Results from Eli Lilly’s TRAILBLAZER-ALZ 2 Randomized Clinical Trial looking at the use of donanemab in early symptomatic Alzheimer’s disease has been published in JAMA.
Tara Spires-Jones, President of the British Neuroscience Association and Professor at the UK Dementia Research Institute at the University of Edinburgh, said:
“It is fantastic news that another treatment has been successful in slowing the progression of Alzheimer’s disease. The study by Sims and colleagues published in the Journal of the American Medical Association was well-conducted and shows a significant slowing of disease symptoms with donanemab treatment. The drug is an antibody that attacks amyloid plaques, one of the sticky proteins that clumps in the brains of people with Alzheimer’s disease. As well as slowing symptom worsening, treatment also lowered blood levels of another pathological protein called tau, indicating that the treatment may protect the brain to some extent from both pathologies. While very promising, it is important to note that this treatment has rare serious side effects including small strokes and brain swelling and less serious reactions to the monthly infusion of the drug. This treatment is not a cure and more work is needed to find treatments that can halt instead of just slow progression. The effects of the current drug are very similar to another treatment recently approved in the US (lecanemab) that also attacks amyloid, adding weight to the idea that Alzheimer’s disease can be effectively treated. Overall, this is an excellent example of translation of years of fundamental neuroscience research into an effective treatment to slow Alzheimer’s disease. With more research, treatments will get even better in future.”
Dr Mark Hibberd, Chief Medical Officer, Pharmaceutical Diagnostics, GE HealthCare, said:
“This is another exciting development for patients and caregivers, though limitations to access this class of therapies remain. Amyloid-targeted therapies first require confirmation of amyloid beta pathology, but access to positron emission tomography (PET) amyloid imaging – the only method to directly visualize amyloid brain depositions in patients – is limited, primarily due to PET scanner access and a lack of reimbursement. We are optimistic that coverage for amyloid PET scans will follow as disease modifying therapies are more widely adopted.”
Prof Giles Hardingham, Interim Director of the UK Dementia Research Institute, said:
“It is terrific to see these results published in full today. We have waited a long time for Alzheimer’s treatments, so it’s really encouraging to see tangible progress continuing to gather pace in the field. We’re on the edge of exciting and significant change in the landscape of treatment for people affected by or at risk of dementia.
“Donanemab is the most recent anti-amyloid drug to be developed, lecanemab having recently been approved by the FDA. These first-generation drugs are by no means perfect, but represent an important breakthrough that will pave the way for many future therapies.
“At the same time, amyloid is just one part of the complex picture of Alzheimer’s. At the UK Dementia Research Institute, we are also undertaking vital discovery research into additional disease mechanisms. This, we hope, will ultimately lead to a suite of treatment options tailored to the individual person dependent on their type and stage of dementia.”
Prof Gill Livingston, Professor of Psychiatry of Older People, University College London, said:
“This is important as it is a well conducted trial with overall good news showing that while both groups with mild cognitive impairment or mild dementia due to Alzheimer’s disease continue to deteriorate, the group treated with donanemab deteriorates slightly more slowly over 72 weeks. This is the third similar trial and it is clear that in the short term these drugs help a little in the populations tested. They also reduced amyloid plaques by 88%. As in the other trial there are significant side effects including reactions to the infusion (9% treatment and .5% placebo) and 24% in the treated group versus 2.1% developing brain abnormalities There are also 3 deaths in the treated group and 1 in the placebo group which the raters who did not know what people were on considered to be due to treatment.
“One strength of this study is the population is more ethnically disparate than in other studies although the US group were disappointingly 96% White. People were also highly educated. We cannot see the full inclusion criteria but people with other concurrent illnesses or aged over 85 were excluded thus meaning the study took place in an atypical population and may not apply to those with typical Alzheimer’s who usually have other illnesses.
“We do not know if the treatment will continue to make more difference over a longer period. This is the hope but not what we know. Thus, it is a beginning and important but with a small change in a relatively physically well population and significant side effects, there is still a lot of work to do to know what it means for most people with Alzheimer’s dementia. We also do not know its cost and therefore whether it will reach UK value thresholds.”
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:
“These results are really promising. Rapid and dramatic amyloid removal was achieved and significant slowing of decline. Those who were less affected at baseline derived greater benefit with 30-40% slowing across a range of clinical measures – but the whole (combined) group still saw 20-30% slowing on these measures, which is very encouraging.”
Dr Liz Coulthard, Associate Professor in Dementia Neurology, University of Bristol, said:
“This is a robustly conducted and innovative trial. The results are exciting and mean that over the next year or two we may well be able to offer patients a choice of treatments that slow down progression of Alzheimer’s disease. Some patients did not worsen significantly during the trial and on average progression of disease was slowed 4.4-7.5 months over 18 months. The drug seems to have a meaningful benefit, at least for some patients.
“We do not yet know whether this benefit would continue after 18 months.
“There were significant side effects and patients will need to be aware of risks of treatment so they can choose whether they take these drugs or not.
“These data start to show how we can tailor treatment to patients who will benefit most (i.e. those with evidence of amyloid without very high levels of tau) – and how we can limit the dosing of medication. This is very important in clinical practice, especially as there are side effects and costs may be significant.
“However, the resource implications of taking this sophisticated approach are enormous. We need to transform our access to brain scans and infusion suites and train a skilled workforce to deliver these treatments. Alzheimer’s is a common condition, and we want people to be eligible for treatment on the basis of need, rather than access being limited to those who can afford private care or live in certain areas of the country.”
Dr Ivan Koychev, Senior Clinical Researcher and Consultant Neuropsychiatrist, Dementia Platform UK, University of Oxford, said:
“The results add further evidence that immune therapies that successfully remove amyloid plaques associate with modest slowing down of Alzheimer’s disease progression. The study is well conducted and notable for the further evidence that therapy in earliest stages of the disease (that is where there is still low levels of tau protein build up in the brain) carries the greatest benefits. Concerns remains over the side effects of these drugs – a significant proportion of patients developed a form of brain oedema. On a positive note, this side effect resolved without causing symptoms for the majority of patients. The next stage is to find out what the long term outcomes are of those have been on therapy – we still do not know when patients would stop treatment in the real world. This is going to have a huge importance on making the health economic case for this type of drug being made available through the NHS. Finally, the effects in early disease raise the question of whether these therapies should be given to people who have evidence of Alzheimer’s disease in their brains but are still symptom free.”
Dr Marc Aurel Busche, Group Leader at the UK Dementia Research Institute, University College London (UCL), said:
“This is encouraging news for people living with Alzheimer’s disease (AD). Donanemab has shown promise in significantly reducing the harmful brain amyloid plaques typically elevated in AD, as well as markedly slowing disease progression, as indicated by multiple clinical readouts.
“A critical observation from the study is that patients with a lower burden of tau tangles in their brains – another key pathological hallmark of AD, which has a stronger correlation with cognitive function than amyloid plaques – demonstrate a better response to Donanemab. This emphasises the crucial importance of initiating treatment early and the concept of therapeutic windows and staging in AD management. Nonetheless, for patients at advanced disease stages (the patient population tested in this trial), characterised by high levels of both amyloid-beta and tau proteins, as well as symptoms, the data suggest that combination treatment involving both anti-amyloid and anti-tau therapies may be even more effective – considering that donanemab does not appear to directly impact tau tangles.
“From a broader clinical perspective, the data underscore the need to invest in diagnostic tools that can detect AD at a stage before overt clinical symptoms and brain atrophy are present, at a time when amyloid plaques have begun to accumulate but tau tangles have not yet spread significantly across the brain. Potential solutions could include the use of blood protein markers in combination with markers of early brain dysfunction.
“While the promise of donanemab is undeniable, it is noteworthy that there were more serious adverse events, such as infusion-related reactions and amyloid-related imaging abnormalities, in the Donanemab group compared to the placebo group, and treatment discontinuation due to adverse events was higher in the Donanemab group. The treatment is additionally linked to a greater decrease in whole brain volume and a greater increase in ventricular volume – observations that have been made with similar monoclonal antibodies but require further exploration and understanding.”
Professor Paresh Malhotra, Head, Division of Neurology, Imperial College London, and Consultant Neurologist, Imperial College Healthcare NHS Trust, said:
“The published results of the donanemab trial again show that treatments that remove the toxic protein amyloid from the brain can slow progression of Alzheimer’s Disease. Overall, this definitely good news. It is important to stress that donanemab does not improve symptoms but slows down deterioration. It should also be noted that the drug seems to be more effective at earlier stages of disease. And although the effect of the drug will be described as being about a third, it consists, on average, of a difference of about 3 points on a 144 point combined scale of thinking and daily activities. If the drug is approved in the UK, then NHS services will need to adapt considerably to provide it and there will need to be honest discussion between patients, carers, and doctors about the benefits and risks associated with this type of treatment. But overall, having drugs that slow progression is a very, very significant step, should encourage researchers to develop and test more treatments, and should help change the way we all think about Alzheimer’s Disease.”
Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said:
“Dementia is the biggest killer in the UK and over 60% of people living with dementia are thought to have Alzheimer’s disease. This is truly a turning point in the fight against Alzheimer’s and science is proving that it is possible to slow down the disease. Treatments like donanemab are the first steps towards a future where Alzheimer’s disease could be considered a long-term condition alongside diabetes or asthma. People may have to live with it, but they could have treatments that allow them to effectively manage their symptoms and continue to live fulfilled lives.
“Today’s full results support what we heard about donanemab back in May, that the drug is able to slow down the progression of Alzheimer’s disease by more than 20%. This study adds to the growing evidence that treating people as early as possible may be more beneficial, with the effects of donanemab greater in people who were at an earlier stage of the disease.
“Diagnosis will be key to the access of any new treatments. We can’t have a situation where treatments are approved for use in the UK but people aren’t diagnosed early or accurately enough to be eligible. We need early, and accurate, diagnoses available for everyone and the NHS ready to roll out treatments such as donanemab and lecanemab if and when they are approved in the UK.
“It’s also important to note that side effects did occur, although serious side effects only occurred in 1.6% of people receiving the drug. Regulators will need to balance these side effects against the benefits of the drug. We should also note that the majority of people who took part in this trial were white – it’s crucial that in future trials we see more diversity to prove that new drug treatments have similar effects for everyone living with Alzheimer’s disease.
“Just as we’ve seen a transformation in cancer treatment in recent decades, we’re really hopeful we’re on the same path for dementia. We’re so proud that research Alzheimer’s Society funded 30 years ago led to the breakthroughs we’re seeing today, and the research we’re funding now will be pivotal in unlocking more breakthroughs.
“We will only see progress in clinical trials for new treatments if people from all backgrounds have the opportunity to join them. It’s not all about taking new drugs or having invasive tests, some trials are as simple as answering surveys and anyone over 18 in the UK can sign up. If you would like to know more, search ‘Join Dementia Research’ or visit Alzheimer’s Society’s website.”
Prof Sir John Hardy, Professor of Neuroscience and Group Leader at the UK Dementia Research Institute, University College London (UCL), said:
“The successful outcome of the Eli Lilly’s anti-amyloid antibody donanemab is great news for Alzheimer’s disease and confirms the positive and similar outcome for Eisai’s lecanemab trial late last year. The results are very similar, and that in itself is reassuring. Disease progression is slowed about 30%, but it too has occasionally serious complications which require monitoring. The basic scientists now need to work to understand what we need to do to stop the disease rather than just slow it, but the major immediate task will be to organise NHS Alzheimer provision to be able to use these therapies.”
Dr Susan Kohlhaas, Executive Director of Research & Partnerships at Alzheimer’s Research UK, said:
“Today’s announcement marks another milestone. Thanks to decades of research, the outlook for dementia and its impact on people and society is finally changing, and we’re entering a new era where Alzheimer’s disease could become treatable.
“As a potential first-generation treatment, donanemab’s effects are modest. But these results provide further confirmation that removing amyloid from the brain can change the course of Alzheimer’s, and may help people affected by this devastating disease if they’re treated at the right time. Set against this, it’s clear that donanemab does come with side effects, which for some can be very serious. Regulators will need to balance these benefits and risks before it is given a license for use.
“People living with Alzheimer’s deserve access to safe and effective treatments urgently. That’s why Alzheimer’s Research UK has written to the drug’s manufacturer, Eli Lilly, calling on them to put donanemab forward for regulatory review in the UK without delay. And this review should be conducted by the UK regulators as a priority.
“Drugs like donanemab will also pose several challenges for the NHS, not least how people eligible to receive these treatments are identified, diagnosed and monitored. This will need collaborative and constructive dialogue between leadership at NHS England, drug manufacturers, the MHRA, NICE, the Association of British Neurologists, the Royal College of Psychiatrists and people affected by Alzheimer’s disease, to make sure any treatments that are licensed can be made available to those who might benefit without delay.
“These drugs are not perfect, but they are a big step in the right direction. We owe it to people living with dementia now, and to future generations, to use this moment to invest in future treatments that will transform the lives of people with dementia even more. We are working towards a cure, but we need more research, more people taking part in research, and more investment to get us there.”
‘Donanemab in Early Symptomatic Alzheimer’s Disease; The TRAILBLAZER-ALZ 2 Randomized Clinical Trial’ was published in JAMA at 10.15am ET time, 3.15pm UK time Monday 17 July 2023.
Prof Tara Spires-Jones: “I have no conflicts with the study.”
Dr Mark Hibberd: GE HealthCare offers a range of products and solutions to support the Alzheimer’s care area across diagnosis and monitoring, including an FDA-approved radiopharmaceutical that can detect, quantify and visualize beta amyloid in the brain.
Prof Gill Livingston: “I have no COI.”
Dr Nick Fox: “I have served on advisory boards for Roche/Genentech, Biogen, Lilly, Ionis, and Siemens – all fees paid to UCL; I served on a Data Safety Monitoring Board for Biogen”
Dr Liz Coulthard: “I have been paid for consultancy or providing educational resources by Eisai, Biogen, Lilly, Novartis and UCB, and I have received grant funding from Biogen.”
Dr Ivan Koychev: is in receipt of a research grant from Novo Nordisk investigating semaglutide in preclinical/prodromal Alzheimer’s disease. He has received speaker fees from Novo Nordisk. He is a paid medical advisor for digital healthcare companies developing solutions for detecting and intervening in dementia risk.
Dr Marc Aurel Busche: “I do not have a conflict of interest.”
Prof Paresh Malhotra: is Deputy Chair of the Alzheimer’s Society Research Council. He leads a NIHR-funded Clinical Trial of a symptomatic treatment in Alzheimer’s Disease for which drug and placebo are provided by Takeda (formerly Shire) pharmaceuticals. He has received a speaker honorarium from GE. He carries out clinical work at Imperial College Healthcare NHS Trust and Cleveland Clinic London.
Prof Sir John Hardy: has consulted for Eli Lilly and Eisai
For all other experts, no reply to our request for DOIs was received.