Image credit: Beta-Amyloid Plaques and Tau in the Brain | Wikimedia Commons
On July 6th, the U.S. FDA announced that it has converted the Alzheimer’s disease therapy Leqembi (lecanemab) to traditional approval after confirming clinical efficacy. According to the FDA news release, Leqembi is the first anti-β amyloid antibody that became conventionally approved Alzheimer’s disease therapy. Industry media Endpoints also pointed out that this is the first time in 20 years that the FDA has fully approved an Alzheimer’s disease drug.
Originally developed jointly by Eisai and BioArctic, Lecanemab binds specifically to soluble oligomers that β amyloid. In the brains of AD patients, elevated levels of β amyloid encourage them to aggregate from monomers to dimers and soluble oligomers, and eventually further to amyloid deposits in the brain. Previous scientific studies have shown that soluble oligomers β amyloid exhibit greater cytotoxicity than monomers. By binding to them, Lecanemab neutralizes and removes toxic soluble oligomers.
In January, the FDA accelerated its marketing approval for the treatment of Alzheimer’s disease based on the effect of lecanemab in reducing amyloid deposition in patients’ brains. New drugs approved for marketing based on the accelerated approval pathway require confirmatory clinical trials to confirm their clinical efficacy. A month ago, at a consultation meeting held by the US FDA, the participating experts voted 1:6 to believe that the results of the Phase 0 clinical trial CLARITY AD support the full approval of Leqembi.
The evaluation materials provided by the FDA to the expert committee meeting showed that in this phase 3 clinical trial, lecanemab significantly reduced the rate of increase in CDR-SB, the primary endpoint of the trial, compared with placebo (higher CDR-SB score means lower clinical function of the patient). At week 79, the change in mean CDR-SB score was reduced by 27% compared to the placebo group. The FDA considers CDR-SB to be a comprehensive indicator that is effective in assessing a patient’s cognitive ability and daily functioning. Statistically significant changes in CDR-SB are clinically significant.
Secondly, the change in the primary endpoint CDR-SB score was supported by improvements in consistency across multiple secondary endpoints, including the ADAS-Cog 14 score, which independently assesses cognitive ability, and the ADCS-ADL-MCI score, which assesses daily activities. The FDA notes that these two clinical endpoints have been used as common primary endpoints in other studies. Significant differences in these clinical endpoints further support the clinically significant improvement in CDR-SB scores.
Further biomarker studies showed a significant decrease in amyloid deposition in the patient’s brain over time, reflecting lecanemab’s interaction with the target and influencing the pathology and neurodegenerative disease of downstream tau. This evidence also supports the clinical benefit of lecanemab.
In terms of safety, the main adverse event of concern was amyloid-related imaging abnormalities (ARIA). In the randomized, double-blind phase of the study, 30 percent of patients with ARIA within 21 days of treatment were in the lecanemab group and 9 percent in the placebo group. The specific data is shown in the table below:
Most cases of ARIA did not show symptoms, and the proportion of symptomatic ARIA patients in the lecanemab group was 3.2% compared with 0.2% in the placebo group. The most common symptoms of ARIA are headache, and other symptoms include dizziness, nausea, visual changes, confusion, etc. Other safety signals include cerebral bleeding and infusion-related reactions. ARIA is associated with the APOE4 gene, and there is an increased risk of developing ARIA in patients with two copies of the gene copy number.
Although there were two deaths due to cerebral haemorrhage and one death related to underlying cerebrovascular events and severe ARIA in the lecanemab group, it is difficult to confirm the exact role of lecanemab in these deaths due to other comorbidities (e.g., amyloid angiopathy in the brain, CAA) and other concurrent therapies. Current lecanemab prescription labels and patient medication guidelines include warnings for high-risk patients and recommend increased monitoring and observation of warning signs like headaches. However, the FDA does not consider the risk of these potentially serious or even fatal intracerebral hemorrhages high enough to rule out lecanemab in such patients. Conditions like CAA are relatively common in Alzheimer’s patients, so it’s still too early to link lecanemab to this type of safety risk, the FDA said. However, during the Q&A session after the FDA report, some panelists’ comments suggested that they preferred lecanemab to have stricter labeling or restrictions to further protect patients at potentially high risk of severe brain hemorrhage.
Dr. Teresa Buracchio, acting director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said this is a drug that targets the underlying pathological process of Alzheimer’s disease and shows clinical benefit in this disease for the first time. “This confirmatory study confirms that this is a safe and effective treatment for Alzheimer’s patients.“
 FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval, Retrieved July 6, 2023, from https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
 FDA grants full approval to Leqembi, opening up coverage of Alzheimer’s drug by Medicare, Retrieved July 6, 2023, from https://endpts.com/alzheimers-drug-leqembi-gets-full-approval-from-fda-allowing-medicare-coverage/
 UPDATED INFORMATION: June 9, 2023: Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement. Retrieved June 8, 2023, from https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-information-june-9-2023-meeting-peripheral-and-central-nervous-system-drugs-advisory#event-materials
 FDA adcomm votes unanimously in favor of full approval for Eisai’s new Alzheimer’s drug. Retrieved June 9, 2023 from https://endpts.com/fda-adcomm-votes-unanimously-in-favor-of-full-approval-for-eisais-new-alzheimers-drug/
 FDA panel unanimously endorses Eisai’s Alzheimer’s drug. Retrieved June 9, 2023 from https://www.statnews.com/2023/06/09/leqembi-alzheimers-eisai/