Donanemab, an investigational antibody that targets a modified form of beta amyloid called N3pG, showed significant slowing of decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer's disease compared to placebo in results from phase 2 TRAILBLAZER-ALZ study.
Donanemab met the primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer's Disease Rating Scale ( iADRS ), slowing decline by 32% relative to placebo, which was statistically significant. The iADRS is a clinical composite tool combining the cognitive measure ADAS-Cog13 and functional measure ADCS-iADL, two commonly used measures in Alzheimer's disease.
Donanemab has also shown consistent improvements in all prespecified secondary endpoints measuring cognition and function compared to placebo, but did not reach nominal statistical significance on every secondary endpoint.
By targeting N3pG beta amyloid, Donanemab treatment has been shown to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging.
In TRAILBLAZER-ALZ, Donanemab-treated patients, on average, showed an 84 centiloid reduction of amyloid plaque at 76 weeks compared to a baseline of 108 centiloids ( less than 25 centiloids is typical of a negative amyloid scan ).
In this study, patients stopped receiving Donanemab and switched to placebo once their plaque level was below 25 centiloids for two consecutive measures or below 11 centiloids at any one measure.
This unique mechanism and antibody for clearing plaques has the potential to provide high levels of durable amyloid plaque clearance after limited duration dosing.
The safety profile of Donanemab was consistent with observations from phase 1 data.
Amyloid-related imaging abnormalities ( ARIA ) were observed, which is consistent with amyloid plaque clearing antibodies.
In the Donanemab treatment group, amyloid-related imaging abnormalities – edema ( ARIA-E ) occurred in 27% of treated participants, with an overall incidence of 6% experiencing symptomatic ARIA-E.
TRAILBLAZER-ALZ is a randomized, placebo-controlled, double-blind, multi-center phase 2 study to assess the safety, tolerability and efficacy of Donanemab in patients with early symptomatic Alzheimer's disease.
The trial enrolled 272 patients who were selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau imaging.
The primary endpoint is change from baseline until 76 weeks in iADRS. Key secondary endpoints include changes between baseline and 76 weeks in ADAS-Cog13, ADCS-iADL, MMSE, and CDR-SB scores. Other secondary biomarker endpoints include changes from baseline to week 76 in brain amyloid deposition and brain tau deposition.
Alzheimer's disease is a fatal illness that causes progressive decline in memory and other aspects of cognition.
Dementia due to Alzheimer's is the most common form of dementia, accounting for 60 to 80% of all cases.
There are currently over 50 million people living with dementia around the world, with numbers expected to increase to nearly 152 million by 2050.
Almost 10 million new cases of dementia are diagnosed each year worldwide. ( Xagena )
Source: Lilly, 2021