FDA's dilemma with the aducanumab approval: public pressure and hope, surrogate markers and efficacy, and possible next steps Skip to main contentSubscribe Log In Basket Search Latest content Current issue Archive Authors AboutYou are hereHome Archive Volume 28, Issue 2Email alertsArticleTextArticleinfoCitationToolsShareRapid ResponsesArticlemetricsAlertsPDFEBM analysisFDA’s dilemma with the aducanumab approval: public pressure and hope, surrogate markers and efficacy, and possible next stepshttp://orcid.org/0000-0002-5216-8695John G Rizk1, John C Lewin2Correspondence to Dr John G Rizk, University of Maryland Baltimore, Baltimore, Maryland, USA; john.rizk@umaryland.eduAbstractAccelerating Food and Drug Administration (FDA) product approval to market based on surrogate markers in the absence
Aducanumab (Aduhelm) - For treatment of Alzheimer’s disease Drug Approval Package: Aduhelm (aducanumab-avwa) * Skip to main page content * Skip to search * Skip to topics menu * Skip to common linksHHS U.S. Department of Health and Human Services U.S. Food and Drug Administration * Follow FDA * En EspañolSearch FDASubmit search * Popular Content * Home * Food * Drugs * Medical Devices * Radiation-Emitting Products * Vaccines, Blood & Biologics * Animal & Veterinary * Cosmetics * Tobacco Products * Home * Drugs * Drug Approvals and Databases * Drugs@FDADrug Approval Package: Aduhelm (aducanumab-avwa) * Share * Tweet * Linkedin * Pin it * More sharing options * Linkedin * Pin it * Email * Print Company: Biogen, Inc. Application Number: 761178 Approval Date: 06/07
Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease. Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aβ) load in patients with Alzheimer's disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood-brain barrier with the goal of enhancing amyloid removal in selected brain regions in three
Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies. Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies ; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond influence risk of ARIA in aducanumab-treated patients. We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due
Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations. Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes , and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions
Lessons Learned from Approval of Aducanumab for Alzheimer's Disease. When the US Food and Drug Administration used the accelerated approval process to authorize the use of the antiamyloid drug aducanumab to treat Alzheimer's disease (AD), many people hoped this signaled a new era of disease-modifying treatment. But 2 years later, aducanumab's failure to launch provides a cautionary tale about the complexities of dementia and the need for a thorough and transparent review of the role that regulatory agencies and various stakeholders play in approving AD drugs. We highlight the events leading to aducanumab's controversial approval and discuss some of the key lessons learned from the drug's failure to deliver the hoped-for benefits. These lessons include the inherent limitations of antiamyloid
Results from the long-term extension of PRIME: A randomized Phase 1b trial of aducanumab. Aducanumab selectively targets aggregated forms of amyloid beta (Aβ), a neuropathological hallmark of Alzheimer's disease (AD). PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab
Refractory Status Epilepticus in a Patient With Aducanumab-Induced Amyloid-Related Imaging Abnormalities. To report a case of fatal super-refractory status epilepticus associated with amyloid-related imaging abnormalities (ARIA). We describe the history, neuroimaging, EEG, and brain pathology findings of a 75-year-old patient with mild cognitive impairment due to Alzheimer disease (homozygous ε4 apolipoprotein status) and a remote history of 3 asymptomatic ARIA episodes, who developed super-refractory status epilepticus related to severe ARIA. The patient was participating in an extended open-label trial of aducanumab when she was admitted to hospital for focal seizures and ARIA in 2 noncontiguous regions of the left frontal and occipital lobes. Despite aggressive treatment with high-dose
Variation in Medicaid and commercial payer coverage of aducanumab for Alzheimer's disease. Ever since the United States Food and Drug Administration (FDA) approved aducanumab and Centers for Medicare & Medicaid Service (CMS) restricted coverage for the drug, a crucial question has been how other payers will behave. This study examined how Medicaid and commercial plans cover aducanumab. We created a database of aducanumab coverage policies issued by Medicaid fee-for-service programs (50 states and DC) and 35 of the largest commercial plans (covering ∼ 84% of the commercially insured population). We found that only 41% of Medicaid fee-for-service plans have issued a publicly available coverage policy for aducanumab and that there is wide variation in these coverage criteria. Although
Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab. Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer's disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab in EMERGE and 1647 in ENGAGE. In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data
CSF biomarker concordance with amyloid PET in Phase 3 studies of aducanumab. We assessed the use of cerebrospinal fluid (CSF) biomarkers as an alternative to positron emission tomography (PET) for brain amyloid beta (Aβ) pathology confirmation in the EMERGE and ENGAGE clinical trials. EMERGE and ENGAGE were randomized, placebo-controlled, Phase 3 trials of aducanumab in participants with early with single CSF biomarkers, CSF biomarker ratios showed better agreement with amyloid PET visual reads, demonstrating high diagnostic accuracy. These analyses add to the growing body of evidence supporting CSF biomarkers as reliable alternatives to amyloid PET imaging for brain Aβ pathology confirmation. CSF biomarkers and amyloid PET concordance were assessed in Ph3 aducanumab trials. Robust concordance
A Bayesian perspective on Biogen's aducanumab trial. This perspective is a companion to a recent editorial on the use of Bayesian analysis in clinical research. We aim to introduce and highlight the relevance and advantages that Bayesian inference offers to clinical trials using the data on the amyloid antibody aducanumab presented at a Food and Drug Administration hearing in November 2020 as an applied example. We apply Bayesian analysis of model plausibility and effect sizes based on simulated data of the two phase 3 trials of aducanumab in prodromal and mild dementia stages of Alzheimer's disease (AD). Bayesian analysis can quantify evidence in favor of, or against, the presence of an effect (i.e., provide evidence of absence), as well as assess the strength of the effect
Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease. Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. These studies involved 348 sites in 20 countries. Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due
Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment
Potential eligibility for Aducanumab therapy in an Irish specialist cognitive service-Utilising cerebrospinal fluid biomarkers and appropriate use criteria. Aducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti-amyloid agent. Retrospective analysis was undertaken of patients with positive AD-biomarker CSF analysis. Data available at time
Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease in the US. Several anti-amyloid monoclonal antibodies have been developed for slowing the progression of Alzheimer disease (AD). Among the furthest developed are aducanumab, which received accelerated approval from the US Food and Drug Administration in 2021, and donanemab, which is currently undergoing phase 3 trials . The cost-effectiveness of these treatments has not been established. To estimate the cost-effectiveness of aducanumab and donanemab relative to standard care for early AD in the US. A decision analytic model was used to estimate the lifetime health and economic outcomes of adults with early AD, from US healthcare sector and societal perspectives. Simulated patients had a mean (SD) age of 75.2 (5.5) years
Knowledge and Attitudes Concerning Aducanumab Among Older Americans After FDA Approval for Treatment of Alzheimer Disease. This survey study examines the understanding of aducanumab and attitudes toward its potential outcomes among older Americans after the drug's approval by the US Food and Drug Administration (FDA) for the treatment for Alzheimer disease.
Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: A Report of the AAN Guidelines Subcommittee. To identify the class of evidence for aducanumab use for the treatment of Alzheimer disease and present clinical considerations regarding use. The author panel systematically reviewed available clinical trial data detailing aducanumab use in individuals with early symptomatic Alzheimer disease. Level of evidence statements were assigned in accordance with the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed. Data were identified from 4 clinical trials, 1 rated Class I and 3 rated Class II. The Class I study showed that single doses of aducanumab up to 30 mg/kg were safe