scotland  Neuroprogressive and Dementia Network, funded by the Chief Scientist Office of the Scottish Government. I receive or have recently received grant funding from Alzheimer Scotland, the Royal Society of Edinburgh, UKRI, BBSRC & ESRC, the Blood Biomarker Challenge, and the Rosetrees Trust. I am a PI on the Evoke and Evoke+ clinical trials but have no financial links with and receive no payments from pharmaceutical companies. I attended the UK Appropriate Use Recommendations meeting for Lecanemab and will be a co-author on the resulting article but received no honorarium and my travel expenses were paid by NHS Research Scotland.”

Prof John Hardy: I have consulted for both Eisia and Eli Lilly.

Dr Mark Dallas: received funding from Alzheimer’s Research UK and The Physiological Society.

Prof Dag Aarsland: Dr Aarsland has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, and GE Health, Sanofi, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Eli Lilly, Enterin, Acadia, EIP Pharma, Biogen, and Takeda, Eli Lilly, Eisai, BioArctic.