Eisai & Biogen Address Lecanemab's Safety Concerns at CTAD


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Full data presented Tuesday afternoon from the Phase III Clarity AD trial show Eisai and Biogen's lecanemab has a favorable safety profile in patients with Alzheimer's disease. 

The presentation at the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference comes amid mounting concerns about lecanemab's safety. 

In October, an unnamed Clarity AD investigator linked a patient's death to lecanemab. Now, a second death reported Monday is also being attributed to the investigational drug by an external expert. Both deaths were due to bleeding in the brain.

During the CTAD session, Marwan Sabbagh, M.D., a behavioral neurologist at the Barrow Neurological Institute, said that in the randomized, placebo-controlled analysis, "there were no ARIA-related deaths." ARIA, or amyloid-related imaging abnormalities, are physiological anomalies in the brain detected by magnetic resonance imaging, often attributed to amyloid-modifying therapies.

Causes of death in the lecanemab arm included cerebrovascular accident, myocardial infarction, respiratory failure, metastases to meninges and COVID-19.

Nevertheless, Sabbagh conceded that two deaths were associated with cerebral microhemorrhages in the open-label extension phase of the study. One of these deaths occurred in the context of a tissue plasminogen activator, which Sabbagh said is thrombolytic with a known potential complication risk of hemorrhage.

The second patient who died was on medication for atrial fibrillation, had had pneumonia and previously experienced many falls.

"These cases show that the causality with lecanemab is a little difficult" to establish, Sabbagh said. Whether treatment with the investigational antibody and deaths are indeed causally related remains under investigation.

ARIA suggestive of edema (ARIA-E) occurred in 12.6% of lecanemab-treated patients, as opposed to only 1.7% of the placebo arm. Nevertheless, most ARIA-E events were mild-to-moderate in severity, with 78% of such episodes being asymptomatic. 

Twenty-five lecanemab recipients had symptomatic ARIA-E, which typically manifested as confusion, headache and visual disturbances. Most ARIA-E episodes occurred within six months of treatment and generally resolved within four months of detection.

"We know when the ARIA-E events are likely to occur and when they are likely to resolve," Sabbagh said.

Questions About Clinical Meaningfulness Remain 

Tuesday's presentation follows an earlier efficacy readout in September, which showed lecanemab was indeed effective at slowing cognitive decline in Alzheimer's disease patients. 

These data, confirmed at CTAD, indicate that lecanemab slowed clinical decline by 27% as compared with placebo, as measured by the Clinical Dementia Rating scale Sum of Boxes (CDR-SB).

Lecanemab also outperformed placebo on all key secondary endpoints. For instance, at 18 months, the drug candidate slowed cognitive decline by 26%, as measured by the ADAS-Cog14 scale, and disease progression by 24%, as assessed by the ADCOMS tool. 

Biomarker analysis also revealed that lecanemab treatment reduced amyloid levels in the patients' plasma and cerebrospinal fluid. Positron emission tomography likewise showed that at 18 months, amyloid levels had dropped below the positivity threshold. 

As its primary metric for lecanemab efficacy, Clarity AD used CDR-SB, a validated scale used in many Alzheimer's trials. The CDR-SB score is obtained through interviews with patients and their care partners and evaluates cognition across six domains: memory, orientation, personal care, home and hobbies, community affairs and judgment and problem-solving.

While these domains have been established as important and relevant for the patients and caregivers, a New England Journal of Medicine article published Tuesday, along with the CTAD presentation, reported that "a definition of clinically meaningful effects in the primary endpoint of the CDR-SB score has not been established."

Despite meeting its predefined treatment target, Clarity AD needs to be followed up with longer trials "to determine the efficacy and safety of lecanemab in early Alzheimer's," the authors of the NEJM article recommended.

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