Donanemab is a monoclonal antibody which targets a specific form of the amyloid beta protein that is present in mature amyloid plaques, which accumulate in the brains of people with Alzheimer’s disease (AD). The clinical efficacy of donanemab was evaluated in the TRAILBLAZER-ALZ study, a phase 2, placebo-controlled randomized clinical trial that was conducted in the US and Canada between 2017 and 2020. TRAILBLAZER-ALZ met its primary objective, with monthly doses of donanemab slowing the clinical decline of AD by 32% compared to placebo. This slowing of clinical decline was associated with substantial amyloid plaque lowering, with 68% of donanemab-treated participants achieving amyloid-negative status after 76 weeks of treatment. On 12 September, researchers published the results of post-hoc analyses of TRAILBLAZER-ALZ data, in the JAMA Neurology journal. These analyses were aimed at mapping the course of amyloid clearance by donanemab, and also looked at correlations between amyloid clearance and clinical decline, as well as the amount of tau tangles in the brain. The post-hoc analyses showing that participants who experienced complete clearance of amyloid plaques often had lower amounts of brain amyloid at baseline. Once complete amyloid clearance was achieved and participants switched to placebo infusions, plaques did not regrow substantially over 1 year without treatment. Donanemab also slowed tau accumulation in a region-dependent manner, as measured using brain PET imaging. Statistical analyses found an association between percentage amyloid reduction and clinical decline, but only in carriers of the apolipoprotein E (APOE) ε4 risk gene. Further studies are now required to confirm these trends.
Exploratory post-hoc analyses of TRAILBLAZER-ALZ study are published in JAMA Neurology