Researchers at the University of Cambridge have cast doubt on whether new amyloid immunotherapy drugs will have the desired effect of significantly reducing the impact of Alzheimer’s disease.
The team from Cambridge Public Health argue that substantial challenges including the risk-benefit ratio, limited eligibility and high cost of roll-out will limit any benefits of these treatments.
Dr Sebastian Walsh, NIHR Doctoral Fellow in Public Health Medicine at Cambridge Public Health, University of Cambridge, is the study’s lead author:
The researcher said: “If approved, the drugs are likely to be relevant only for a relatively small cohort of Alzheimer’s patients, so potential recipients will need to undergo a range of assessments before being given access to the drugs.
“Plus, effect sizes seen in the trials are very small and the drugs will need be administered as early in the disease process as possible, when symptoms are mild – and people in these phases of disease can be hard to identify.”
Alzheimer’s disease is often quoted as causing 70 per cent of the 55 million cases of dementia worldwide, though the definition of what constitutes the disease is hotly debated.
One characteristic of Alzheimer’s is the build-up of clusters of misfolded proteins, one of these being a form of amyloid, leading to plaques in the brain.
The cascade hypothesis, a dominant theory in the field, suggests that this triggers a series of processes which together lead to dementia symptoms.
Advances in developing treatments to reduce symptoms and slow down the progression in the early stages of Alzheimer’s has been slow.
However, there has been recent excitement surrounding amyloid immunotherapy agents, drugs that harness the immune system to remove amyloid pathology.
Two completed phase III randomised controlled trials of amyloid immunotherapy reported statistically significant reductions in the rate of cognitive and functional decline compared to the placebo.
But as the Cambridge team point out, the effect sizes were small – small enough that a doctor would struggle to tell the difference between the average decline of a patient on the drug and another on placebo, after 18 months.
The drugs were also associated with significant adverse events, including brain swelling and bleeding; during the phase III trial of one agent, donanemab, there were also three deaths attributed to the treatment.
Crucially, there is little known about the long-term effects of the drugs beyond the 18 month trial periods.
Long-term placebo-controlled trials, which would be needed to see if there is any clinically meaningful slowing of decline, are unlikely to be feasible where drugs are already approved.
Despite this, the US Food and Drug Administration has licensed two such drugs.
The European Medicines Agency (EMA) has recommended rejecting one (lecanemab) predominantly on the grounds that the small effects seen do not outweigh the risk from side effects; it is reviewing the other. The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) is expected to take a decision on both drugs imminently.
Edo Richard, Professor of Neurology at Radboud University Medical Centre in Nijmegen, The Netherlands, and co-author, said: “If these drugs are approved by regulators in the UK and Europe, and become available, it is understandable that some people with early Alzheimer’s will still want to try these drugs, given their despair living with this dreadful disease.
“But there is a lot of hyperbole around the reporting of these drugs, and significant effort will be needed to provide balanced information to patients to enable informed decisions.”
Press coverage of the drugs has implied they are suitable for anyone with a diagnosis of Alzheimer’s.
However, while the trials included those with ‘early symptomatic Alzheimer’s disease’, it excluded those with other conditions that may have been contributing to their symptoms.
Evidence suggests that the people in the trials represent less than 8 per cent of those in the community with early Alzheimer’s disease.
Those in the trials were up to 10 to 15 years younger than those typically presenting to health services with early symptoms.
The resource requirements for rolling out new treatments are likely to be considerable, explained Professor Carol Brayne, Co-director of Cambridge Public Health.
The researcher said: “Even in high-income countries, rolling out such types of treatments at scale is highly challenging, but most dementia occurs in low- and middle-income countries”
Professor Brayne added: “With an ageing population, we urgently need effective ways to support people living with dementia, but while the current amyloid immunotherapies may show a glint of promise for very selected groups, it’s clear these drugs will not address dementia risk at scale.”
