NEW YORK – The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) on Friday recommended against marketing authorization for Eisai and Biogen's Alzheimer's disease drug Leqembi (lecanemab).
The CHMP determined that the "observed effect of Leqembi on delaying cognitive decline does not counterbalance the risk of serious side events associated with the medicine." The European Commission will consider the CHMP's opinion when deciding whether to make Leqembi available to patients in the EU.
Leqembi has been approved in the US since last year, as well as in Japan, China, South Korea, Hong Kong, and Israel. At least in the US, despite regulatory approval, doctors are not of one mind about the drug's risk/benefit profile, and many question whether Leqembi's clinical benefits seen in clinical trials will actually improve their patients' daily lives.
Eisai has reported that patients in its CLARITY AD Phase III trial treated with Leqembi experienced a 27 percent slower rate of cognitive decline compared to the placebo group based on the 18-point Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale. That is, after 18 months, Leqembi-treated patients on average scored 0.45 points better on this scale than patients on placebo.
"Although patients given Leqembi had lower CDR-SB scores than those given placebo, the difference between the two groups was small," the CHMP said after reviewing the same data.
In particular, committee members raised concerns about the occurrence of a side effect known as amyloid-related imaging abnormalities (ARIA), which can include temporary swelling or bleeding in the brain. Most patients with ARIA are asymptomatic, but the condition can be associated with headache, dizziness, nausea, and, infrequently, serious brain edema and severe neurological symptoms.
In the CLARITY AD study, ARIA due to edema (ARIA-E) occurred in 12.6 percent and 1.7 percent of patients who received Leqembi and placebo, respectively. ARIA due to hemosiderin deposition (ARIA-H) occurred in 16.9 percent of treated patients and 8.9 percent of patients who received placebo.
Most of these cases were asymptomatic, with symptomatic ARIA-E observed in 2.8 percent of treated patients and in none of the patients in the placebo group. Researchers observed symptomatic ARIA-H in 0.7 percent and 0.2 percent of Leqembi-treated and placebo patients, respectively.
In the US, the FDA has placed boxed warnings about the risk of ARIA on the labels of Leqembi and Eli Lilly's Kisunla (donanemab), another beta-amyloid-targeting Alzheimer's drug approved in the US earlier this month. In the warnings, the agency also recommends genetic testing to assess if patients carry two copies of the APOE4 allele, which is a risk factor for ARIA.
Eisai, which leads Leqembi's development and regulatory submissions globally, said it will ask the CHMP to reexamine its opinion. "We are extremely disappointed by the CHMP's negative opinion and understand that this may also be disappointing for the wider Alzheimer's disease community," Lynn Kramer, Eisai's chief clinical officer, said in a statement.
The negative regulatory news from the EU comes as Eisai and Biogen are trying to grow Leqembi's adoption in the market amid slower-than-projected uptake. Eisai had initially said it expected 10,000 US patients to be taking Leqembi and around ¥10 billion ($63.3 million) in sales by March 2024, the end of its last fiscal year. However, Eisai in May reported ¥4.26 billion in Leqembi sales during fiscal 2023. And as of late January — the last time the firm disclosed patient numbers — Eisai reported around 2,000 patients had received Leqembi but claimed about 8,000 patients were on waiting lists.