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.

Keywords: Alzheimer's disease; dementia; donanemab; mild to moderate; tolerability.

FIGURE 1

Overview of seamless single‐ascending dose phase followed by multiple‐ascending dose phase. Abbreviations: D, drug/placebo; F, florbetapir; FU, 3‐month follow‐up; IV, intravenous; MAD, multiple‐ascending dose; MRI, magnetic resonance imaging; PK, pharmacokinetic; S, Florbetapir and MRI scan; SAD, single‐ascending dose; SC, subcutaneous. The number of patients administered LY3002813 or placebo in each cohort was as follows: Cohort 1 (0.1 mg/kg IV)–4 LY3002813: 2 placebo; cohort 2 (0.3 mg/kg IV)–7 LY3002813: 2 placebo; cohort 3 (1 mg/kg IV)–9 LY3002813: 2 placebo; cohort 4 (3 mg/kg IV)–11 LY3002813: 3 placebo; cohort 5 (10 mg/kg IV)–6 LY3002813: 3 placebo; cohort 6 (3 mg /kg SC)–8 LY3002813; cohort 7 (1 mg/kg IV in healthy volunteers)–6 LY3002813

FIGURE 2

Donanemab (LY3002813) mean plasma concentration‐time profile after the administration of a single dose of donanemab in patients with mild cognitive impairment due to Alzheimer's disease or mild to moderate Alzheimer's disease dementia. HV, heathy volunteers; IV, intravenous; SC, subcutaneous

FIGURE 3

Donanemab (LY3002813) trough concentrations after single and multiple doses (A) and donanemab (LY3002813) concentrations ≈3 days after the first dose and 4 days after the last dose (B). In (A), the solid black line indicates the lower limit of quantification. Data points below the line indicate samples in which concentrations were determined to be below the limit of quantification. All samples were collected 28 days postdose, with the exception of day 85, which occurred after the first dose of donanemab (ie, 84 days after the first dose). All assayed samples are plotted unless the patient missed the previously scheduled dose. In (B), the solid black line indicates the lower limit of quantification. Data points below the line indicate samples in which concentrations were determined to be below the limit of quantification. All samples are plotted from patients receiving donanemab on study day 1 or day 169

FIGURE 4

Centiloid change of florbetapir scans from baseline at 28 weeks for donanemab (A). Baseline and follow‐up centiloid values in 10 mg/kg donanemab and pooled placebo arms (B). IV, intravenous

FIGURE 5

Mean antidrug antibodies titers by time for dose groups. HV, healthy volunteers; LS, least squares; LY, LY3002813 (donanemab); SC, subcutaneous