Analysis of recent failures of disease modifying therapies in Alzheimer’s disease suggesting a new methodology for future studies

ABSTRACT

Introduction: Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer’s disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer’s disease.

Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked.

Expert commentary: We suggest a new methodology for future treatment research in Alzheimer’s disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period.

KEYWORDS:

• Alzheimer’s disease
• disease-modifying therapies
• methodology
• Intravenous Immunoglobulin (IVIG)
• bapineuzumab
• solanezumab
• avagacestat
• dimebolin

Declaration of interest

GT Grossbrg discloses: Consultant: Acadia, Allergan, Daiichi/Sankyo, GE, Genetech, Lundbeck, Novartis, Otsuka, Roche, Takeda. Research Support: Accera, Eli Lilly, Noven. Safety Monitoring Committee: EryDel, Merck, Newron. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.