Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective

Abstract

the US Food and Drug Administration (FDA) approved aducanumab (Aduhelm; Biogen Inc), the first new drug for the treatment of Alzheimer disease in 2 decades. Alzheimer disease, the sixth leading cause of death in the US, is a neurodegenerative disease leading to a progressive, irreversible destruction of neurons resulting in loss of cognitive function and memory. Over time, patients develop severe dementia, loss of independence, and death. 1 Unfortunately, pharmacologic treatment options have been extremely limited, with the few previously approved drugs providing only symptomatic improvement, but not modifying disease progression. Undoubtedly, there is a substantial unmet medical need in patients with Alzheimer disease. In this Viewpoint, we discuss the complexities of the data supporting the aducanumab application and the rationale for the FDA's decision to grant it accelerated approval.Aducanumab is administered monthly as an intravenous infusion. The drug is an IgG1 anti-amyloid-β (Aβ) antibody targeting Aβ aggregates-a pathological hallmark of Alzheimer disease-with binding intended to lead to Aβ plaque clearance. The decision to approve this drug was based on our review of data in the application, including 3 clinical studies providing the primary evidence concerning the effectiveness of this drug: study 103 (NCT01677572), study 301 (NCT02477800), and study 302 (NCT02484547). The first (study 103) was an early-phase randomized sequential cohort doubleblind study with 197 participants, evaluating doses up to 10 mg/kg every 4 weeks. Results showed clear dosedependent and time-dependent reduction in Aβ plaque and dose-related improvements in standard Alzheimer disease end points, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and the Mini Mental Status Examination (MMSE), with statistical significance at the 10 mg/kg dose for both of these end points.The other 2 studies (301 and 302) were randomized double-blind placebo-controlled, similarly designed, adequate, and well-controlled phase 3 studies, which included 1647 and 1638 participants, respectively. These studies provided conflicting results. Study 302 showed significant improvement in CDR-SB and 3 other secondary end points at the high dose (now the approved dose of 10 mg/kg after titration). These secondary end points (Alzheimer Disease Assessment Scale, Cognitive Subscale [13 items; ADAS-Cog 13]; Alzheimer Disease Cooperative Study, Activities of Daily Living Inventory [Mild Cognitive Impairment version; ADCS-ADL-MCI] and MMSE) evaluate cognitive function, memory, and social and personal functioning using different approaches and scales. They are only modestly correlated with the primary end point (CDR-SB) and each other; of note, the P values for the differences between

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

“…Curcumin is able to scavenge free radicals (ROS or reactive nitrogen species) [ 389 ], inhibit the activity of enzymes involved in free radical generation such as cyclooxygenases and xanthine oxidase [ 390 ], to modulate the activity of endogenous antioxidants such as glutathione peroxidase, catalase, and superoxide dismutases [ 391 ], to diminish lipid peroxidation, and to reduce the expression of NF-κB, ERK, inducible nitric oxide synthase, and inflammatory cytokines IL-1β and IL-6 [ 392 ]. The efficacy of 24-week curcumin supplementation on AD progression has been evaluated with inconclusive results in a phase 2 randomized, double-blind, placebo-controlled trial (NCT 00099710) [ 393 ], followed by a second pilot study of curcumin and Gingko extracts administered over 6 months (NCT00164749), the results of which were not released to date [ 394 ].…”

Protein clearance strategies for disease intervention

“…Unfortunately, these studies came to a halt when early clinical trials resulted in serious side effects, including a death due to meningoencephalitis (NCT00021723) (Neugroschl and Sano 2010 ). In June 2021, the United States Food and Drug Administration (FDA) approved aducanumab, a monoclonal antibody targeting Aβ in brains of patients in early stages of AD, providing a new hope for immunization against proteinopathies (Dunn et al 2021 ). A similar immunization strategy was also investigated for aggregated SOD1 in ALS.…”

A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics

“…Aducanumab (Aduhelm) is the first disease-modifying drug approved for AD patients, and was approved in June 2021 [52]. It is administered as an intravenous (IV) infusion over approximately one hour every four weeks.…”