The US approval this week of a drug to treat Alzheimer's disease is being seen by some as crucial in the fight against a condition that affects more than 44 million worldwide.
After dozens of candidate drugs failed during clinical trials over the years, aducanumab could be the first therapy to actually slow the disease's progression, rather than just treat the symptoms.
But opinion is divided on whether the Food and Drug Administration was right to give the green light to a new Alzheimer's drug for the first time in two decades.
The FDA says there is "substantial evidence" the drug, marketed as Aduhelm, reduces beta amyloid plaques, which are aggregations of proteins that develop in the brains of many Alzheimer's patients.
This is despite a major international aducanumab trial involving thousands of patients having been cut short about two years ago because the drug appeared to be no better than the placebo it was compared to.
“For us clinical scientists, this [approval] has come as a bit of a surprise,” says Prof Paul Morgan, of the UK Dementia Research Institute at Cardiff University.
“The FDA has been persuaded because the drug is having an effect on the amyloid load in the brain, which seems to be clear, without any evidence it has an effect on cognition. They’ve tried to stretch the data to have a very small effect on a very small subset [of patients].”
Because of the burden that Alzheimer’s creates, and the lack of drug treatments, Prof Morgan says aducanumab has been “treated differently”.
“The need for something is huge, and because of that huge need, they’ve been pushed quite hard to approve something that in other circumstances wouldn’t have met the threshold for approval,” he says.
In this context, it is perhaps unsurprising that major organisations are split over the FDA’s decision.
The Alzheimer’s Association in the US says it “enthusiastically welcomes” the “historic” approval, but in a letter to the FDA, The American Geriatrics Society branded the decision “premature given the lack of sufficient evidence” aducanumab works.
The FDA's approval is conditional, in any case, on the success of confirmatory Phase 4 trials.
A desperate need for a treatment
Several drugs that have shown promise in experiments on mice have failed in clinical trials, something that has been all the more concerning given Alzheimer’s increasing prevalence in ageing societies.
Responsible for about two-thirds of cases of dementia and characterised by a loss of connection between the nerve cells or neurons that make up the brain, the disease causes memory loss, problems with speech and behavioural changes, as well as other effects.
Patients typically die within a decade of diagnosis, although the whole course of the disease lasts about a quarter of a century, including a lengthy period before symptoms emerge.
Aducanumab, an antibody treatment consisting of multiple identical proteins, attacks the beta amyloid plaques in patients' brains. In doing so, it may slow, but not stop, the progression of the disease.
While a major clinical trial seemed to show aducanumab was ineffective, reanalysis of results by the company behind the drug, the Massachusetts-based Biogen, appeared to indicate benefits at higher doses.
Not everyone is convinced. Among the critics of the FDA’s approval is Prof Rob Howard, professor of old age psychiatry at University College London, who says the stalled clinical trials “should really have been the end of it”.
He says data has been “cherry-picked” to demonstrate efficacy.
“Biogen have been so persistent and audacious in the way they continued to push,” he says. “The feeling of many of us is that you have to be led by the science. It’s a huge mistake to cave in to commercial pressure, and pressure from patient groups.”
Prof Howard says patients administered aducanumab are at risk of being exposed to “a placebo that has unpleasant side effects”, which include, in about one-third of those on high doses, a type of brain swelling that results in nausea and headaches.
In recent years, the FDA has reportedly rejected half a dozen other amyloid-based treatments, decisions that caused drug makers to scale back research into this field. With aducanumab’s approval, this may change.
“It’s going to distort the field in terms of what’s researched and trialled in the next five to 10 years,” says Prof Howard.
“In the meantime, other promising new treatments will be shut down because they will be considered too risky.”
A chance to slow the disease
Others, such as Prof Paul Matthews, head of the Department of Brain Sciences at Imperial College London, see the FDA’s decision as a positive.
The change in focus that may result from the approval will give “renewed confidence” amyloid is central to the cascade of damage caused to the brain by Alzheimer’s, Prof Matthews says.
"That will allow drug developers to target development around that concept in ways that likely will be able to move forward faster," he says.
While the effects in the Phase 3 trials were "modest or uncertain", he says the trials were short, and studies of the disease show that rapid, dramatic reversals should not in any case be expected.
"By getting [the drug] into the community, we will not only … help people, but we'll learn a great deal about it faster," he says.
“It’s a glass half-full and glass half-empty situation. This specific drug is a small step forward. The fact there’s been a drug approved I think is hugely significant.”
It has been suggested that the approval will, in addition, stimulate research into the use of multiple drugs to combat Alzheimer’s, an approach shown to be effective against, for example, cancer and HIV.
Not giving approval would, by contrast, have meant "another few years of no treatments", says Dr Liz Coulthard, an associate professor in dementia neurology at the University of Bristol in the UK.
Cautioning that aducanumab is “hardly a panacea”, Dr Coulthard, who points out that she was involved in one of the aducanumab trials and has undertaken work for Biogen, says it’s “a drug with a relatively small effect”.
Dr Coulthard would herself be willing to prescribe the drug to patients who fit the criteria, such as having early-stage disease.
“People with mild cognitive decline would still develop dementia,” she says. “But people will have more time, months or years, before progressing to full-blown dementia.”
She sees aducanumab being used as part of a multipronged approach that also includes lifestyle interventions to slow the progression of the disease.
European approval uncertain
Given the trial results, it is uncertain whether other regulatory agencies, such as the European Medicines Agency, will follow the FDA’s lead.
In some countries, such as the UK, aducanumab will have to additionally demonstrate it is value for money, which could be a significant hurdle given that the estimated annual cost of the intravenous infusions is $50,000.
Decisions are likely to be finely balanced, suggests Dr Ivan Koychev, a senior clinical researcher at the University of Oxford’s Department of Psychiatry and a consultant neuropsychiatrist.
“Normally you would say that whatever is approved by the FDA will get approval from Europe. In this case, because the data is so controversial, it’s a difficult one to call,” he says.
“Especially for the UK and other European countries, they will take a hard look at the cost-effectiveness of the drug.”
While aducanumab and the decision to approve it are controversial, the drug may offer reason for optimism after many years of frustration.
“It should give everyone who’s been affected by Alzheimer’s personally, or who has a relative or friend, hope that treatment is possible,” says Prof Matthews.