Eli Lilly Submits New Drug Application in China for Donanemab, a Monoclonal Antibody Targeting Early Symptomatic Alzheimer's Disease

On October 31, the CDE website showed that Eli Lilly's new Alzheimer's drug donanemab has been accepted for marketing application. Previously, the NMPA granted donanemab a Breakthrough Therapy Designation for the treatment of Alzheimer's disease, targeting early symptomatic Alzheimer’s disease, including mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease.

Donanemab is a monoclonal antibody that binds to the N3pG subtype of amyloid-beta protein. It can bind to amyloid-beta protein deposits in the brains of Alzheimer's disease patients, thereby promoting the clearance of amyloid plaques in the patient’s brain.

In May this year, Eli Lilly announced that the Phase III TRAILBLAZER-ALZ 2 study of donanemab for the treatment of patients with early symptomatic Alzheimer's disease (AD) had met its primary endpoint. The results showed that donanemab significantly slowed cognitive decline in patients with early symptomatic AD, with nearly half of the participants (47%) showing no disease progression within one year (defined as no decline in clinical dementia rating), compared to 29% in the placebo group. Eli Lilly expects to submit a marketing application for donanemab to the FDA in the second quarter to seek accelerated approval.

TRAILBLAZER-ALZ 2 is a randomized, double-blind, placebo-controlled Phase III clinical trial, with the primary analysis population (n=1182) being patients with moderate tau levels and significant AD clinical symptoms. The primary endpoint is the change in scores on the AD Composite Score (iADRS, which assesses cognitive abilities and activities of daily living) from baseline to 18 months. Key secondary endpoints include changes in scores from baseline to 18 months on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB, assessing cognitive abilities), the ADCS Instrumental Activities of Daily Living (ADCS-iADL) scale, and the AD Assessment Scale-Cognitive Subscale (ADAS-Cog13).

Results showed that, compared with the placebo group, the decline in iADRS scores was slowed by 35% (p<0.0001) in the donanemab-treated group; at 18 months, the rate of decline in CDR-SB scores in the donanemab group was 36% slower than in the placebo group (p<0.0001); ADCS iADL scores indicated that disease progression in the donanemab group was slowed by 40% at 18 months (p<0.0001). Additionally, donanemab reduced the risk of patients progressing to the next stage of the disease by 39% (HR=0.61; p<0.001).

After pooling the results of the moderate tau level population with the higher tau level population (n=552) (n=1736), the donanemab treatment group still showed positive outcomes across all clinical endpoints (p<0.001), with the rate of decline in CDR-SB and iADRS scores slowed by 29% and 22%, respectively.

In terms of safety, 24% of subjects in the donanemab group experienced amyloid-related imaging abnormalities-edema (ARIA-E), with a symptomatic ARIA-E rate of 6%; 31.4% of patients in the donanemab group had cerebral microhemorrhages and superficial siderosis (ARIA-H), compared to 13.6% in the placebo group. The majority of ARIA cases were mild to moderate in severity, with a serious ARIA rate of 1.6%, including two subjects who died from ARIA and one patient who died after experiencing serious ARIA; 8.7% of patients had infusion-related reactions, most of which were mild to moderate.

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