donanemab

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donanemab

GtoPdb Ligand ID: 8357

Synonyms: donanemab-azbt | Kisunla® | LY-3002813 | LY3002813

donanemab is an approved drug (FDA (2024))

Comment: Donanemab (LY3002813) is a monoclonal antibody developed from the murine monoclonal mE8-IgG2a [1]. It binds to N-terminally, pyroglutamate-modified amyloid β proteins (abbreviated as Aβ_p3-x or N3pG) which are found extensively in the amyloid plaques of the brains of Alzheimer's disease (AD) patients. The removal of Aβ_p3-x was advanced to cliniucal evaluation as a novel mechanism to treat AD.

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Summary of Clinical Use
Donanemab (LY3002813) was advanced to clinical evaluation in AD patients. The studies were particulary focussed on patients with early symptomatic AD. Safety and tolerability data (from phase 1 NCT02624778) was published in early 2021 [3]. Results from the TRAILBLAZER-ALZ study suggested that donanemab reduced brain amyloid and slowed tau accumulation. A correlation between amyloid reduction and slowed disease progression was only observed in patients with the apolipoprotein E (APOE) α4 AD risk variant. An Eli Lilly press release in May 2023 announced that donanemab slowed cognitive and functional decline (in patients with early symptomatic AD) in the phase 3 TRAILBLAZER-ALZ 2 study. However, as has been observed with lecanemab, some patients receiving donanemab infusions experienced serious or fatal cerebral swelling (amyloid-related imaging abnormalities, or ARIA). The FDA approved donanemab in July 2024, as a once-monthly intravenous infusion to treat patients with early symptomatic AD (with mild cognitive impairment or mild dementia stage disease, and confirmed cerebral amyloid β pathology) [2]. The drug carries a boxed warning concerning the risk of ARIA.

Summary of Clinical Use

Donanemab (LY3002813) was advanced to clinical evaluation in AD patients. The studies were particulary focussed on patients with early symptomatic AD. Safety and tolerability data (from phase 1 NCT02624778) was published in early 2021 [3]. Results from the TRAILBLAZER-ALZ study suggested that donanemab reduced brain amyloid and slowed tau accumulation. A correlation between amyloid reduction and slowed disease progression was only observed in patients with the apolipoprotein E (APOE) α4 AD risk variant. An Eli Lilly press release in May 2023 announced that donanemab slowed cognitive and functional decline (in patients with early symptomatic AD) in the phase 3 TRAILBLAZER-ALZ 2 study. However, as has been observed with lecanemab, some patients receiving donanemab infusions experienced serious or fatal cerebral swelling (amyloid-related imaging abnormalities, or ARIA).
The FDA approved donanemab in July 2024, as a once-monthly intravenous infusion to treat patients with early symptomatic AD (with mild cognitive impairment or mild dementia stage disease, and confirmed cerebral amyloid β pathology) [2]. The drug carries a boxed warning concerning the risk of ARIA.

Mechanism Of Action and Pharmacodynamic Effects
Results with previous immunotherapies which target various soluble or insoluble Aβ proteins have largely been unsuccessful as they fail to clear existing Aβ. LY3002813 has been designed to target deposited plaque, as clearance of the existing amyloid burden is believed to be essential for any AD therapy to be effective. The mE8 antibody upon which LY3002813 was based, is reported to clear plaques in mice without causing microhemorrhages (a serious adverse event reported with previously trialled anti-Aβ monoclonals) [1].

Mechanism Of Action and Pharmacodynamic Effects

Results with previous immunotherapies which target various soluble or insoluble Aβ proteins have largely been unsuccessful as they fail to clear existing Aβ. LY3002813 has been designed to target deposited plaque, as clearance of the existing amyloid burden is believed to be essential for any AD therapy to be effective. The mE8 antibody upon which LY3002813 was based, is reported to clear plaques in mice without causing microhemorrhages (a serious adverse event reported with previously trialled anti-Aβ monoclonals) [1].

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT05108922	A Study of Donanemab (LY3002813) Compared With Aducanumab in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ 4)	Phase 3 Interventional	Eli Lilly and Company
NCT05738486	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer's Disease (TRAILBLAZER-ALZ 6)	Phase 3 Interventional	Eli Lilly and Company
NCT05026866	A Donanemab (LY3002813) Prevention Study in Participants With Alzheimer's Disease (TRAILBLAZER-ALZ 3)	Phase 3 Interventional	Eli Lilly and Company
NCT04437511	A Study of Donanemab (LY3002813) in Participants With Early Alzheimer's Disease (TRAILBLAZER-ALZ 2)	Phase 2 Interventional	Eli Lilly and Company	Results for this study (TRAILBLAZER-ALZ 2) were published in July 2023.	5
NCT03367403	A Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ)	Phase 2 Interventional	Eli Lilly and Company		4,6
NCT05508789	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ 5)	Phase 3 Interventional	Eli Lilly and Company