The pharmaceutical company Novo Nordisk announced the top-line results from their evoke and evoke+ phase 3 trials, which tested the weight-loss drug semaglutide in people with early-stage symptomatic Alzheimer’s disease. The trials found that the drug did not demonstrate a statistically significant reduction in Alzheimer's progression.
The two trials were randomised, double-blinded, enrolled a total of 3808 adults and evaluated the efficacy and safety of oral semaglutide compared to placebo on top of standard of care.
Here, UK DRI researchers respond to the news.
Prof Sir John Hardy, Group Leader at the UK Dementia Research Institute at UCL, said:
“There is no mechanistic evidence linking Alzheimer’s disease and type 2 diabetes (see Hardy et al 2022) and on that basis, it would be expected that the anti-diabetic GLP-1 agonist would have no beneficial effect in AD. However, when drugs have been shown to be relatively safe, the bar towards testing them even in “long shot” trials is worth it and it is, of course, disappointing that this trial has failed. We do now have drugs (Dononamab and Lecanemab) which show some benefit and one might consider whether these should be the placebo treatments against which new drugs are tested.”
Prof Paresh Malhotra, Group Leader at the UK Dementia Research Institute Care Research & Technology Centre and Head of the Division of Neurology at Imperial College London said:
"These two linked trials show that, unfortunately, semaglutide appears to have no effect on progression in people with established Alzheimer’s disease, including people who have evidence of some damage to brain blood vessels. This is disappointing but it is very important that these trials have been carried out. By using clinically relevant outcome measures the investigators have taken the most robust approach to testing whether semaglutide was effective. It is essential that we continue to explore the most promising treatments, whether newly developed or ‘repurposed’ from other disease areas, and that we do this systematically and efficiently. We must try to give all people affected by Alzheimer's the opportunity to take part in clinical trials and other research as well as ensuring that we evaluate potential new treatments for every stage of the disease process.”
Prof Paul Morgan, Director of the UK DRI at Cardiff, said:
“The failure of semaglutide therapy to impact disease progression in patients with mild cognitive impairment and mild Alzheimer’s disease (AD) in the EVOKE phase 3 trials is, of course, disappointing but perhaps not surprising. The logic behind these trials was solid – diabetes and obesity are both significant risk factors for AD so a drug that impacts these risk factors might impact AD progression.
“One clear difference between the trials and real-life disease development is time. In the trials, subjects were treated for two years, while the impacts of obesity and diabetes on dementia likely accumulate over many years. As huge numbers of individuals are now taking these types of drugs to control diabetes or for weight loss it will be interesting to evaluate at a population level whether they have any impact on AD risk in the long term.
“Drug trials in AD are, because of the slowly evolving nature of the disease, expensive and time-consuming. This has made pharma reluctant to progress to clinical trials of potential new therapies, a situation improved in recent times with the success, albeit limited, of anti-amyloid drugs in slowing disease progression. I sincerely hope that the failure of semaglutide in a sensible and well-conducted trial does not further discourage future studies. We need new therapeutic approaches above and beyond the anti-amyloid drugs if we are to meaningfully impact AD progression and need to be able to test these when the evidence supports.”
Prof Tara Spires-Jones, Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, Group Leader at the UK DRI at Edinburgh, and Past President of the British Neuroscience Association said:
“Novo Nordisk reported that semaglutide failed to slow the progression of Alzheimer’s disease in two well-conducted phase III clinical trials. While these results will be disappointing for people living with dementia, the company reported that treatment did improve Alzheimer’s-related biomarkers leaving open a tiny window of hope that in future this drug might be effective if used earlier as a preventative strategy. Diabetes and obesity are both associated with increased risk of developing Alzheimer’s, and these conditions are effectively treated by GLP-1 drugs including semaglutide. Future trials are needed to confirm whether GLP-1 drugs might be effective in preventing Alzheimer’s disease.”
Declared interests:
Prof Sir John Hardy: I have consulted for Eisai and Eli Lilly
Prof Paresh Malhotra: I receive research funding from NIHR, MRC, Dementia Platforms UK, Alzheimer’s Research UK, the Football Association, British Heart Foundation and Alzheimer’s Society. I am a Trustee for Alzheimer’s Society, Group leader of the UK Dementia Research Institute, and am the National Specialty Lead for Dementia and Neurodegeneration in the NIHR Research Delivery Network. I have sat on two NHS England policy working groups looking at diagnostic pathways and delivery issues relating to lecanemab treatment for Alzheimer’s Disease. I practise clinically at Imperial College Healthcare NHS Trust and also carry out a fortnightly private clinic at Cleveland Clinic London.
Prof Paul Morgan: No 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, 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.
Links