Researchers performed a meta-analysis of randomized trial studies that compared the use of amyloid-reducing monoclonal antibodies (MABs) in patients with Alzheimer dementia at a dose consistent with that used in Phase 3 or FDA approval trials with the use of a placebo. Their purpose was to evaluate clinically meaningful benefits and harms of MABs to these patients. For inclusion in this meta-analysis, the RCT studies had to include adult participants with cognitive impairment or Alzheimer disease of any severity and report at least one clinically relevant benefit or harm to participants after at least one year. The research team identified 19 such publications that evaluated the effects of 8 different MABs on a total of 23,202 participants. Neither the results of any single study nor the results of all combined studies showed quantitative evidence that MABs improved cognitive or day-to-day functional abilities beyond the measure of minimal clinically important differences (MCIDs). Conversely, the studies indicated that MABs consistently cause statistically significant harms and could increase patients' risk of serious harms such as cerebral edema, hemorrhage, serious adverse events, and death. Additionally, these drugs are prohibitively expensive ($26,500 to $28,200 per year) and require regular MRI monitoring.
What We Know: The theory that amyloid deposition is part of the causal pathway in the development of Alzheimer dementia has led to the development of MABs to reduce amyloid deposition. FDA approval of these drugs was based primarily on improvements to laboratory measures such as medical imaging and biomarkers. However, the failure of MABs to provide clinically significant improvement in patient-oriented outcomes such as reduced mortality or morbidity has resulted in controversy. Previous systematic reviews evaluating the efficacy and harms of using MABs to target amyloid did not include recent studies that were critical to drug approval, and some included Phase 1 and 2 trials that used different doses from those used in later trials and did not interpret the findings in the context of minimal clinically important differences for patient outcomes.
What This Study Adds: Although lab-based evidence shows that MABs may be a promising treatment for Alzheimer dementia, focusing on actual patient outcomes can provide a greater understanding of the potential benefits and harms of using MABs. This meta-analysis of recent clinical trials involving over 20,000 participants with Alzheimer dementia or similar cognitive impairments suggests that MABs have not been shown to lead to clinically significant improvements in cognitive or functional abilities and could potentially cause serious harm to patients taking these drugs.
Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis
Mark H. Ebell, MD, MS, et al.
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, GA
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