[사이언스미디어센터] 전문가 의견(V2) <항아밀로이드 알츠하이머 치료제, 임상적으로 유의미한 효과 없어 (코크란 데이터베이스)>

cjl@ibs.re.kr  

아래는 호주 사이언스미디어센터(Aus SMC)에서 수집한 전문가 반응입니다. 호주 SMC 홈페이지에서도 확인할 수 있습니다.

Professor Amy Brodtmann is from the Cognitive Health Initiative in the School of Translational Medicine at Monash University

"The authors concluded that the effects of these therapies on cognitive function and dementia severity were trivial to small, while increasing the risk of adverse events such as brain swelling and bleeding. The findings concord with the decisions of several international governmental agencies to deny approval based on efficacy, including the Australian PBAC, but differ from others, such as the USA.

Cochrane reviews represent the highest standard of evidence-based healthcare. They have included all major trials published to 7 August 2025. However, the inclusion of older trials known to be negative does skew the findings somewhat, as we know that these agents had less amyloid clearance than newer agents. It would have been interesting to have a pooled analysis of the 3 agents with positive trials, aducanumab, lecanemab, and donanemab.

In addition, their sobering conclusions that “Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects … future research … should focus on other mechanisms of action” will be contentious. The Alzheimer’s disease field still contains a solid majority of adherents to the amyloid hypothesis, and these comments will spark intense debate. However, there will be many clinicians who welcome this objective guidance for evidence-based care."

COI declaration: Scientific Advisory Committees Eisai (lecanemab), Lilly (donanemab), Roche (gantenerumab). Paid travel to Australian Dementia Research Forum June 2025. Honorary Medical Advisor Dementia Australia. AFL Brain Health Collective Committee Member.

Amy is travelling to the US, so will only be contactable via email on amy.brodtmann@monash.edu

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Dr Nikki-Anne Wilson is a Lecturer in the School of Psychology at The University of New South Wales, and a Conjoint Research Fellow at NeuRA

"This review provides important context within the evolving clinical landscape of the treatment and prevention of Alzheimer’s disease. While the lack of improvement in clinical outcomes may be disheartening to hear, two key messages are important to keep in mind.

One, the findings should refocus our attention on addressing the 14 modifiable approaches to dementia risk reduction identified by the Lancet commission – particularly early in the disease course. Two, the use of these drugs has always been limited to very specific cases meeting distinct criteria, however, the brain is complex and what this review highlights is a single mechanism is unlikely to offer the magic bullet we seek. One of the reasons multi-domain approaches have shown promise as being potentially more beneficial than single domain interventions for reducing dementia risk may be due to their ability to target different mechanisms.

For example, exercise may offer neuroprotective effects by reducing inflammation, building cognitive reserve, and reducing depression. Effective pharmacological disease modifying therapies for Alzheimer’s disease may still be a while away. However, what we have now is robust evidence-based approaches for supporting brain health across life which, if broadly implemented, will likely reduce the number of people being diagnosed with Alzheimer’s disease and dementia in the future and help slow disease progression."

Nikki has not declared any conflicts of interest.
She is contactable on nikkianne.wilson@unsw.edu.au

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Professor Bryce Vissel is from the Faculty of Medicine at The University of New South Wales

"After decades without a meaningful breakthrough, Australia has recently approved lecanemab and donanemab,  anti-amyloid drugs hailed as the first medicines that might finally slow Alzheimer’s disease rather than simply manage symptoms. The question is the extent of their benefit, especially given the costs. For families watching a loved one lose memory, judgement and independence, the promise has carried enormous hope. But a major Cochrane review, pooling 17 trials involving 20,342 people, delivers a far more sobering verdict: overall, it says, these drugs do not provide a benefit that most people in the early stages of Alzheimer’s would find meaningful, while brain swelling occurred in about 119 per every 1000 on treatment. 

Dementia affects about 57 million people worldwide, and Alzheimer’s is its leading cause. It is a progressive brain disease in which nerve cells and the connections between them are damaged and lost, leading to worsening memory, thinking, language, judgement and day-to-day function. For more than 40 years, one dominant idea has guided the field: that amyloid-beta, a sticky protein fragment, builds up into clumps called plaques in the brain, helps drive this damage, and therefore must be removed if the disease is to be slowed.

Anti-amyloid drugs were developed based on that idea. They are laboratory-made antibody drugs, given by repeated intravenous infusion, designed to bind to amyloid and clear it from the brain. The plaques can be seen on special amyloid PET brain scans, and these drugs are very effective at reducing that plaque signal. Because the drugs can also cause brain swelling and small bleeds in the brain, treatment has to be monitored with repeated MRI scans.

That is why this Cochrane review is so dramatic. It is not a paper based on one company trial but assesses a large number of studies. It is the best independent test of whether a dramatic effect on amyloid PET scans translates into a meaningful benefit for patients. Its answer is sobering: even when plaques are successfully cleared, the hoped-for improvements in memory, thinking, daily function and independence do not meaningfully follow. In plain English, these drugs clear plaques far more convincingly than they preserve memory, thinking and independence.

This Cochrane review forces a blunt question: if these drugs remove the very plaques long thought to drive Alzheimer’s, why are patients not getting a meaningful improvement in memory, thinking, daily function or independence? In sum:

• This Cochrane review says the drugs are very good at clearing amyloid plaques from the brain but overall benefit of the current anti-amyloid drugs is not sufficiently clinically meaningful. 
• The numbers show how small the effect was. Across 13 trials over 18 months, the average advantage on the main memory and thinking test, the ADAS-Cog, was just 0.85 points on a scale that runs to about 70 points. Across nine trials over 18 months, the average advantage on the main dementia severity measure, the CDR-SB, was just 0.29 points on an 18-point scale. These are very small changes,  unlikely to be truly noticeable to most patients or families in daily life.
• On day-to-day function, the picture was much the same. The average advantage was 1.32 points on the 78-point ADCS-ADL scale, 1.75 points on the 56-point ADCS-iADL scale, and 1.90 points on the 53-point ADCS-ADL-MCI scale. In plain English, any slowing of decline was small at best and far from the kind of change patients and families would recognise as a breakthrough.
• These are average trial results, and individual responses will vary. But the overall signal from more than 20,000 participants is clear: strong plaque removal has not translated into meaningful gains in memory, thinking, daily function or independence.
• The safety signal is notable. Brain swelling was seen in about 119 of every 1000 treated patients, compared with 12 of every 1000 on placebo. Symptomatic brain swelling rose from about 1 per 1000 on placebo to about 30 per 1000 on treatment. The review also suggested more tiny brain bleeds on scans, although results varied across trials.
• The review did not show more overall serious adverse events or more deaths at 18 months, but that is not the same as a clean safety bill. Symptom reporting was inconsistent, the longer-term picture remains unsettled, and these are intensive, expensive treatments that require repeated infusions and repeated MRI monitoring.
• Our wider concern is that the safety story may still be more serious than is often presented. Other work has raised concerns about accelerated brain volume loss and possible treatment-related deaths. Those questions deserve independent scrutiny.
• This review does not prove amyloid has no role in Alzheimer’s, and it does not rule out future amyloid-directed therapies that may yet help patients. But it does show that the current generation of anti-amyloid drugs is not delivering the promise that has surrounded it.

Alzheimer’s is the progressive failure and loss of synapses and nerve cells, which patients experience as failing memory, failing thinking and lost independence. We and our collaborators have been raising concerns in the scientific literature for years about the dominance of the amyloid hypothesis. We have long argued that while amyloid has role in the disease, it alone does not explain Alzheimer’s dementia and a new way forward is needed The way forward is to widen the lens: focus on the molecular and cellular biology of what is going wrong inside vulnerable brain cells and synapses, and develop genuinely individualised treatments judged by meaningful gains in cognition, daily function and independence.

No patient can derive benefit from plaque clearance unless it translates into tangible improvements in quality of life. Until we identify and target root disease causes and achieve profound clinical benefit, no therapy can be called disease modifying. Amyloid may still play a role, and future therapies aimed at it may yet prove useful, but the field now needs a broader, more individualised medicine approach with a sharp focus on preserving cognition, daily function and independence."

Bryce has not declared any conflicts of interest.
He is contactable on +61 412 522 148 and b.vissel@unsw.edu.au

  

아래는 영국 사이언스미디어센터(UK SMC)에서 수집한 전문가 반응입니다. 영국 SMC 홈페이지에서도 확인할 수 있습니다.

Prof Ian Maidment, Professor in Clinical Pharmacy, Aston University, said:

“Alzheimer's is a devastating disease and we desperately need more effective treatments. Drugs, called anti-amyloid drugs, which reduce the build-up of amyloid seen in Alzheimer’s disease have been suggested as effective treatments. They are administered as an infusion usually every two or four weeks.

“This research used “gold standard” methods and summarized all the evidence from the key clinical trials. The review included 17 studies involving 20,342 participants and focused on cognitive function and the severity of dementia after 18 months of treatment. Six studies are currently ongoing, which were not included in the review. One limitation of the included 17 studies was that they contained few people from Black or Hispanic/Latino ethnic groups limiting generalisability.

“The team concluded that while the drugs may show a statistical effect on key symptoms of dementia, this effect was unlikely to be clinically relevant for patients. The research also identified key risks particularly bleeding and swelling in the brain, although the risk was small.

“This issue is currently particularly topical. Originally NICE did not approve the use of two of the anti-amyloid treatments, namely lecanemab and donanemab, on the NHS. Last month NICE announced that they will reassess this original decision. This reassessment will be conducted under the new cost effectiveness thresholds agreed following the USA-UK trade deal last year.

“We don’t yet know the likely cost of these drugs for the NHS. The price for donanemab, in the USA, has been estimated at around $32,000 per year (approximately £24,000 per year). There are also likely to be additional costs associated with monitoring for side-effects and administration; 18 months of Donanemab from private providers including the care package is quoted at £87,507.

“In summary, whilst there is a clear need for effective treatment for Alzheimer's disease, anti-amyloid drugs may not represent the solution.”

 

Prof Sir John Hardy, Group Leader at the UK Dementia Research Institute at UCL, said: 

“This paper compares the effects of seven different amyloid beta targeting monoclonal antibodies. The issue is that it conflates different therapies with different mechanisms: for example, aducanumab works by removing existing plaques from the brain, whereas lecanemab primarily binds to soluble forms of amyloid to prevent plaques from forming in the first place. I would refer the readers to the short review by Cath Mummery and I which show that successful therapies follow the disease and treatment modelling predictions proposed by Karran and De Strooper.Successful therapies remove amyloid from the brain, and unsuccessful ones do not."

 

References:

Hardy J, Mummery C. An anti-amyloid therapy works for Alzheimer's disease: why has it taken so long and what is next? Brain. 2023 Apr 19;146(4):1240-1242. doi: 10.1093/brain/awad049. PMID: 36797987; PMCID: PMC10115350.

Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022 Apr;21(4):306-318. doi: 10.1038/s41573-022-00391-w. Epub 2022 Feb 17. PMID: 35177833.

 

Prof Robert Howard, Professor of Old Age Psychiatry, UCL, said:

“This is a well-conducted review examining the overall effects of 18 months of treatment with seven different amyloid-targeting antibodies in patients with mild cognitive impairment or mild dementia caused by Alzheimer’s disease. The review concludes that treatment made little or no difference to cognitive functioning, dementia severity or functional ability.

“While disappointing, the results and conclusions should not come as a surprise to those who have appreciated the very small benefits of treatment (generally around 2% of the range of changes measured by validated tests of cognitive functioning or functional ability) seen in the individual clinical trials of these drugs. While these benefits may have achieved statistical significance within clinical trials where very large numbers of participants allowed the detection of tiny differences, they did not achieve accepted levels of clinical efficacy or what would be appreciable in an individual patient.

“It’s unfortunate and unfair to people with dementia and their families that some commentators and organisations – internationally and in the UK - have presented the effects and benefits of these treatments in an over-optimistic manner, not supported by robust science and that will have raised false hopes in people affected by dementia. This Cochrane Review should be seen as a potential corrective to some of the misinformation that has come to surround what can be realistically expected from these drugs.

“The review only looked at data from 18 months of treatment with these drugs compared to placebo. Some have argued that longer treatment periods of treatment and follow-up would reveal benefits that increased with the passage of time – as you would anticipate from a treatment that successfully modified the progressive course of Alzheimer’s disease. Unfortunately, the emerging trial data from extended treatment with donanemab and lecanemab that has allowed comparison between those patients who started treatment in the trials 18 months earlier with those who began with placebo, suggests that after three years there is no difference between early and delayed-start participants. This suggests that the drugs do not modify disease course and appear much more likely to be acting as a symptom-improving treatment, in much the same way as seen with the earlier “symptomatic” treatments that we have had for nearly 30 years.”

 

Prof Paresh Malhotra, Head of Division of Neurology, Imperial College London, said:

“Several amyloid-targeting antibody treatments for Alzheimer’s Disease have been tested in individual trials over recent years.  In the UK and elsewhere, this has resulted in the licensing of two drugs - lecanemab and donanemab-  after well-conducted trials showed that they had an effect on multiple measures ofcognition and the ability to carry out everyday activities. They have not been approved by NICE and there has been extensive discussion regarding the side effect profiles of the drugs as well as the meaningfulness of their clinical effects. At the moment there is ongoing work evaluating these drugs as well as other agents that target amyloid plaques.

“The authors of this review have pooled multiple studies that evaluate different drugs with different specific amyloid targets, and their analysis shows ‘small-to-absent’ effects. This is not surprising given that most of these trials have negative effects, but does not take into account the key differences between individual drugs and the trials assessing them. There are many questions that still need to be answered about the licensed drugs including methods and duration of administration.  I agree with the authors that other mechanisms of action beyond targetting amyloid for treatment of Alzheimer’s should be explored. However, the findings to-date do not justify ’throwing the baby out with the bathwater’ and dismissing all the results of well-conducted individual studies. The results of ongoing amyloid-targeting trials will help us understand these treatments better, and we should continue to explore all promising avenues for the treatment of Alzheimer’s and other dementia-causing diseases.”

 

Prof B. Paul Morgan, Director, UK DRI Cardiff, Cardiff University, said: 

“This systematic review explored the benefits and harms of anti-amyloid mAbs in patients with MCI or early AD by reviewing data from publications and clinical trials databases. After exclusion criteria were applied, 17 informative studies including ~20,000 patients were included; notably, these involved seven different anti-amyloid mAbs, all compared with placebo.

“The overall conclusion was that treatment with anti-amyloid mAbs, while highly effective at clearing amyloid, had minimal impact on cognition, dementia severity or functional capacity, while increasing the incidence of ARIA with its concomitant risks to health. An issue highlighted in the report was the inconsistency in selection of tests applied to measure cognition and disease severity.  The authors conclude that anti-amyloid mAb therapies have minimal impact on key outcomes in patients with MCI or early AD and carry significant risks, highlighting the need to seek alternative approaches beyond the current focus on amyloid removal.  

“The findings, while not unexpected by many observers in the field, will likely generate vigorous debate in what has become a key controversy. They support the growing view that removal of amyloid is not, alone, sufficient to significantly improve cognition or slow disease progression when administered early in the disease course. There is an urgent need to understand the drivers of continued disease progression after successful amyloid clearance to identify complementary targets for therapy.

“One could speculate that targeting existing amyloid pathology and efficiently removing plaques is “shutting the stable door after the horse has bolted”. Earlier interventions with anti-amyloid mAbs to prevent plaques from forming in the first place might deliver more impact on the disease, although this requires ways of identifying those at risk before the appearance of overt pathology. Evolving genetic and biomarker tests may soon provide this capacity, although the costs and benefits of population screening are unknown.”

 

Prof Dag Aarsland, Director of the Centre for Healthy Brain Ageing at King’s College London, said:

“The conclusions of this review are based on a meta-analysis of 17 randomized controlled trials involving more than 20,000 participants. This represents a substantial body of evidence, and the authors should be commended for undertaking such an extensive and important analysis. The overall findings are, however, disappointing.

“That said, there are reasons to interpret the results with caution. The included studies are heterogeneous in both design and outcome measures. Most importantly, the decision to pool all seven drugs into a single class-level analysis is open to question. While all of these therapies aim to reduce amyloid, they do so through different mechanisms and target different epitopes. These differences may be clinically meaningful, both in terms of effectiveness and safety.

“It is also notable that, among the 17 trials, only two evaluated the drugs that have more recently been approved by European regulators on the basis of what was considered an acceptable balance between benefit and risk. In my view, the conclusions supporting those individual approvals remain valid, despite the findings of this pooled, class-level meta-analysis.”

 

Prof Andrew Doig, Professor of Biochemistry, University of Manchester, said:

“There has been much excitement in recent years over antibodies that bind to various forms of amyloid-b, as therapies against Alzheimer’s Disease (AD), with claims that some can slow down the loss of cognition that is typical of AD.

“This is a comprehensive and careful study of the effects of these antibodies in clinical trials, focussing on effects on cognitive symptoms and possible harmful effects from brain swelling and bleeding. Only the most reliable trials are considered, leaving seven antibodies studied in 17 separate trials. Overall, the results are a big disappointment. While a beneficial effect on brain function is just about detectable when the results are pooled, the effect is so small that it would never be noticed in practice. In addition, the risk of brain swelling from the drugs is real, even though only a small fraction of patients is affected. The drugs can remove amyloid-b from the brain, as they were designed to do, but this does not translate into benefitting brain function or reducing dementia.

“The authors claim that the entire strategy of targeting amyloid-b is invalidated by their results, particularly as a few studies that remove amyloid-b before any symptoms were apparent are also unsuccessful. I still think that it is premature to be that pessimistic.Targetting subsets of people who have a genetic predisposition to AD, or who show AD biomarkers in the blood may still work, though we cannot expect a large effect. In any case, other strategies against AD must be vigorously pursued.”

Prof Bart De Strooper, Group Leader at the UK Dementia Research Institute at UCL, said: 

“This review does not clarify the evidence, it blurs it. By mixing failed drugs with the only antibodies that have actually changed clinical practice, it turns therapeutic progress into statistical noise. The flaw in this review is fundamental. In the review itself, the authors acknowledge that while several first-generation antibodies failed, newer antibodies have produced positive clinical effects, yet they still pool them together and treat the resulting average as if it were an informative judgment on the entire field. That inevitably dilutes the signal from the only agents that have successfully changed clinical practice. 

“For journalists and non-specialists, the key point is simple. Anti-amyloid antibodies are not one uniform group of medicines. They are different molecules, developed at different times, directed against different forms of amyloid, and associated with very different trial outcomes. Some of the earlier antibodies failed to show meaningful clinical benefit. More recent agents, most notably lecanemab and donanemab, did show measurable slowing of decline in large trials and have therefore changed the therapeutic landscape.

“That is why this review is problematic: once failed and successful programmes are combined into a single pooled estimate, the average will inevitably look weaker than the best performing agents. That is not a biological insight, it is simply the arithmetic consequence of mixing negative and positive studies together. The authors then present that blurred average as though it were a meaningful verdict on anti-amyloid therapy as a whole.

“My concern is not that the review asks a difficult question, it is that it answers in a way that erases the distinctions that matter most. The public is left with the impression that anti-amyloid therapy has broadly failed and that the field should move on. Comparatively, what the literature shows is that many early programmes failed, but that newer antibodies have delivered modest yet real clinical benefit, alongside important safety, cost, and implementation challenges. A serious review should help readers understand that complexity. This one risks obscuring it.”

 

Prof Tara Spires-Jones, Professor of Neurodegeneration at the University of Edinburgh, Division Lead in the UK Dementia Research Institute, and Past President of the British Neuroscience Association said:

“This review by Nonino and colleagues examined data from randomized control trials of antibodies to amyloid beta, one of the proteins that clumps in the brains of people with Alzheimer’s disease.  While reviewing clinical trial data is useful, the authors of this study combined analyses of 5 drugs that did not succeed in their trials and 2 drugs that did succeed in slowing disease progression and have been approved to treat early Alzheimer’s disease in several countries.  The authors’ conclusion that anti-amyloid antibodies do not provide clinically meaningful benefits is weakened by including 5 drugs that did not pass their clinical trials and are not available.  Emerging data on long-term use of the approved drugs and careful analyses by regulators including the European Medicines Agency and UK Medicines and Healthcare products Regulatory Agency (MHRA) support the use of two amyloid antibodies, lecanemab and donanemab, to slow decline in early Alzheimer’s disease.  As the authors of this study point out and as was previously published in the original trials, these drugs are not perfect, they come with risks of serious side effects and only modestly slow progression.  Due to the limited benefit and high costs accompanied by risks of brain bleeding and swelling, these drugs are not covered by the NHS. However, newer research into both more advanced amyloid targeting drugs and other targets shows promise for improved treatments on the horizon.”

 

Prof Jonathan Schott, Professor of Neurology and Group Leader, UK Dementia Research Institute, UCL, said:

“It is clearly important to distinguish between statistical significance and clinical meaningfulness when considering the effect of any drug. However, I question the rationale of jointly analysing trials of multiple different amyloid targeting therapies only two of which (i) have been shown to have robust statistical benefits compared to placebo and (ii) are licensed for clinical use anywhere in the world. By combining studies of different drugs, many of which have long since been disbanded, several of which had little or no effects on beta-amyloid, and most of which have failed in randomised clinical trials, it is almost inevitable that the conclusion will be that as a group they are clinically ineffective. Importantly, however, this does preclude individual drugs from having clinically meaningful benefits.”

 

 

Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said: 

“It’s not the case that all amyloid-targeting drugs are ineffective. This review’s conclusions make the picture look bleaker than it really is, as authors combined results for a majority of failed drug trials with a small number of more recent successful trials. This includes the trials for lecanemab and donanemab which the UK medicines regulator agreed bring a modest but meaningful benefit for people with early-stage Alzheimer’s.   

“It’s essential that we interpret this review with nuance and avoid taking a sledgehammer to decades of pioneering scientific study. 

“Alzheimer’s is highly complex and a combination of treatments will likely be needed to target a range of processes involved in its development. Anti-amyloid drugs are just one treatment avenue and not a silver bullet. We consider anti-amyloid drugs still to be a valid avenue to explore and optimise, reducing side effects, understanding their longer term impacts and ultimately bringing us closer to tackling Alzheimer’s for the millions of people affected globally.” 

 

Dr Susan Kohlhaas, Executive Director of Research at Alzheimer’s Research UK, says: 

“This review attempts to assess the impact of anti-amyloid drugs for Alzheimer’s, but it has major limitations for people affected by the disease. Much of the evidence it relies on comes from older experimental drugs that were discontinued from development due to failed trials.

“Crucially, this study is attempting to paint an entire class of drugs with the same brush even though we know different anti-amyloid treatments can act in different ways. 

“Only two of the 17 studies included were for the medicines now approved in the UK, lecanemab and donanemab. The rest focused on drugs that were not pursued after failing to show meaningful benefit, inevitably shaping the review’s conclusions. 

“Although the review highlights the known risk of ARIA on brain scans, the studies it looked at don’t consistently report how often this led to symptoms or how those symptoms were managed. The review itself doesn’t fill an important gap in our understanding of how safe these drugs are in a healthcare setting.

“The review also suggests these treatments are not ‘clinically meaningful’. But there is no agreed definition on what that means and current trial measures don’t always reflect what matters most to people with dementia. We regularly hear from families affected by dementia that even a delay of several months in decline could provide valuable, meaningful time with loved ones and that shouldn’t be minimised.

“Newer, longer-term evidence suggests that the approved treatments may deliver modest but sustained benefits beyond the 18-month horizons of earlier studies, yet this emerging data is not reflected in the review.

“That is why Alzheimer’s Research UK is clear that longer‑term evidence from routine healthcare settings is needed, to understand how these treatments should be used in practice. Initiatives like ACCESS AD will be crucial to further our understanding, as this is designed to show how these medicines perform when offered through standard NHS pathways.

“Anti-amyloid treatments will not be the whole answer to curing Alzheimer’s, and research is already moving towards a wider range of biological targets. But it’s not accurate to dismiss their impact as ‘trivial’, especially when the analysis has clear constraints that limit what it can tell us.” 

 

Declared interests

Prof Ian Maidment: No conflicts of interest.

Prof Sir John Hardy: John has consulted for Eisai and Lilly 

Prof Robert Howard: Unpaid consultancy for Synaptogenix in 2023.

Prof Paresh Malhotra: National Specialty Lead for Dementia and Neurodegeneration, NIHR Research Delivery Network

Honorary Consultant Neurologist, Imperial College Healthcare NHS Trust

Group Leader, UK Dementia Research Institute

Serviced Practice Consultant Neurologist, Cleveland Clinic London

NHSE Working Group Member (Lecanemab and Amyloid PET)

Task and Finish Group, Modern Service Framework for Frailty and Dementia

Trustee, Alzheimer’s Society 

Clinical Committee, ARUK

Recipient of ‘Drugs Only’ Grant for NIHR funded Trial, Shire/Takeda

Independent Data Monitoring Committee, J&J

Research funding from NIHR, ARUK, Alzheimer’s Society, MRC, DPUK, BHF, Lifearc, FIFA, FA, UK DRI

Prof B. Paul Morgan: No conflicts.

Prof Dag Aarsland: I have been paid consultant to several of the drug companies with relevant drugs, including Eisai, BioArctic and Eli Lilly.

Prof Andrew Doig: He is a founder and director of PharmaKure, a spin-out company working on diagnostics and drugs for Alzheimer’s Disease and other neurodegenerative conditions.

Prof Bart De Strooper: I have been consultant and advisor for many pharmaceutical companies, including EISAI, Eli Lilly, Johnson & Johnson, and I have been founder of two spin off companies (Augustine TX and Muna TX).

Prof Tara Spires-Jones: I have no conflicts with this study but have received payments for consulting, grant reviews, scientific talks, or collaborative research over the past 10 years from AbbVie, Sanofi, Merck, Scottish Brain Sciences, Jay Therapeutics, Cognition Therapeutics, Ono, Novo Nordisk, Eisai, and Boehringer Ingelheim, and direct a company Spires-Jones Neuroscience, Ltd to act as a consultant. I am also Charity trustee for the British Neuroscience Association and the Guarantors of Brain and serve as scientific advisor to several charities and non-profit institutions.

Prof Jonathan Schott: Jonathan Schott reports providing consultancy or serving on advisory boards for Roche, Eli Lilly, Receptive Bio, Eisai and Biogen and is Chief Medical Officer for Alzheimer’s Research UK.

Dr Richard Oakley: No interests to declare.

Dr Susan Kohlhaas: “Dr Kohlhaas has no declarations of interest.”

아래는 아일랜드 사이언스미디어센터(SMC All Ireland)에서 수집한 전문가 반응입니다. 아일랜드 SMC 홈페이지에서도 확인할 수 있습니다.

아래는 스페인 사이언스미디어센터(SMC Spain)에서 수집한 전문가 반응입니다. 스페인 SMC 홈페이지에서도 확인할 수 있습니다.

“Este artículo de Cochrane recopila 17 ensayos clínicos aleatorizados que incluyen diferentes fármacos con una capacidad demostrada para eliminar el amiloide. Existe una fuerte correlación positiva entre la eliminación de placas de beta-amiloide y la eficacia clínica en la fase temprana de la enfermedad de Alzheimer, de modo que una mayor reducción de las placas conduce a un deterioro cognitivo y funcional más lento.

En los tratamientos con anticuerpos antiamiloides, no es estrictamente necesario reducir las placas hasta un nivel negativo en la PET [prueba diagnóstica de imagen] de amiloide para observar un efecto clínico, pero esto está altamente correlacionado con mayores beneficios. Los estudios muestran que tratamientos como el lecanemab y el donanemab producen una eliminación significativa de las placas y ralentizan el deterioro cognitivo (entre un 27 % y un 35 %), incluso antes de alcanzar niveles totalmente negativos en la PET, aunque el beneficio máximo se observa cuando los pacientes alcanzan el estado de amiloide negativo.

También es importante la velocidad de eliminación del amiloide. Tanto el lecanemab (55 centiloides en 18 meses) como el donanemab (88 centiloides en 18 meses) son los mejores anticuerpos monoclonales descritos en el mercado, junto con otros como el trintinemab (90 centiloides en tres meses)”.

“Resumen del trabajo

En esta revisión se evalúan los beneficios y riesgos clínicos derivados del uso de anticuerpos monoclonales anti-Aβ (antiAβ-mAbs) en individuos aquejados de deterioro cognitivo leve (DCL) o de demencia leve de tipo Alzheimer, un estadio temprano de la enfermedad.

La enfermedad de Alzheimer es un trastorno cognitivo incurable habitualmente asociado a la edad que aparece por la muerte neuronal en distintas áreas cerebrales. En un primer momento afecta al hipocampo y regiones asociadas, lo que se traduce en la existencia de problemas de memoria, pero con el tiempo la enfermedad va evolucionando y afectando a distintas áreas del cerebro de la persona. La muerte neuronal, que solo produce manifestaciones clínicas cuando ya ha desaparecido un importante número de neuronas de esas áreas, está relacionada con la aparición de depósitos extracelulares de Aβ e intracelulares de proteína tau, en ambos casos con otras moléculas acompañándolas.

Esta es una enfermedad con solo tratamiento sintomático, muy poco efectivo, que en algunos individuos consigue retrasar el avance de la enfermedad unas pocas semanas o meses.

Recientemente, se ha autorizado una nueva familia de tratamientos basados en anticuerpos monoclonales contra la Aβ. La idea tras este tratamiento es que los anticuerpos puedan ‘marcar’ los depósitos de Aβ y así activar la maquinaria celular que se encargue de retirar ese péptido del cerebro.

Esta revisión ha analizado el efecto de los diferentes antiAβ-mAbs que se están comercializando actualmente, ya que todos ellos actúan de forma similar y centran su mecanismo de acción en el mismo proceso: la unión al péptido Aβ y su eliminación del entorno cerebral. Cabe recordar que los procesos de autorización de estos tratamientos, especialmente en el caso de los primeros —aducanumab y donanemab—, no estuvieron exentos de cierta polémica académica al valorar varios miembros de comisiones de autorización de la FDA y la EMA que el efecto clínico era muy escaso. Finalmente, tras una revisión de los criterios de efectividad de los tratamientos y de su efecto, se produjo la autorización de los primeros y, tras ellos, del resto. En este sentido, esta revisión resulta oportuna al abordar una cuestión de gran relevancia clínica.

Utilizando una metodología habitual en estudios de metaanálisis concluyen que, a los 18 meses del tratamiento, aprecian poca o ninguna diferencia en función cognitiva en individuos tratados respecto a los tratados con placebo. Utilizando como criterio la mejora en el test ADAS Cog SMD, observan que los individuos tratados muestran una muy ligera mejoría (de menos de 1 punto, cuando se considera como necesario un cambio de al menos 2-4 puntos). Si se analiza el efecto a los 24 meses, el resultado es aún más incierto. Este escaso o nulo efecto también se observa con otras medidas de función cognitiva. Los autores concluyen que estas ligeras mejoras en distintos test difícilmente implicaban mejoras significativas en funcionamiento diario o capacidad de mantener una cierta independencia.

Por otro lado, estos tratamientos también presentan efectos secundarios, como son las anomalías de imagen relacionadas con el amiloide (ARIA), que se dan con mayor frecuencia en personas tratadas, mientras que otros efectos secundarios adversos no sucedían con mayor frecuencia que en individuos tratados con placebo.

Finalmente, los portadores del alelo e4 en el gen APOE presentan una mayor probabilidad de desarrollar ARIA. Este alelo es el principal factor genético de riesgo conocido para la enfermedad de Alzheimer, y un relativamente elevado número de personas con la enfermedad son portadores de dicho alelo. Esta revisión no pudo analizar con suficiente detalle el papel de este gen en la efectividad del tratamiento ya que, a pesar de estas evidencias, en muchos trabajos no se llevó a cabo el genotipado de las personas participantes por las implicaciones familiares que esto conlleva.

La “Cochrane”, como es conocida habitualmente, es una organización internacional sin ánimo de lucro dedicada a elaborar evidencia de calidad que apoye la toma de decisiones en salud. Su área más reputada son las Cochrane Systematic Reviews, vista como el patrón oro de resumen de evidencias en salud. Estas revisiones se elaboran con una estructura determinada y enfocada en considerar la evidencia existente y la evaluación de riesgo de sesgos en los trabajos publicados. Sus revisiones son habitualmente utilizadas en organizaciones internacionales (OMS, EMA, FDA) y en distintas comisiones nacionales. Además, las revisiones se actualizan periódicamente según van apareciendo nuevas evidencias, lo que refuerza su relevancia clínica.

Este estudio sigue el riguroso proceso de revisión de esta organización.

Las implicaciones de este estudio son claras desde el punto de vista de gestión de la sanidad pública. El coste anual de estos tratamientos está en torno a los 25.000 €. Si no hay evidencias de que tenga un efecto clínico significativo, ¿tiene sentido seguir utilizándolos? Durante los procesos de aprobación de estos tratamientos, la presión de empresas y pacientes jugó un papel importante en su llegada al mercado, pero no fueron pocas las voces de expertos recomendando su no aprobación. Con la evidencia que se va acumulando con su uso, queda bastante claro que los beneficios son extraordinariamente escasos. Y no sabemos aún si sostenidos en el tiempo. El único punto que queda por despejar es qué sucede si se estratifican los pacientes por la presencia de determinados factores genéticos de riesgo.

El trabajo en sí no tiene mayor limitación que las de los trabajos de los que se nutre. Así, los autores señalan que no se pueden generalizar los resultados al conjunto de la población enferma, ya que la edad media de inicio está alrededor de los 80 años, mientras que los grupos estudiados en la revisión tienen una edad de inicio de entre 69,5 y 73,9 años. Además, el tiempo de seguimiento es relativamente escaso. Los autores también identifican algunas limitaciones relacionadas con los trabajos analizados, como que muchos de ellos están financiados por la propia industria farmacéutica que produce estos tratamientos.

En relación con el trabajo en sí, los autores no identifican limitaciones acerca del análisis realizado.

Este trabajo supone un esfuerzo por demostrar, a partir de las publicaciones que van apareciendo sobre la eficacia de estos tratamientos, hasta qué punto esta terapia resulta efectiva. Cabe esperar que en futuros meses podamos ver una actualización de esta revisión que incluya seguimiento durante periodos más largos, con poblaciones más diversas, no solamente mayoritariamente de origen caucásico, con mayor detalle sobre el perfil genético de los participantes y con edades más cercanas a las de la población de enfermos general”.

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