The experimental drug lecanemab shows “potential” as an Alzheimer’s disease treatment, according to new Phase 3 trial results, but the findings raise some safety concerns because of its association with certain serious adverse events.
Lecanemab has become one of the first experimental dementia drugs to appear to slow the progression of cognitive decline.
The long-awaited trial data, published Tuesday in the New England Journal of Medicine, comes about two months after drugmakers Biogen and Eisai announced that lecanemab had been found to reduce cognitive and functional decline by 27% in their Phase 3 trial.
A Phase 2 trial did not show a significant difference between lecanemab and a placebo in Alzheimer’s disease patients in 12 months – but the Phase 3 trial data suggests that at 18 months, lecanameb was associated with more clearance of amyloid and less cognitive decline.
“In persons with early Alzheimer’s disease, lecanemab reduced brain amyloid levels and was associated with less decline on clinical measures of cognition and function than placebo at 18 months but was associated with adverse events,” the researchers wrote. “Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
The Alzheimer’s Association said in a statement Tuesday that it welcomes and is further encouraged by the full Phase 3 data.
“These peer-reviewed, published results show lecanemab will provide patients more time to participate in daily life and live independently. It could mean many months more of recognizing their spouse, children and grandchildren. Treatments that deliver tangible benefits to those living with mild cognitive impairment (MCI) due to Alzheimer’s and early Alzheimer’s dementia are as valuable as treatments that extend the lives of those with other terminal diseases,” it says.
Clearing the amyloid
The Phase 3 trial was conducted at 235 sites in North America, Europe and Asia from March 2019 through March 2021. It involved 1,795 adults, ages 50 to 90, with mild cognitive impairment due to early Alzheimer’s disease or mild Alzheimer’s disease-related dementia.
About half of the participants were randomly assigned to receive lecanemab, given intravenously every two weeks, and the others received a placebo.
The researchers found that participants in both groups had a “clinical dementia rating” or CDR-SB score of about 3.2 at the start of the trial. Such a score is consistent with early Alzheimer’s disease, with a higher number associated with more cognitive impairment. By 18 months, the CDR-SB score went up 1.21 points in the lecanemab group, compared with 1.66 in the placebo group.
“Significant differences emerge as early as the six-month timepoint,” Dr. Christopher van Dyck, an author of the study and director of the Yale Alzheimer’s Disease Research Center, said Tuesday during a presentation at the Clinical Trials On Alzheimer’s Disease Conference in San Francisco.
“The lecanemab treatment met the primary and secondary endpoints,” he said.
Lecanemab, a monoclonal antibody, works by binding to amyloid beta, a hallmark of the degenerative brain disorder. At the start of the study, the participants’ average amyloid level was 77.92 centiloids in the lecanemab group and 75.03 centiloids in the placebo group.
By 18 months, the average amyloid level dropped 55.48 centiloids in the lecanemab group and went up 3.64 centiloids in the placebo group, the researchers found.
Based on these results, “lecanemab has the potential to make a clinically meaningful difference for people living with the early stages of Alzheimer’s disease and their families by slowing cognitive and functional decline,” Dr. Lynn Kramer, chief clinical officer of Alzheimer’s disease and brain health at Eisai, said in a news release.
Evaluating the safety
About 6.9% of the trial participants in the lecanemab group discontinued the trial due to adverse events, compared with 2.9% of those in the placebo group. Overall, there were serious adverse events in 14% of the lecanemab group and 11.3% of the placebo group.
The most common adverse events in the drug group were reactions to the intravenous infusions and abnormalities on their MRIs, such as brain swelling and brain bleeding called amyloid-related imaging abnormalities, or ARIA.
“Lecanemab was generally well-tolerated. Most adverse events were infusion-related reactions, ARIA-H and ARIA-E and headache,” Dr. Marwan Sabbagh, an author of the study and professor at the Barrow Neurological Institute, said during Tuesday’s conference. He added that such events resolved within months.
ARIA brain bleeding was seen among 17.3% of those who received lecanemab and 9% of those in the placebo group; ARIA brain swelling was documented in 12.6% with lecanemab and 1.7% with placebo, according to the trial data.
Some people who get ARIA may not have symptoms, but it can occasionally lead to hospitalization or lasting impairment. And the frequency of ARIA appeared to be higher in people who had a gene called APOE4, which can increase the risk of Alzheimer’s disease and other dementias. ARIA “were numerically less common” among APOE4 noncarriers, the researchers wrote.