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A press release from Eli Lilly states that their antibody treatment, donanemab, significantly slowed cognitive and functional decline in phase 3 study of early Alzheimer’s disease.
Prof Bart De Strooper, Director of the UK Dementia Research Institute, said:
“This is extremely exciting news for the Alzheimer’s research community and the millions of people affected by the condition worldwide.It is very encouraging to see a second anti-amyloid drug showing success in trials, especially using a completely independent approach.
We will need to wait for the full results to be presented in the summer to assess the data in more detail, but the effects are convincing and these initial results confirm that amyloid beta is a good target, and that treating people earlier is going to give better results. This reinforces the need for effective diagnostics alongside these emerging treatments.
Interestingly, the results suggest treatment is only required until the plaques have been cleared from the brain, which means this will be cheaper, safer and more practical than continued treatment with a drug such as lecanemab.”
Prof Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, UK Dementia Research Institute Group leader, and president of the British Neuroscience Association, said:
“This press release from Eli Lilly and Company sounds very promising. While the full data have not been shared with the scientific community, meaning we can’t yet judge how robust they are, the company reports that their drug donanemab slowed decline in people with early Alzheimer’s disease. The effects are very similar to other recently reported trials of drugs that act on the same target, showing remarkable consistency in the ability to slow cognitive decline in early Alzheimer’s disease by around 30-35% with drugs that lower amyloid levels. It is important to note that there were rare serious side effects of the treatment with brain swelling and small strokes that seem to have contributed to the death of 3 of the participants in the trial. Regulators will have to decide whether the benefits of treatment outweigh these risks. This positive result and the two recent similar successful trials are very welcome good news after decades of clinical trial failures. This is an excellent example of how fundamental neuroscience research into the brain changes that cause Alzheimer’s can be translated into effective treatments.”
Dr Jina Swartz FMedSci, Chief Medical Officer at Exciva, said:
“These results look very impressive, although the side effect profile in terms of high incidence of ARIA remains concerning (to me, both as a Neurologist clinician and a drug developer).
“Certainly, Lilly’s Alzheimer’s disease Donanemab TRAILBLAZER programmes, which take into account tau levels and the extent of tau dissemination in the cortex, are the best and most well thought out in the field. We have all been waiting for these results with anticipation. Certainly, it looks like the landscape for treating AD (with these amyloid monoclonal antibody amyloid-targeting therapies, including Eisai’s lecanumab) is on the cusp of changing clinical practice in this field. However, these therapies will not prevent disease progression ultimately, so ongoing work and development of symptomatic strategies to treat the neuropsychiatric disturbances of Alzheimer’s disease dementia is still of the utmost importance – to allow people to live well with Alzheimer’s disease dementia and maintain their quality of life and that of their family members and/ or caregivers.
“In addition, it needs to be understood that these therapies are very expensive, require monthly infusions, regular MRI scans to monitor for AEs like ARIAs and the requirement to make a diagnosis of cortical amyloid (and tau) – using PET, which is prohibitively expensive. There are many parts of the world where the diagnostic and therapeutic requirements cannot be met, nor can the cost of the drugs be afforded. And even in the developed world (USA, Western Europe, parts of Asia-Pacific), patients will still require geographical access to a PET scanner and an infusion centre. So it will be interesting to see if/how this creates a significant disparity in access between the wealthy, developed nations (or even regions within a country) and those parts of the world where this cannot be afforded.”
Dr Tom Russ, Director of the Alzheimer Scotland Dementia Research Centre; Consultant Psychiatrist & Honorary Clinical Reader, University of Edinburgh, said:
“The results of the Donanemab trial are very welcome and will bring many people with dementia and their families some much-needed hope. The top line results do not give much detail and the publication of the full results in the Summer will be very helpful. While this is another encouraging development, the UK NHS is not ready to implement an infusion-based therapy such as Donanemab or Lecanemab (results reported last year), should they become licensed treatments in the UK. There needs to be significant support for struggling dementia assessment services which are still emerging from the Covid-19 pandemic to continue to diagnose, treat, and support people currently presenting while developing new ways to implement the disease-modifying treatments of the (near) future.”
Prof Paresh Malhotra, Professor of Clinical Neurology, Imperial College London, said:
“Following on from last year’s lecanemab trial results, these new findings from the TRAILBLAZER-ALZ 2 trial provide further evidence that antibody treatments that reduce amyloid in the brain can slow decline in thinking and the ability to carry out everyday activities in people with early Alzheimer’s Disease. These are really encouraging results and show that targeting fundamental mechanisms in Alzheimer’s can potentially make a difference to people’s lives. I look forward to seeing more data and getting the chance to see the details of the study findings in the next few months.”
Dr Marc Busche, UK Dementia Research Institute Group Leader, University College London (UCL), said:
“This clinical trial is a real breakthrough, demonstrating a remarkable 35% slowing of cognitive decline in Alzheimer’s patients with high amyloid-beta but low tau burden. I believe this therapy has the potential to significantly improve patients’ and families’ lives today. Notably, the beneficial effect was smaller in those with high tau levels, suggesting a potential interaction between these pathogenic proteins. Looking ahead, I anticipate that concurrently targeting amyloid-beta and tau could lead to even better patient outcomes, making this a crucial focus for future research and the next generation of clinical trials.”
Dr Liz Coulthard, Associate Professor in Dementia Neurology, University of Bristol, said:
“At face value, these data look positive, but we need to see the full dataset.
“Donanemab seems to help people with early Alzheimer’s retain cognitive function for longer – and this effect looks to be clinically meaningful. Donanemab might help people live well with Alzheimer’s for longer. If approved alongside lecanemab, this potentially brings a choice of treatments for patients.
“The trial design means that we may be able to target the drug towards people who will benefit most.
“There are significant side effects, and we need to know more about how these have affected people. We also need to know the longer-term effects of donanemab.”
Dr Nick Fox, Professor of Neurology and Group Leader at the UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), said:
“Although we only have a press release, this announcement is consistent with earlier phase 2 results – and confirms that we are in a new era of disease modification for Alzheimer’s disease. Dramatic and rapid amyloid removal was accompanied by slowing of cognitive decline. The challenge now is to be able to deliver these therapies in already stretched health care systems and to do so safely.”
Dr Cath Mummery, Consultant Neurologist and Clinical Lead for the Cognitive Disorders Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), said:
“This result confirms that we are now entering the treatment era of Alzheimer’s disease. After many years of negative trials, we now have consistent results across several anti-amyloid antibodies showing that removal of amyloid does change the course of the disease. This historic result suggests that in a group of patients with intermediate levels of tau, the secondary abnormal protein that accumulates in AD, the cognitive decline can be slowed by over a third over 18 months, and in almost half of the patients there was no cognitive progression over one year. Importantly, this trial met its primary and secondary endpoints, strengthening the findings.
“In addition, the method of administration of this drug might reduce burden and cost of treatment – this drug was only given until amyloid was lowered to a low enough point, then stopped – which was 52% over 12 months and 72% over 18 months – this may provide a way of ‘inducing remission’ in Alzheimer’s and then monitoring without treatment.
“These drugs are not without risk and we need to learn more about the commonest side effects – brain swelling or oedema due to the drug. While rarely serious, we need to be able to predict who is more at risk and how to minimise this.
“It is difficult to clearly compare this drug with leqembi or aducanumab as there are differences in the study design, but the overall results are at least as good, and the results in the subgroup more impressive. Results of ongoing studies in those with earlier disease and no symptoms are keenly awaited.
“The decades long battle to find treatments that change Alzheimer’s disease is changing; we are now entering the time of disease modification, where we might realistically hope to treat and maintain someone with Alzheimer’s disease, with long term disease management, rather than palliative and supportive care. This is the beginning of that journey, but this result can give real optimism and hope to our patients.”
Dr Susan Kolhaas, Executive Director of Research & Partnerships at ARUK, said:
“This is incredibly encouraging, and another hugely significant moment for dementia research. A second drug for Alzheimer’s has been shown to slow people’s cognitive decline in a rigorous phase 3 trial. We’re now on the cusp of a first generation of treatments for Alzheimer’s disease, something that many thought impossible only a decade ago.
“The treatment effect is modest, as is the case for many first-generation drugs, and there are risks of serious side effects that need to be fully scrutinised before donanemab can be marketed and used. However, this news underlines the urgency of preparing the NHS to make these treatments available should regulators deem them safe and effective. People should be really encouraged by this news, which is yet more proof that research can take us ever closer towards a cure.”
Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, said:
“After 20 years with no new Alzheimer’s drugs, we now have two potential new drugs in just twelve months – and for the first time, drugs that seem to slow the progression of disease. This could be the beginning of the end of Alzheimer’s disease.
“Based on today’s early results, donanemab appears to slow the progression of Alzheimer’s symptoms by 36 % (as compared with 27% of last year’s breakthrough drug lecanemab). Promisingly, the trial also demonstrated a 40% slowing in decline of everyday activities such as driving, doing hobbies and managing finances.
“While we’ve seen lecanemab could slow progression by over seven months, we’ll need to see the full results to know if donanemab could do the same or even better. We’re so proud that Alzheimer’s Society funded researchers discovered the role of amyloid in Alzheimer’s disease over 30 years ago which made today’s breakthrough possible.
“We need decisions as quickly as possible from the regulators MHRA and NICE. But that’s not the end of the story – we can’t end up in a situation where there are new drugs being approved but people can’t get access to them early in their dementia journey when they work best – we need more accurate, earlier dementia diagnosis in the NHS.”
Prof John Hardy, Professor of Neuroscience and Group Leader at the UK Dementia Research Institute, University College London (UCL), said:
“It is great news to have a success with a second anti-amyloid Alzheimer drug. This should dispel any lingering doubts about this approach. Having two drugs is great for competition.
“There is much work still to do if these drugs are approved as they should be. From a practical perspective we need to organise how to get these drugs into patients safely, and from a research perspective we need to understand why they slow disease but do not – yet at least – seem to stop progression.”
Dr Charles Marshall, Clinical Senior Lecturer and Honorary Consultant Neurologist, Queen Mary University of London (QMUL), said:
“This is hugely exciting news, as it provides further evidence that it is possible to slow down Alzheimer’s disease. When the full results are published as a paper we will be able to start carefully balancing the risks and benefits, and this will inform decisions about whether donanemab should be routinely given to patients with Alzheimer’s disease. For this to be possible, we will also need substantial new investment in dementia clinics that can deliver accurate diagnosis, treatments that are given as infusions, and appropriate safety monitoring. Without this there is a very real risk that existing health inequalities are exacerbated as only a few patients living near large teaching hospitals will be able to benefit.”
All our previous output on this subject can be seen at this weblink: https://www.sciencemediacentre.org/?s=donanemab&cat=
Declared interests
Prof Hardy: I have consulted for Eli Lilly’s and Eisai
Dr Marshall: No relevant interests
Dr Fox: I have served as a consultant or on advisory boards for Biogen, Ionis, Lilly, Roche and Siemens – any payments are to UCL.
Dr Coulthard: I have received funding/payment from Biogen, Lilly, Novartis, UCB, Eisai for consultancy and developing educational resources.
Dr Busche: I do not have any relevant conflict of interest
Prof Malhotra: I lead a NIHR-funded symptomatic trial of a repurposed medication in Alzheimer’s Disease and receive research funding from Alzheimer’s Society, Dementias Platform UK and NIHR.
Dr Russ is a Consultant Psychiatrist in NHS Lothian and an honorary Clinical Reader in Old Age Psychiatry at the University of Edinburgh. He is Director of the Alzheimer Scotland Dementia Research Centre at the University of Edinburgh and Clinical Research Champion of the NHS Research Scotland Neuroprogressive & Dementia Network. He is a PI on the Evoke and Evoke+ trials but has no financial involvement with any pharmaceutical company.
Dr Swartz: I am a global expert in Neuroscience and Alzheimer’s disease drug development, having worked in this area for over twenty years as a Neurologist and Neuroscientist. I led the Phase I development of lecanumab (then called BAN-2401) at Eisai about 15 years ago. I am currently Chief Medical Officer of a Neuroscience biotech dedicated to developing novel therapies for symptomatic treatment of neuropsychiatric disturbances in patients with Alzheimer’s disease (AD) dementia. Until recently, I was Therapeutic Area Head of Neuroscience Global Clinical Development at Merck and Co (MSD, in Europe). I have held senior positions in Research and Development in Neuroscience at Takeda, Eisai and GSK. I was also previously Vice President and Therapeutic Area Head of Neurology at Signant Health (then called Bracket). I have held positions as an honorary Neurology Consultant at Imperial College London, invited lecturer on neuropsychopharmacology at Kings College London. I am an elected Fellow of the Academy of Medical Sciences. I also sit on the boards of the following Neuroscience charities: Alzheimer’s Research UK, Ataxia UK, British Neuroscience Organisation (BNA) and Arts 4 Dementia. I have just been appointed to the boa rd of Parkinson’s UK.
For all other experts, no reply to our request for DOIs was received.