Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb 14;7(1):e12112.
doi: 10.1002/trc2.12112. eCollection 2021.

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

Stephen Loucian Lowe  1 , Brian A Willis  2 , Anne Hawdon  3 , Fanni Natanegara  2 , Laiyi Chua  2 , Joanne Foster  3 , Sergey Shcherbinin  2 , Paul Ardayfio  2 , John R Sims  2
Affiliations

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

Stephen Loucian Lowe et al. Alzheimers Dement (N Y). .

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.

PubMed Disclaimer

Conflict of interest statement

Authors are employees and minor stockholders of Eli Lilly and Company. Anne Hawdon is a former employee of Eli Lilly and Company.

Figures

FIGURE 1
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
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
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
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
FIGURE 5
Mean antidrug antibodies titers by time for dose groups. HV, healthy volunteers; LS, least squares; LY, LY3002813 (donanemab); SC, subcutaneous
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. DeMattos RB, Lu J, Tang Y, et al. A plaque‐specifc antibody clears existing β‐amyloid plaques in Alzheimer's disease mice. Neuron 2012;76(5):908‐920. - PubMed
    1. Barthel H, Gertz H‐J, Dresel S, et al. Florbetaben Study Group . Cerebral amyloid‐β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 2011;10(5):424‐435. - PubMed
    1. Clark CM, Schneider JA, Bedell BJ, et al. AV45‐A07 Study Group . Use of florbetapir‐PET for imaging beta‐amyloid pathology. JAMA 2011;305(3):275‐283. - PMC - PubMed
    1. Navitsky M, Joshi AD, Kennedy I, et al. Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale. Alzheimers Dement 2018;14(12):1565‐1571. - PubMed
    1. Carlson C, Siemers E, Hake A, et al. Amyloid‐related imaging abnormalities from trials of solanezumab for Alzheimer's disease. Alzheimers Dement 2016;2:75‐85. - PMC - PubMed