US regulators have approved the first new Alzheimer’s drug for nearly 20 years, raising hopes that British patients could benefit from disease-slowing treatment within months.
Charities last night called on UK watchdogs to submit aducanumab to a Covid vaccine-style fast-track appraisal process following the Food and Drug Administration (FDA) green light.
A monoclonal antibody that clears amyloid protein plaques in the brain, the drug is the first to target the disease itself, rather than its symptoms.
If approved, between 100,000 and 130,000 people in the UK with mild or moderate Alzheimer’s could be eligible.
The FDA gave approval after Biogen, the manufacturer, submitted evidence suggesting that a high dose can slow cognitive decline by about 22 per cent.
The decision was hailed as a "victory for patients", ushering in a new era for Alzheimer’s treatment and research, while stimulating new investment in what is an underfunded sector.
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However, the decision instantly polarised the scientific community, with some experts criticising the US regulator for approving the drug based on highly equivocal evidence.
Two Phase 3 trials comparing aducanumab to a placebo were halted in March 2019 after independent scientists decided the drug was not working.
Biogen later re-analysed the results and found evidence that it slowed cognitive decline in the high-dose cohort of one the trials, but not in the other.
An application has already been lodged with the UK’s Medicines and Healthcare products Regulatory Agency, the safety watchdog, with a decision expected this autumn.
If approved, the drug would then be assessed for its value for money on the NHS by the National Institute of Health and Care Excellence, which could take nearly another year.
Last night, Alzheimer’s Research UK said the Covid-19 vaccines showed how much quicker the process might be achieved.
David Thomas, head of policy, said: "Covid-19 has shown us that where there is leadership from government, high quality evaluation can be done more quickly.
"If the FDA approves the use of aducanumab today, we will be pushing for assessment in the UK as soon as possible."
Evidence proving the efficacy of aducanumab at slowing the progression of memory and thinking problems is highly disputed
Credit: David A. White /Biogen/AP
Professor Bart De Strooper, director of the UK Dementia Research Institute, said: "With no effective therapies currently available to modify the progression of this devastating condition, this is a major milestone for the millions of people living with the Alzheimer’s.
"However, I fear the controversy and uncertainly surrounding the trials will limit the impact of this new treatment for the disease."
Prof Robert Howard, professor of old age psychiatry at University College London, said the evidence showed the drug "probably doesn’t work".
"As a dementia clinician and researcher with personal family experience of Alzheimer’s disease, I want to see effective dementia treatments as much as anyone," he said.
"I consider the approval of aducanumab represents a grave error that will have only negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade."
Drug faces multiple hurdles before securing UK approval
The US regulator’s decision to approve aducanumab is understandably a moment of real optimism for many Alzheimer’s patients and their loved-ones.
It is, after all, the first medication to get the green light since 2003, and the first ever that tackles the disease process itself, rather than merely the symptoms.
The Food and Drug Administration (FDA) are not pushovers. They will not have given their consent unless they believed the evidence suggested at least a reasonable chance that some patients will benefit.
These are likely to be those in the early stages of the disease.
But before getting too optimistic, it is worth understanding just how murky that evidence is, plus the further hurdles aducanumab must overcome before becoming available in the UK.
A monoclonal antibody, it targets the buildup of amyloid protein plaques in the brain, which are believed to cause Alzheimer’s. This, its manufacturer Biogen claims, can slow the progression of memory and thinking problems. The conclusion is highly disputed.
Two Phase 3 aducanumab trials were halted in March 2019 after an independent monitoring committee said the drug did not appear to be working.
At the time, Biogen said the medication was unlikely to improve memory and thinking.
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However, the firm later announced that it had performed a re-analysis of data from 318 participants in one of the trials who had finished the 78-week course.
It said those taking a high dose of aducanumab enjoyed a slowing of cognitive decline of 22 per cent, equivalent to roughly four months over 18 months.
Neither patients taking a lower dose in that same trial, or either the high or low dose groups in the other trial, showed a benefit.
Critics dismissed the re-analysis as akin to the "Texas sharpshooter fallacy", where a gunman shoots wildly but subsequently draws a bullseye around a cluster of bullet holes.
Last November, the FDA’s advisory committee voted decisively against recommending approval, concluding that the trials had failed to show that the drug slowed mental decline.
The uncertain benefit came alongside evidence of potential harmful side effects, namely brain swelling or bleeding experienced by approximately four in 10 of the trial participants who received the high dose.
Despite this, patient groups on both sides of the Atlantic have strongly welcomed aducanumab, pointing out that even equivocal evidence of efficacy is an improvement on the current situation.
MHRA urged to approve drug rapidly
Citing the example of Covid-19 vaccines, Alzheimer’s Research UK has called for British regulators to conduct a rapid appraisal process.
The first stage would be appraisal by the drug safety watchdog, the Medicines and Healthcare products Regulatory Agency.
As ministers and the agency itself never tires of telling us in relation to Covid, the agency is supposed to be fiercely independent in weighing up effectiveness versus risk. A green light from the FDA, therefore, does not necessarily mean the MHRA will follow suit, although it would be naive to assume that the US decision will count for nothing.
A bigger hurdle is likely to be the value-for-money appraisal that would then have to be performed by the National Institute of Health and Care Excellence (Nice), the body which decides what drugs and treatments the NHS should buy.
With ambiguous efficacy data on the one hand, and a potential cost of tens of thousands per patient each year for the drug on the other, there is no guarantee Nice will say yes.
Yesterday’s FDA decision does not in itself vindicate the so-called "amyloid hypothesis", the theoretical basis behind aducanumab and arguably the dominant theory in Alzheimer’s drug development over the last 30 years. But it keeps it alive.
For the first time scientists will have the chance to scrutinise the effect of an amyloid-clearing drug on hundreds of thousands, perhaps millions of patients, potentially affording them new insights to tailor better follow-ups.
The decisions should also renew the confidence of investors in amyloid-clearing drugs – and in the field of Alzheimer’s pharmaceuticals more widely.
However, there are scientists who worry that by approving aducanumab, with its equivocal evidence, regulators have lowered the bar for the future.