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

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 ≈4 days, increasing to ≈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.