The initial surge of hope following the recent release of results from the Phase 2 clinical study of BAN2401, a joint venture between Eisai and Biogen, has been tempered. Following a jubilant data presentation at the Alzheimer’s Association International Conference in Chicago in late July, questions arose about the study’s methodology which cast doubt on both the future of the drug, and the amyloid theory that drove its creation.
When Biogen and Eisai initially released data from their 856 patient Phase 2 clinical study of the efficacy of BAN2401 in patients with early Alzheimer’s disease, the results were viewed as possibly the first positive news in the hunt for an effective drug to tackle Alzheimer’s in years. Researchers found that after 18 months, subjects treated with the highest dose of BAN2401 showed between 26 to 30 percent slower decline in cognitive function tests, and more than 70 percent showed marked decrease in the presence of amyloid plaque in the brain. The subjects were people with mild cognitive malfunction or mild Alzheimer’s dementia.
“These were people with very mild impairments, some confusion, forgetting someone’s name on occasion,” said Dr. Lynn Kramer, chief clinical and medical officer for Eisai. “That’s our goal: to stop Alzheimer’s disease when it’s in the mildest presentation.”
The amyloid theory is one of two prominent hypotheses in vogue to explain how Alzheimer’s disease works. According to this school of thought, a small, sticky protein known as amyloid beta accumulates in the spaces between neurons, impeding communication between nerve cells, which may then trigger inflammation and eventually cause the death of the cell. BAN2401 is an anti-amyloid beta profibril antibody intended to slow the progression of the disease and improve cognition in affected patients. Though the 12-month results showed no significant change in treated patients, encouraging results emerged by the 18-month mark.
The initial positive results sent Biogen stock up nearly 20 percent, but those gains have been lost as the study has undergone increased scrutiny. What is causing the uncertainty about the results? The revelation that European regulators had a critical group of subjects removed from the high-dose subject group, but left them in the placebo-control group, thus throwing the whole study into question.
One of the common side effects of anti-amyloid drugs is amyloid-related imaging abnormalities (ARIA), which can create headaches, confusion, visual disturbances and ARIA-edema (ARIA-E), with presenting brain swelling. Both conditions tend to ameliorate when the anti-amyloid drug is stopped. One group of Alzheimer’s patients is particularly prone to ARIA and ARIA-E—those who carry APOe4, a protein which has also been a strong indicator of a higher risk of the disease as well as a faster progression.
Out of concern for the risk of edema posed to APOe4 carriers, European regulators moved them out of the high-dose patient group, but allowed them to remain in the placebo group. Once this anomaly was revealed, the data became markedly less optimistic. According to one explanation, if two people with the same baseline severity of symptoms were followed for a year, the individual with the APOe4 protein would be in worse cognitive condition than the one without it because of the disease acceleration caused by the protein. In excluding the population most prone to rapid progression from the therapeutic study, the results lost some of their luster, especially when viewed alongside a series of failed amyloid-targeting drugs from other pharma giants as Eli Lilly, Pfizer and Merck.
Biogen and Eisai project cautious optimism and intend to continue the testing process, hoping to receive accelerated approval from the FDA. In order to meet the regulatory threshold of substantial evidence of efficacy, more studies will need to be conducted on a larger test group that does include patients with the highest risk. Biogen is simultaneously exploring its aducanumab drug, another experimental therapy intended to reduce the amyloid buildup in the brain. That drug is currently in Phase 3 trials, with results expected in 2020. The two drugs offer the most promising current opportunity to definitively underpin the amyloid theory, which could drive further successful therapies. For Alzheimer’s patients experiencing the heartbreaking decline caused by the disease, any deeper understanding of the disease will be welcome.