The experimental drug lecanemab shows “potential” as a treatment for Alzheimer’s disease, according to new results from the phase 3 trial, but the findings raise safety concerns because of its association with certain serious side effects.
Lecanemab has become one of the first experimental dementia drugs to appear to slow the progression of cognitive decline.
The highly anticipated study data, published Tuesday in the New England Journal of Medicine, comes about two months after drugmakers Biogen and Eisai announced that lecanemab reduced cognitive and functional decline by 27% in their Phase 3 trial.
A phase 2 study showed no significant difference between lecanemab and placebo in patients with Alzheimer’s disease at 12 months – but the data from the phase 3 study suggests that lecanameb was associated with more amyloid clearance and less at 18 months cognitive decline.
“In subjects with early-stage 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-stage Alzheimer’s disease.”
The Alzheimer’s Association said in a statement Tuesday that it welcomes the full Phase 3 data and is further encouraged.
“These peer-reviewed, published results demonstrate that lecanemab will allow patients more time to participate in daily life and live independently. It could mean many more months to acknowledge their spouse, children and grandchildren. Treatments that provide tangible benefits for people with mild cognitive impairment (MCI) due to Alzheimer’s disease and early Alzheimer’s dementia are as valuable as treatments that extend the life of people with other terminal illnesses,” it says.
The Phase 3 trial 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 onset Alzheimer’s disease or mild Alzheimer’s-related dementia.
About half of the participants were randomly assigned to receive lecanemab, administered intravenously every two weeks, and 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 start of the trial. Such a score is consistent with early-stage Alzheimer’s disease, where a higher number is associated with more cognitive impairment. After 18 months, the CDR-SB score increased by 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,” said 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’ mean amyloid levels were 77.92 centiloids in the lecanemab group and 75.03 centiloids in the placebo group.
After 18 months, mean amyloid levels fell by 55.48 centiloids in the lecanemab group and 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 clinical officer of Alzheimer’s disease and brain health at Eisai, said in a press release.
About 6.9% of study participants in the lecanemab group discontinued the study due to side effects, compared to 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 side effects in the drug group were reactions to the intravenous infusions and abnormalities on their MRIs, such as brain swelling and cerebral hemorrhage, called amyloid-related imaging abnormalities, or ARIA.
“Lecanemab was generally well tolerated. Most side effects were infusion-related reactions, ARIA-H and ARIA-E, and headache,” said Dr. Marwan Sabbagh, an author of the study and a professor at the Barrow Neurological Institute, at Tuesday’s conference. He added that such events were resolved within months.
ARIA cerebral hemorrhage was observed 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 any symptoms, but it can occasionally lead to hospitalization or permanent disability. And the frequency of ARIA was found to be higher in people with a gene called APOE4, which may increase the risk of Alzheimer’s disease and other dementias. ARIA “was 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, which equates to six documented deaths in the lecanemab group and seven in the placebo group. “The investigators did not consider any deaths 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, the press release said. 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 process, the company said. The program allows for earlier approval of drugs that treat serious conditions and “fill an unmet medical need” while the drugs are studied in larger and longer trials.
If the studies confirm that the drug provides a clinical benefit, the FDA grants traditional approval. But if the confirmatory trial shows no benefit, the FDA has regulatory procedures that could result in the drug being withdrawn from the market.
“The FDA is expected to decide on January 6, 2023 whether to grant accelerated approval for lecanemab,” the Alzheimer’s Association statement said. “Should the FDA do that, the flow [Center for Medicare and Medicaid Services] policy will prevent thousands upon thousands of Medicare beneficiaries with terminal, progressive illness from accessing this treatment within the limited time they will have to access it. If a patient decides with their health care provider that a treatment is right for them, Medicare should be behind them, just as they would for beneficiaries with any other illness.
“If and when this drug is approved by the FDA, it will be some time before clinicians can parse out 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 of side effects. said dr. Richard Isaacson, an 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, it remains to be seen how this translates into clinical practice, real world clinical practice,” he said of the data from the Phase 3 trial.
In general, “doctors are starving for every possible therapy that can help our patients. I have four relatives with Alzheimer’s disease. If I have a family member come up to me and say, “Should I take this medicine?” 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. ”
He added that the experimental drug exemplifies the great 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 individualise the approach to a disease. the care of the patient.
“This is just the first chapter in what I hope will be a very long book on disease-modifying therapies for Alzheimer’s disease,” he said.
According to the Alzheimer’s Association, there are more than 300 treatments for Alzheimer’s disease 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 now affects more than 6 million adults in the United States.
There is no cure for Alzheimer’s disease, but several prescription drugs are available to help manage 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.
While lecanemab is being tested as a drug for Alzheimer’s disease, it is not a cure, said Tara Spiers-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 didn’t have that much of a decline in their cognitive abilities,” Spiers-Jones said in a written statement distributed by the UK-based Science Media Centre. “Longer trials will be needed to make sure the benefits of this treatment outweigh the risks.”
Overall, Alzheimer’s disease remains a “complex” disease, said Bart De Strooper, director of the UK Dementia Research Institute, in a statement distributed 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, and by doing so we can also identify new targets for which we can develop therapies that we could use in combination with anti-amyloid drugs such as lecanemab,” said De Strooper, who is a consultant to a range of pharmaceutical companies, including Eisai, but has not consulted on lecanemab.
“This trial proves that Alzheimer’s disease can be treated,” he said. “I hope we will see a turnaround in the chronic underfunding of dementia research. I look forward to a future where we treat these and other neurodegenerative diseases with a range of medicines tailored to the individual needs of our patients.”