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 it’s been 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 trial data were published in the New England Journal of Medicine on Tuesday, about two months after drugmakers Biogen and Eisai announced that they found lecanemab could Reduced cognitive and functional decline by 27%.
Phase 2 trial didn’t show significant difference between lecanemab and placebo in Alzheimer’s patients at 12 months — but data from phase 3 trial showed lecanemab was associated with greater amyloid clearance and greater amyloid clearance at 18 months Associated with less cognitive decline.
“In individuals with early-stage Alzheimer’s disease, lecanemab reduced brain amyloid levels and clinical measures of cognition and function decreased less than placebo, but compared with placebo,” the researchers wrote. adverse events.” “Longer trials 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 more before they recognize their spouses, children and grandchildren.” Treatments that bring tangible benefits to people with mild cognitive impairment (MCI) in Alzheimer’s disease and early Alzheimer’s dementia are just as valuable as treatments that prolong the lives of people with other terminal illnesses,” it said.
The Phase 3 trial was conducted from March 2019 to March 2021 at 235 sites in North America, Europe and Asia. It involved 1,795 adults between the ages of 50 and 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 intravenously every two weeks, and the others received a placebo.
The researchers found that participants in both groups had a “clinical dementia scale” or CDR-SB score of about 3.2 at the start of the trial. Such scores are consistent with early Alzheimer’s disease, with higher scores associated with more cognitive impairment. At 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 were seen as early as the six-month time point,” said Dr. One of the study’s authors, Christopher Van Dyke, director of the Yale Alzheimer’s Disease Research Center, said Tuesday in a presentation at the Alzheimer’s Disease Clinical Trials Conference in San Francisco.
“Lecanemab treatment with primary and secondary endpoints,” he said.
Lecanemab is a monoclonal antibody that works by binding to amyloid, a hallmark of degenerative brain disease. At the start of the study, participants’ mean amyloid levels were 77.92 cSt in the lecanemab group and 75.03 cSt in the placebo group.
The researchers found that at 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, in a statement. said at a press conference.
Some 6.9% of trial participants in the lecanemab group discontinued the trial due to adverse events, compared with 2.9% 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 fluids and MRI abnormalities, such as brain swelling and cerebral hemorrhage, known as 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,” study co-author Marwan Sabbagh, a professor at the Barrow Neurological Institute, said at Tuesday’s meeting . Such incidents were resolved within months, he added.
ARIA cerebral hemorrhage occurred in 17.3% of lecanemab-treated patients and 9% of placebo-treated patients; according to the trial data, ARIA brain swelling occurred in 12.6% and 1.7% of patients treated with lecanemab and placebo, respectively.
Some people with ARIA may have no symptoms, but occasionally it can lead to hospitalization or permanent damage. The frequency of ARIA appears to be higher in people who carry the APOE4 gene, which increases the risk of Alzheimer’s disease and other dementias. ARIA was “quantitatively less common” in APOE4 noncarriers, the researchers wrote.
The researchers also wrote that approximately 0.7% of participants in the lecanemab group and 0.8% of participants in the placebo group died, corresponding to 6 deaths recorded in the lecanemab group and 7 deaths recorded in the placebo group. “The investigators considered no deaths related to lecanemab or related to ARIA,” they wrote.
The company aims to file for approval of the drug in the U.S. by the end of March, according to its press release. The U.S. Food and Drug Administration has granted “priority review” to lecanemab.
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 diseases and “fill an unmet medical need” while they are being studied in larger and longer trials.
If the trials demonstrate that the drug has clinical benefit, the FDA grants traditional approval. But if confirmatory trials don’t show benefit, the FDA’s regulatory process could lead to the drug being withdrawn from the market.
“The FDA is expected to make a decision on whether to grant accelerated approval to lecanemab by January 6, 2023,” the Alzheimer’s Association statement said. “If the FDA does this, the current [Center for Medicare and Medicaid Services] The policy would prevent thousands of Medicare beneficiaries with advanced, progressive disease from getting it for the limited time they must. If patients and their health care providers decide that a certain treatment is right for them, then Medicare must support them, just as it supports beneficiaries with all other illnesses. ”
“If this drug is approved by the FDA, it will take some time for clinicians to analyze why this drug may or may not be effective in their own patients,” especially since carriers of the APOE4 gene may be at higher risk of side effects, Dr. said. Richard Isaacson, Adjunct Associate Professor of Neurology at Weill Cornell Medicine, was not involved in the research of lecanemab or its development.
“While this study is certainly encouraging, it remains to be seen how this translates into clinical practice, real-world clinical practice,” he said of the phase 3 trial data.
In general, “doctors are eager to find any possible therapy that can help our patients. I have four family members with Alzheimer’s disease. If my family members come to me and say, ‘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 this drug is a viable option,” Isaacson said. “I’d even say an important choice.”
He added that the experimental drug is an example of the important need for personalized medicine in the United States, especially in Alzheimer’s disease, such as the use of genetic testing to identify the APOE gene in clinical practice to better personalize treatment Methods of patient care.
“This is just the first chapter of what I hope will be a long book on disease-modifying therapies 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 brain tissue changes in a woman with memory loss, language problems and unpredictable behavior changed. This debilitating 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 that can help manage symptoms. Last year, the FDA approved Aduhelm for the early stages of Alzheimer’s disease. Prior to this, the FDA had not approved a new treatment for the condition since 2003.
While lecanemab is being tested as an Alzheimer’s drug, it is not a cure, said Tara Spires-Jones, deputy director of the Brain Science Discovery Center at the University of Edinburgh, who was not involved in the trial.
“Both groups in the trial had worsening symptoms, but those who took the drug did not experience as much cognitive decline,” Spiers-Jones said in a written statement distributed by Britain’s Science Media Centre. “Longer trials are needed to ensure that the benefits of this treatment outweigh the risks.”
Overall, Alzheimer’s remains a “complex” disease, Bart De Strooper, director of Dementia Research UK, said in a statement released by the Science Media Centre.
“We still have a lot to learn about the underlying causes. So we must continue to invest in discovery research, and by doing so, we can also identify new targets against which we can develop anti-amyloid drugs that we can interact with.” (such as lecanemab) in combination,” said De Strooper, who is an advisor to a string of pharmaceutical companies, including Eisai, but has not consulted on lecanemab.
“This trial demonstrates that Alzheimer’s disease is treatable,” he said. “It is my hope that we will begin to see a reversal of the chronic underfunding of dementia research. I look forward to a future where we can treat this and other neurodegenerative diseases with a range of drugs tailored to a patient’s individual needs. ”