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A platform trial published in The Lancet Neurology looks at the efficacy of anti-amyloid drugs that could delay the onset of Alzheimer’s disease.
Dr Sebastian Walsh, NIHR Doctoral Fellow in Public Health Medicine, University of Cambridge, said:
“We all agree there is an urgent need to improve treatment options and other support for people with, or at risk of, dementia. This paper, as written, and the authors’ comments on it will generate considerable excitement, especially for those families affected by dementia (who will also have seen similar recent headlines based on trials of similar drugs to treat those with early symptoms of Alzheimer’s). Unfortunately, significant caution is required when interpreting these findings, for two key reasons:
“Firstly, the results of this very small trial are actually ’null’ – meaning there is no strong evidence of a positive finding. That the authors have suggested otherwise is a regrettable deviation from standard scientific practices of trustworthy communication. A more accurate interpretation of the findings would be that this drug, like several other drugs before, demonstrated its effectiveness at removing the amyloid protein from the brain. But there was no convincing evidence in this trial that this led to any actual benefit for the participants in terms of the development or worsening of dementia symptoms. This is either because the effects were too small, or the study was too small, or a combination of both of these.
“Another important related point is that for the latter half of this study, the participants knew they were taking the treatment – whereas normally in a trial participants wouldn’t know if they were taking a drug or a placebo in order to reduce the very real risk of bias – which reinforces the need for caution in interpreting what these results actually mean for the people in this study.
“Secondly, the people in the study were a highly selected group with rare genes that put them at risk of a very specific type of Alzheimer’s disease. Evidence from population studies tells us that we cannot assume that findings from groups like this will translate to the majority of people who develop clinical Alzheimer’s disease – who often have other things going wrong in their brain, beyond the amyloid protein being targeted in this study, and typically also have other medical conditions affecting the rest of the body. These people are mostly older, frailer, and more complex. We would expect that such treatments would achieve smaller benefits (if any) and the risk of side effects (brain swelling and brain bleeding) may be higher even than those seen in this study. We just don’t know.
“Finally, the authors suggest in their comments that if ongoing trials of similar drugs for people without symptoms and without these rare genetic risk factors show similar results, that “there soon could be Alzheimer’s preventions available for the general population…One day soon, we may be delaying the onset of Alzheimer’s disease for millions”. Unfortunately, this statement again needs to be put into some perspective. Most people who have raised amyloid in their brain but no symptoms will die without dementia. The idea that we would screen the whole population so that we can offer these people, most of whom by definition cannot benefit, drugs that frequently cause bleeding, swelling, and in very rare cases death, is difficult to agree with – even if these studies, all of which so far have been null, start reporting positive findings. This is before considerations of the exorbitant costs, and the need to know everyone’s genetic status in order to inform them of the higher risk of side effects for the people with the highest genetic risk.
“There are plenty of things we can do as individuals and at the policy-level to improve brain health, such as lowering blood pressure, being physically active, and reducing smoking rates; and to better support people with symptoms, for example action to reduce waiting lists for memory clinics which are up to 1 year in some areas of the UK, and improving access to support services for people living with dementia and their carers. Every pound spent, and every hour spent by a doctor or nurse, on pursuing wonder drugs or hypothetical screening programmes is a resource we don’t use for these other desperately needed services – which is why we need to set realistic expectations for the public.”
Dr Susan Kohlhaas, Executive Director of Research, Alzheimer’s Research UK, said:
“This follow-up study of gantenerumab, an anti-amyloid drug that previously failed to slow cognitive decline in people at risk of Alzheimer’s disease, suggests that extended use of anti-amyloid treatments may delay or prevent the onset of dementia symptoms.
“Whether these findings apply to current approved anti-amyloid treatments needs further work, but these results highlight the importance of early intervention and longer-term follow-up in determining the benefits and risks of dementia treatments.
“This was a small scale study in people with a rare genetic form of Alzheimer’s, but suggests that the efficiency of amyloid removal and the length of treatment may lead to significant effects in people over an extended period of time.
“With people now receiving approved anti-amyloid therapies in health services around the globe, it will be vital to continue collecting data on how these medicines are working in real world settings, alongside clinical trials.
“We’re in a period of uncertainty for global investment into research. Now, more than ever, we must collaborate to collect valuable long-term data, and the government has a vital role to play to ensure the UK remains at the forefront of dementia research.”
Prof Robert Howard, Professor of Old Age Psychiatry, UCL, said:
“The press release claims that gantenerumab treatment can delay or prevent the appearance of dementia, but this is not supported by the data and could give false hope to patients and their families about what treatments for Alzheimer’s disease are able to do.
“Anyone who understands how to look at the results of a clinical trial will recognise that this paper reports the failure of gantenerumab to show treatment efficacy on any prespecified clinical outcomes in randomised controlled comparisons between drug and placebo. And, sadly, because of this and other negative trials, development of gantenerumab has been abandoned.
“However, the authors carried out many further analyses from a small number of participants who chose to continue treatment in an open-label extension to the randomised controlled trial. Because this was an open-label extension, there was no randomly allocated placebo group to compare the effects of treatment to. Instead, the results from an “extended control” group were used for comparison and a large number of differently defined treatment groups were run through the analyses, increasing the risk that any apparent differences with treatment would be due to chance. For these reasons, no responsible clinical trialist should claim on the basis of these data to have shown a 50% lowering of the risk of developing dementia symptoms. If you look at the wording of the Summary of the published paper, you will see that such a claim does not appear, as presumably the scientific peer reviewers and editorial staff would not have permitted such a misleading overstatement to be published in the Journal.
“I hope that journalists will question why the conclusions of the peer reviewed article are so different from the headline content of the press release and won’t disseminate what is unhelpful misinformation about the potential of a drug to prevent Alzheimer’s disease.
Dr Richard Oakley, Associate Director of Research and Innovation, Alzheimer’s Society, said:
“As with all antiamyloid trials, this study stemmed from research funded by Alzheimer’s Society, shedding light on the role of amyloid in Alzheimer’s disease.
“These exciting early-stage results hint that long-term antiamyloid treatments, started before Alzheimer’s disease symptoms appear, could potentially delay symptom onset.
“However, these results need to be treated with caution; this trial focuses on a very small group of individuals with genetic forms of Alzheimer’s disease. Longer-term follow up of this group and larger studies will tell us more about the effect of these drugs in these types of Alzheimer’s.
“Ultimately, the field hopes to see similar progress in preventative trials of antiamyloid treatments in people at risk of Alzheimer’s disease later in life, which affects the majority of people with dementia.
“This is a hugely exciting time in dementia research and there is hope on the horizon for all affected by this condition – research will beat dementia.”
Prof Charles Marshall, Professor of Clinical Neurology, Queen Mary University of London, said:
“This study focusses on a rare group of people with genetic mutations that cause Alzheimer’s disease that runs in famiilies. These people are of particular interest because we know for certain that they will develop Alzheimer’s disease, and can estimate when they are likely to develop it, making them an ideal group to evaluate preventive treatments.
“It seems from these results that if treated for long enough with a drug that reduces amyloid beta protein in the brain we can delay the development of symptoms in those who will go on to develop Alzheimer’s disease, and this is very exciting. There are two major limitations of the study. The first is that it was a secondary evaluation of a relatively small number of people who were treated for a long time, and therefore the results are not as certain as they would have been if they were the main trial result. The other limitation is that gantenerumab is not nearly as effective as some of the other amyloid reducing treatments that are now available, suggesting that we may be able to do even better than these results suggest.
“I look forward to seeing more results from the other treatments that are now being given in this trial. It is giving tremendous hope to the families that have these rare genetic mutations, and these results suggest that in years to come we may have preventive treatments to offer them.”
Prof Tara Spires-Jones, Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, Group Leader in the UK Dementia Research Institute, and President of the British Neuroscience Association said:
“This study by Bateman and colleagues shows promising preliminary results of an experimental treatment in people with rare inherited forms of Alzheimer’s disease. People who inherited a gene that causes early onset Alzheimer’s disease received the drug gantenerumab to remove sticky amyloid pathology before they developed symptoms. Scientists observed that the 22 people who took the drug for the longest (an average of 8 years) had delayed progression of cognitive symptoms. While this study is important scientifically as evidence that amyloid-lowering drugs may potentially be able to delay symptom onset, there are several important limitations to consider. As the authors acknowledge, the delay in symptom onset with treatment was only found in people who were treated for an average of 8 years, probably because amyloid pathology accumulates in the brain for at least 10 years before symptom onset. This study also did not include a control group receiving placebo alongside the drug which is a very important control. Further, the drug used in this study, gantenerumab, has been discontinued by the company that developed it because it did not slow symptoms of the more common non-genetic forms of Alzheimer’s disease in a trial with over 1,900 participants. While this study does not conclusively prove that Alzheimer’s disease onset can be delayed and uses a drug that will not likely be available, the results are scientifically promising.”
‘Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer’s disease: an open label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU Trial’ by Bateman et al. was published in Lancet Neurology at 23:30 UK time on Wednesday 19th March.
Declared interests:
Dr Sebastian Walsh “No COIs”
Dr Susan Kohlhaas “None”
Prof Robert Howard “No COIs”
Dr Richard Oakley “this study stemmed from research funded by Alzheimer’s Society” as this is factually accurate.”
Prof Charles Marshall “I have no relevant conflicts”
Prof Tara Spires-Jones “I have no conflicts with this study but have received payments for consulting, scientific talks, or collaborative research over the past 10 years from AbbVie, Sanofi, Merck, Scottish Brain Sciences, Jay Therapeutics, Cognition Therapeutics, Ono, and Eisai. 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.”