Alzheimer’s ‘breakthrough’ is stalling: why a much-hyped drug is facing approval delays
IIt was heralded in news articles as a “breakthrough,” a “turning point” and a “gamechanger” for Alzheimer’s disease. Some experts even went so far as to call the drug, donanemab, the “beginning of the end” for the debilitating condition.
Pharmaceutical company Eli Lilly released data from a clinical trial in May 2023 that it said showed donanemab slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease by 35% over 18 months.
The findings prompted the head of Alzheimer’s Research UK and other experts to call on drug regulators to quickly approve the treatment for use in patients.
But despite reports from the The US drug regulator would approve donanemab “any day”.Instead, on March 8, the Food and Drug Administration (FDA) announced that it had postponed its decision.
The FDA said it wants an independent panel to further examine the data on donanemab’s safety and efficacy, with a decision now expected later in 2024. British, European and Australian regulators are also still reviewing the drug.
In a statement, Eli Lilly executive vice president Anne White said, “We are confident in donanemab’s potential to provide highly meaningful benefits to people with early symptomatic Alzheimer’s disease.”
“It was unexpected to learn that the FDA will convene an advisory committee at this stage of the review process, but we look forward to the opportunity to further present the (trial) results and place donanemab’s strong efficacy in the context of safety ,” she said. . “We will work with the FDA and community stakeholders to make that presentation and answer any questions.”
Dr. Timothy Daly, a dementia researcher at Sorbonne University in Paris, says the delay is no surprise to him.
He says the benefits of donanemab and similar much-hyped drugs, including aducanumab and lecanemab, have proven harder to quantify than their potential harm.
“This story of drug success comes with some very strong side effects,” Daly told Guardian Australia.
This is a type of drug known as novel monoclonal antibodies and they target amyloid proteins in the brain. Many researchers believe that the buildup of these proteins contributes to Alzheimer’s disease.
The drugs have been shown to lower amyloid levels in the brain. But about three in 10 people taking lecanemab or donanemab in clinical trials developed a condition known as amyloid-related imaging abnormalities, abbreviated as ARIA, a condition that can cause brain swelling or bleeding.
“Usually these appear to be small, without any symptoms, and follow-up scans show that they appear to have disappeared,” said Dr. Sebastian Walsh, a public health physician who studies dementia risk reduction at the University of Cambridge in Britain.
“In a small percentage of participants it appears to be much more severe, and there have been some deaths – especially among those taking blood-thinning medications.”
Some trial participants also experienced brain shrinkage – and the long-term effects of this are unknown.
‘It’s pure speculation’
In the donanemab study, patients who received the drug fell an average of 10 points on a 144-point scale that combined cognitive and functional scores. The placebo group that did not receive the drug dropped by 13 points.
This data was used by researchers to argue that the drug slowed cognitive and functional decline by “more than a third” and offered people “additional months” or “up to a year of life” without further disease progression.
Walsh says attempts to translate clinical data into terms more meaningful for people to understand mean the drug’s effects have been exaggerated in media reports.
“While it’s understandable that people want to come up with other ways to present these numbers, it still has to be scientifically valid,” he says.
“Those who have reported that it is ‘an extra six months in a senior position’ are on shaky ground scientifically, I think. The studies did not measure the recognition of a loved one, driving skills and all these things. Extrapolating in this way is not really justified by the evidence we have. It’s pure speculation.”
Professor of neurology at Radboud University Medical Center in the Netherlands, Edo Richard, told news channel Al Jazeera the drugs clearly “remove” amyloid proteins from the brain “very successfully.”
But a reduction in amyloid proteins does not necessarily lead to a slowing of cognitive decline, he said.
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Research into the disease over 25 years ago showed that amyloid proteins are present in the brains of people with dementia. But they are also found in people who do not have dementia and will never develop it, Richard told Al Jazeera.
While many drugs tested in the past have reduced amyloid levels, donanemab, aducanumab and lecanemab appear to be the first to also lead to a change in cognitive decline. But Richard claimed the change was “statistically significant, but clinically irrelevant”.
When the FDA approved aducanumab in 2021, three members of the FDA advisory committee who recommended against approval due to a lack of efficacy data resigned. One of the people who resigned described it as “probably the worst drug approval decision in recent US history.”
As for implementation, the US health insurance program Medicare said it would not cover it, and doctors have also been cautious and used the drug sparingly.
Australia’s regulator, the Therapeutic Goods Administration, ruled in June that there is “no evidence of clinically meaningful efficacy” of aducanumab.
A ‘collective despair’
In addition to the minimal meaningful clinical benefits of donanemab, patients must also receive the drugs by intravenous infusion at a medical clinic or hospital once every two to four weeks, at a cost of approximately US$26,500, or A$40,500, per year, plus regular therapy. to test. A lot is asked of vulnerable people and their families.
Those who participate in clinical trials are also a highly selective group. In the donanemab study, 1,320 participants with amyloid and early disease symptoms completed the study. Of every 10 people screened for eligibility for the studies, about eight were found to be ineligible.
In a commentary written for the conversationWalsh said that if, when prescribed in the real world, “drug eligibility is limited to trial eligibility, then very few people will qualify. If eligibility is broader, the already small effects will likely be even smaller and the side effects more pronounced.”
The Director of Internal Medicine and Clinical Epidemiology at Princess Alexandra Hospital in Queensland, Australia, Prof. Ian Scott, published an article in the February edition of the journal Age and Aging with similar concerns. He wrote that studies of amyloid-targeting monoclonal antibodies to date “do not provide high-quality evidence of clinically meaningful effects at an affordable price.”
Daly believes much attention is being paid to the potential of drugs that target amyloid buildup, despite a lack of efficacy has been reductivebecause less attention has been paid to alternative hypotheses about the cause of the disease and ways to address it.
A 2020 report from the Lancet Commission on Dementia It is estimated that 40% of cases of age-related dementia are associated with twelve potentially modifiable risk factors across the lifespan, including air pollution, obesity, depression and less education.
Daly says that while such findings make it tempting to list lifestyle changes that people can make to reduce the risk of dementia, this is also too simplistic because it places the responsibility on individuals rather than governments.
“Working conditions, Forms of oppression and things that cannot easily be seen as a risk of dementia are just as important in preventing disease,” says Daly.
“There is an iceberg here – don’t just look at the surface, at drugs and lifestyle. There are living conditions and social structures that make a deeper contribution to the risks among the population, and interventions aimed at this, are needed by governments to make our society fairer and more dementia-proof.”
Walsh says there is understandably “a collective desperation” among scientists and patients for better treatments and preventive options for Alzheimer’s disease, the most common cause of dementia in Western societies and for which there is no cure.
“But this cannot cloud objectivity when we look at the evidence,” he says.