The lecanemab decision follows the controversial 2021 approval of aducanumab, which led to tight coverage restrictions for monoclonal antibodies directed against amyloid for the treatment of Alzheimer disease.
The FDA approved lecanemab (Leqembi; Eisai) to treat Alzheimer disease (AD). The anti-amyloid antibody slowed the pace of cognitive decline, according to a phase 3 trial.
The FDA approved the therapy through the accelerated approval pathway based on data from the phase 2b Study 201 trial. According to Eisai, treatment should be initiated in patients with mild cognitive impairment or mild dementia.
“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, MD, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said in a statement. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”
The approval for lecanemab follows the controversial approval of aducanumab (Aduhelm), which the FDA granted accelerated approval to on June 7, 2021, despite the FDA advisory committee’s lack of a recommendation for approval. The aducanumab approval was the first new AD therapy in nearly 2 decades, but the decision was met with intense scrutiny and debate because of the small amount of evidence proving that the drug’s reduction of amyloid actually helps patients and improves their memory and cognitive problems.
In 2022, CMS made the decision that it would only cover aducanumab and other approved monoclonal antibodies directed against amyloid for the treatment of AD for patients in “qualifying clinical trials” that meet specific criteria set by CMS. For now, lecanemab is also affected by this decision.
After lecanemab's approval was announced, CMS released a statement about coverage.
"CMS is examining available information and may reconsider its current coverage based on this review," according to CMS. "If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage using the framework we announced last year, under coverage with evidence development, on the same day."
Additional research on lecanemab from the phase 3 Clarity AD trial is still being reviewed by the FDA. Clarity AD found the drug reduced cognitive and functional decline by 27% at 18 months compared with placebo.1 Clarity AD was a global confirmatory phase 3 placebo-controlled, double-blind, parallel-group, randomized study. There were 1795 people with early AD who were randomized 1:1 to receive either placebo (n = 897) or lecanemab 10 mg/kg intravenously biweekly (n = 898).
There were highly statistically significant changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) as early as 6 months on treatment from baseline. From baseline to 18 months, the mean change in CDR-SB was 1.21 for lecanemab and 1.66 for placebo. Compared with placebo, lecanemab reduced clinical decline on the global cognitive and functional scale at 18 months by –0.45 (95% CI, –0.67 to –0.23; P = .00005).
At 18 months, the study found that lecanemab:
The rate of abnormalities–edema/effusion (ARIA-E) was 12.6% on lecanemab vs 1.7% on placebo and the rate of ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis) was 17.3% on lecanemab vs 9.0% on placebo. Of patients who experienced ARIA-E events, 91% were mild to moderate radiographically, 78% were asymptomatic, and 71% occurred within the first 3 months of treatment. In addition, 81% of those who had ARIA-E saw the events resolve within 4 months of detection.
In the lecanemab group, deaths occurred in 0.7% of participants compared with 0.8% of those on placebo. None of the deaths were related to the drug or occurred with ARIA during the study period. Overall, 88.9% on lecanemab and 81.9% on placebo experienced treatment-emergent adverse events. Of these, 14.0% of patients on lecanemab and 11.3% on placebo experienced serious adverse events.
However, lecanemab won't be without its own controversy. Just days prior to the approval, clinicians raised concerns about lecanemab after a patient who was treated in Clarity AD died. The 65-year-old patient presented to the emergency department just 4 days after the final infusion after suffering multiple brain bleeds. The patient had been treated with lecanemab and intravenous tissue plasminogen activator (t-PA), a common clot-dissolving treatment for strokes
In a letter published in New England Journal of Medicine,2 researchers noted that this development raises concerns about "cerebral hemorrhages and necrotizing vasculopathy associated with t-PA infusion in a patient with cerebrovascular amyloid who had received lecanemab."
The death occurred in the open-label extension of the trial, and it was not the first. Eisai issued a rebuttal of the letter.3 While the letter acknowledges "this case raises important management issues," it highlights that this was an unusual case and the first such event occurring from the Clarity AD trial after treatment with t-PA. The letter goes on to note that "there have been earlier reports of fatal large catastrophic intracerebral hemorrhages after t-PA treatment in persons with cerebral amyloid angiopathy (CAA) in the absence of any antiamyloid medications."
1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948
2. Reish NJ, Jamshidi P, Stamm B, et al. Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Eng J Med. Published online January 4, 2022. doi:10.1056/NEJMc2215148
3. Sabbagh M, van Dyck CH. Response to: multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Eng J Med. Published online January 4, 2022. doi:10.1056/NEJMc2215907