Donanemab (LY3002813) dose-escalation study in Alzheimer's disease.

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Lowe SL, Willis BA, Hawdon A, Natanegara F, Chua L, Foster J, Shcherbinin S, Ardayfio P, Sims JR

Donanemab (LY3002813) dose-escalation study in Alzheimer's disease.

Alzheimers Dement (N Y). 2021 Feb 14;7(1):e12112. doi: 10.1002/trc2.12112. eCollection 2021.

PubMed ID
33614890 [ View in PubMed
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Abstract

Introduction: This study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia. Methods: Patients with AD were enrolled into the single-ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients proceeded into the multiple-ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12-week follow-up period. The relative exposure assessment of an unblinded, single, subcutaneous 3-mg/kg dose of donanemab in patients with AD was also performed, followed by a 12-week follow-up period. One cohort of healthy subjects received an unblinded, single, IV 1-mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase. Results: Donanemab was generally well tolerated up to 10 mg/kg. After single-dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half-life was approximately 4 days, increasing to approximately 10 days at 10 mg/kg. Only the 10-mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti-drug antibodies at 3 months after a single intravenous dose. Discussion: Intravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half-life.

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