Aducanumab is a novel disease‐modifying anti‐amyloid‐beta (Aβ) human monoclonal antibody specifically targeted to the pathophysiology of Alzheimer's disease (AD). It was granted for treating AD in June 2021 by the United States Food and Drug Administration. We systematically analyzed available trials to evaluate the efficacy and safety of aducanumab treating AD. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analysis) guidelines. We conducted an extensive literature search using the electronic databases MEDLINE through PubMed, EMBASE, Cochrane, Web of Science, and Scopus for suitable studies on aducanumab. We considered human clinical trials of aducanumab, assessing its efficacy and adverse effects in treating AD, excluding any experimental animal studies. We included three randomised controlled trials. Studies reported that aducanumab reduced brain amyloid‐beta plaques in a time‐ and dose‐dependent manner (dose–response, P < 0.05) and a slowed decline in cognition (22% reduction) in the high‐dose treated group, difference of −0.39 versus placebo in Clinical Dementia Rating Scale Sum Boxes (95% CI, −0.69 to −0.09; P = 0.012) along with a reduced amyloid positron emission tomography standard uptake value ratio score (P < 0.001) and plasma p181‐tau (phosphorylated tau) level. Amyloid‐related imaging abnormality was reported as a serious adverse event and was profound in high‐dose treated group (425/1029 in 10 mg/kg). Aducanumab has been reported to affect two main pathophysiologic hallmarks (Aβ and tau) of AD. We suggest future studies addressing aducanumab's efficacy and safety to confirm that the benefit of this drug outweighs the risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

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Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

The primary objective of this study is to evaluate the absolute bioavailability of a single, fixed subcutaneous (SC) dose of aducanumab compared with a single weight-based intravenous (IV) dose of aducanumab in healthy volunteers.

The secondary objectives of this study are to assess the safety and tolerability of aducanumab administered SC in healthy volunteers and to characterize additional pharmacokinetic (PK) parameters of a single, fixed SC dose of aducanumab and a weight-based IV dose of aducanumab in healthy volunteers.

Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.

The primary objective is to evaluate the safety and tolerability of aducanumab over 100 weeks of treatment after a wash-out period imposed by discontinuation of feeder studies in participants who had previously received aducanumab (i.e. previously treated participants) or who had previously received placebo (i.e. treatment-naïve participants).

Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive cognitive decline. Cholinesterase inhibitors are commonly used to manage symptoms but have limited efficacy as the disease progresses. Aducanumab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has emerged as a novel therapeutic approach. Despite its Food and Drug Administration (FDA) approval, its efficacy and safety remain contentious, particularly following the European Medicines Agency's (EMA's) rejection. This systematic review aims to evaluate the efficacy, safety, and clinical outcomes of aducanumab in treating mild AD. Adhering to Preferred Reporting Items for Systematic Reviews (PRISMA) 2020 guidelines, we conducted a comprehensive search of PubMed and Science Direct databases, including randomized controlled trials (RCTs), cohort studies, and case-control studies focusing on aducanumab versus placebo in mild AD. Studies were screened based on predefined inclusion and exclusion criteria, and data were extracted on clinical outcomes, biomarkers, and neuroimaging markers. The risk of bias was assessed using the Cochrane Handbook and Newcastle-Ottawa Scale. Out of 967 identified records, seven studies met the inclusion criteria. Findings indicated a dose-dependent reduction in Aβ plaques with aducanumab, but clinical outcomes varied. High-dose aducanumab (10 mg/kg) demonstrated significant improvements in some studies but not others. Adverse events, notably amyloid-related imaging abnormalities (ARIA), were frequent, especially at higher doses. The studies exhibited heterogeneous treatment effects and underscored the potential of cerebrospinal fluid biomarkers as an alternative to amyloid positron emission tomography (PET) scans. Aducanumab shows promise in reducing Aβ plaques and has potential clinical benefits at high doses; however, its safety profile, particularly concerning ARIA, remains a significant concern. The variability in clinical efficacy highlights the need for further research to optimize dosing regimens and identify patient populations most likely to benefit from treatment. Future studies should focus on refining treatment protocols and exploring alternative biomarkers to improve therapeutic outcomes for AD.

Inclusion criteria: Key Inclusion Criteria: ‐ Must meet all of the following clinical criteria for MCI due to AD or mild AD and must have: ‐ A Clinical Dementia Rating (CDR)‐Global Score of 0.5. ‐ A Repeatable Battery for Assessment of Neuropsychological Status (RBANS) score of 85 or lower indicative of objective cognitive impairment ‐ An MMSE score between 24 and 30 (inclusive) ‐ Must have a positive amyloid Positron Emission Tomography (PET) scan ‐ Must consent to apolipoprotein E (ApoE) genotyping ‐ Must have stable symptomatic AD medications ‐ Must have a reliable informant or caregiver LTE specific Criteria at week 78: ‐ Must have completed the placebo‐controlled period of the study. ‐ MMSE score > 15 at the Week 78 Visit. ‐ Must (or the subject’s legally authorized representative) understand the purpose and risks of the study and provide signed consent (or assent) ‐ Apart from a clinical diagnosis of AD, subject must be in good health as determined by the Investigator, based on medical history. ‐ Must have the ability to comply with procedures for protocol‐related tests. ‐ Must have reliable informant or caregiver

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Other protocol defined Inclusion criteria may apply Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 600 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 750 Exclusion criteria: Key Exclusion Criteria: ‐ Any medical or neurological condition (other than Alzheimer's Disease) that might be a contributing cause of the subject's cognitive impairment ‐ Have had a stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year ‐ Clinically significant psychiatric illness in past 6 months ‐ History of unstable angina, myocardial infarction, chronic heart failure, or clinical significant conduction abnormalities within 1 year prior to Screening ‐ Indication of impaired renal or liver function ‐ Have human immunodeficiency virus (HIV) infection ‐ Have a significant systematic illness or infection in past 30 days ‐ Relevant brain haemorrhage, bleeding disorder and cardiovascular abnormalities ‐ Any contraindications to brain magnetic resonance imaging (MRI) or PET scans ‐ Alcohol or substance abuse in past 1 year ‐ Taking blood thinners (except for aspirin at a prophylactic dose or less) ‐ Use of AD medications at doses that have not been stable for at least 8 weeks prior to Screening Visit 1 Subjects will be excluded from entering the LTE if at Week 78 they have: ‐ any medical or psychiatric contraindication or clinically significant abnormality that, in the opinion of the Investigator, will substantially increase the risk associated with the subject's participation in the study.

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Other protocol defined Exclusion criteria may apply Product Name: Aducanumab Product Code: BIIB037 Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed

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Aducanumab CAS Number: N/A Current Sponsor code: BIIB037 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Solution for injection/infusion Route of administration of the placebo: Intravenous use Main Objective: Placebo‐controlled period: To evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the CDR‐SB score as compared with placebo in subjects with early AD. Long‐term Extension: To evaluate the long���term safety and tolerability profile of aducanumab in subjects with early AD. ? To evaluate the long‐term efficacy of aducanumab treatment as measured by clinical, radiological, and additional assessments reported by the subject and informant/care partner.;Secondary Objective: To assess the e fect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by the MMSE. To assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by ADAS‐Cog 13. To assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by ADCS‐ADL‐MCI. ;Primary end point(s): Primary endpoint: Change from baseline in CDR‐SB score at Week 78. LTE period endpoints: The incidence of AEs and/SAEs; brain MRI findings (including the incidence of ARIA‐E and ARIA‐H); and the incidence of anti‐aducanumab antibodies in serum over the placebo‐controlled and LTE periods of the study. Change in the following measures over the placebo‐controlled and LTE periods of the study: CDR‐SB score. MMSE score. ADAS‐Cog 13 score. ADCS‐ADL‐MCI score. Amyloid PET signal (in a subset of subjects). Whole brain volume, hippocampal volume, ventricular volume, and cortical gray matter volume measured by MRI. Functional connectivity as measured by tf‐fMRI (where available). Cerebral blood flow as measured by ASL‐MRI (where available). Disease‐related biomarker levels in CSF which will include, but are not limited to, amyloid and tau proteins (in a subset of subjects). Disease‐related biomarker levels in blood which may include, but are not limited to, amyloid and tau proteins. NPI‐10 total score. Informant‐rated EQ‐5D index score. Informant/care partner’s own self‐reported EQ‐5D index score. Caregiver burden measures.;Timepoint(s) of evaluation of this end point: Primary endpoint: Week 78 LTE endpoints: On‐going over the course of the study Secondary end point(s): Change from baseline in MMSE score at Week 78. Change from baseline in ADAS‐Cog 13 score at Week 78. Change from baseline in ADCS‐ADL‐MCI score at Week 78.;Timepoint(s) of evaluation of this end point: Week 78

The blood-brain barrier (BBB) presents a significant challenge in treating Alzheimer's disease, as it restricts the delivery of therapeutic medications to brain tissue. Reversible breaking of the BBB using low-intensity focused ultrasound guided by magnetic resonance imaging (MRI) may benefit patients with Alzheimer's disease and other neurological illnesses, such as brain tumors, amyotrophic lateral sclerosis, and Parkinson's disease. This systematic study and meta-analysis aimed to assess aducanumab and the ultrasonography of BBB opening in Alzheimer's patients. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), the study was conducted by searching six digital repositories for relevant scholarly literature, focusing on English papers published between 2015 and 2024; the data was extracted using an Excel sheet, and data was analyzed using Revman 5.4.1 software. The study's findings indicate that the groups receiving ultrasound and aducanumab treatment benefited from it; however, overall, the effect was not statistically significant (P=0.29) at 95% CI 0.86 (0.75, 1.00). With regard to side effects, the results indicate that the treatment had fewer side effects compared to the control group; however, the difference was not statistically significant (p=0.94) at 95% CI 0.93 (0.70, 1.22). The study found a positive effect of ultrasound and aducanumab on the treatment groups, but it was not statistically significant. The control group had less side effects than the treatment group. Therefore, future studies should focus on the quantity or combination of the drug that yields more effective results.

This is a prospective, single-arm, multicenter, non-interventional study of aducanumab-avwa as prescribed in the post-marketing setting in the US. Investigators will be prescribing aducanumab-avwa and participants will be treated according to the standard of care (SoC). Participants will be followed up to 5 years after enrollment and data will be collected at routine visits every 6 to 12 months.