Perspectives on future Alzheimer therapies: Amyloid-β protofibrils-A new target for immunotherapy with BAN2401 in Alzheimer's disease

Abstract

The symptomatic drugs currently on the market for Alzheimer's disease (AD) have no effect on disease progression, and thi creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be mad highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatmen effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-Amyloid-beta (anti-Aβ vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-u study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis tha Aβ immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclona antibody targeting fibrillar Aβ, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly an Company) was developed to target soluble, monomeric Aβ. In two phase 3 studies, Solanezumab did not meet primar endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing o cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation o soluble Aβ protofibrils, an Aβ species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclona antibody, mAb158, was developed to target Aβ protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity fo protofibrils as compared with monomers of Aβ, thus targeting the toxic species of the peptide. A humanized version o mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisa without the safety concerns seen in previous phase 1 and 2a trials. Experiences from the field indicate the importance o initiating treatment early in the course of the disease and of enriching the trial population by improving the diagnosti accuracy. BAN2401 is a promising candidate for Aβ immunotherapy in early AD. Other encouraging efforts in immunotherap as well as in the small-molecule field offer hope for new innovative therapies for AD in the future.