A widely-anticipated drug treatment for Alzheimer’s disease has shown promising results in clearing amyloid plaques from the brain in a phase 2 study – but questionable effects on cognitive outcomes.
Trial results for the Biogen/Eisei BAN2401 molecule were presented at the Alzheimer’s Association International Conference in Chicago on 25 July showing that the anti-amyloid drug produced dose-related effects on amyloid conversion and some cognitive measures.
The study, conducted in 800 patients with early Alzheimers disease and confirmed amyloid pathology confirmed compared five different dosing regimens of the drug with placebo over 18 months.
Over the study period, there was a dose dependent reduction in amyloid PET values by 0.30 units and a 70 unit reduction in Centiloid units compared to placebo. Likewise there was dose dependent conversion of patients from amyloid positive to negative compared to placebo, with an 81% conversion rate at the highest dose (10mg bi weekly) of BAN2401.
There was also a 30% slower rate of cognitive decline with the highest dose of BAN2401 compared to placebo, according to ADS-cog measures. However, the trial did not meet its primary endpoint for a significant effect on cognitive decline according to the ADCOMS measure .
Adverse effects leading to discontinuation occurred in 6.1% of placebo patients and 14.9% of patients taking the highest dose of BAN2401.
The study authors said this it was the first large clinical trial to support the amyloid hypothesis in Alzheimers, and the slowing in cognitive decline was clinically significant.
Australian neurology researchers gave a cautious welcome to the trial results, noting the BAN2401 study did not meet its primary endpoint and saying the results were not large enough to definitely demonstrate cognitive efficacy.
Professor Ashley Bush, Director of the Melbourne Dementia Research Centre at the Florey Institute of Neuroscience and Mental Health and University of Melbourne, noted that 70% of patients in the placebo group were ApoE4 positive, whereas only 30% in the high-dose group carried the high-risk genetic marker for Alzheimer’s related cognitive decline. This means the encouraging result may not hold up in a larger, more randomly distributed population, he said.
“This is a big problem with interpreting the results, diminishing the likelihood that the treatment actually helped with the dementia.
“Additionally, the high-dose ApoE4 group suffered a brain swelling side effect called ARIA-E, which means that treating this high-risk group in the clinic may be too problematic.”
Other concerns included the trial size, with only 161 patients in the high-dose group, and the fact that the significant results only emerged at 18 months following treatment onset.
Professor Bush added, “It is interesting that there was clearly a drop in amyloid in the brain in the various treatment groups, yet each dosing group still deteriorated clinically during the study. Therefore, removing amyloid does not guarantee clinical improvement.”