Cambridge experts question efficacy and practicality of new amyloid immunotherapy drugs

Cambridge researchers have raised doubts about whether new amyloid immunotherapy drugs will have the desired effect of significantly reducing the impact of Alzheimer’s disease.

Writing in the diary Alzheimer’s and Dementia: The Journal of the Alzheimer’s Associationthe Cambridge Public Health team argues that substantial challenges, including the risk-benefit ratio, limited eligibility and the high cost of rollout, will limit the benefits of these treatments.

It is often cited that Alzheimer’s disease is responsible for 70% of the 55 million cases of dementia worldwide, although the definition of what constitutes the disease is hotly debated. A hallmark of Alzheimer’s disease is the buildup of clusters of misfolded proteins, one of which is a form of amyloid, leading to plaques in the brain. The cascade hypothesis, a dominant theory in this field, suggests that this sets in motion a series of processes that together lead to symptoms of dementia.

Progress in developing treatments to reduce symptoms and slow progression in the early stages of Alzheimer’s disease has been slow. However, there has been a lot of excitement recently surrounding amyloid immunotherapy agents, drugs that harness the immune system to eliminate amyloid pathology.

Two completed phase III randomized controlled trials of amyloid immunotherapy reported statistically significant reductions in the rate of cognitive and functional decline compared to placebo.

But as the Cambridge team notes, the effect sizes were small – small enough that a doctor would have difficulty telling the difference between the average decline of a patient taking the drug and that of another patient taking placebo, after 18 months . The drugs were also associated with significant side effects, including swelling and bleeding of the brain; During the phase III trial of one agent, donanemab, three deaths were also attributed to the treatment.

Crucially, little is known about the long-term effects of the drugs beyond the 18-month trial periods. Long-term placebo-controlled trials, which would be necessary to see if there is any clinically meaningful slowing of decline, are unlikely to be feasible if drugs have already been approved.

Despite this, the US Food and Drug Administration has licensed two such drugs. The European Medicines Agency (EMA) has recommended rejecting one drug (lecanemab), mainly on the grounds that the observed small effects do not outweigh the risk of side effects; it judges the other. The UK Medicines and Healthcare Products Regulatory Agency (MHRA) is expected to make a decision on both drugs soon.

Edo Richard, Professor of Neurology at Radboud University Medical Center in Nijmegen, Netherlands, and co-author, said: “If these drugs are approved by regulators in Britain and Europe, and become available, it is understandable that some people with early Alzheimer’s patients will still want to try these drugs, given their desperation at living with this terrible disease. But there is a lot of exaggeration surrounding the reporting of these drugs, and significant efforts will be needed to provide balanced information to patients to enable informed decisions.

Press coverage of the drugs has suggested that they are suitable for anyone diagnosed with Alzheimer’s. Although the studies also included people with “early symptomatic Alzheimer’s disease,” they excluded people with other conditions that may have contributed to their symptoms. Evidence suggests that the people in the studies represent less than 8% of those in the community with early Alzheimer’s disease. Those who participated in the studies were up to 10 to 15 years younger than those who typically presented to health care with early symptoms.

Lead author Dr. Sebastian Walsh, NIHR Doctoral Fellow in Public Health Medicine at Cambridge Public Health, University of Cambridge, added: “If approved, the drugs are likely to only be relevant to a relatively small cohort of Alzheimer’s patients, so potential recipients will need to consider a ​undergo a series of assessments before being given access to the medicines, the effect sizes observed in the studies are very small and the medicines will need to be administered as early as possible in the disease process, when symptoms are mild – and in people who suffer from them . disease stages can be difficult to identify.”

The resources required to roll out such treatments are likely to be significant. Even if approval only covers a small proportion of Alzheimer’s patients, a much wider group of people will need to be assessed for eligibility, requiring rapid specialist clinical assessment and testing. The authors question whether this is the best use of these resources, given the pressures healthcare systems are already experiencing. Support would also be needed for the large number of Alzheimer’s patients (possibly as many as 92%) who would not qualify. Those found to have insufficient amyloid to qualify may then require follow-up assessments to determine future eligibility, with the further implications for services this would entail.

Even in high-income countries, rolling out these types of treatments on a large scale is a major challenge, but most dementia occurs in low- and middle-income countries. It is very unlikely that the healthcare systems in these countries have the resources necessary to offer these new medicines, even to a very small group.

Other compelling evidence suggests that focusing on inequalities and health experiences across people’s lives could have a greater impact on rates of dementia in the population. Most dementia is more complicated than a single protein.”

Professor Carol Brayne, co-director of Cambridge Public Health

The team concludes that based on current evidence it is far from clear whether amyloid immunotherapy can ever reduce the suffering caused by dementia on a large scale in the community, and that we should continue to explore other approaches.

Professor Brayne added: “With an aging population we urgently need effective ways to support people with dementia, but while current amyloid immunotherapies may hold promise for very select groups, it is clear that these drugs can increase the risk of dementia. will not tackle on a large scale. .”