A participant died in a clinical trial of a Federal Drug Administration-approved antibody treatment for Alzheimer’s disease, and the death may be linked to the drug, a new case report reveals.
The case, published in May in the Journal of Alzheimer’s Disease, details unreported adverse outcomes associated with the use of Lecanemab (Lequembi), an anti-amyloid plaque therapy intended to slow disease progression.
Despite receiving accelerated approval from the FDA in January, the drug faced a setback when the Center for Medicaid Services rejected a petition for broader coverage under Medicaid just a month later, maintaining a restrictive policy for this class of Alzheimer’s treatment. CMS’ analysis, which differs from FDA criteria, highlights lingering concerns regarding the drug’s safety and effectiveness, as outlined in their rejection letter.
Researchers examined the case of a 65-year-old woman with Alzheimer’s disease who underwent three open-label infusions of Lecanemab. This experimental antibody targets amyloid protein plaques, a characteristic feature of Alzheimer’s disease. The trial, spanning 18 months, enrolled 1,795 participants aged 50 to 90 with early-stage Alzheimer’s disease. The aim of the trial was to assess the safety and effectiveness of Lecanemab as a potential treatment option for the condition
The authors determined that the patient’s brain tissue and blood supply were impacted by “therapy-induced Aβ phagocytosis,” a process typically involved in clearing debris and protecting neurons. Lecanemab, in this case, triggered the stimulation of this process, ultimately resulting in the patient’s unfortunate demise.
While clinical trials have been conducted for over 20 years and have revealed known adverse reactions, researchers still have a limited understanding of how cells respond to experimental antibodies and how amyloid protein is cleared from the brain, Dr. Rudolph J. Castellani, the lead investigator and a Professor at Northwestern University Feinberg School of Medicine, said in a statement. “In my view, it is evident in this case that the patient’s response to the anti-Aβ therapy resulted in clinical symptoms and created a condition that led to hemorrhage despite therapeutic intervention, highlighting the possibility of a potentially fatal drug interaction,” he said.
He added that this raises questions about whether patients receiving anti-Aβ treatments can be adequately assessed for the extent of cerebral amyloid angiopathy (CAA), which can vary in Alzheimer’s disease, as observed in this case.
On a positive note, there appeared to be some degree of amyloid clearance and possibly even a reduction in phosphorylated tau, another protein associated with neurodegenerative disease, which has not been previously reported.
“In summary, while improvement was achieved, it came at the cost of collateral damage to small blood vessels affected by CAA,” Castellani said.
Dr. M Marsel Mesulam, the chief of behavioral neurology in the Department of Neurology at Northwestern University Feinberg School of Medicine, noted that while the benefits of the drug may be modest at the group level, the individual patient’s response remains uncertain.
Furthermore, this case report underscores the potential devastating consequences of Lecanemab’s side effects, emphasizing the importance of screening patients for cerebrovascular disease before prescribing the medication. Additionally, patients should be informed about the increased risks associated with anticoagulant treatment for stroke, if it occurs.
In other trials, patients who died while treated with Lecanemab were also given a drug called tissue plasminogen activator (tPA). Dr. Marc Gordon, chief of neurology at Zucker Hillside Hospital, told The Epoch Times that the issue may not be that the Lecanemab caused a stroke.
“I think the issue is that when this patient who was on Lecanemab presented with stroke-like symptoms, she was given this tPA, this clot-busting drug and developed hemorrhage from that,” he said. “That hemorrhage may have been because she had this underlying condition, cerebral amyloid angiopathy, which makes the blood vessels more prone to bleed, particularly when they’re exposed to this type of a drug.”
According to Gordon, accelerated FDA approval process for Lecanemab was based on phase II data and not the Clarity phase III data published in the New England Journal of Medicine in November. The phase III study data are currently under consideration by the advisory committee. It is crucial to interpret events like these seriously but understand that it does not imply that nobody should ever receive this medication.
Rebecca Edelmayer, Ph.D., senior director of scientific engagement at the Alzheimer’s Association, said that the organization is “very encouraged” about the increasing number of new treatments being approved and in the clinical trial pipeline for Alzheimer’s disease. “But, no matter what [the] treatment pipeline looks like, it’s always going to be a discussion about both the benefits and potential risks for patients as they think about opportunities to have options, and what their treatment and care plan looks like,” she said.
The cost of Lecanemab treatment, estimated at $37,600 a year according to drugmaker Eisai (in partnership with Biogen), poses a challenge for Medicaid recipients who would have to pay out-of-pocket due to the CMS decision.
While CMS will continue to reimburse the drug’s costs in clinical trial settings under the “coverage with evidence development,” lack of coverage for approved treatments in this class is concerning and creates barriers to access, according to Edelmayer.
“The Centers for Medicaid decision to continue to deny coverage of an FDA approved Alzheimer’s treatment in this class of treatment is really disconcerting, it’s appalling, and it’s really creating barriers to access,” she said.
This is not the first time that a CMS decision has impacted drugs in this class, as Aducanumab (Aduhelm), also produced by Eisai in partnership with Biogen, with an estimated cost of $28,200 per year (recently reduced from $56,000), faced similar coverage restrictions after an accelerated approved by the FDA.