Six years ago, Genevieve Lane, seeking more time after an early Alzheimer's diagnosis, enrolled in a trial for a promising new drug, Leqembi. Soon after starting treatment, she died, and an autopsy revealed severe cerebral inflammation likely due to the drug. This case highlights growing concerns about the safety and efficacy of new Alzheimer's drugs like Leqembi and Kisunla. Despite being hailed as breakthroughs, investigations reveal potential harms may be downplayed while benefits are exaggerated.
Safety Concerns and Adverse Events
While Eisai, the maker of Leqembi, reported no drug-related deaths during its initial 18-month study, four deaths occurred during the study's extension phase. During the main trial, some patients experienced disability, and 22% of patients taking Leqembi developed brain hemorrhage or swelling, more than double the 10% in the placebo group. Similarly, studies of Kisunla showed higher rates of drug-associated brain injuries than Leqembi.
Neuropathology professor Rudolph Castellani from Northwestern University worries that widespread prescription of these drugs could lead to a public health disaster due to their toxic effects. He explains that the drugs' mechanism of action, removing amyloid from blood vessel walls, can cause blood vessels to shred, leading to inflammation, hemorrhage, and, in severe cases, cell death.
Efficacy and Clinical Significance
Despite the risks, the manufacturers of Leqembi and Kisunla claim their studies and the FDA's approval confirm that the potential benefits outweigh the risks. However, experts question the clinical significance of the drugs' effects on cognition and function.
In Leqembi's trials, Eisai used the Clinical Dementia Rating-Sum of Boxes (CDR-SB) test to measure changes in cognition. The difference between patients receiving Leqembi and those on placebo after 18 months was only 0.45 points. According to a 2019 Eli Lilly study, a change of at least one full point on the CDR-SB is needed for patients with mild cognitive impairment to notice a difference, and 1.6 points for those with early Alzheimer's. Leqembi failed to meet this standard.
Lon Schneider, a professor at the University of Southern California, calls the claim that Leqembi slows the progression of dementia by 27% a "meaningless number" and a misuse of data. Jerome Hoffman, a professor emeritus at UCLA, adds, "Twenty-seven percent of almost nothing is still almost nothing."
Regulatory Scrutiny and Conflicts of Interest
The FDA's approval process for these drugs has also faced scrutiny. The Lever uncovered that the FDA initially rejected Kisunla due to an "imbalance in deaths" and missing data. Additionally, three of the four FDA physician advisers who voted in favor of Leqembi had financial ties to the manufacturers.
When Leqembi came up for review, the FDA replaced its advisory committee, which had previously rejected Aduhelm. The new committee included members with financial conflicts of interest with Biogen, Eisai's partner in developing Leqembi.
The Amyloid Hypothesis and Alternative Approaches
The development of these drugs is based on the amyloid hypothesis, which posits that Alzheimer's is primarily caused by the buildup of amyloid beta protein in the brain. However, experts have questioned this theory, and some research suggests that amyloid reduction may not correlate with improved cognitive function.
George Perry, a neuroscience professor at the University of Texas at San Antonio, states that Aduhelm, Leqembi, and Kisunla are essentially the same, working by the same mechanism and demonstrating the same insignificant efficacy and serious harms.
Patient Perspectives and Treatment Decisions
Given the potential risks and limited benefits, many neurologists remain hesitant to prescribe these new drugs. Madhav Thambisetty, an executive director at Novartis and former senior investigator with the National Institutes of Health, would only prescribe Leqembi after cautioning patients about the potential side effects. Reshma Ramachandran, an expert in clinical trials at Yale, believes Leqembi and Kisunla pose serious safety risks and offer, at best, unclear benefits, giving patients and doctors false hope.
With ongoing studies and assessments, the benefits and harms of these drugs may change. However, experts emphasize the need for open access to manufacturer data to allow independent observers to study the drugs' effects more closely. In the meantime, patients and physicians must carefully weigh the potential risks and benefits when considering these new Alzheimer's treatments.
