To rephrase a well-known saying, you wait decades for an Alzheimer’s breakthrough to come along, and then two potential new drugs that could slow the progression of the disease are unveiled within months of each other.
This week American pharmaceutical company Eli Lilly reported its donanemab drug has shown positive results in a late-stage trial, slowing the progress of cognitive decline in patients with early symptomatic Alzheimer’s by 35%.
According to the Indianapolis headquartered firm, the experimental drug also resulted in 40% less decline in the ability of the 1,736 patients involved in the trial, to perform activities of daily living, such as managing finances, driving, engaging in hobbies, and conversing about current events.
Almost half (47%) of those on donanemab had no clinical progression of disease at one year compared with 29% on placebo (defined as no decline in the commonly-used Clinical Dementia Rating Scale Sum of Boxes score).
Furthermore, Eli Lilly said participants on donanemab experienced a 39% lower risk of progressing to the next stage of disease compared to placebo.
It wasn’t all good news. Two volunteers – and possibly a third – died as a result of swelling in the brain.
But the announcement has come less than six months after lecanemab hit the headlines as a game changer in the treatment of Alzheimer’s – the first new such drug for 20 years.
Like lecanemab – which was approved by the US Food and Drug Administration (FDA) in January this year – donanemab is an antibody similar to those the body makes to fight viruses.
But these two drugs have been engineered to clear a protein called beta-amyloid, which forms sticky plaques on the brain, leading to nerve cell death. It has been strongly implicated in Alzheimer’s disease.
Based on its own results, Eli Lilly has indicated it plans to file for approval for donanemab with the FDA within weeks.
With one in nine of the world’s population aged 65 and over currently living with Alzheimer’s, finding a cure has become the pot of gold for scientists.
Until now, existing drugs have only been able to treat Alzheimer’s symptoms, not the root cause of this harrowing disease which slowly erodes a person’s memories, comprehension, judgement, and eventually even their ability to function.
According to the UK-based Alzheimer’s Society, there are currently 141 drugs being tested in clinical trials for the treatment of the disease. Of these, 78% are intended to try and slow the progress of Alzheimer’s.
So does donanemab mark the “significant step forward for people with early symptomatic Alzheimer’s disease” that Eli Lilly believes?
Here some of the world’s leading Alzheimer’s experts share their views on this latest disease-modifying treatment.
Maria Carrillo, the American Alzheimer’s Association’s chief science officer:
“These are the strongest phase 3 data for an Alzheimer’s treatment to date. This further underscores the inflection point we are at for the Alzheimer’s field. The progress we’ve seen in this class of treatments, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease.”
She said she looked forward to additional data, and if consistent with what had already been announced regarding donanemab’s efficacy and safety, supported FDA approval.
Dr Jina Swartz, chief medical officer at Exciva, a clinical stage biopharmaceutical company focused on delivering an innovative treatment to address symptoms of Alzheimer’s patients, headquartered in Heidelberg, Germany:
“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 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):
“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.”
“After 20 years with no new Alzheimer’s drugs, we now have two potential new drugs in just 12 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.
“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.”
Dr Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, launched in 1998 by co-chairmen Leonard A. Lauder and Ronald S. Lauder of the Estée Lauder Companies cosmetics family:
“This is very encouraging news for the millions of patients and families suffering from Alzheimer’s disease. These data are another proof point that amyloid-targeting drugs are a first step to slowing cognitive and functional decline, providing a clinically meaningful benefit to patients.
“Based on our understanding of the biology of aging, we know the accumulation of misfolded proteins is one pathway, among others, that contributes to the onset of Alzheimer’s. Our job now is to develop the next generation of drugs that can target all these pathways and be used in combination with one another for a precision medicine approach enabled by new biomarkers.
“While the results from this trial are highly significant, further progress is needed to achieve 100% slowing of cognitive decline.”
Dr Marc Busche, UK Dementia Research Institute group leader, University College London (UCL):
“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 at the 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.”