New Alzheimer’s drug straddles uneasy gulf between help and harm

The writer is a science commentator

The perfect drug would be effective, free of side-effects, cheap and easy to administer. Lecanemab, which won accelerated approval from the US Food and Drug Administration on Friday to treat early-stage Alzheimer’s disease, can claim to meet one of those criteria — but only to a degree.

It does not halt or reverse the decline associated with the neurodegenerative condition, which erodes memory, language and the ability to live independently, but it is the first Alzheimer’s drug to pull off a statistically significant, if modest, slowing in the rate of that decline. That is a step up from current drugs that treat only symptoms: a landmark success in a desert strewn with pharmaceutical failures.

Side-effects, cost and convenience, though, sit on the debit side of the ledger. Lecanemab, a collaboration between Tokyo-based Eisai and the American firm Biogen which will be sold under the name Leqembi, has been linked to brain bleeding and seizures, with three deaths during an extended clinical trial involving about 1,800 people. It is priced at $26,500 a year; treatment requires intravenous infusions and regular monitoring for potentially dangerous side-effects. Patient groups and Eisai are upbeat but many doctors remain unconvinced and healthcare providers are restricting reimbursement. Lecanemab, for all its landmark status, may end up representing a triumph of hope over evidence.

Like Biogen’s Aduhelm, fast-tracked through approval as an Alzheimer’s treatment last year but a subsequent commercial flop, lecanemab is an antibody therapy designed to clear brain plaques made up of a substance called beta-amyloid. The plaques are suspected to be a driving factor in Alzheimer’s; removing them has long seemed a sensible therapeutic strategy. While multiple plaque-busting candidates based on the “amyloid hypothesis” have fallen by the wayside, lecanemab is an improvement even on Aduhelm, producing a measurable clinical difference. About 900 patients were given the drug; they saw a 27 per cent slowdown in their disease progression over 18 months compared to a placebo group, assessed against scales of cognition and function. The results, Eisai claimed, suggested it would take the lecanemab group about 25 months to show the same decline as the control group displayed over 18 months. The analysis was published in the New England Journal of Medicine in November.

Still, a thorny truth remains: the slowdown in deterioration can be both statistically significant and extremely small. Robert Howard, professor of old age psychiatry at University College London, said the difference in overall scores between the treatment and placebo groups fell short of what most specialists would regard as clinically relevant. Plaque removal may weaken blood vessels in some patients, increasing the chance of haemorrhage (lecanemab is not recommended for patients on blood thinners). Howard would not advise his patients to take it “because the benefits don’t justify the risks”.

Jeffrey Browndyke, assistant professor of psychiatry and surgery at Duke University Medical Centre in North Carolina, said he would not rule out the drug but that it was “still unclear to many that there is clinical effectiveness that significantly improves function”. Browndyke added that he expected adverse incidents, including deaths, to rise if lecanemab was used more widely.

Where does that leave us? One takeaway is just how differently patients, insurers and physicians view lecanemab. The Alzheimer’s Association welcomed FDA approval but said it was wrong for medical insurers not to fork out for it. Browndyke believes the approval partly reflects lobbying from industry and patients. Howard fears that overblown hopes will blind desperate patients to the risks. While a fresh drug approval should signal a joyous moment in the treatment of a disease that accounts for most of the world’s 55mn dementia cases, it is now fuelling an unhappy difference of opinion.

The second takeaway is that lecanemab is still not a full-throated vindication of the amyloid hypothesis, which contends that plaques cause the disease. As pharma blogger Derek Lowe pointed out, the drug removes plaques but doesn’t slow the disease all that much. Worse, clearing the plaques carries risks. We may need to look for the causative roots of Alzheimer’s elsewhere.

Careful patient selection may yet cast lecanemab in a better light but, for now, the drug is stranded in that unsatisfactory space between success and failure. It seems somehow appropriate for a disease that remains both familiar and mysterious.