Objective:

To assess efficacy and safety of donanemab in participants at earlier clinical (mild cognitive impairment [MCI]) and pathological (low-medium tau) stages of Alzheimer’s disease (AD).

Background:

Compared with other contemporary early symptomatic AD studies, TRAILBLAZER-ALZ 2 (TB2) for donanemab included a broad and more clinically advanced population (Mini-Mental State Examination [MMSE] score 20-28 [inclusive]) with higher pathological disease burden (participants with low-medium and high tau and higher baseline amyloid, as measured by positron emission tomography [PET]). 

Design/Methods:

A pre-specified subpopulation analysis of participants (placebo N=105; donanemab N=123) with MCI (baseline MMSE score ≥ 27) and low-medium tau PET burden from TB2 for efficacy and safety. 

Results:

The MCI and low-medium tau subpopulation had relatively lower baseline plasma P-tau217 and similar amyloid burden (106 Centiloids) compared with the overall TB2 population (MCI or mild dementia due to AD with confirmed amyloid and tau pathology [low-medium or high tau PET level]). In the MCI and low-medium tau subpopulation, participants experienced 60% slowing of disease progression in the integrated Alzheimer's Disease Rating Scale (22% slowing in the overall population); 46% slowing in Clinical Dementia Rating Scale–Sum of boxes (29% slowing in the overall population) at Week 76. Comparable to the overall population, amyloid-related imaging abnormalities of edema or effusion occurred in 25.2% of participants in the MCI and low-medium tau subpopulation donanemab group. At Week 76, 71% of MCI and low-medium tau level participants completed treatment based on reduction of amyloid levels to below predefined thresholds on PET imaging; treatment completion frequencies were comparable in the overall population.

Conclusions:

Pre-specified analysis of the MCI and low-medium tau subpopulation suggests that initiating donanemab at an earlier clinical and pathological stage of disease may offer more favorable benefit/risk. The results reinforce importance of diagnosing and treating at the earliest symptomatic stages of AD.