In early July, Biogen and Eisai announced that analysis of their 18-month Phase 2 trial of BAN2401 revealed encouraging results, showing an effect on both lowering of amyloid levels and slowing of cognitive decline in patients treated with the highest dose of the drug. This spurred some analysts to hail the news as encouraging support for the hypothesis that lowering amyloid plaque deposition is the key to treating Alzheimer’s disease — or at least preventing or slowing its onset.
However, after the full details of the findings were presented at the Alzheimer’s Association International Conference later in the month, some observers remained uncertain about both the effectiveness of BAN2401 and the validity of the amyloid hypothesis.
The companies presented data from their multi-national study of 856 patients from the United States, Europe and Japan with early symptoms of cognitive decline who had been diagnosed with either mild cognitive impairment or early Alzheimer’s disease. All had been confirmed by PET scan to have significant accumulation of amyloid protein in their brains.
The data showed that of the 161 patients receiving the highest dose of BAN2401 (an injection every two weeks of 10mg/kg body weight), 81% showed significant drops in amyloid levels — a clear demonstration that the experimental drug was working as designed. In addition, the performance decline over the 18 months was 30% slower than in the placebo group on a battery of cognitive and functional tests to measure memory and mental skills, like planning and reasoning. This was a considerable difference from the 12-month analysis of the trial, announced in December 2017, which at that time concluded the study may not meet its endpoint. The drug also appeared to have an acceptable safety profile, with fewer than 10% of treated patients experiencing serious adverse events of dangerous swelling or bleeding in the brain.
However, some experts voiced concerns around the trial design, likely requiring additional data to move BAN2401 forward. Rather than using a widely accepted set of cognitive measurements, the researchers selected three established tests seen as sufficiently sensitive to measure changes at early stages of dementia to create their own “Alzheimer’s Disease Composite Score” (ADCOMS). Moreover, some patients carrying the APOe4 mutation were moved out from the high dose group to lower dose ones, leaving only 31% APOe4 patients in the high dose group compared to 71% APOe4 patients in the placebo group. This was done at the request of a European regulator, due to concerns that the APOe4 patients would be at higher risk of brain swelling. APOe4 carriers have nearly three times the risk of developing Alzheimer’s and faster progression of the disease compared to other people. This change raised the possibility that the high-dose group more easily hit statistical significance compared to placebo. Further analysis is underway to determine whether the difference in cognitive decline persists across patients in all treatment groups who are not APOe4 carriers.
While Biogen and Eisai intend to discuss their findings with the U.S. Food and Drug Administration, it is likely that more trials of BAN2401 will be initiated. Meanwhile, Biogen and Eisai are also partnered in developing aducanumab, which showed early promise in reducing amyloid and slowing cognitive decline in a Phase 1 trial. Biogen is currently conducting two large trials of aducanumab, which are scheduled to report results in 2020. Like BAN2401, aducanumab is a monoclonal antibody that targets amyloid, although a different subtype from that targeted by BAN2401.