The experimental drug lecanemab shows “potential” as a treatment for Alzheimer’s disease, according to new phase 3 study results, but the findings raise some safety concerns due to its association with certain serious side effects.
Lecanemab has become one of the first experimental dementia drugs that appears to slow the progression of cognitive decline.
The long-awaited study 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 study did not show a significant difference between lecanemab and placebo in patients with Alzheimer’s disease over 12 months – but the data from the phase 3 studies suggest that at 18 months, lecanemab was associated with more clearance of amyloid and less cognitive decline.
“In subjects with early Alzheimer’s disease, lecanemab reduced brain amyloid levels and was associated with less decline in clinical measures of cognition and function than placebo at 18 months, but was associated with side effects,” 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 that lecanemab will give patients more time to participate in daily life and live independently. That could mean many more months of acknowledging their spouse, children and grandchildren. Treatments that provide 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 illnesses,” it says.
The Phase 3 study was conducted at 235 sites in North America, Europe and Asia from March 2019 to March 2021. It involved 1,795 adults aged 50 to 90 years, 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 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 study. Such a score is consistent with early Alzheimer’s disease, with a higher number associated with more cognitive impairment. After 18 months, the CDR-SB score increased 1.21 points in the lecanemab group, compared to 1.66 in the placebo group.
“Significant differences emerge as early as the six-month time point,” Dr. Christopher van Dyck, study author 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 disease. 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.
After 18 months, the average amyloid level fell by 55.48 centiloids in the lecanemab group and increased by 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 of the Alzheimer’s Disease and Brain Health Clinic at Eisai, said in a press release.
About 6.9% of study participants in the lecanemab group discontinued the study due to adverse events, compared with 2.9% of those in the placebo group. Overall, there were serious side effects in 14% of the lecanemab group and 11.3% of the placebo group.
The most common side effects in the drug group were reactions to intravenous infusions and abnormalities on their MRIs, such as brain swelling and brain bleeding called amyloid-related imaging abnormalities, or ARIAs.
“Lecanemab was generally well tolerated. Most of the side effects were infusion-related reactions, ARIA-H and ARIA-E and headache,” said Dr. Marwan Sabbagh, author of the study and professor at the Barrow Neurological Institute, during Tuesday’s conference. He added that such events was resolved within months.
ARIA cerebral hemorrhage was seen in 17.3% of those receiving 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 study data.
Some people who get ARIA may not have symptoms, but it can occasionally lead to hospitalization or permanent debilitation. And the rate 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 “was numerically less common” among APOE4 non-carriers, 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 judged by the investigators to be related to lecanemab or occurred with ARIA,” they wrote.
The company aims to apply for approval of the substance in the US by the end of March, according to the press 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 medicines that treat serious conditions and “fill an unmet medical need” while the medicines are being studied in larger and longer studies.
If the trials confirm that the drug provides a clinical benefit, the FDA grants traditional approval. But if the confirmatory trial doesn’t show benefit, the FDA has regulatory procedures that could lead to the drug being taken off the market.
“The FDA is expected to decide whether to grant accelerated approval to lecanemab by January 6, 2023,” the Alzheimer’s Association said. “Should the FDA do it, applicable [Center for Medicare and Medicaid Services] the policy will prevent thousands and thousands of Medicare beneficiaries with a terminal, progressive disease from accessing this treatment within the limited time period they will have to access it. If a patient with a health care provider decides that a treatment is right for them, Medicare must stand behind them as it does for beneficiaries with all other diseases.”
“If and when this drug is approved by the FDA, it will take some time for clinicians to be able to analyze how this drug may or may not be effective in their own individual patients,” especially since carriers of the APOE4 gene may be at higher risk for side effects , said Dr. Richard Isaacson, assistant professor of neurology at Weill Cornell Medicine, who is not involved in studying lecanemab or its development.
“While this study is certainly encouraging, it remains to be seen how this translates into clinical practice, the real clinical practice,” he said of the phase 3 study data.
Overall, doctors are hungry 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 who comes to me and says, ‘Should I use 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 the use of genetic testing in clinical practice to identify the APOE gene to better individualize the approach to a the patient’s care.
“This is just the first chapter in what I hope will be a very long book in disease-modifying therapies for Alzheimer’s disease,” he said.
More than 300 Alzheimer’s treatments are in clinical trials, according to the Alzheimer’s Association.
Alzheimer’s disease was first documented in 1906, when Dr. Alois Alzheimer discovered changes in the brain tissue of a woman who had memory loss, language problems and unpredictable behavior. The devastating disease now affects more than 6 million adults in the United States.
There is no cure for Alzheimer’s disease, but there are several prescription medications available to help manage the symptoms. Last year, the FDA approved Aduhelm for early stages of Alzheimer’s disease. Before that, the FDA had not approved a new therapy for the condition since 2003.
Although lecanemab is being tested as an Alzheimer’s drug, it is not a cure, said Tara Spires-Jones, deputy director of the Center for Discovery Brain Sciences at the University of Edinburgh, who was not involved in the trial.
“Both groups in the study had worsening symptoms, but people taking the drug did not decline as much in cognitive skills,” Spiers-Jones said in a written statement distributed by Britain’s Science Media Centre. “Longer trials will be needed to be sure that the benefits of this treatment outweigh the risks.”
Overall, Alzheimer’s continues to be a “complex” disease, Bart De Strooper, director of the UK Dementia Research Institute, said in a statement distributed by the Science Media Centre.
“We still have a lot to learn about the underlying causes. It is therefore important that we continue to invest in discovery research, and by doing so we can also identify new targets for which we can develop therapies in combination with anti-amyloid drugs such as lecanemab, says De Strooper, who is a consultant for a number of pharmaceutical companies, including Eisai, but have not consulted on lecanemab.
“This study proves that Alzheimer’s disease is treatable,” he said. “I hope we will start to see a reversal in the chronic underfunding of dementia research. I look forward to a future where we treat this and other neurodegenerative diseases with a battery of medicines tailored to the individual needs of our patients.”