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YoIt was heralded in newspaper articles as a “breakthrough,” a “turning point,” and a “game changer” for Alzheimer’s disease. Some experts went so far as to call the drug donanemab the “beginning of the end” of this debilitating disease.
In May 2023, the pharmaceutical company Eli Lilly published data from a clinical trial that it said showed that donanemab slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease by 35% over 18 months.
Following the findings, the director of Alzheimer’s Research UK and other experts called on drug regulators to quickly approve the treatment for use in patients.
But despite the reports, US drug regulator ready to approve donanemab ‘any day’The Food and Drug Administration (FDA) announced on March 8 that it had delayed its decision.
The FDA said it wants an independent panel to further examine data on the safety and effectiveness of donanemab, with a decision now expected later in 2024. Regulators in the United Kingdom, Europe and Australia are also evaluating the drug.
In a statement, Eli Lilly Executive Vice President Anne White said, “We are confident in the potential for donanemab to deliver very significant 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 hope to have the opportunity to further present the [trial] results and put the strong efficacy of donanemab in the context of safety,” he said. “We will work with the FDA and community stakeholders to make that presentation and answer all questions.”
Dr. Timothy Daly, a dementia researcher at Sorbonne University in Paris, says he’s not surprised by this delay.
He says the benefits of donanemab and similar well-publicized drugs, including aducanumab and lecanemab, have proven harder to quantify than their potential harms.
“Underneath this narrative of drug success, there are some really strong side effects,” Daly told Guardian Australia.
These are a type of drug known as new 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 reduce amyloid levels in the brain. But about three in 10 people who took lecanemab or donanemab in clinical trials developed a condition known as amyloid-related imaging abnormalities, abbreviated ARIA, a condition that can cause inflammation or bleeding in the brain.
“For the most part, these appear to be minor, they don’t present any symptoms, and follow-up scans show that they appear to have resolved,” says Dr. Sebastian Walsh, a public health doctor who researches dementia risk reduction at the University of Cambridge. in the United Kingdom.
“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 its long-term effects are unknown.
“It’s pure speculation”
In the donanemab trial, patients who received the drug decreased 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 decreased by 13 points.
The researchers used this data to claim 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 efforts to translate clinical data into more meaningful terms for people to understand mean the drug’s effects have been exaggerated in media reports.
“While it’s understandable that people want to think of other ways to present these figures, they still need to be scientifically valid,” he says.
“I think those who have reported that it is ‘an additional six months with higher function’ are on scientifically shaky ground. The trials did not measure recognition of a loved one, the ability to drive, or any of these things; Extrapolating in this way is not really justified by the evidence we have. “It’s pure speculation.”
Edo Richard, professor of neurology at Radboud University Medical Center in the Netherlands, he told Al Jazeera news channel The drugs “clearly eliminate” 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 dating back more than 25 years has found 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 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 cause a change in cognitive decline. But Richard said the change was “statistically significant, but clinically irrelevant.”
When the FDA approved aducanumab in 2021, three members of the FDA advisory committee who advised against approval due to what they believed was 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.”
When it comes to implementation, the US health insurance program Medicare said it would not cover it, and doctors have also been cautious, with little use of the drug.
The Australian regulator, the Therapeutic Goods Administration, found in June that there is “no evidence of clinically significant efficacy” of aducanumab.
A ‘collective despair’
In addition to the minimal significant clinical benefits of donanemab, patients also need to receive the drugs via intravenous infusion in a medical clinic or hospital once every two to four weeks at a cost of approximately US$26,500 or AU$40,500 per year, in addition to undergo regular treatments. evidence. It is a lot to ask of vulnerable people and their families.
Those who participate in clinical trials are also a highly selective group. In the donanemab trial, 1,320 participants with amyloid symptoms and early symptoms of the disease completed it. For every 10 people screened for trial eligibility, about eight were found to be ineligible.
In a written comment for the ConversationWalsh said that if, when prescribing in the real world, “the eligibility of the drug is restricted to match the eligibility of the trial, then very few people will be eligible. If eligibility is broader, then the already small effects will likely be even smaller and the side effects more pronounced.”
The director of internal medicine and clinical epidemiology at the Princess Alexandra Hospital in Queensland, Australia, Professor Ian Scott, published an article in February issue of Age and Aging magazine with similar concerns. He wrote that amyloid-targeting monoclonal antibody trials to date “do not provide high-quality evidence of clinically meaningful impacts at an affordable cost.”
Daly believes there is a need to focus on the potential of drugs that target amyloid buildup despite their lack of effectiveness. has been reductiveas it has been observed that less attention is paid to alternative hypotheses about the cause of the disease and ways to address it.
A 2020 report from The Lancet commission on dementia. An estimated 40% of age-related dementia cases are associated with 12 potentially modifiable risk factors throughout life, including air pollution, obesity, depression and less education.
Daly says that while these findings make it tempting to list lifestyle changes people can make to reduce their risk of dementia, this is also overly simplistic, placing the responsibility on individuals rather than governments. .
“The working conditions, Forms of oppression and things that cannot so easily be considered a risk for dementia are equally important in preventing disease.”Daly says.
“There is an iceberg here: let’s not just look at the surface of drugs and lifestyle. There is living conditions and social structures “They represent deeper contributions to risk in the population, and governments need interventions aimed at these to make our society fairer and more resilient to dementia.”
Walsh says it’s understandable that there is “a collective desperation” among scientists and patients for better treatments and preventive options for Alzheimer’s disease, which is the most common cause of dementia in Western societies and has no cure.
“But this cannot cloud objectivity when we analyze the evidence,” he says.