Hasty approval for Alzheimer’s drug offers a cautionary tale

The writer is a science commentator

The first approval of an Alzheimer’s drug for 18 years should have been cause for celebration. But aducanumab seems to have broken new ground in all the wrong ways. This month, it became the first US-approved drug that will not be routinely covered by government healthcare schemes. It may also be unintentionally displacing or delaying more productive approaches to treatment.

Globally, around 55mn people live with dementia, and Alzheimer’s accounts for an estimated 60-70 per cent of cases. These patients, who suffer problems with memory, language and thinking, have clumpy plaques of amyloid protein in the brain. The “amyloid hypothesis” — the idea that clearing the plaques will improve the condition — has dominated the field for more than two decades, despite previous amyloid-busting drugs failing to show their worth. In its favour, genes that make amyloid more “sticky” are implicated in hereditary Alzheimer’s, which accounts for around 1 per cent of cases. A healthy, sociable and mentally active lifestyle is thought to be protective in non-familial cases.

Aducanumab, marketed as Aduhelm by its maker Biogen, is an antibody therapy that is engineered to attack the plaques, by summoning immune cells to destroy them. Biogen proposed abandoning the drug in 2019 because of mixed results from two trials. But, on reanalysis, the company spied a modest signal of reduced neurological decline among patients given higher doses, though some also suffered swelling and bleeding in the brain. The US Food and Drug Administration lowered its usual regulatory bar of proving clinical effectiveness: the drug needed only to reduce amyloid levels.

The FDA’s fast-track approval in June 2021 — against a unanimous advisory committee, three of whom later quit — and mandated a post-approval “confirmatory” trial within nine years. Biogen priced it at $56,000 a year (since cut), alienating patient groups. The medicine, which is targeted at early-stage sufferers and requires monthly intravenous infusions and expensive scans, has since been rejected by the European Medicines Agency. Biogen is appealing.

The FDA’s approval was unjustified, thinks Robert Howard, professor of old age psychiatry at University College London and a dementia clinician, because of equivocal data, safety concerns and the unproven assumption that less amyloid means improved cognition. “Removing amyloid is a bit like removing smoke from a fire,” he explains. “You don’t put the fire out by doing that.”

But the greater ripple may be the effect on research. Aduhelm’s regulatory success has encouraged the pursuit of similar antibody treatments (a decision on Eli Lilly’s donanemab may come this year). Some suggest the medicines should be given earlier, to maximise benefit, even though many people with plaques will never develop Alzheimer’s.

Rather than blaming patients for not presenting early enough, Howard says, “the message we should take away is that aducanumab is the wrong strategy. Had the FDA not given that approval, we would have to look elsewhere.”

A protein called tau, which forms brain “tangles”, is another therapeutic target. Inflammation is also a possible culprit. Brains are protected by immune cells called microglia; one theory is that Alzheimer’s develops when these cells malfunction and cause inflammation and damage to brain cells.

Given that the disease unfolds at a glacial pace and trials take time to report, Howard estimates it may take a decade before the research juggernaut can be steered in a new direction. There are projected to be at least 78m sufferers by then, who will be hoping the prolonged gamble on the amyloid hypothesis does not become unstuck.