The European Medicines Agency (EMA) has recommended market approval for Alzheimer’s antibody Leqembi (lecanemab), reversing its previous recommendation.
The treatment from Biogen and Eisai was approved in 2023 in the US and Japan, after studies showed that it can slow progression of the disease. It does this by removing amyloid plaques from patient’s brains. But European regulators decided that the observed delay in cognitive decline did not outweigh the risks of serious side effects, especially various types of brain swelling and bleeding, collectively called amyloid-related imaging abnormalities (ARIA) because of their appearance on brain scans.
The reversal came after a re-examination of trial data – requested by Eisai – that removed the data of patients with two copies of Apoe4, a gene that has been linked to greater risk of Alzheimer’s and younger age at onset. Patients with one or no copies of Apoe4 were less likely to experience ARIA side effects.
The EMA has now recommended Leqembi for this subset of patients, with MRI scans to monitor for ARIA before and regularly during treatment. No deaths from ARIA were reported during the 18-month clinical trial, but some deaths have been reported in the US since.
I’m happy that we in Europe are not now being put in a kind of waiting room, watching what happens in the rest of the world
Bart De Strooper, University College London, UK
The move in Europe was praised by patient organisations such as the Alzheimer’s Association and Alzheimer Europe. ‘I’m happy that we in Europe are not now being put in a kind of waiting room, with clinicians and researchers like me watching what happens in the rest of the world,’ says Bart De Strooper, a neuroscientist at University College London, UK, and the Crick Institute.
Experts across the Alzheimer’s community have strong, often opposing, views about Leqembi and related anti-amyloid antibodies. ‘The drugs are effective at removing amyloid from the brain,’ says Seb Walsh, public health researcher at the University of Cambridge, UK. ‘But the effects on people’s cognition and quality of life are small.’
He says that those selected in the drug trial were at the earliest stages of cognitive symptoms, when the illness progresses quite slowly. ‘After 18 months of treatment, a doctor would not be able to tell the difference between the average person on the drug and the average person on placebo,’ suggests Walsh.
The drugs are effective at removing amyloid from the brain, but the effects on people’s cognition and quality of life are small
Seb Walsh, University of Cambridge, UK
De Strooper acknowledges that the drugs are far from perfect, but he believes the EMA’s advisors mainly have late-stage Alzheimer’s in mind. ‘People like me are more thinking about the pre-clinical phase of Alzheimer’s, where we want to prevent further degeneration,’ he explains. That would require earlier diagnosis and screening, as well as more stratified studies to narrow down populations of patient who would benefit most from the treatment.
Walsh raises concerns that the population that is likely to benefit from the drug is quite small. ‘Only about 8% of people with early Alzheimer’s in the community would have met the eligibility criteria [for the clinical trials],’ he says. He and others also have concerns over long-term adverse effects for a drug that would need to be taken for long periods. He also worries about enormous diversions of resources to screen and deliver the treatment.
While Lecanemab was approved in the UK in August, the National Institute for Health and Care Excellent (Nice) concluded that it does not represent good value, meaning it will not be provided by the National Health Service. It noted the high costs of providing the treatment, ‘including fortnightly infusions in hospital and intensive monitoring for side effects, combined with relatively small benefits’.
This disappointed De Strooper. ‘The UK has made a very narrow-minded decision based on money only and has not gotten a bigger vision of improving diagnostics and trying to find out which part of their population could be helped,’ he says.
More antibodies are on the way. Eli Lilly has submitted its antibody donanemab for regulatory approval after positive phase 3 results. It received marketing approval by the US FDA in July, then Japan, and the UK.
There is also optimism around trontinemab, an amyloid-clearing antibody from Roche paired with technology to cross the blood-brain barrier, with positive interim results from early trials in Alzheimer’s patients.
Walsh remains concerned about perceptions, and wants ‘to temper some of the headlines in UK newspapers about miracle and wonder drug. We felt it is giving false hope to patients,’ he concludes.
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