IThis was heralded in news articles as a “breakthrough,” “tipping point,” and “game changer” for Alzheimer’s disease. Some experts have even called the drug donanemab “the beginning of the end” for this debilitating disease.
In May 2023, pharmaceutical company Eli Lilly announced clinical trial data showing donanemab slowed cognitive decline by 35% over 18 months in patients with early-stage symptomatic Alzheimer’s disease.
The findings prompted the head of Alzheimer’s UK Research and other experts to call on the medicines regulator to quickly approve the treatment for use in patients.
However, despite the reports, US drug regulators expected to approve donanemab ‘at any time’the Food and Drug Administration (FDA) instead announced on March 8 that it had postponed its decision.
The FDA said it wants an independent panel to further review the data on donanemab’s safety and efficacy, and said a decision is expected in late 2024. Regulators in the UK, Europe and Australia are also still evaluating the drug.
“We believe that donanemab has the potential to provide very meaningful benefits for patients with early symptomatic Alzheimer’s disease,” Eli Lilly Executive Vice President Anne White said in a statement.
“While it was unexpected to learn that FDA would convene an advisory committee at this stage of the review process, we look forward to the opportunity to provide further input.” [trial] “We have derived results and are positioning the strong efficacy of donamab from a safety perspective,” she said. “We will work with FDA and community stakeholders to provide presentations and answer all questions.”
Dr. Timothy Daly, a dementia researcher at Sorbonne University in Paris, says the delay is not surprising.
He says the benefits of donanemab and similar highly touted drugs such as aducanumab and lecanemab have proven harder to quantify than the potential harms.
“Beneath the success story of this drug there are some very strong side effects,” Daly told Guardian Australia.
These are a class of drugs known as novel monoclonal antibodies that target amyloid proteins in the brain. Many researchers believe that the accumulation of these proteins contributes to Alzheimer’s disease.
These 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-associated imaging abnormalities (ARIA), which can cause swelling and bleeding in the brain. be.
Dr Sebastian Walsh, a public health physician who studies dementia risk reduction at the University of Cambridge in the UK, said: “Most of these symptoms appear to be mild and asymptomatic, and follow-up studies have shown that symptoms do not subside. It seems like it’s resolved.”
“A small proportion of participants had more severe symptoms and even death, especially in those taking blood-thinning medications.”
Some trial participants experienced brain atrophy, but the long-term effects are unknown.
“That’s pure speculation.”
In the donamab trial, patients who received the drug experienced an average decrease of 10 points on a 144-point scale that combines cognitive and functional scores. The placebo group, which did not receive the drug, lost 13 points.
The researchers used this data to show that the drug slowed cognitive and functional decline by “more than a third,” allowing people to live “a few more months” or “up to a year” without the disease progressing further. ”.
Mr Walsh said efforts to translate clinical data into more meaningful terms that people could understand meant the effects of drugs were being exaggerated in media reports.
“It’s understandable that people would want to think of other ways to present these numbers, but it still needs to be scientifically valid,” he says.
“I think the people who reported ‘6 more months of high functioning’ are in a precarious position scientifically. In this case, their loved one’s cognitive ability, driving ability, and other things were not measured. We didn’t. Extrapolating like this isn’t really justified by the evidence we have. It’s pure speculation.”
Ed Richard, professor of neurology at Radboud University Medical Center in the Netherlands. He told news channel Al Jazeera. The drug “clearly” removes amyloid protein from the brain “very well.”
However, reducing amyloid protein does not necessarily slow cognitive decline, he said.
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Research into the disease dating back more than 25 years has revealed the presence of amyloid proteins in the brains of people with dementia. But these are also seen in people who don’t have dementia or who don’t develop dementia, Richard told Al Jazeera.
Many drugs tested in the past reduced amyloid levels, but donanemab, aducanumab, and lecanemab appear to be the first to also alter cognitive decline. But Richard insisted that this change was “statistically significant but clinically irrelevant”.
When the FDA approved aducanumab in 2021, three members of the FDA advisory committee who recommended against the approval, believing there was a lack of efficacy data, resigned.Among those who quit I explained it as follows “This is probably the worst drug approval decision in recent U.S. history.”
The drug is rarely used, with clinicians being cautious and not covered by Medicare, the US health insurance program.
In June, Australia’s regulator, the Medicines Agency, said there was “no evidence of clinically meaningful efficacy” for aducanumab.
“Collective despair”
Not only is there minimal meaningful clinical benefit with donamab, but patients receive the drug via intravenous infusion once every two to four weeks in a clinic or hospital at a cost of approximately US$26,500 or AUD40,500. In addition to this, it is necessary to receive regular treatment. Under test. There is much to ask of vulnerable people and their families.
People participating in clinical trials are also a highly selective group. In the donemab trial, 1,320 participants with amyloid and early symptoms completed the trial. For every 10 people tested to see if they were eligible to participate in the trial, about eight were found to be ineligible.
in Comments written for conversation, Walsh said that when prescribed in the real world, “if drug eligibility is restricted to match trial eligibility, very few people will be eligible.” Wider eligibility could make already small effects even smaller and side effects more pronounced. ”
Professor Ian Scott, Head of Internal Medicine and Clinical Epidemiology at the Princess Alexandra Hospital in Queensland, Australia, said: Published a paper on The February issue of the journal Age and Aging has similar concerns. He wrote that trials of amyloid-targeting monoclonal antibodies to date “have not provided high-quality evidence of clinically meaningful impact at an affordable price.”
Daly believes there is a lot of focus on the potential of drugs to target amyloid buildup, despite the lack of efficacy. It was reductiveThis is because alternative hypotheses about the causes of the disease and ways to address them have received less attention.
2020 report Lancet Commission on Dementia An estimated 40% of age-related dementia cases are associated with 12 underlying risk factors that are modifiable throughout the lifespan, including air pollution, obesity, depression, and low education.
Daly said that while such findings are tempting to list lifestyle changes people can make to reduce their risk of dementia, this is too restrictive as it places responsibility on individuals rather than governments. He also said it was too simple.
“Working conditions, Forms of oppression and those that are not as easily recognized as dementia risk are equally important in disease prevention” Daly says.
“There’s an iceberg here. Don’t just look at drugs and lifestyle at the surface.” Living environment and social structure These represent a deeper contribution to people’s risk and require targeted government interventions to make our societies fairer and more dementia-resilient. ”
Professor Walsh said there was a “collective desperation” among scientists and patients seeking better treatments and prevention measures for Alzheimer’s disease, the most common cause of dementia in Western societies and for which there is no cure. Of course, he said.
“But that doesn’t cloud our objectivity when looking at the evidence,” he says.
