Lessons Learnt from the Second Generation of Anti-Amyloid Monoclonal Antibodies Clinical Trials

Background: Alzheimer disease (AD) is a chronic neurodegenerative disorder with complex pathophysiology that affects over 50 million people worldwide. Most drug therapies, to date, have focused on targeting the amyloid-beta (A beta) pathway, but clinical outcomes of anti-A beta antibodies have been unsuccessful and unable to meet their primary endpoints. Similar trends have also been observed in treatments that target the tau pathway. Summary: This paper reviews recent anti-A beta passive monotherapies, since Bapineuzumab, that have progressed to phase 3 clinical trials. Specifically, we discuss the 4 clinical trial programs of Solanezumab (targets A beta monomers), Aducanumab (targets A beta oligomers and plaques), Crenezumab (targets A beta oligomers), and Gantenerumab (targets A beta fibrils) which are all exogenous monoclonal antibodies. We conclude with potential reasons for why they have not met their primary endpoints and discuss lessons learnt from these trials. Key Message: Future disease-modifying trials (DMTs) for AD should be conducted in asymptomatic, A beta-positive individuals. Moreover, potential additive and/or synergistic benefits focusing on anti-A beta and anti-tau drug combinations merit further investigation.