Another controversial FDA approval for a new Alzheimer's medication
The U.S. Food and Drug Administration (FDA) has approved a new drug for patients in the early-stages of Alzheimer's disease. Called Leqembi (lecanemab) the treatment was heralded last year as a major breakthrough in Alzheimer's therapy following early Phase 3 data indicating it could slow the progression of cognitive decline. But growing concerns over the drug's safety and real-world efficacy have led to acrimonious division amongst researchers, with some suggesting the drug should not be authorized for wide use.
Leqembi is the second drug to be approved in a new class of Alzheimer's monoclonal antibody medications designed to reduce brain accumulations of a protein called amyloid beta, suspected to be the main pathological cause of the disease. The first drug of its class to be approved was Aduhelm, back in 2021. Aduhelm's market approval was subject to the most vociferous criticism of a drug approval in decades. Questions over its efficacy, safety and ultimate price led to a number of FDA advisors resigning, with one expert calling it “probably the worst drug approval decision in recent US history.”
Despite Aduhelm's FDA approval the drug failed to be widely taken up by doctors or Alzheimer's patients. Not only did the European Medicines Agency reject the drug for use in Europe but a US congress investigation into the FDA's authorization of Aduhelm found it breached a number of standard approval practices.
The same pharma companies behind Aduhelm's development, Eisai and Biogen, are now taking a second shot at an Alzheimer's monoclonal antibody with Leqembi. Recently published Phase 3 clinical trial data found patients taking the drug for 18 months displayed a 27% slower rate of cognitive decline compared to those in the placebo group.
Since that Phase 3 data was announced in late 2022 a number of neurologists have questioned the real-world relevance of the cognitive benefits reported in Leqembi's clinical studies. An open-letter co-authored by 12 researchers recently argued against Leqembi's approval, suggesting the clinical benefits of the drug are uncertain.
"Analysis of the available data from CLARITY-AD suggests that Lecanemab’s efficacy is below that accepted as clinically meaningful," the article states. "There are potential biases in the cohort from inclusion bias, unblinding, and dropouts, among other issues, which may affect the veracity of the data. Substantial adverse effects and subgroup heterogeneity is clearly present. Thus, the translation of the clinical trial data into real world effects is very uncertain."
Perhaps even more serious, however, have been reports of several deaths in recent months of patients taking part in the extension of the Phase 3 clinical trial. Three deaths have recently been reported in the media as being due to brain swelling and microhemorrhages.
Independent neuroscientists asked to review the patient records by news outlet Science concluded the deaths were likely caused by the antibody treatment. But pharma company Eisai has said the deaths were unrelated to Leqembi, and all patient information has been disclosed to the FDA prior to the drug's approval.
FDA's approval announcement for Leqembi does note a risk of brain swelling, referred to as "amyloid-related imaging abnormalities (ARIA)," and the prescribing information calls for patients to undergo several brain scans during the first four months of treatment to monitor for ARIA.
In contrast to the critics of Leqembi, nearly 230 doctors and researchers have co-signed a letter supporting clinical approval of the drug. The letter states Leqembi is not a cure for Alzheimer's, and it may not work for every patient, but it is a foundational advance in treatment for a disease that currently has no pharmaceutical options.
"Autonomy and justice dictate that our patients have equitable access and the opportunity to make informed choices regarding reasonable treatments that can impact their lives and well-being," the letter states. "No barrier can be allowed to stand between our patients and a treatment that has a reasonable risk-benefit ratio and significantly reduces the causative pathology."
Rob Howard, a professor of old age psychiatry at University College London, is circumspect regarding the safety and efficacy of Leqembi. He sees the side effect concerns of the drug as "understandable" and suggests doctors be cautious about prescribing it.
"Individual doctors will make their own decisions about prescribing lecanemab to their patients, based on the efficacy data from the clinical trials and their perception of the risks associated with treatment," said Howard. "My own view would be that the benefits of the treatment appear to be too tiny to justify the risks and I wouldn’t recommend this for my own patients.”
Leqembi is administered through fortnightly infusions and Eisai has priced the treatment at around US$26,500 per year.