aducanumab

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Ligands
aducanumab

GtoPdb Ligand ID: 8325

Synonyms: aducanumab-avwa | Aduhelm® | BART | BIIB-037 | BIIB037

aducanumab is an approved drug (FDA (2021))

Comment: Aducanumab is a fully human IgG1-kappa monoclonal antibody directed against the amyloid beta (Aβ) found in the amyloid plaques in the brain tissue of patients with Alzheimer's disease (AD).
Peptide sequences and structural information about this antibody are available from its IMGT/mAb-DB record. A patent search reveals Biogen Idec's patent submission WO2014089500 [2].

No information available.

No information available.

Summary of Clinical Use
Preliminary results from Phase 1 trial NCT01677572, published in Nature in September 2016 [7], suggested the antibody reduced brain Aβ in a dose- and time-dependent manner, and this led to continued progression, culminating in Phase 3 clinical trials to evaluate aducanumab's effect on cognitive decline in AD patients (see EMERGE NCT02484547 and ENGAGE NCT02477800). Futility analysis (i.e. concluding that the antibody would not delay cognitive decline) led to the decision by aducanumab's developer Biogen, to terminate these trials but to complete patient follow-ups and closing out activities. Although designed as a duplicate of EMERGE, ENGAGE failed to replicate the efficacy seen in EMERGE. Following anaysis of the larger dataset collected from all of the patients from both trials who completed 18 months follow up, Biogen claimed that extended exposure to the higher 10 mg/kg dose used in their trials was effective [3], and they declared their intention to seek FDA approval for this treatment regimen in early 2020 [1]. Biogen's claims about aducanumab's efficacy have been highly scrutinised (and criticised) [4-6]. Despite ambiguous data with no clear demonstration of clinical benefit, and the adverse events ascribed to aducanumab therapy (cerebral oedema), it is clear that a well designed and powered confirmatory RCTs are essential. Despite the lack of evidence of efficacy, the FDA accepted Biogen's regulatory submission for adacanumab in August 2020, and granted priority review, with a planned decision date of early March 2021. In fact it took until June 2021 for the FDA's decision to grant accelerated approval for adacanumab as a treatment for AD to be announced. Continued approval for this indication will depend on verification of clinical benefit in confirmatory trial(s). Biogen have been given nine years to complete such trials.

Summary of Clinical Use

Preliminary results from Phase 1 trial NCT01677572, published in Nature in September 2016 [7], suggested the antibody reduced brain Aβ in a dose- and time-dependent manner, and this led to continued progression, culminating in Phase 3 clinical trials to evaluate aducanumab's effect on cognitive decline in AD patients (see EMERGE NCT02484547 and ENGAGE NCT02477800). Futility analysis (i.e. concluding that the antibody would not delay cognitive decline) led to the decision by aducanumab's developer Biogen, to terminate these trials but to complete patient follow-ups and closing out activities. Although designed as a duplicate of EMERGE, ENGAGE failed to replicate the efficacy seen in EMERGE. Following anaysis of the larger dataset collected from all of the patients from both trials who completed 18 months follow up, Biogen claimed that extended exposure to the higher 10 mg/kg dose used in their trials was effective [3], and they declared their intention to seek FDA approval for this treatment regimen in early 2020 [1]. Biogen's claims about aducanumab's efficacy have been highly scrutinised (and criticised) [4-6]. Despite ambiguous data with no clear demonstration of clinical benefit, and the adverse events ascribed to aducanumab therapy (cerebral oedema), it is clear that a well designed and powered confirmatory RCTs are essential. Despite the lack of evidence of efficacy, the FDA accepted Biogen's regulatory submission for adacanumab in August 2020, and granted priority review, with a planned decision date of early March 2021. In fact it took until June 2021 for the FDA's decision to grant accelerated approval for adacanumab as a treatment for AD to be announced. Continued approval for this indication will depend on verification of clinical benefit in confirmatory trial(s). Biogen have been given nine years to complete such trials.

Mechanism Of Action and Pharmacodynamic Effects
Epitope mapping reveals that aducanumab (BIIB037) binds to residues 3-6 of human Aβ [2]. In vivo studies show that chronic administration of the antibody in mice induces microglia-mediated clearance of amyloid plaques [2].

Mechanism Of Action and Pharmacodynamic Effects

Epitope mapping reveals that aducanumab (BIIB037) binds to residues 3-6 of human Aβ [2]. In vivo studies show that chronic administration of the antibody in mice induces microglia-mediated clearance of amyloid plaques [2].

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT01677572	Multiple Dose Study of Aducanumab (BIIB037) (Recombinant, Fully Human Anti-Aβ IgG1 mAb) in Participants With Prodromal or Mild Alzheimer's Disease	Phase 1 Interventional	Biogen
NCT02477800	221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease	Phase 3 Interventional	Biogen
NCT02484547	221AD302 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease	Phase 3 Interventional	Biogen