US FDA. Photo: Reuters
- The US Food and Drug Administration has approved a second drug to treat Alzheimer’s disease. The drug reduces amyloid beta plaque deposits in the brain, which are believed to cause cognitive decline.
- While clinical trials have shown that the drug is efficient in cleaning up these deposits, questions remain about the scale of benefits – with one neurologist describing it as “modest”.
- Scientists have also expressed safety concerns, as three people who participated in clinical trials for the drug died after suffering brain bleeds or swelling.
New Delhi: The US Food and Drug Administration (FDA) on January 6 approved a second drug to treat Alzheimer’s disease, even as doubts remain about the benefits and concerns have been raised about potentially serious side effects.
The drug, called Leqembi, was approved via the FDA’s ‘Accelerated Approval’ pathway for the treatment of Alzheimer’s disease, an irreversible neurodegenerative disorder that hampers memory and thinking skills. It is the second of a “new category” of medications approved by the FDA that target the pathophysiology of the disease, the agency said in a release.
“Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones,” Billy Dunn, the director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, said. “This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease.”
The causes of Alzheimer’s are not fully known but researchers have identified changes in the brains of patients – such as deposits of plaques called “amyloid beta” and neurofibrillary tangles – that result in the loss of neurons and their connections.
The FDA’s ‘Accelerated Approval’ allows approval for drugs that treat serious conditions “where there is an unmet medical need” and if the drug is shown to “have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients”.
“The results of a Phase 3 randomized, controlled clinical trial to confirm the drug’s clinical benefit have recently been reported and the agency anticipates receiving the data soon,” the FDA release said.
The agency said that Leqembi’s efficacy was evaluated in a double-blind, placebo-controlled, parallel-group, dose-finding study of 856 patients with Alzheimer’s disease. Treatment was initiated in patients with mild cognitive impairment or mild dementia stage of disease and confirmed presence of amyloid beta pathology. “Patients receiving the treatment had significant dose- and time-dependent reduction of amyloid beta plaque, with patients receiving the approved dose of lecanemab, 10 milligram/kilogram every two weeks, having a statistically significant reduction in brain amyloid plaque from baseline to Week 79 compared to the placebo arm, which had no reduction of amyloid beta plaque,” the FDA said.
However, the agency also acknowledged potential serious side effects – the drug’s label will include a warning for amyloid-related imaging abnormalities (ARIA), a type of brain swelling or bleeding. According to Science, at least three people who were part of a clinical trial and were given Leqembi died after brain bleeds or swelling. Some others had serious brain injuries, it said. While the drug’s makers, Eisai and Biogen, say Leqembi wasn’t necessarily at fault, the FDA has recommended that anyone taking lecanemab should have three MRIs in roughly the first 6 months of treatment to watch for ARIA.
The label will also suggest “additional caution” before giving blood thinners to patients on lecanemab as two of the trial participants who died had been on these drugs.
Also Read: Alzheimer’s Research in Turmoil as Sleuths Cast Doubt on Field-Defining Paper
Do risks outweigh benefits?
Scientists are divided over the drug. While many agree that it presents a step in the right direction, there are others who believe that the risks outweigh the benefits.
Joy Snider, a neurologist, is “excited about the drug” but stressed that it should be “only the beginning”, according to Science. She hoped that other, better therapies will follow. Snider flagged the potentially high cost of the drug – the manufacturer Eisai suggested it would have an annual cost of more than $25,000 for an average person, while infusions and monitoring will cost more.
Alberto Espay of the University of Cincinnati told Science that the benefits of lecanemab across a population “are minimal and its risks significant”. He said that the FDA, by approving the drug aducanumab in 2021, had set “an artificially low bar” for drugs that treat Alzheimer’s. The FDA’s approval for aducanumab was opposed by its own advisory committee, while a Congressional report described the approval process as “rife with irregularities”, according to Science.
The report added that while clinical trials showed lecanemab was remarkably efficient in clearing amyloid plaques, its effect on cognition were “modest”. “On a commonly used 18-point cognition scale, derived from the experience of patients and their caregivers, those getting the drug on average declined 0.45 points less than those getting placebo after 18 months,” Science said.
While supporters of the drug, like Snider, believe that patients and caregivers would notice this lesser decline, opponents like Espay say the catastrophic risk of ARIA should take precedence over the projected gains.
Amyloid theory under scanner
The results of phase 3 clinical trials of drugs that target amyloid deposits hold could answer a larger question: Does the hypothesis that amyloid plauqes cause neurodegeneration still hold water?
Last year, the field of Alzheimer’s research was thrown into turmoil after sleuths identified numerous instances of image tampering and falsifications in a field-defining paper. For more than a decade, clinical trials on treating Alzheimer’s were driven by a 2006 study that claimed that deposits of a particular species of amyloid deposits – Aβ*56 – were the primary cause of cognitive decline.
But neurologist Matthew Schrag identified several manipulations, which Science also verified independently. The manipulations were made to show that Aβ*56 played a role in causing Alzheimer’s, but that may not have been the case.
Researchers still reposed faith in the amyloid theory, saying that even if the role of Aβ*56 – or indeed its very existence – is questionable, the hypothesis should not yet be abandoned. If phase 3 clinical trials of drugs that clean up amyloid oligomers fail to provide results then the hypothesis would be “very much under duress”, they said.
However, research published in June 2022 found that mice that had been given a form of Alzheimer’s disease “showed damage inside neurons of the brain which occurred prior to the formation of amyloid-containing plaques”. The paper suggested that amyloid plaques may not be causing Alzheimer’s disease but maybe “a consequence of disease progression in certain cases or even coincidental”.