Scientists from Cambridge University have cast doubt on the efficacy and long-term benefits of two new drugs for Alzheimer’s disease, highlighting “concerning” side effects, small proven benefits and challenges in their administration.
Lecanemab and donanemab, are the most recent medicines to enter the market to treat Alzheimer’s, a disease which is more prevalent in older people. With populations increasingly aging, there is a huge need to find effective treatments for the disease. But the researchers question whether these drugs will have any great impact.
“Based on current evidence, it is far from clear whether [these types of therapies] can ever significantly reduce population-level dementia morbidity at scale,” they write.
Both drugs target a protein called amyloid that builds up to form plaques in the brain. Some scientists hypothesize that these plaques are one of the main causes of Alzheimer’s disease.
Alzheimer’s is the most common form of dementia, accounting for up to 70 percent of the more than 55 million cases worldwide, according to the World Health Organization. Dementia is currently the seventh leading cause of death among older people globally.
Late-stage trials of the two drugs showed that they slowed the progression of Alzheimer’s disease. For donanemab, developed by Eli Lilly, participants in a Phase 3 trial who received the drug showed a 22 percent to 29 percent slowing in cognitive decline after 76 weeks, compared to those who received a placebo.
For lecanemab, developed by Japan’s Eisai and U.S. biotech Biogen, those who received the drug declined 1.21 points on an 18-point cognition scale, while those who received the placebo declined 1.66 points, the companies the companies reported.
But the latest analysis, published on Tuesday in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, points out that the absolute effect sizes were small and “clearly below previously established thresholds of the minimum clinically important difference.”
Additionally, the researchers point out that the potential side effects to both drugs are “concerning” and “frequent.”
Around three in every 10 people using the treatment experienced brain edema and/or hemorrhage, the researchers report: 21.5 percent of those taking lecanemab and 36.8 percent of those using donanemab, compared with 9.5 percent and 14.9 percent for the respective placebo groups. Three participants who received donanemab died during the trial, which researchers at Lilly viewed as likely a result of receiving the drug.
Long-term effects of the drugs beyond the 18-month trial period are also unknown, and there are challenges for health systems, as roll out of treatment will involve “considerable resources including personnel, with profound opportunity costs.” That includes multiple tests to identify those who are eligible and frequent hospital visits for infusions and follow-up care.
“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,” said Carol Brayne, co-director of Cambridge Public Health, which conducted the study.
In addition, only a relatively small cohort of Alzheimer’s patients would be eligible for treatment, lead author Sebastian Walsh, NIHR doctoral fellow in public health medicine at the University of Cambridge, said.
“Diagnosing early Alzheimer’s disease can be challenging for many reasons, including a reluctance to discuss symptoms due to fear and stigma, and limited access to effective testing,” Eisai told POLITICO in a statement. “For change to happen, health systems and society must adapt to newer models of care that recognize the value of early diagnosis.”
Eisai also said the company is “dedicated to collecting ongoing and long-term efficacy and safety data for lecanemab.”
Eli Lilly and Biogen could not immediately be reached for comment.
These drugs have also divided regulators.
The U.S. Food and Drug Administration approved lecanemab last year and donanemab this year. Last month, however, the European Medicines Agency opposed a license for Leqembi — the brand name for lecanemab — arguing that the small benefits of the drug on delaying cognitive decline did not outweigh the risk of serious side effects.
The U.K.’s drugs regulator, the Medicines and Healthcare products Regulatory Agency (MHRA), is still assessing lecanemab with a decision expected imminently.
“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,” said co-author Edo Richard, a professor of neurology at Radboud University Medical Centre in Nijmegen, the Netherlands. “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,” Richard said.
“Few in the research community ever believed that the recent amyloid-targeting medicines would be the ultimate solution to Alzheimer’s disease,” Mark Dallas, associate professor in cellular neuroscience at the University of Reading, U.K., said. The Cambridge study highlights the limitations of these therapies and underscores the “urgent need for alternative strategies to improve the lives of those living with dementia,” he added.
But others stress that the drugs still play a significant role in the fight to find a treatment for Alzheimer’s.
“We do not yet know whether longer-term treatment will continue to cause treated and placebo curves to diverge … but we now have disease modifying therapy and it would be unfortunate if those in the UK who would benefit from this therapy had to fly to the US to receive it,” John Hardy, professor of neuroscience and group leader at the U.K. Dementia Research Institute at University College London (UCL), said.
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