Post by Admin on Jul 16, 2021 11:21:32 GMT
Alzheimer's Disease Treatment on the Horizon or False Dawn?
William H. Hung, MD, MPH
DISCLOSURES July 14, 2021
www.medscape.com/viewarticle/954015
Dementia is a devastating age-related illness that causes significant morbidity, functional decline, and mortality. Alzheimer's disease (AD), characterized by the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, is the most common cause of dementia. In this research update, I discuss three recently published articles that have important implications for the treatment and prevention of dementia, including AD.
On June 7, 2021, the US Food and Drug Administration (FDA) approved aducanumab, an amyloid monoclonal antibody that targets and reduces beta-amyloid deposits in the brain, for treatment of AD. This decision has triggered substantial controversy, as the drug was approved through the FDA's Accelerated Pathway, and the decision to approve was contrary to the advice of the FDA advisory committee that reviewed the clinical trial data for efficacy. The first article I discuss is a viewpoint whose authors include a member of the advisory committee that reviewed the clinical trial data submitted by the pharmaceutical company. After summarizing their concerns regarding the evidence for aducanumab, the authors conclude that, although there is evidence that the drug clears beta-amyloid protein deposits, data showing clinical efficacy are lacking. The second article presents the results of a phase 2 randomized trial of donanemab, another medication that targets beta-amyloid protein in the pathogenesis of AD. The trial results suggest a modest clinical benefit in cognitive decline and ability to perform activities of daily living. A phase 3 trial will follow these promising results. The third article explores the association between when diabetes mellitus is diagnosed and the subsequent risk of developing dementia, highlighting a potential modifiable factor that may reduce the risk for dementia in late life.
Mixed Evidence for Benefit of Aducanumab in Early Alzheimer's
Medications previously approved for AD have targeted symptoms of the disease, delivering modest improvements in cognition and function, but no treatments can yet modify the disease's clinical progression. Efforts to develop disease-modifying drugs have focused on hallmark pathologic features such as the build-up and reduced clearance of beta-amyloid protein in the brain, which leads to neuronal death and, eventually, cognitive impairment. Aducanumab is a monoclonal antibody against beta-amyloid protein that may modulate the immune system to remove the beta-amyloid plaques. On the basis of early imaging-based clinical trials that demonstrated reduced beta-amyloid plaques with aducanumab treatment, two large phase 3 clinical trials (ENGAGE [NCT02477800] and EMERGE [NCT02484547]) were conducted to examine its effect on clinical outcomes, including cognition and function. The studies were stopped early because interim review of trial data (futility analysis) indicated that the drug was unlikely to produce clinical benefit if the trials were carried to fruition. However, examination of follow-up data collected after the trials were stopped suggested that one of the clinical trials, EMERGE, did demonstrate clinical benefit. A possible explanation for the divergent outcomes between the two trials, suggested by the trials' sponsor, was that more patients in the EMERGE trial received the high-dose regimen of aducanumab, leading to a difference in high-dose aducanumab exposure. However, the lack of clinical effectiveness in the trials as originally designed, coupled with the disparate results in the post-hoc analysis in the high-dose group across the two trials, leaves considerable doubt that the treatment is effective clinically.
The safety and cost of aducanumab must also be considered, given the limited evidence of the drug's clinical effectiveness. Amyloid-related imaging abnormalities (ARIA) have been reported in patients treated with the drug, with a higher incidence among those who received higher doses. Some individuals who experienced ARIA had neurologic symptoms, including confusion and visual disturbance, among other adverse effects. Aducanumab has a wholesale yearly cost of $56,000, as well as costs for administration and imaging to confirm the presence of beta-amyloid plaques and assess response, making this a very costly treatment, particularly for a medication that has limited clinical benefit but high risk for harm. Clinicians considering aducanumab for their patients with early AD should discuss these issues and the potential risks and benefits based on available data.
William H. Hung, MD, MPH
DISCLOSURES July 14, 2021
www.medscape.com/viewarticle/954015
Dementia is a devastating age-related illness that causes significant morbidity, functional decline, and mortality. Alzheimer's disease (AD), characterized by the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, is the most common cause of dementia. In this research update, I discuss three recently published articles that have important implications for the treatment and prevention of dementia, including AD.
On June 7, 2021, the US Food and Drug Administration (FDA) approved aducanumab, an amyloid monoclonal antibody that targets and reduces beta-amyloid deposits in the brain, for treatment of AD. This decision has triggered substantial controversy, as the drug was approved through the FDA's Accelerated Pathway, and the decision to approve was contrary to the advice of the FDA advisory committee that reviewed the clinical trial data for efficacy. The first article I discuss is a viewpoint whose authors include a member of the advisory committee that reviewed the clinical trial data submitted by the pharmaceutical company. After summarizing their concerns regarding the evidence for aducanumab, the authors conclude that, although there is evidence that the drug clears beta-amyloid protein deposits, data showing clinical efficacy are lacking. The second article presents the results of a phase 2 randomized trial of donanemab, another medication that targets beta-amyloid protein in the pathogenesis of AD. The trial results suggest a modest clinical benefit in cognitive decline and ability to perform activities of daily living. A phase 3 trial will follow these promising results. The third article explores the association between when diabetes mellitus is diagnosed and the subsequent risk of developing dementia, highlighting a potential modifiable factor that may reduce the risk for dementia in late life.
Mixed Evidence for Benefit of Aducanumab in Early Alzheimer's
Medications previously approved for AD have targeted symptoms of the disease, delivering modest improvements in cognition and function, but no treatments can yet modify the disease's clinical progression. Efforts to develop disease-modifying drugs have focused on hallmark pathologic features such as the build-up and reduced clearance of beta-amyloid protein in the brain, which leads to neuronal death and, eventually, cognitive impairment. Aducanumab is a monoclonal antibody against beta-amyloid protein that may modulate the immune system to remove the beta-amyloid plaques. On the basis of early imaging-based clinical trials that demonstrated reduced beta-amyloid plaques with aducanumab treatment, two large phase 3 clinical trials (ENGAGE [NCT02477800] and EMERGE [NCT02484547]) were conducted to examine its effect on clinical outcomes, including cognition and function. The studies were stopped early because interim review of trial data (futility analysis) indicated that the drug was unlikely to produce clinical benefit if the trials were carried to fruition. However, examination of follow-up data collected after the trials were stopped suggested that one of the clinical trials, EMERGE, did demonstrate clinical benefit. A possible explanation for the divergent outcomes between the two trials, suggested by the trials' sponsor, was that more patients in the EMERGE trial received the high-dose regimen of aducanumab, leading to a difference in high-dose aducanumab exposure. However, the lack of clinical effectiveness in the trials as originally designed, coupled with the disparate results in the post-hoc analysis in the high-dose group across the two trials, leaves considerable doubt that the treatment is effective clinically.
The safety and cost of aducanumab must also be considered, given the limited evidence of the drug's clinical effectiveness. Amyloid-related imaging abnormalities (ARIA) have been reported in patients treated with the drug, with a higher incidence among those who received higher doses. Some individuals who experienced ARIA had neurologic symptoms, including confusion and visual disturbance, among other adverse effects. Aducanumab has a wholesale yearly cost of $56,000, as well as costs for administration and imaging to confirm the presence of beta-amyloid plaques and assess response, making this a very costly treatment, particularly for a medication that has limited clinical benefit but high risk for harm. Clinicians considering aducanumab for their patients with early AD should discuss these issues and the potential risks and benefits based on available data.