The experimental drug lecanemab shows “potential” as a treatment for Alzheimer’s disease, according to new Phase 3 trial results, but the findings raise some safety concerns as it is linked to some serious adverse events.
Lecanemab was 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 nearly two months after drugmakers Biogen and Eisai announced that lecanemab reduced cognitive and functional decline by 27% in Phase 3 trials.
A Phase 2 trial showed no significant difference between lecanemab and placebo in Alzheimer’s disease patients at 12 months – but Phase 3 trial data showed that at 18 months, lecanameb was associated with greater clearance of amyloid and less cognitive decline.
“In people with early Alzheimer’s disease, lecanemab reduced brain amyloid levels and was associated with less decline in clinical measures of cognition and function at 18 months than placebo, but was associated with adverse events,” the researchers said. “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 on Tuesday that it welcomes the full Phase 3 data and is encouraged by it.
“These peer-reviewed, published results show that lecanemab will give patients more time to participate in daily life and live independently. This may mean more months to get to know your spouse, children and grandchildren. “Treatments that financially benefit those living with mild cognitive impairment (MCI) due to Alzheimer’s and early Alzheimer’s dementia are just as valuable as treatments that extend life for those with other terminal illnesses,” he says.
The Phase 3 trial was conducted from March 2019 to March 2021 at 235 sites in North America, Europe and Asia. It included 1,795 adults between the ages of 50 and 90 who had mild cognitive impairment due to early 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 rating” or CDR-SB score of about 3.2 at the start of the trial. Such a score corresponds to early Alzheimer’s disease, with a higher number associated with more cognitive impairment. By 18 months, the CDR-SB score increased by 1.21 points in the lecanemab group compared to 1.66 in the placebo group.
The author of the study and director of the Yale Alzheimer’s Disease Research Center, Dr. “Significant differences emerge at the six-month time point,” Christopher van Dyk said during a presentation at the Alzheimer’s Disease Clinical Trials Conference in San Francisco on Tuesday.
“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, participants’ mean amyloid levels were 77.92 centiloids in the lecanemab group and 75.03 centiloids in the placebo group.
By 18 months, the researchers found that mean amyloid levels decreased by 55.48 centiloids in the lecanemab group and increased by 3.64 centiloids in the placebo group.
Based on these results, “lecanemab has the potential to make a clinically meaningful difference for people living with early stages of Alzheimer’s disease and their families by slowing cognitive and functional decline,” said Dr. Lynn Kramer, chief clinical officer of Alzheimer’s disease and the brain. Health at Eisai, says a press release.
Approximately 6.9% of trial participants in the lecanemab group discontinued the trial due to adverse events, compared with 2.9% of those in the placebo group. Overall, serious adverse events occurred 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 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 adverse events were infusion-related reactions, ARIA-H and ARIA-E, and headache,” he said, adding that such events resolved within months.
ARIA cerebral hemorrhage occurred in 17.3% of the lecanemab group and 9% of the placebo group; According to trial data, ARIA brain swelling was documented in 12.6% with lecanemab and 1.7% with placebo.
Some people who receive ARIA may not have symptoms, but it can sometimes lead to hospitalization or long-term impairment. People with a gene called APOE4, which can increase the risk of Alzheimer’s disease and other dementias, had a higher incidence of ARIA. ARIA was “numerically less common” among non-APOE4 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 documented deaths in the lecanemab group and seven in the placebo group. “The investigators considered that no deaths were related to lecanemab or caused by ARIA,” they wrote.
The company plans to apply for the drug’s approval in the US by the end of March. The US Food and Drug Administration has given lecanemab a “priority review”.
In July, the FDA accepted Eisai’s Biologics License Application for lecanemab through accelerated approval, the company said. The program allows drugs that treat serious conditions and “fill an unmet medical need” to be approved earlier while the drugs are being studied in larger and longer trials.
If trials confirm that the drug provides clinical benefit, the FDA grants traditional approval. But if a confirmatory trial doesn’t show benefit, the FDA has regulatory procedures that can lead to taking a 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 said in a statement. “If the FDA does it, current [Center for Medicare and Medicaid Services] the policy will prevent thousands and thousands of Medicare beneficiaries with terminal, progressive disease from seeking this treatment during the limited time to access it. If a patient decides that treatment with a health care provider is right for them, Medicare must stand behind them, just as it does for all other disease beneficiaries.
“If and when this drug is approved by the FDA, it will take some time for clinicians to analyze how effective this drug is in individual patients,” especially those who may be carriers of the APOE4 gene. higher risk of side effects, said Dr. Richard Isaacson said.
“While this study is certainly encouraging, it remains to be seen how this translates into clinical practice, real-world clinical practice,” said the Phase 3 trial data.
In general, “doctors are hungry for any treatment that can help our patients. I have four family members with Alzheimer’s. The person who comes to me and says, “Should I use this drug?” If I had a family member who said, In the right patient, at the right dose, for the right duration, with adequate and careful monitoring of side effects, yes, I would suggest that this drug is a viable option,” Isaacson said. “I would even say an important option.”
He added that the experimental drug is an example of the important need for personalized medicine in the United States, especially when it comes to Alzheimer’s disease, for example, which is used to better personalize the approach to identifying the APOE gene in clinical practice using genetic testing. patient care.
“This is the first chapter in what I hope will be a really long book in disease-modifying treatments for Alzheimer’s disease,” he said.
According to the Alzheimer’s Association, more than 300 Alzheimer’s treatments are in clinical trials.
Alzheimer’s disease was first documented in 1906, when Dr. Alois Alzheimer discovered changes in the brain tissue of a woman with memory loss, language problems, and unpredictable behavior. The debilitating disease currently affects more than 6 million adults in the United States.
There is no cure for Alzheimer’s disease, but there are several prescription medications that can help manage symptoms. Last year, the FDA approved Aduhelm for the early stages of Alzheimer’s disease. Before that, the FDA had not approved a new treatment for the condition since 2003.
Although lecanemab is being tested as an Alzheimer’s drug, it is not a cure, said Tara Spiers-Jones, deputy director of the University of Edinburgh’s Brain Science Discovery Center, who was not involved in the trial.
“During the trial, both groups had worsening symptoms, but people taking the drug did not decline as much in their cognitive skills,” Spiers-Jones said in a written statement released by the UK-based Science Media Center. “Longer trials will be needed to make sure the benefits of this treatment outweigh the risks.”
Overall, Alzheimer’s remains a “complex” disease, said Bart De Strooper, director of the UK’s Dementia Research Institute, in a statement released by the Science Media Centre.
“We still have a lot to learn about the underlying causes. It is therefore imperative that we continue to invest in discovery research, so that we can also identify new targets where we can develop treatments that can be used in combination with anti-amyloid drugs such as lecanemab,” said De Strooper. He is a consultant for a number of pharmaceutical companies, including Eisai, but has not consulted on lecanemab.
“This trial proves that Alzheimer’s disease is treatable,” he said. “I hope we will start to see a turnaround in chronic funding for dementia research. I look forward to the future when we treat these and other neurodegenerative diseases with a battery of drugs tailored to the individual needs of our patients.”