Investigational drug lecanemab shows “potential” for treating Alzheimer’s disease, according to new results from a phase 3 study, but the results raise some safety concerns because it was linked to some serious adverse events.
Lecanemab has become one of the first experimental dementia drugs that appears to slow the progression of cognitive decline. The long-awaited study data were published in the New England Journal of Medicine on Tuesday, about two months after drugmakers Biogen and Eisai announced they were reducing cognitive and functional decline in a Phase 3 study. rate increased by 27%.
A phase 2 study showed no significant difference between lecanameb and placebo in Alzheimer’s patients at 12 months — but data from a phase 3 study showed lecanameb was linked to greater amyloid clearance associated with cognitive decline at 18 months.
“In people with early-stage Alzheimer’s disease, lecanemab reduced brain amyloid levels and was associated with less cognitive and functional decline than placebo but was associated with adverse events,” the researchers wrote. “Longer studies are needed to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
In a statement Tuesday, the Alzheimer’s Association said it welcomed the full phase 3 data and was further encouraged.
“These peer-reviewed published results suggest that lecanemab will give patients more time to participate in daily life and live independently. This could mean months before you recognize your spouse, children and grandchildren. Because Treatments that bring tangible benefits to patients with mild cognitive impairment (MCI) caused by Alzheimer’s disease and early Alzheimer’s dementia are as valuable as treatments that prolong the lives of patients with other incurable diseases.
The Phase 3 study was conducted at 235 sites in North America, Europe and Asia between March 2019 and March 2021. It included 1,795 adults, ages 50 to 90, who had mild cognitive impairment from early-stage Alzheimer’s disease or mild Alzheimer’s-related dementia.
About half of the participants were randomly assigned to receive lecanemab intravenously every two weeks, while the others received a placebo.
The researchers found that participants in both groups had a “clinical dementia score,” or CDR-SB score, of about 3.2 at the study’s baseline. Such scores are consistent with early Alzheimer’s disease, with higher scores associated with more severe cognitive impairment. After 18 months, the CDR-SB score increased by 1.21 points in the lecanemab group compared with 1.66 points in the placebo group.
“Significant differences can already be seen after six months,” said Dr. Christopher Van Dyke, the study’s author and director of the Yale Alzheimer’s Disease Research Center, spoke Tuesday at the Alzheimer’s Disease Clinical Trials Conference in San Francisco.
“Treatment with lecanemab met its primary and secondary endpoints,” he said.
Lecanemab is a monoclonal antibody that works by binding to amyloid-beta, a hallmark of degenerative brain disease. At the start of the study, participants in the lecanemab group had an average amyloid level of 77.92 cSt compared with 75.03 cSt in the placebo group.
The researchers found that after 18 months, average amyloid levels fell by 55.48 percentage points in the lecanemab group, while they rose by 3.64 percentage points in the placebo group.
Based on these results, “lecanemab has the potential to make a clinically meaningful difference in early-stage Alzheimer’s disease patients and their families by slowing cognitive and functional decline,” said Lynn Kramer, Chief Clinical Officer, Alzheimer’s Disease and Brain Health, Eisai said in a press release.
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.
The researchers also wrote that about 0.7% of participants in the lecanemab group and 0.8% of those in the placebo group died, corresponding to six deaths documented in the lecanemab group and seven in the placebo group. “No deaths were considered by the investigators to be related to lecanemab or occurred with ARIA,” they wrote.
The company aims to file for approval of the drug in the United States by the end of March, according to its news release. The US Food and Drug Administration has granted lecanemab “priority review.”
In July, the FDA accepted Eisai’s Biologics License Application for lecanemab under the accelerated approval pathway, according to the company. The program allows for earlier approval of drugs that treat serious conditions and “fill an unmet medical need” while the drugs are being studied in larger and longer trials.
If the trials confirm that the drug provides a clinical benefit, the FDA grants traditional approval. But if the confirmatory trial does not show benefit, the FDA has regulatory procedures that could lead to taking the drug off the market.
“The FDA is expected to decide whether to grant accelerated approval to lecanemab by January 6, 2023,” the Alzheimer’s Association statement says. “Should the FDA do so, the current [Center for Medicare and Medicaid Services] policy will prevent thousands and thousands of Medicare beneficiaries with a terminal, progressive disease from accessing this treatment within the limited span of time they will have to access it. If a patient decides with their health care provider that a treatment is right for them, Medicare must stand behind them as it does for beneficiaries with every other disease.”
‘This is just the first chapter’
“If and when this drug is approved by the FDA, it will take clinicians some time to be able to parse out how this drug may or may not be effective in their own individual patients,” especially since carriers of the APOE4 gene could be at higher risk of side effects, said Dr. Richard Isaacson, adjunct associate professor of neurology at Weill Cornell Medicine, who is not involved in studying lecanemab or its development.
“While this study is certainly encouraging, how this translates to clinical practice, real-world clinical practice, remains to be seen,” he said of the Phase 3 trial data.
Overall, “physicians are starving for any possible therapy out there that can help our patients. I have four family members with Alzheimer’s disease. If I have a family member that comes to me and says, ‘Should I be on this drug?’ In the right patient, at the right dose, for the right duration, with adequate and careful monitoring for side effects, yes, I would suggest that this drug is a viable option,” Isaacson said. “I would say even an important option.”
He added that the experimental drug serves as an example of the important need for personalized medicine in the United States, especially when it comes to Alzheimer’s disease, such as using genetic testing in clinical practice to identify the APOE gene to better individualize the approach to a patient’s care.
“This is just the first chapter in what I hope to become a really long book in disease-modifying therapies for Alzheimer’s disease,” he said.