Swedish biotech BioArctic, in collaboration with Japanese firm Eisai, has seen positive Phase IIb results for its BAN2401 antibody – potentially the first disease-modifying treatment for Alzheimer’s Disease and the next global blockbuster.
The results from the Phase IIb study strengthen BioArctic’s belief that BAN2401’s unique binding profile is important
Gunilla Osswald, BioArctic
In the early 1900s, Dr Alois Alzheimer observed a patient at the Frankfurt Asylum named Auguste Deter with strange behavioural symptoms including short-term memory loss, language problems, and unpredictable behaviour. After she died, he examined her brain and found many abnormal clumps. Today, it is known that anomalous deposits of the amyloid-beta protein are responsible for the formation of these clumps called amyloid plaques. However, more than a hundred years later, there is still no treatment that can stop or slow down the progression of Alzheimer’s Disease. Many drugs that try to prevent or clear amyloid deposits have failed to improve cognition in early Alzheimer’s patients. For instance, at the beginning of this year, Roche discontinued its two pivotal trials, CREAD 1 and 2, for monoclonal antibody crenezumab. In March, Eisai and Biogen also decided to stop their two global Phase III trials for aducanumab after a futility analysis indicated they were unlikely to meet their primary endpoint upon completion.
These two successive failures prompted analysts to ask if the amyloid theory is now dead. But only 24 hours after burying aducanumab, Eisai announced the start of a new Phase III trial for BAN2401, another antibody focused on amyloid. It was originally developed by BioArctic, a Swedish biotech company based in Stockholm focused on developing disease-modifying treatments for neurodegenerative disorders. One of its founders, Professor Lars Lannfelt from Uppsala University, was behind the groundbreaking discovery in Swedish Alzheimer’s Disease patients of two mutations – dubbed the Swedish and Arctic mutations – occurring in the gene which encodes amyloid-beta leading to abnormal accumulation of the protein in the brain. This research has attracted much attention internationally and led to the development of new treatment strategies such as crenezumab and aducanumab.
But can BAN2401 succeed where others have failed? It certainly looks promising. The Phase IIb trial was the first late clinical phase study to demonstrate a potential disease-modifying effect on clinical function as well as clearance of amyloid-beta in the brain and a decrease in nerve degeneration as shown by four different biomarkers. In addition, BAN2401 has shown a good tolerability profile after 18 months of treatment. The results were presented at the Alzheimer’s Association International Conference 2019 in Los Angeles last week.
The BAN2401 antibody presents unique characteristics compared to previous attempts. Professor Lannfelt observed that in patients with the Arctic mutation, amyloid-beta monomers start to misfold and aggregate to form soluble types of neurotoxic oligomers and protofibrils. If they continue to aggregate, they form amyloid plaques that are insoluble and inert. Aducanumab was developed to target the plaque, which turned out to be an erroneous approach since plaque is a largely non-toxic form of amyloid-beta. On the other hand, BAN2401 has a unique binding profile selectively targeting neurotoxic misfolded formations of amyloid-beta oligomers/protofibrils, offering a potentially significant advantage in terms of both efficacy and safety over aducanumab and other less selective antibodies. According to BioArctic CEO Gunilla Osswald, “the results from the Phase IIb study strengthen BioArctic’s belief that BAN2401’s unique binding profile is important, which is supported also by the stopped trials with other companies’ antibodies.”
The Phase III study initiated by Eisai in March, dubbed Clarity AD, will look to confirm the positive results from the Phase IIb study. If results are conclusive, BAN2401 could very well be the first disease-modifying treatment for Alzheimer’s Disease on the market, and the next blockbuster drug.