‘Breakthrough’ Alzheimer’s drugs can shrink brain, scientists warn

‘breakthrough’ alzheimer’s drugs can shrink brain, scientists warn

Alzheimer’s

The Alzheimer’s drugs touted as a turning point in the fight against the disease can cause the brain to shrink, scientists have warned.

Lecanemab and donanemab are two drugs that have been hailed as an Alzheimer’s breakthrough and work by clearing out amyloid in the brain. Amyloid is the protein that aggregates on neurons and stops the organ working properly, causing dementia.

Data from the companies making the drugs, Eisai and Eli Lilly, respectively, shows a 27 per cent and 35 per cent slowing of cognitive decline in people with Alzheimer’s compared to a placebo.

But experts have raised concerns about side-effect data, which shows the drugs can cause the brains of patients to shrink by as much as the volume of three teaspoons.

Other serious side effects can include amyloid-related imaging abnormalities (ARIA), which are characterised by swelling and bleeding of the brain, and can be fatal. As many as a third of patients have ARIA and around 1 per cent have a serious case that is either fatal or requires hospitalisation.

Lecanemab has been given Food and Drug Administration (FDA) approval in the US but with a “black-box warning” that indicates the drug comes with a risk of extreme adverse effects.

UK decision expected soon

Neither of the drugs have yet been approved by UK regulators, but the decision from the Medicines and Healthcare products Regulatory Agency (MHRA) is expected as soon as next week, a year after the US FDA approved lecanemab.

Dr Madhav Thambisetty, a senior clinical investigator at the US National Institute on Aging, has called for more transparency of the safety data by the manufacturers.

Prof Rob Howard, of the University College of London Institute of Mental Health, said: “When I look at an MRI scan that shows ARIA, it reminds me of looking at MRI scans of patients who’ve had strokes or some sort of traumatic brain injury.

“Also, patients who’ve had these drugs, their brains seem to shrink faster than people who get placebo.

“Obviously, losing brain volume is something we’ve always regarded as being a very bad thing. It means that you have more neurons that have died and you’ve lost more capacity.

“The imaging data does seem to suggest that people are actually losing probably slightly more than a teaspoon full of brain.”

‘Three teaspoons of brain volume’

Dr Thambisetty said that study participants receiving the largest dose lost up to three teaspoons of brain volume.

Brain shrinkage has historically been a reliable indicator of Alzheimer’s itself and the reduction in volume following the drugs is cause for concern, the scientists say.

Both the drugs cost around £20,000 a year and are given as an intravenous drip, a process that takes about an hour, with lecanemab given every fortnight and donanemab once a month.

The lecanemab trial has led to three reported deaths, including one woman who had a 7cm haemorrhage and died in hospital.

For donanemab there were three deaths following ARIA and up to a third of people had brain bleeds and a quarter had swelling, with the majority asymptomatic.

Some individuals who suffered ARIA while on the drugs saw their cognitive ability deteriorate five times faster than an average Alzheimer’s patient not on the medication.

The scientists are calling for the companies to publish more information on the long-term status of the patients who had bleeds or swelling but no symptoms to enable clinicians, regulators and patients to be better informed of the risk-reward balance of these groundbreaking treatments.

Dr Thambisetty said there is clear evidence the drugs flush out amyloid very effectively, but warned it is still unknown if this translates into a noticeable improvement in the condition of a patient.

Slow down cognitive decline

The drugs slow down cognitive decline by around a third when compared to placebo and the relationship was statistically significant. However, this translates to an absolute improvement of just 0.45 points on a standard 18-point scale used to assess Alzheimer’s symptoms.

Dr Thambisetty told the American Association for the Advancement of Science annual meeting in Denver that an improvement is not noticeable by either patient or doctor until there is at least a one-point difference.

“The difference is absolutely, literally, too small to be noticeable by the patient or their doctor,” said Prof Howard. “It is about half the size of what that difference would be. It’s a sort of sleight of hand, the way that they’ve chosen to portray the results. It’s not what the data shows.”

Dr Alex Osborne, policy manager at the Alzheimer’s Society, said: “Regulators will decide this year whether donanemab and lecanemab will be approved for use in the UK.

“A drug will not become available in the UK without having strong evidence to show that it is both safe and effective as a treatment.”

A spokeswoman for Eisai said any volume loss in the brains of patients “was not associated with worsening in measured neurodegenerative outcomes”.

‘Managing the risks’

A spokeswoman for Eli Lilly said: “Brain volume change with potential Alzheimer’s disease therapies has broadly been observed though admittedly not well understood.

“Some experts believe it may be an effect seen on MRI resulting from amyloid plaque removal itself or from reducing inflammation in the brain.

“We are committed, and encourage others in the field, to also continue to initiate research to manage the risks for this class of agents.”

The scientists are also concerned that a move to diagnosing patients via blood tests for amyloid, and not taking into account cognitive assessments, could lead to people with no symptoms who may never develop Alzheimer’s, going on to take the drugs.

“Because the treatment has to be given really early I am extremely worried about the risks of people being misdiagnosed and being given a treatment that can’t help them and can only hurt them,” Prof Howard said.

“My anxiety is that there’s a population of people out there who, if they’re diagnosed because they’ve got amyloid present, might find themselves in a trial despite never developing dementia.

“I’m really worried about people like that who could not be helped at all by these treatments, only hurt. It’s all risk and no reward.”

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