Zoom in / MRI of a human brain.
The Food and Drug Administration on Friday granted accelerated approval to a new Alzheimer’s disease treatment that may slightly slow the progression of cognitive decline in the early stages of the disease, but also raises the risks of brain hemorrhages and swelling.
The treatment – lecanemab, brand name Leqemb, made by pharmaceutical companies Eisai and Biogen – is an intravenous monoclonal antibody that targets amyloid-beta proteins that build up in plaques in the brains of people with Alzheimer’s. Researchers have not yet definitively determined whether amyloid plaques are the root cause of the disease, nor whether clearing them can significantly slow or stop cognitive decline.
The FDA’s approval of lecanemab is through an accelerated pathway that uses a “surrogate endpoint that is reasonably likely to predict clinical benefit to patients.” In this case, the surrogate endpoint was the ability of lecanemab to reduce amyloid beta plaques in the brains of Alzheimer’s patients.
Uncertain efficacy
But the significance of this and the drug’s efficacy are still uncertain. In a phase III clinical trial published this week in the New England Journal of Medicine, treatment with lecanemab for 18 months only slightly slowed cognitive decline in patients with early Alzheimer’s disease. The study included 1,795 participants – 898 were assigned to receive lecanemab and 897 were assigned to placebo. Their cognitive abilities were assessed using an 18-point scale from an established clinical dementia test. At the beginning of the trial, both groups (treatment and placebo) had a baseline score of about 3.2 on the test. After the 18-month trial, the lecanemab treatment group’s score fell by 1.21 points, while the placebo group fell by 1.66 points—a difference of 0.45 points that represented a 27% slower decline in the treatment group.
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It is unclear whether this change makes sense. Dr. Madhav Thambisetty, a neuroscientist and senior researcher at the National Institute on Aging who spoke to The New York Times, said the drug’s ability to clear amyloid plaques is “exciting” from a scientist’s perspective. But “from the perspective of a physician who cares for Alzheimer’s patients, the difference between lecanemab and placebo is well below what is considered a clinically meaningful treatment effect.”
The researchers behind the clinical trial noted in their conclusion that “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
Safety considerations
Meanwhile, the treatment has raised safety concerns, particularly amid reports that three patients given the drug died of brain swelling and bleeding. This included a 65-year-old woman with early cognitive decline who died of a massive cerebral hemorrhage. Rudolph Castellani, a neurologist at Northwestern Medicine who studies Alzheimer’s disease and performed an autopsy on the woman at her husband’s request, told Science last November that he believed the drug weakened the woman’s blood vessels, which then ruptured more than usual. treatment for blood clots after she had a stroke.
“It was a one-two punch,” Castellani told Science, which first reported the death. “There is no doubt in my mind that this was a treatment-induced illness and death. If the patient had not been on lecanemab, she would be alive today.”
A report of the woman’s death was also published this week in the New England Journal of Medicine.
Lecanemab prescribing information includes warnings and cautions for brain bleeding and swelling and the use of blood thinners.
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The FDA approval comes just a week after lawmakers released the results of an 18-month congressional investigation into the agency’s much-criticized approval of a similar Alzheimer’s drug, Aduhelm. The data for this amyloid-targeting antibody therapy were even less compelling than those for lekanamab, and the FDA granted approval despite the objections of its external advisory panel and internal experts.
Irregularities
The congressional investigation found that the FDA’s approval process was “riddled with irregularities” and “inappropriate” communications between the FDA and Aduhelm’s maker, Biogen. The report also criticized Biogen for setting an “unreasonably high price” of $56,000 per year for Aduhelm.
“This report documents the atypical FDA review process and corporate greed that preceded the FDA’s controversial decision to grant accelerated approval to Aduhelm,” incoming Energy and Commerce Committee member Frank Pallone, Jr. (D-NJ) said at the time ).
Following lecanemab’s approval, Pallone released a statement saying, “I am hopeful that lecanemab will fulfill its promise to slow the progression of Alzheimer’s disease for patients and their loved ones. I also hope that Eisai and Biogen have learned from past mistakes and will price lekanemab fairly to ensure that patients have fair access to this drug.
In a press release Friday afternoon, Eisai announced that lecanemab prices are $26,500 for a year’s supply. That’s above the range the Institute for Clinical and Economic Review estimated would make the drug cost-effective, which the analyst group pegged at between $8,500 and $20,600 for a year’s worth of treatment.
It is unclear whether Medicare will cover lecanemab, which would dramatically affect its marketability. Medicare has severely limited coverage of Aduhelm because of its high cost, lack of evidence of benefit, and risks. Only Medicare beneficiaries in the clinical trials have coverage for the cost of Aduhelm, which has since been reduced to $28,200 for a year’s supply.
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