Donanemab Induces Amyloid Clearance in Early Alzheimer Disease

A robust decrease in amyloid plaque levels was observed among patients with early symptomatic Alzheimer disease who received donanemab.

Donanemab therapy is associated with amyloid clearance among some patients with early symptoms of Alzheimer disease (AD), according to a post hoc analysis published in JAMA Neurology.

Donanemab therapy has been found to rapidly clear amyloid plaques among patients with AD. To evaluate outcomes of donanemab more in depth, including its effect on Tau deposits, data for this analysis were sourced from The Study of LY3002813 in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ; ClinicalTrials.gov Identifier: NCT03367403) trial. The multicenter, double-blind, placebo-controlled, randomized, phase 2 trial was conducted at 56 centers in the United States and Canada between 2018 and 2020.

In the TRAILBLAZER-ALZ trial, patients (N=272; 46.7% men; aged mean, 75.2 years) with elevated amyloid, intermediate tau levels, memory decline, or symptomatic early AD were randomized to receive 700 mg donanemab for the first 3 doses followed by 1400 mg donanemab for the remaining doses every 4 weeks for 72 weeks (n=131), placebo (n=126), or donanemab and beta-site amyloid precursor protein cleaving enzyme (discontinued study arm; n=15).

The primary outcomes for this analysis were change in amyloid and tau levels.

These results underscore the importance of amyloid plaques in AD and understanding amyloid status for treatment decision.

Compared with placebo, donanemab induced amyloid plaque reduction by week 24 and 40% of patients who received donanemab had complete amyloid clearance, defined as 24.1 centiloids (CL).

Stratified by amyloid clearance, those who achieved clearance had significantly lower amyloid at baseline compared with those who only had partial clearance (mean, 92.8 vs 117.4 CL), respectively. Similarly, the average amyloid level was lower (7.7 CL) among the cleared group than among the partially cleared group (56.7 CL) at week 24.

Donanemab-induced amyloid clearing had a correlation between baseline plaque level and amount cleared (r, -0.54; 95% CI, -0.66 to -0.39; P <.001) that was stronger than placebo-induced clearing (r, -0.194; 95% CI, -0.372 to -0.002; P =.04).

In addition, tau accumulation slowed by 34% among those who received donanemab compared with placebo.

Individuals who had complete amyloid clearance had significantly lower mean change in tau standardized uptake value ratios (SUVRs) over 76 weeks in the frontal (P <.01), parietal (P <.01), temporal (P <.05), and weighted neocortical SUVR (P <.05) regions compared with placebo.

In a simulated model, the decreased amyloid plaque levels from baseline were found to decrease disease progression according to the integrated AD Rating Scale (iADRS) scale (23%; 95% CI, 3%-40%; P <.001). However, when apolipoprotein (APOE) ε4 carrier status was added to the simulations, slowed disease progression was only significant for carriers (44%; 95% CI, 24%-59%; P <.001).

Results of the simulation analysis should be interpreted with caution as patients were not evaluated by the iADRS instrument in this trial.

This study found that donanemab therapy may induce complete amyloid clearance among patients with AD, especially for those with lower baseline amyloid levels. Amyloid clearance may be associated with slower disease progression.

“These results underscore the importance of amyloid plaques in AD and understanding amyloid status for treatment decision,” the researchers concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

This article originally appeared on Neurology Advisor

References:

Shcherbinin S, Evans CD, Lu M, et al. Association of amyloid reduction after donanemab treatment with tau pathology and clinical outcomes: the TRAILBLAZER-ALZ randomized clinical trial. JAMA Neurol. Published online September 12, 2022. doi:10.1001/jamaneurol.2022.2793