Leading pharmaceutical companies have spent more than a decade researching and advancing clinical studies of anti-amyloid Alzheimer’s drugs, and have so far generated sufficient evidence to support FDA approval of three of the drugs. But after years of questions and some successes, the new analysis throws even more cold water on the treatment.
Drugs in a class of drugs such as Biogen and Eisai’s Requemby and Eli Lilly’s Kisunra are “likely to have no clinically meaningful positive effects,” according to a press release from the nonprofit health research organization Cochrane. Additionally, the research group found that the drug likely increases the risk of brain swelling.
To reach this conclusion, the research team compiled the results of 17 studies that evaluated seven different monoclonal antibodies targeting amyloid beta, including the failed Aduhelm, Rekenbi, Kisunra, and several drugs that never made it to market.
The studies all used placebo-controlled cohorts and enrolled more than 20,000 people in total.
Overall, the results showed that these drugs “probably produced little difference” on measures of cognitive function and functional capacity, the researchers said. The evaluation said these drugs “may make little difference” when it comes to the severity of dementia.
“The effects of amyloid beta-targeted monoclonal antibodies on cognitive function and dementia severity at 18 months in patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease are modest, but at best small in terms of functional capacity,” the researchers concluded.
“Successful removal of amyloid from the brain does not appear to be associated with clinically meaningful benefits for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease,” the researchers added. “Future research on disease-modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.”
In addition to Aduhelm, Rekembi and Kisunla, the Cochrane team investigated the clinical performance of bapineuzumab, crenezumab, gantenerumab and solanezumab. Each of these drugs has experienced high-profile clinical trial setbacks over the years.
Although this group had its fair share of clinical shortcomings, it is important to note that Rekenbi demonstrated statistically significant reductions in clinical decline in placebo-controlled trials, allowing the FDA to convert initial FDA consent into full approval. Similarly, Kisunla boasts full approval and has proven its value by demonstrating statistically significant reductions in clinical decline in unique placebo-controlled studies.
An Eli Lilly spokesperson said the review was “built on an inherently flawed methodology.”
“We pool data across multiple amyloid-targeted therapies as a class, including molecules that did not meet clinical trial endpoints and did not receive regulatory approval,” the Lilly spokesperson added. “Combining data on unsuccessful molecules with approved drugs artificially dilutes the observed effects and leads to class-level conclusions that do not reflect the evidence for individual approved treatments.”
As for safety, drugs that target amyloid “will probably slightly increase the incidence of edema, ARIA E, which stands for amyloid-associated imaging abnormality, which is swelling or fluid in the brain that can be seen on an MRI.” Analysis showed that these drugs did not significantly differ in symptomatic ARIA E.
Regarding ARIA H (cerebral hemorrhage), the research team noted that the three studies that evaluated side effects showed different results, making it impossible to perform a pooled analysis.
Researchers have been studying amyloid-beta plaques and their potential impact on Alzheimer’s patients for decades. In biopharmaceuticals, targeting these plaques to treat diseases has led to several high-profile drug candidates, most of which have not reached clinical evaluation.
In 2022, it was revealed that a large body of research in the field appeared to contain fabricated material, further raising doubts about anti-amyloid treatments and prompting pharmaceutical companies to look elsewhere in the search for future Alzheimer’s drugs.
