Top drugmakers have spent more than a decade investigating and advancing anti-amyloid Alzheimer's medicines in clinical studies, generating enough evidence to support FDA approvals for three of them so far. But a new analysis throws more cold water on the treatment approach after years of doubts—and some successes.
Medicines in this class, which include Biogen and Eisai's Leqembi and Eli Lilly's Kisunla, "likely have no clinically meaningful positive effects," according to a press release from the nonprofit health research organization Cochrane. Further, the meds likely increase the risk of brain swelling, the group's review found.
To reach this conclusion, the team compiled results from 17 studies assessing seven different amyloid‐beta‐targeting monoclonal antibodies, including the failed Aduhelm, Leqembi, Kisunla and several medicines that failed to reach the market.
The studies, which all used placebo control cohorts, altogether enrolled more than 20,000 people.
Overall, the results showed the drugs "probably result in little to no difference" on measures of cognitive function and functional ability, the team said. On dementia severity, the drugs "may result in little to no difference," according to the assessment.
"The effect of amyloid‐beta‐targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease is trivial, while on functional ability, it is small at best," the researchers concluded.
"Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease," the team added. "Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action."
Besides Aduhelm, Leqembi and Kisunla, the Cochrane team looked at the clinical track record for bapineuzumab, crenezumab, gantenerumab and solanezumab. Each of those drugs saw high-profile trial setbacks over the years.
It's important to note that while the group has had its share of clinical blemishes, Leqembi did show a statistically significant reduction in clinical decline in a placebo-controlled trial, enabling the FDA to convert its initial FDA nod into a full approval. Likewise, Kisunla boasts a full approval and proved its worth by demonstrating a statistically significant reduction in clinical decline in its own placebo-controlled study.
A spokesperson for Eli Lilly said the review is "built on an inherently flawed methodology."
"It pools data from across multiple amyloid-targeting therapies as a class, including molecules that did not achieve their clinical trial endpoints and were never granted regulatory approval," Lilly's spokesperson added. "Combining data on unsuccessful molecules with approved medicines artificially dilutes the observed benefit and produces class-level conclusions that do not reflect the evidence for any individual approved therapy."
On the subject of safety, the amyloid-targeting drugs "probably result in a small increase in the occurrence of any ARIA E," the shorthand for amyloid-related imaging abnormalities-edema, or brain swelling or fluid that's visible on an MRI. The meds aren't associated with any significant difference in symptomatic ARIA E, the analysis found.
As for ARIA H, or brain bleeding, three studies assessing the side effect showed divergent results, which prevented a pooled analysis, the team noted.
Researchers have been studying amyloid beta plaques and their potential ramifications for patients with Alzheimer's disease for decades. Within biopharma, treating the disease by targeting these plaques has yielded several high-profile drug candidates—with most failing to make the grade in the clinic.
In 2022, it was revealed that a vast amount of research in the field appeared to contain fabricated materials, adding to doubts about anti-amyloid treatments and calls for drugmakers to look elsewhere in the quest for future Alzheimer's drugs.