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Drug Development

Experimental Alzheimer’s treatment nails Phase 3 clinical trials

Lecanemab slowed cognitive decline in patients with a mild form of the disease

by Shi En Kim
September 29, 2022 | A version of this story appeared in Volume 100, Issue 35

Images of top-view brain scans.
Credit: Shutterstock
Brain scans are often used to evaluate people with Alzheimer's disease.

The highly anticipated clinical trial results for an experimental Alzheimer’s treatment are in: the antibody lecanemab met its primary endpoint of delaying the progression of Alzheimer’s in people with early onset of the disease. The positive outcome increases the odds that lecanemab, being developed by Biogen and Eisai, will sail through regulatory approvals, analysts say.

Lecanemab works by dissolving amyloid-beta plaques, a hallmark of Alzheimer’s, in the brain. Experts have questioned, though, whether clearing this plaque necessarily holds off the disease, as suggested by the controversial amyloid hypothesis.

An earlier Biogen-Eisai monoclonal antibody, aducanumab, also showed similar plaque-busting capabilities. However, the delay in disease progression among patients was marginal, and the drug is not being actively marketed. Some experts predicted that lecanemab would have similar efficacy—or lack thereof.

The CLARITY-AD trial sought to confirm the benefits of lecanemab’s plaque-clearing abilities in the clinic. Ongoing since March 2021, the study enrolled nearly 1,800 people with mild Alzheimer’s disease symptoms across the US, Europe, and Japan for 18 months. The patient pool included 25% Hispanic and African American people, which is comparable to the ethnic makeup of the Medicare population in the US. Participants received an intravenous infusion of lecanemab every two weeks.

The results reveal that lecanemab succeeded where its embattled predecessor could not. Compared to those who received a placebo, patients who took lecanemab showed a 27% slower decline in cognitive function. In contrast, aducanumab stemmed cognitive decline by 22% in one trial and demonstrated no clinical benefit in another.

Lecanemab “made a definite step forward,” says David Knopman, a professor of neurology at the Mayo Clinic who was a clinical investigator for aducanumab but did not participate in the lecanemab trials. However, he notes that 27% “is a small benefit. I wouldn’t use the word huge.”

The antibody also hit its secondary endpoints of reduction in brain amyloid levels, and it raised no new safety issues. The incidence of brain abnormalities that are often associated with monoclonal antibody treatments, which include side effects of bleeding and swelling, was around 20%, better than aducanumab. The drug is “reasonably well tolerated,” Knopman says, and the complications are “manageable but not trivial.”

The greater efficacy and safety compared to aducanumab may be due to the antibodies’ different binding profiles, says Michael Irizarry, senior vice president for Alzheimer’s and brain health at Eisai. For example, he says lecanemab has a 10-fold higher affinity for the soluble, oligomeric intermediates of amyloid-beta than for the plaque itself; previous studies have claimed the intermediates could be more effective disease targets. Still, Irizarry emphasizes that “we don’t know how that necessarily translates to the differences that we see clinically.”

Experts remain cautious on whether the positive CLARITY-AD results will translate to tangible benefit for patients in the real world. The trial outcome is “important from a conceptual standpoint in showing that amyloid removal can move the needle on clinical outcomes,” Knopman says. But whether it’s meaningful for patients can only be determined in the long term, beyond the course of an 18-month trial. “Will this slowing that lecanemab causes be durable and persistent?” he asks.

The results will likely bolster lecanemab’s case for passing US Food and Drug Administration priority review by Jan. 6 of next year. Armed with the positive CLARITY-AD results, Eisai plans to file for full traditional approval in the US and seek marketing authorization in Japan and Europe by the end of March.


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