Two phase III clinical trials of an Alzheimer's drug failed to demonstrate significant improvements in cognitive function, calling into question the theory of the etiology of Alzheimer's disease as a neurodegenerative disease.
The so-called "amyloid hypothesis" proposes that the accumulation of a protein called β amyloid causes nerve cell death and degeneration, which is a characteristic pathophysiological feature of Alzheimer's disease. More than a century ago, plaques of an unknown protein were found in the brains of people with dementia. In 1984, β amyloid was discovered and remains a central suspect in the etiology of Alzheimer's disease.
However, because these plaques are also found in the normally cognitive brains of many older adults, and because years of research into Alzheimer's disease treatment have failed to make progress, some have questioned the validity of this hypothesis. There are even claims that there is fabricated evidence in a highly cited paper that supported the theory last year. Two recent trials do not appear to confirm the reliability of this hypothesis.
The two trials, involving nearly 1,000 people in total, tested a drug called Gantetanil to treat people with early-stage Alzheimer's disease. Although monoclonal antibody treatment resulted in a reduction in the burden of β amyloid in the brain, there were no signs of cognitive function associated with this improvement compared to placebo.
This is "surprising", as Lon Schneider wrote in an editorial published. Gantetanil is similar to two other drugs, aducanumab and lecanemab, both of which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of early Alzheimer's disease, Schneider explains. All three drugs contain synthetic antibodies that bind to β amyloid in the brain and help reduce plaque, although whether this translates into improvements in dementia symptoms is debatable, especially given recent findings.
The investigators randomized participants to receive either gantetanil or placebo every two weeks for 116 weeks. To assess the severity of dementia symptoms in patients before and after the trial, the researchers used the Clinical Dementia Rating Scale (Sum of Boxes) (CDR-SB) – giving each person a scale of 0 to 18, with higher scores indicating more severe cognitive impairment.
After more than two years, there was no significant difference between changes in CDR-SB scores between those who took the drug and those who received placebo, demonstrating that Gantetanil did not significantly improve cognitive function in either trial.
Schneider concludes: "There is variable, small evidence of the clinical effect of anti-amyloid antibodies. According to one person, the results of antibody therapy to date can both reinforce confidence in this treatment and its clinical significance, as well as support the perception that its effects are small, unreliable, and almost indistinguishable from those that are ineffective. ”
However, Schneider also pointed out some shortcomings of the trials, including the risk of bias and insufficient masking of the drug and placebo, and suggested that the trials may not be long enough to see a true difference in Alzheimer's disease symptoms.
"If there is no significant effect after 1.5 to 2 years of treatment, there may be hope for the future. ”
After decades of research on amyloid plaques in Alzheimer's disease, it seems like we're still going to have to wait for a definitive answer.
"There's a lot we don't know about targeting amyloid in patients with Alzheimer's disease, maybe we'll learn more from the ongoing anti-amyloid antibody prophylaxis trials or clinical practice registry trials," Schneider said. ”
The results of these trials were published in the New England Journal of Medicine.