A high-cost Alzheimer’s drug that virtually eliminates amyloid plaques but lacks convincing evidence of clinical benefit has divided experts in Australia, as the Therapeutic Goods Administration (TGA) considers an application for registration.
Aducanumab, a monoclonal antibody, is considered the first modifying therapy for Alzheimer’s disease because it reverses beta-amyloid deposition, widely believed to be the most likely cause of the disease.
The drug was approved by the US Food and Drug Administration (FDA) in June 2021 – the first new treatment for Alzheimer’s disease (AD) in nearly two decades. It is indicated for patients with mild cognitive impairment or a dementia stage of the disease.
However, the approval challenged the advice of the FDA’s own expert panel, which concluded there was insufficient evidence that it slowed cognitive decline. Three committee members resigned in protest, and the FDA commissioner was forced to call for an independent investigation to determine whether manufacturer Biogen had improper influence over the drug’s approval process.
The road to approval for aducanumab has been unconventional to say the least.
Two global Phase 3 trials of the drug, ENGAGE and EMERGE, were halted in March 2019 when an independent data monitoring board found they were unlikely to meet primary endpoints.
Six months later, the company that produces aducanumab announced that a new analysis of a larger dataset, which became available after the pre-specified futility analysis, showed the drug reduced clinical decline in patients with early AD and that, on that basis, seek FDA approval. The new positive results, the company said, were primarily due to greater exposure to high-dose aducanumab in the larger dataset, compared to data available when the trials were halted.
The FDA noted that while the evidence from the updated EMERGE and ENGAGE studies was mixed, both “consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent manner.” .
“The reduction in amyloid plaque is expected to lead to a reduction in clinical decline,” the FDA said.
Based on this, the FDA approved aducanumab through a “fast track,” which allows drugs for serious or life-threatening conditions to be approved based on a surrogate rather than a primary clinical endpoint.
The FDA gave Biogen 9 years to conduct a post-approval clinical trial to verify the clinical benefits of the drug.
Meanwhile, aducanumab costs Americans US$28,200 per patient per year (AU$40,000).
From a critical perspective published in the MJAAustralian experts, led by Professor Ashley Bush, director of the Melbourne Dementia Research Center at the Florey Institute of Neuroscience and Mental Health, compared the evidence behind the FDA’s decision to “win a sniper contest in Texas by drawing a bull’s eye around a bullet”. hole”.
“Premature approval without evidence of clinically significant benefit from controlled clinical trials is costly for the government as well as for patients (who are exposed to side effects), may make it more difficult to recruit for experimental placebo-controlled clinical trials and could divert research funding from the development of more effective treatments,” they wrote.
“Disease-modifying treatments for AD are urgently needed, but science, not desperation, should guide the approval process,” they added.
Talk with InSight+, Professor Bush said he no longer believed anti-amyloid therapies held much promise.
“There have been over 30 phase 3 clinical trials targeting amyloid, and many have removed amyloid, but even with aducanumab, which is very effective at removing amyloid, the clinical benefits are even more subtle than with available drugs – acetylcholinesterase inhibitors and [N-methyl D-aspartate (NMDA)] memantine antagonist,” he said.
“Aducanumab also takes significantly longer to work than currently available drugs, with a slight slowing of deterioration after 18 months of treatment, if the data is to be believed.”
Professor Bush noted that aducanumab was strongly associated with a poorly understood but potentially serious adverse event known as amyloid-related imaging abnormality (ARIA), which can cause brain haemorrhages.
The most common edematous form of the disease, ARIA-E, occurred in 35% of the treatment cohort compared to 3% on placebo. Professor Bush said this had the effect of “unblinding” 35% of the cohort, potentially influencing the results of both trials.
Professor Bush commented:
“There are concerns about the tendency of anti-amyloid drug candidates to accelerate brain volume loss, but these data have not been reported by either Biogen or the FDA, although they are a pre-specified endpoint.”
Aducanumab is just one of many anti-amyloid drugs for AD, with ongoing trials of lecanemab and donanemab.
“We need to be open-minded about the possibility that removing amyloid might be beneficial, but it also might not be, and there may still be better therapeutic targets, such as tau or the iron depot,” Professor Bush said.
By contrast, Professor Ralph Martins, Foundation Chair in Aging and Alzheimer’s Disease at Edith Cowan University and professor of neurobiology at Macquarie University, said he and many colleagues remained firmly convinced of the amyloid hypothesis and hoped that aducanumab would soon be approved in Australia and listed on the drug benefits scheme.
“There is an enormous amount of evidence in the literature to support the amyloid hypothesis,” he said.
“For example, people with Down syndrome who often become demented have an extra copy of the amyloid gene, and there are also two major genes intimately linked to the amyloid pathway – APPLICATION and PS1 – and these occur in a vast majority of familial onset cases.
Professor Martins said there was a compelling explanation why aducanumab had not been associated with dramatic clinical improvements in trials, despite clearing amyloid.
“It’s because of the cascade of events that contribute to AD,” he said. “Amyloid deposition comes first, which triggers a series of events, such as tau buildup, and once these events occur, the brain can be damaged beyond repair.”
“Horse has already bolted for many patients in clinical trials,” he said, “However, anti-amyloid therapies are likely to be most useful in the early and especially preclinical stage of Alzheimer’s disease.”
Professor Martins said the FDA rightly recognized the urgent burden of Alzheimer’s disease and that aducanumab effectively targeted the underlying biology of the disease.
“Maybe the approval was a bit too early, but when do we start?” he said. “If you ask the families, everyone would say they want it now.”
Professor Martins said patients needed a [positron emission tomography (PET)] amyloid scan to confirm the presence of amyloid before undergoing treatment with aducanumab. They must also undergo [magnetic resonance imaging (MRI)] monitoring for ARIA, with closer follow-up of patients APOe4 gene because they were at increased risk of side effects.
If aducanumab becomes available in Australia for patients with mild AD, it is estimated that around 150,000 Australians would be eligible.
Professor Bush and his colleagues estimated that if all of these patients were treated under the Pharmaceutical Benefits Scheme (PBS), PBS expenditure would increase by around 50%. The actual costs would be much higher, they said, given the resources needed for infusions, MRI monitoring and adverse event management.
One thing Australian experts agree on is the cost of the drug.
Professor Martins said the price of the drug had been a weak point for many doctors who welcomed the FDA approval.
“It’s just crazy, unacceptable,” Professor Martins said. “Many medical centers in the United States have chosen not to use aducanumab in protest of its cost, and I hope this will have a positive effect on reducing the cost, as well as the exit of certain anti-amyloid drugs even more powerful ones that are now in the pipeline,” he said.
A TGA spokesperson said the Independent Expert Medicines Advisory Committee was due to review Biogen Australia’s application in April, with the TGA expected to make a regulatory decision later in 2022.
Also online at mja.com.au
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