Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes

• Published in: Clinical and translational science Vol. 11; no. 2; pp. 147 - 152
• Main Author: Cummings, Jeffrey
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2018; John Wiley and Sons Inc
• Subjects: Alzheimer's disease; Amyloid; Animal cognition; Animal models; Biomarkers; Clinical trials; Cognitive ability; Dementia; Diagnosis; Drug development; Drug dosages; Hypotheses; Immunotherapy; Nervous system; Neurodegenerative diseases; Review; Reviews; Success; United States > US
• ISSN: 1752-8054; 1752-8062; 1752-8062
• DOI: 10.1111/cts.12491

Improved interpretation of animal models, better pharmacologic characterization in phase I and phase II trials, appropriate sample size, diagnosis of AD with biomarker support, optimization of global recruitment, and avoiding inappropriate subgroup analyses can improve drug development success rates. Some immunotherapies (e.g., AN1792, bapineuzumab, and gantenerumab) have been shown to have target engagement and reduce plaque amyloid without producing a corresponding clinical benefit. [...]engaging the target is necessary for treatment response but does not insure that cognitive benefit will ensue. LESSON 10: COLLECT MULTIPLE BIOMARKERS TO ASSESS OUTCOMES Knowledge of the neurobiology of AD is incomplete. [...]AD biology is complex, and biomarkers provide limited windows into this complex and ill‐understood disease. Better preclinical models of AD, better knowledge of BBB penetration, MTD, dose response, demonstration of target engagement, more accurate diagnosis using biomarkers, select use of regional populations in trials, adequate trial size, construction of trial populations that exhibit decline in the placebo group, improvement in an active comparator group, and avoidance of misleading subgroup analyses can all contribute to greater success in AD drug development.