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Results of the phase 3 trial of lecanemab for early Alzheimer’s disease has been published in New England Journal of Medicine (NEJM).
Comments after the CTAD conference presentation of results Prof John Hardy, Group Leader at the UK Dementia Research Institute at UCL, said:
“This is a very impressive trial. I think everyone in the audience was impressed by the data. There was some ARIA in treated individuals but the majority were asymptomatic. This means the patient was not aware of it and it was only picked up by imaging, and in most cases treatment was continued.
“There were no treatment related deaths (two deaths, one had atrial fibrillation, the other was having TPA treatment for other reasons which can cause haemorrhage).
“One very important point is that the lecanemab change was getting more over time implying treatment should have more benefit as treatment continues longer.
“This was also a brave trial. People could be in the trials even if they had comorbidities so the trial was closer to ordinary clinical practice than many are. They showed efficacy in Asians and African Americans and Hispanics as well as whites. The trial met not only its major endpoint but also met all the secondary endpoints too.
“There is a long way to go for approval and the use of these drugs in standard clinical practice… but undoubtedly this is the first stage.”
Prof Bart De Strooper, Director of the UK Dementia Research Institute, and Group Leader at the UK Dementia Research Institute at UCL, said:
Trial results
“The full trial data confirms that treatment with lecanemab clearly removes amyloid protein deposits from the brain in a period of months and also has beneficial effects on other hallmarks of Alzheimer’s disease, including tau. This is remarkable as amyloid accumulates over decades in the brain. Therefore, it is extremely encouraging to see positive effects of lecanemab in a trial of just 18 months.
“These results demonstrate that a reduction in amyloid can slow the progress of Alzheimer’s disease. This is the first drug that provides a real treatment option for people with Alzheimer’s. While the clinical benefits appear somewhat limited, it can be expected that they will become more apparent if the drug is administered over a longer time period.
Side effects
“The benefits of the drug need to be balanced against the side effects. ARIA is a known side effect that involves a bleed or build up of fluid in the brain. It can vary from mild and negligible to quite severe. The study reports that the number of deaths in the placebo and in the lecanemab treated groups are similar, i.e. 6 and 7 respectively. Further follow up is needed to understand whether ARIA in the context of anticoagulation therapy in certain patients is life threatening. It may be that patients receiving such treatments need to be excluded. Further studies will be able to identify the patients at risk and those patients who will maximally profit from the treatment.
Patient access
“The participants of this trial were all people with very early-stage Alzheimer’s disease, which raises the question of how we ensure that people can access these drugs at the right stage in their disease course. In parallel, we must focus on making early diagnosis easier and more accessible, so that treatments can be administered when they are most likely to have a positive impact, before amyloid levels are too high and start to cause damage to the brain.
Future considerations
“Alzheimer’s is a complex disease, and we still have a lot to learn about the underlying causes. It is therefore imperative that we continue to invest in discovery research, and through doing so, we may also identify new targets for which we can develop therapies we could use in combination with anti-amyloid drugs like lecanemab.
“The overall conclusion is extremely positive. This trial proves that Alzheimer’s disease can be treated. I hope we will start to see a reversal in the chronic underfunding of dementia research. I look forward to a future where we treat this and other neurodegenerative diseases with a battery of medications adapted to the individual needs of our patients.”
Prof John Hardy, Group Leader at the UK Dementia Research Institute at UCL, said:
“This trial is an important first step, and I truly believe it represents the beginning of the end. The amyloid theory has been around for 30 years so this has been a long time coming. It’s fantastic to receive this confirmation that we’ve been on the right track all along, as these results convincingly demonstrate, for the first time, the link between removing amyloid and slowing the progress of Alzheimer’s disease.
“The first step is the hardest, and we now know exactly what we need to do to develop effective drugs. It’s exciting to think that future work will build on this, and we will soon have life-changing treatments to tackle this disease.
“The trial results have shown us that there is a risk of side effects, including brain bleeds in a small number of cases. This doesn’t mean the drug can’t be administered, but that will be important to have rigorous safety monitoring in place for people receiving lecanemab, and further trials to fully understand and mitigate this risk.”
Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead and Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:
“Van Dyke and colleagues report that lecanemab treatment in Early Alzheimer’s disease reduced markers of brain pathology and resulted in “modestly” less cognitive decline than placebo in a large clinical trial. While this is good news from a well-conducted trial, it is important to note that this is not a cure. Both groups in the trial had worsening symptoms, but people taking the drug did not decline as much in their cognitive skills. As the authors point out, there is not an accepted definition of clinically meaningful effects in the cognitive test they used, and it is not clear yet whether the modest reduction in decline will make a big difference to people living with dementia. Longer trials will be needed to be sure that the benefits of this treatment outweigh the risks. As a scientist working on Alzheimer’s disease for many years, it is wonderful news that years of fundamental neuroscience research have resulted in a treatment can slow the progression of Alzheimer’s disease and reverse some of the pathological changes in the brain. This result will boost research and gives hope that the treatments based on ongoing neuroscience research will be even better. ”
Prof Rob Howard, Professor of Old Age Psychiatry, UCL, said:
“This is an important dataset from the first clinical trial of a potential Alzheimer’s disease-modifying agent to show statistically significant differences between drug and placebo. As a dementia clinician and researcher, I have a heart and a head. My heart says that this is wonderful and hope-filled news for the field. At long last, we have gained some traction on this most terrible and feared of diseases and the years of research and investment in dementia have finally paid off. It feels momentous and historic. This will encourage real optimism that dementia can be beaten and one day even cured.
“I have a head too. This is concerned about three aspects of today’s data. First, are the trial’s results valid? Did opportunities for unblinding of treatment allocation arising from infusion-related reactions (seen in a quarter of treated patients) and occurrence of ARIA side-effects (swelling and bleeding in the brain), and the larger number of lecanemab-treated participants who dropped out before they had completed the 18-month assessment, introduce unfair bias in favour of the drug? It will be difficult to answer this with certainty until the US Food and Drug Administration report their independent analyses of the data and examine these effects as part of the drug licensing process.
“Second, the magnitude of any treatment benefits were extremely small. For example, lecanemab was associated with a 1.4 point advantage on the ADAS-cog14 (a 90-point scale used to measure memory, attention, language function and other thinking abilities). This is just too small a difference to be noticed in an individual patient and none of the reported results, including the primary outcome, reached accepted levels of improvement to constitute a clinically meaningful treatment effect.
“Third, is it safe? Recent reports of two deaths from strokes, attributed to a side-effect of the drug, are concerning. The data published today indicate that six lecanemab-treated patients suffered strokes during the trial compared with two in the placebo group. Treatment therefore does carry risks, and in some rare cases this can be severe or life-threatening.
“I suspect that the lack of demonstrable clinical effectiveness will mean that lecanemab will not be taken up widely within healthcare systems around the World, although there will always be those whose heart rules their head. We need to keep looking for better and safer dementia treatments and today’s results show that we are now on a believable path to doing so.”
Prof Nick Fox, Director of the UCL Dementia Research Centre and Professor of Clinical Neurology, said
“This is a very important result and paper.
“The full data support the promise of disease modification press released and indeed shown in the phase 2b study – presented back in 2018.
“The results confirm a robust effect of slowing of cognitive decline of 27% on the primary outcome.
“I believe, it confirms the a new era of disease modification for Alzheimer’s disease. An era that comes after more that 20 years of hard work on anti-amyloid immunotherapies – by many many people – and many disappointments along the way
“Not only did the trial hit is primary endpoint – but it also showed positive effects on a wide range of secondary outcome – including benefit in terms of activities of daily living even in this very mild AD population.
“As was to be expected the treatment produced a dramatic reduction in brain amyloid (as measured by PET). The level of amyloid PET binding hardly changed in the placebo arm but in the lecanemab arm mean amyloid PET binding fell to below the level of what is considered “positive” – in other words the amyloid reduction was so large that many or most participants would no longer have been eligible even to enter the study – on average they would no longer have had enough PET evidence of Alzheimer’s disease to fulfil inclusion criteria… this recapitulates the phase 2b finding and what is seen in other therapies to lesser or greater extent (e.g. donanemab).
“The study fits the idea – that amyloid levels need to be reduced low enough and for long enough to see benefit on clinical measures – it is notable that the phase 2b did not hit its primary outcome at 12 months but did so at 18 months … it could have been deemed ineffective.
“Is this 27% slowing “meaningful”? There is no simple answer to this – certainly trials are often powered to show disease slowing of 20% or 25% so this study hit what many in the filed regarded as a minimum level. A really key question is whether clinical benefits are progressive, if they continue beyond the 18 months, if they are sustained and cumulative. The trial was not powered to address whether benefits were progressive over the 18 months but the graphs of change (e.g. on the primary outcome) do suggest a widening of the gap between treatment and placebo arms.
“On just about every metric the phase 2b predicted what was seen in this phase 3 study – from the level of clinical benefit through to the proportion who would get ARIA-E.
“There have been lots of understandable concerns raised about safety of this class of therapies – in particular concerns about the impact of ARIA-E (amyloid related imaging abnormalities) seen on MRI. These do need to be taken seriously but also in a balanced way . ARIA-E refers to changes oedema (swelling) and effusions seen on MRI brain – that are likely a result of amyloid removal (amyloid is widely distributed in the brain – including, importantly, in the walls of blood vessels in the brain).
“The headline figure for ARIA-E in this trial is of 12.6% (or 1 in 8) of those who received lecanemab, while 1.7% (less than 1 in 50) developed it in the placebo arm – but I believe that one needs to look beyond these numbers and look at the number who had symptoms – most (80%) of these ARIA-E cases did not have discernible symptoms and overall 2.8% (less than 1 in 30) had any symptoms (headaches, confusion etc).
“Notably the number of deaths in the treatment and placebo arms were essentially identical – slightly fewer in those on lecanemab (0.7) of than on placebo (0.8%) – and the study investigators did not feel that any of the deaths were related to treatment or ARIA.
“Any risk is clearly important but I believe that many of my patients would be very willing to take such a risk.
“These treatments are however not for the faint hearted – the study involved intravenous infusions every 2 weeks – that is real burden on families.
“This is also a massive challenge to health systems – systems will struggle to deliver therapies – huge resources would be needed just to deliver therapies – but also many just do not currently have the investigation capacity to assess amyloid status by PET or CSF or even to provide the MRI scans needed for inclusion in the study and monitoring – in this trial the participants had 6 MRI scans (weeks 9, 13, 27, 53, and 79 as well as at the 3-month follow-up visit) for safety monitoring – even for those without any ARIA.
“This does represent a really important moment for the field – and an important a source of hope for patients and families.
“If indeed the benefits are progressive and do extend beyond 18 months this does offer the potential of clinically meaningful benefits that could change outcomes significantly and change the outlook for this devastating disease.
“It also raises lots of challenges
– we will need to find ways of delivering therapies safely and more easily – sub-cutaneous treatments would be a step in the right direction
– does treatment need to continue or can it be paused?
– how early should it be started?
– cumulative benefits logically mean that the earlier that treatment is started the greater the difference that is made in terms of preserving function for longer
– most of us would want our disease slowed when we still had a good quality of life and independent functioning – conversely if disease slowing is delivered late we could prolong individuals in a dependent state
– we will need resources for timely assessment and investigation.
“Until now we have only had symptomatic therapies for Alzheimer’s disease That meant that delays in starting treatment did not “cost brain cells” or alter ultimate outcomes – unlike treatments for cancer (and many other areas of medicine) time was not of the essence. Now it is. There will be many challenges and problems to address – from cost to logistics to ethics – but for the millions of present and future patients globally – better to have these problems than no problems and no prospects …”
Dr Ivan Koychev, Senior Clinical Researcher at the University of Oxford, said:
“This paper shows that an antibody treatment that clears amyloid in the brain of patients with mild form of Alzheimer’s disease has efficacy in slowing down the rate of decline in terms of cognitive skills and daily function. This is significant as it is the first study to show an unambiguous relationship between amyloid clearance and modest slowing down of Alzheimer’s disease. However, there is also concern about the safety of the drug with further evidence that this drug class is linked to brain swelling and small haemorrhages seen on imaging. Most of these resolve without symptoms but case reports exist that link these abnormalities to individual fatalities. In summary, while this is a step-change for Alzheimer’s disease treatment, a careful examination of the risks and benefits of this novel therapy.”
Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, said:
“Today’s exciting results could be game-changing. They give us hope that in the future people with early Alzheimer’s disease could have more time with their loved ones. Our research over thirty years ago was pivotal in highlighting the importance of amyloid protein in Alzheimer’s disease, laying the foundations for billions of pounds of investment into many of the drugs like lecanemab being tested today, with 117 other drugs currently in trials.
“This isn’t the end of the journey for lecanemab – it’s being explored in further trials to see how well it works over a longer period of time. The safety of drugs is crucial and lecanemab did have side effects, but they will be closely looked at when decisions are made about whether or not to approve lecanemab, to see if the benefits outweigh the risks.
“There is still a long way to go before we could see lecanemab available on the NHS, and we await clarity for how and when the approval process will take place in the UK, and whether regulators believe it is cost-effective. We mustn’t forget that lecanemab can only be given to people with early Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or in the later stages of Alzheimer’s disease, can’t benefit from this drug.
“We were excited to see a recommitment to the National Dementia Mission on Monday. This crucial doubling of dementia research funding must be delivered urgently, and must prioritise early diagnosis, through wider access to PET brain scans and research to get blood tests into the clinic, so people can access these drugs when they become available. With 900,000 people living with dementia in the UK, this crucial investment must boost research for all types of dementia so no one is forgotten.”
Prof Sir John Hardy, Chair of Molecular Biology of Neurological Disease and Group Leader at the UK Dementia Research Institute at UCL and Alzheimer’s Society funded researcher said:
“Today marks a truly exciting day for dementia research. I’m incredibly proud of how far we’ve come since our Alzheimer’s Society funded research in 1989, which showed for the first time that a toxic protein called amyloid played a role in the cascade of brain changes leading to Alzheimer’s disease. This discovery would not have been possible without the selfless dedication of families affected by dementia who took part in this research. A drug like lecanemab becoming available on the NHS would be a massive triumph, but challenges remain around getting drugs to the right people at the right time – we need changes in our health system’s infrastructure to make sure we’re ready.”
Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, said:
“These exciting findings represent a major step forward for dementia research and could herald a new era for people with Alzheimer’s disease. This is the first time a drug has been shown to both reduce the disease in the brain and slow memory decline in clinical trials.
“Lecanemab works by clearing the amyloid protein that builds up in the brain in people with Alzheimer’s disease. In this trial, the drug slowed down participants’ decline in memory and thinking, and their ability to carry out day-to-day activities. Although the benefits were small and came with significant side effects, it marks the arrival of a treatment that can slow the course of Alzheimer’s disease.
“With all this excitement, there are still many questions and challenges we need to address.
“The treatment window in the trial was for 18 months, so we don’t yet know whether there will be impacts to people that last beyond this. Longer-term studies that are ongoing will tell us whether the modest improvements seen in the trial change the trajectory of the disease longer-term.
“Lecanemab was associated with severe side effects, and it will be important for regulators to understand the safety profile of the drug before it is given a full license for use.
“The benefits of taking lecanemab in the trial were modest but the challenge and opportunity remains within dementia research to build on these findings into an era where we’re developing multiple treatments against different aspects of Alzheimer’s disease to slow and stop the disease.
“It’s safe to say that the NHS is not ready for a new era of dementia treatment.
“We estimate that unless there are drastic changes in how people access specialist diagnostic tests for Alzheimer’s disease, only 2% of people eligible for drugs like lecanemab will be able to access them. We recommend, through the new Dementia Mission, the government take urgent steps to bring together regulators, industry, clinicians and decision-makers in our health system to put a clear plan in place to ensure people in the UK are among the first in the world to access new treatments once they are licensed.”
“This is truly a historic moment for dementia research. This year is the 30th anniversary of the seminal work that revealed the central role of amyloid protein in Alzheimer’s. The road to an anti-amyloid treatment has been a long one and people with Alzheimer’s have seen many disappointing setbacks. We hope that this drug will make it to patients, but it won’t be suitable for everyone with Alzheimer’s, and it’s only a first step on the journey towards a cure.”
‘Lecanemab in Early Alzheimer’s Disease’ by Christopher H. van Dyck et al. was published in NEJM at 00:50 UK time on Wednesday 30 November.
Declared interests
Prof Bart De Strooper: “I have been consultant for a series of pharmaceutical companies, including Eisai, and I am myself scientific founder of two biotech companies. However I have never consulted for their antibody programs and I have myself no direct interest in antibody therapies.”
Prof Tara Spires-Jones: “No conflicts.”
Prof Rob Howard: “No conflicts.”
Prof Nick Fox:
Dr Ivan Koychev is in receipt of an investigator-initiated clinical trial grant by Novo Nordisk testing semaglutide’s effects on Alzheimer’s pathology.
Prof Sir John Hardy has consulted for Eisai, Roche and Eli Lilly in the last year (but not on their antibody trials)
Dr Susan Kohlhaas: “I don’t do any consultancy for Industry. I’m a Trustee of the UK DRI and Associate Director for Dementias Platform UK.”
For all other experts, no reply to our request for DOIs was received.