The ground-breaking new Alzheimer’s drugs – and when they are likely to be available in the UK
Hundreds of thousands of people in the UK with Alzheimer’s disease, the most common form of dementia, may stand to benefit from two ground-breaking new drugs in the coming years, which represent the first glimmers of hope for tackling this devastating disease.
On Monday, the US pharmaceutical company Eli Lilly released the results of a Phase III trial called TRAILBLAZER-ALZ 2 for a drug called donanemab which they tested on 1,736 people with mild symptoms of Alzheimer’s disease. Published in the Journal of the American Medical Association, it was found that donanemab slowed the rate of cognitive decline by 35 per cent over the course of 18 months.
This latest breakthrough follows swiftly on from the success of another drug called lecanemab, made by Japanese company Eisai, which was found to slow cognitive decline in early-stage Alzheimer’s patients by 27 per cent in a clinical trial last year. Lecanemab has recently been greenlighted for clinical use by regulators in the US.
Jonathan Schott, a neurology professor at the Dementia Research Centre, University College London, described the findings as a “turning point” in Alzheimer’s treatment, comparing it to similar breakthroughs which have been made in treating stroke and multiple sclerosis in recent years.
“The bigger picture here is that after many, many years of failed trials, we now have two agents, which are both able to make fundamental changes to the biology of Alzheimer’s disease,” says Schott. “Both of them have an impact on cognitive function for patients, and that in itself is an incredibly exciting development.”
But neither of these drugs are available yet in the UK. To be able to get them to large numbers of patients in the future, Schott and others feel that radical changes will need to happen within the NHS, particularly investments in diagnostic technologies which can identify people in the earliest stages of the disease.
So, if you or a member of your family has been diagnosed with Alzheimer’s, what does the emergence of these new drugs mean for you?
What are donanemab and lecanemab and how do they work?
Both drugs are injectable antibodies which target and remove amyloid, a sticky protein which forms toxic clumps in the brains of Alzheimer’s patients. Without intervention, amyloid contributes to cognitive decline by slowly destroying the brain’s neurons over time. For the past three decades, this has been the main theory for how Alzheimer’s disease progresses.
“Amyloid can be just one piece at a time, or it can form clumps of different sizes,” explains Percy Griffin, director of scientific engagement for the Alzheimer’s Association. “Lecanemab goes after smaller clumps, and donanemab goes after the biggest sized clumps.”
Both drugs are administered through regular infusions. Lecanemab is the most intensive, requiring infusions every two weeks, while donanemab involves monthly infusions. Because these two drugs were assessed in separate clinical trials on different patient populations, Griffin says it is still too early to say whether one is more effective than the other, but their success has emanated from the failures of previous amyloid-targeting compounds such as another drug manufactured by Eli Lilly called solanezumab.
“These trials build on the learnings of so many others that have brought us to this point,” he says. “It was the trial of solanezumab that informed us that you need a higher dose of these antibodies to get them into the brains of people.”
Griffin was particularly encouraged by the finding that 52 per cent of the patients in the TRAILBLAZER-ALZ 2 trial were able to cease donanemab treatment altogether after one year because sufficient amounts of amyloid had been cleared from their brains.
However, these drugs do not halt cognitive decline altogether. Because Alzheimer’s disease is thought to be driven by a complex mixture of factors, Griffin predicts that in the future these drugs could represent the first stage of a multi-pronged treatment approach.
“Patients could be on treatment for some time and once all the amyloid is gone, they could be taken off the drugs and monitored, or potentially given other treatments that target other aspects of Alzheimer’s biology,” he says.
Who will benefit most from donanemab and lecanemab?
Only a proportion of patients with Alzheimer’s disease will be eligible for one of these drugs. In some cases this will be down to practical limitations – patients will need to be able to travel regularly to an infusion centre to receive the medication – but there are also scientific reasons for why only certain people will benefit.
Schott says that patients will likely require a molecular diagnosis of Alzheimer’s confirming that they have deposits of the amyloid protein within their brain along with another disease-causing protein known as tau. Simply presenting with symptoms of memory loss will not be sufficient.
Right now, a molecular diagnosis can only be achieved through more costly procedures such as an examination of the cerebrospinal fluid or a form of imaging known as PET scanning. However it is hoped that blood tests will soon be available which will make these cheaper and less cumbersome for healthcare systems.
“The evidence also seems to be quite clear that the people who benefit most are those with mild symptoms,” says Schott. “So we will need people to come forward and be recognised at an early stage.”
Neither drug is free from side effects. 36.8 per cent of the patients who received donanemab experienced brain bleeds, while brain swelling was also observed in the trial. Three patients in the trial died as a consequence of taking the medication.
Schott says that one of the next steps for researchers will involve understanding which patients are more vulnerable to experiencing adverse effects than others.
“People are going to need to be carefully selected,” he says. “For example, if they are already taking anticoagulant drugs for other conditions, they might be more prone to side effects. They will need to have regular MRI scans which need to be read by experts to try and find those signs early. We need to be hyper-vigilant as we move into a more community-based setting to make sure that we’re not doing more harm than good.”
When will these drugs be available on the NHS?
While lecanemab has already been approved by the US Food and Drug Administration, it is still far from guaranteed that either will be made freely available on the NHS.
Both drugs will be initially assessed by UK medical regulators. If they are greenlighted, the National Institute for Health and Care Excellence (NICE) watchdog will conduct a further evaluation to determine whether they represent a cost-effective solution for the NHS.
This could prove to be a hurdle because neither drug will be cheap. Eisai announced in January 2023, that the launch price of lecanemab in the US will be $26,500 (￡20,470) per patient.
“Then on top of that, you need to think about the scanning and monitoring costs: these will all need to be weighed up,” says Schott. “But the cost of dementia to the United Kingdom is enormous. It’s by no means certain that NICE will grant approval but there is a huge unmet need here and there will be a lot of pressure on governments with an elderly population to make these drugs available.”
Some researchers, such as Matthew Schrag, a neurologist at Vanderbilt University, have openly questioned whether their ability to slow the rate of cognitive decline is significant enough to warrant making them widely available, particularly in the context of the side effects.
However, the donanemab trial still found that 47 per cent of patients with early Alzheimer’s had no further disease progression on some cognitive tests after one year. Tara Spires-Jones, professor of neurodegeneration at the University of Edinburgh, says that for many patients and their families, being able to perform different day-to-day tasks for just a little bit longer would make a considerable difference.
“They’re slowing the disease process moderately which is amazing because before we didn’t have anything,” she says. “I do know from talking to people, even if it is not a huge effect, it brings a lot of hope. At least being able to say, we might be able to slow it down a bit, it’s very hopeful.”
What changes would the NHS need to make in order to support these drugs?
Being able to identify patients early is crucial to being able to make the most of these drugs, but according to North London GP Semiya Aziz, many GPs lack the resources necessary to spot signs of the disease.
“Generally GPs have found it extremely difficult to diagnose patients with Alzheimer’s disease,” she says. “There are several reasons why. GPs have time constraints of only 10-15 minutes, making it virtually impossible to carry out a detailed history and cognitive assessment.”
In a new paper published in Lancet Neurology, Schott says that the NHS would need to adapt in a number of ways for as many patients to be able to benefit from these drugs as possible.
“We need to upscale everything,” he says. “We’re going to need more infusion centres. There’s a King’s Fund report which looks at the number of MRI and PET scans in this country compared to other OECD [Organisation for Economic Cooperation and Development] countries, and the UK is really very far down the bottom of that list. So we need more of those facilities, and we’re going to need more radiographers to read the PET and MRI scans. So really we’re going to need some very radical shifts.”
One technology that could aid the rollout of Alzheimer’s drugs is the emergence of novel blood tests which can detect the presence of disease-causing proteins. This week, private clinics in Hong Kong have unveiled the PlasmarkAD test which can stratify people into three Alzheimer’s categories – high risk, low risk and somewhere in between. It is expected to be the first of many such tests in the coming years.
“There’s no question that we will be moving towards blood tests in clinical practice fairly soon,” says Schott. “In research settings now we’ve got blood tests that are able to predict whether somebody has the amyloid protein within the brain with more than 90 per cent accuracy. Testing will be available within the next couple of years.”
Schott and others are preparing for clinical studies which will aim to show how blood tests could be used in clinical practice, in memory clinics around the UK. However Aziz feels that there will still be considerable practical problems when it comes to implementing such tests.
“Although this sounds promising, it is not as straightforward as it may seem,” she says. “Implementing a simple blood test to assess Alzheimer’s in general practice would simply be impossible as currently the NHS does not have the infrastructure to process, interpret and then refer for appropriate treatment.”
What is the future for Alzheimer’s treatments?
According to Julie Williams, director of the UK Dementia Research Institute at Cardiff University, lecanemab and donanemab represent the beginning of a coming wave of new treatments which will attempt to tackle different aspects of Alzheimer’s.
“It’s a step forward, but it’s addressing just a single component of a multi-component disease,” she says. “Alzheimer’s is complicated and a combination of a number of things going wrong at the same time.”
Griffin predicts that in future, Alzheimer’s disease will be treated in a similar manner to cancer or cardiovascular disease, with a combination of different medicines.
“We’re not stopping here,” he says. “We’re going to continue investigating other targets, so things like inflammation that changes the brain, changes to the blood vessels in the brain which make them become frail, also changes to metabolism. We need to target this disease from all angles. These drugs are our first in class, we’ll then get our best in class, and then we’ll get combination therapies.”
Another future possibility is that drugs like lecanemab and donanemab might be used as preventative treatments before people begin to develop symptoms of memory loss and cognitive decline at all.
A study known as the British 1946 Birth Cohort found that around 20 percent of people around the age of 70 in the UK already have significant amyloid accumulation within the brain. Eli Lilly are currently recruiting cognitively normal individuals between 65 and 80, who have evidence of abnormal amyloid levels in a blood test, for a new trial called TRAILBLAZER-ALZ 3 which will investigate whether donanemab can prevent them from cognitive deterioration.
“Most of us feel that these drugs have the most benefit during the period of time which we know extends for a decade or more, when people are accumulating amyloid within the brain, before symptoms arise,” says Schott. “So identifying those people and treating them then, that’s where we may head in the future. We would need to be able to accurately predict who has amyloid within the brain and will go on to get dementia, and do trials to show that treating them at that stage has benefits which are cost-effective without significant risks. So that is some way off, but that may well be the direction of travel in the years to come.”
