Over the past two years, two Alzheimer’s disease drugs were approved under accelerated approval. Both drugs are based on popular amyloid beta-plaque theories, yet both have raised questions.
On Jan. 6, the U.S. Food and Drug Administration (FDA) approved Leqembi (lecanemab-irmb), a new monoclonal antibody that seems to slow cognitive decline in some Alzheimer’s patients. In June 2021, Aduhelm (aducanumab) was approved.
Modest Cognitive Improvement
In 1984, researchers first isolated the amyloid protein plaque that has since been identified as the primary sign of Alzheimer’s disease. In the years since that discovery, reducing levels of amyloid has been the goal of scientists seeking effective treatments for this disabling, and ultimately fatal, disease.
Until recently, this approach has failed to produce a single drug that could slow, stop, or reverse cognitive decline. The previously approved drug, aducanumab, eliminated amyloid plaque, but did not slow or stop the progressive decline of cognitive ability.
The newly FDA-approved lecanemab is the first drug that has shown signs of slowing cognitive decline in patients with mild cognitive impairment in clinical trials.
The result “indicates that thorough removal of beta-amyloid from the brain leads to clinical benefit,” Maria C. Carrillo, who holds a doctorate in neuroscience and is the chief science officer of the Alzheimer’s Association, said in an emailed statement to The Epoch Times.
The Phase 3 trial found that lecanemab brought “moderately less decline” in measures of cognition and function than a placebo at 18 months.
It’s important to note that only Phase 2 trial results were used to justify FDA approval, according to a press release from the drugmaker. The Phase 2 study only found that lecanemab decreased brain plaques in 854 participants, without assessing whether this caused cognitive improvement. This is the same kind of data that led to aducanumab’s approval.
Researchers concluded that longer trials are needed to determine the new drug’s efficacy and safety in early Alzheimer’s disease.
“Some physicians may want to wait for the results of these longer and larger studies and for the medication to obtain full FDA approval before prescribing to their patients,” Dr. Zaldy Tan, who holds a master’s degree in public health and is the medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai, told The Epoch Times.
Currently, anyone willing to use lecanemab who relies on Medicaid or Medicare will have to pay out of pocket. At an estimated treatment cost of $26,500 per year, this puts the drug out of reach for many patients.
If lecanemab subsequently receives “traditional FDA approval,” the Centers for Medicare and Medicaid Services (CMS) would provide broader coverage, CMS said in a statement.
Potentially Severe Side Effects
According to the FDA in its approval for the drug, prescribing information for lecanemab includes a warning for amyloid-related imaging abnormalities (ARIA), known to occur with antibodies of this class.
While ARIA typically don’t have symptoms, “serious and life-threatening events” are possible. ARIA often present as temporary swelling in areas of the brain that may be accompanied by spots of bleeding in or on the brain that typically resolve over time. Some people may also develop symptoms that include headache, confusion, dizziness, vision changes, nausea, and seizure.
Another warning for lecanemab concerns the risk of infusion-related reactions, such as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
The most commonly observed adverse events were ARIA, infusion-related reactions, and headaches.
The deaths of three patients who were given the drug in an extension of the study might be associated with these risks.
Tan said this information is especially important for those who are on blood thinners and those who are carriers of the apolipoprotein E gene, or APOE4 allele, “who have been shown in the clinical trials to have higher rates of brain bleeding and swelling from lecanemab,” he explained.
“However, there will be a subset of persons with Alzheimer’s disease who would be willing to accept the expedited FDA review and approval,” Tan added. “These patients will need to be monitored closely and their response to the medication tracked.”
Similarity to Aducanumab Controversy
Aducanumab, also a monoclonal antibody, was granted accelerated approval by the FDA solely on its ability to reduce amyloid plaque in the brain.
In March 2022, the journal American Family Physician published an editorial explaining why doctors shouldn’t prescribe this Alzheimer’s treatment.
The authors conducted their own meta-analysis of available research on the efficacy of aducanumab to find there were no “statistically significant or clinically meaningful” differences in cognition when tested using conventional methods.
“… Thus, the FDA approval was based entirely on amyloid reduction and ignored the absence of a significant symptomatic benefit for patients,” the authors concluded.
Crucially, the side effect profile of the drug is very similar to what is observed with lecanemab.
Aducanumab, which uses a similar mechanism of action as lecanemab, caused harm that included ARIA and cerebral edema in 35 percent of treated patients, and cerebral hemorrhage in about 20 percent of patients.
Serious Questions About Amyloid Research
The successive approval of Alzheimer’s anti-amyloid antibody drugs brought hope, but whether their benefits outweigh the risks is still a question among scientists.
The mechanism of action these two drugs are based on is also in question.
“For years, it was generally accepted that amyloid plaques, the insoluble proteins that are seen in the brains of persons with Alzheimer’s disease, [are] the main cause of the memory loss and inability to perform daily tasks,” said Tan.
But he admits that treating amyloid hasn’t provided the benefits amyloid theory would suggest.
In July 2022, Science reported on doctored images in a series of influential studies on the association between amyloid plaques and Alzheimer’s disease.
An attorney investigating an experimental drug for Alzheimer’s called Simufilam hired Matthew Schrag, a neuroscientist and physician at Vanderbilt University. Schrag looked at published images about the drug and its underlying science and identified altered or duplicated images in dozens of journal articles.
Study authors “appeared to have composed figures by piecing together parts of photos from different experiments,” Elisabeth Bik, a molecular biologist and well-known forensic image consultant, told Science. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”
But this doesn’t necessarily invalidate all previous research. There is evidence that mutated genes can serve as code for precursors to amyloid proteins, which cause the early onset of the disease. The Alzheimer’s Association says this indicates that beta-amyloid protein is a “prime suspect” in the decline and death of brain cells.
Tan considers amyloid plaques to be part of the problem.
“There are other abnormal proteins such as tau, alpha-synuclein, TDP-43, and processes such as inflammation and vascular disease that are involved,” he said. “This discovery [of other abnormal proteins] will help guide future therapies and expand available treatments for Alzheimer’s disease.”