Sim et al. evaluated whether Donanemab, a mono-clonal antibody targeting brain amyloid plaques, can provide clinical benefit in early symptomatic Alzheimer’s disease (AD). They conducted a phase-3, multicentre, randomised clinical trial including 1736 participants with early AD between 60-85 years of age. People were randomised to intravenous Donanemab or placebo administered 4 weekly for 72 weeks. Beta amyloid and tau levels were serially measured using Positron emission tomography (PET). A notable aspect of study design was that patients in the treatment arm whose levels of beta amyloid became undetectable over the course of the trial were reallocated to the placebo arm.
The primary outcome was the change in the integrated Alzheimer’s disease Rating Scale (iADRS) from baseline at 76 weeks. This was used to compute a measure of ‘slowing of clinical disease progression’, which represents the difference in the change in iADRS between treatment and placebo, as a percentage of the change in the placebo group.
iADRS scores decreased from baseline across both groups, however the decrement was significantly smaller in the treatment arm compared to placebo (-10.19 and -13.11, respectively) Critically, this effect was more pronounced in people with low/medium baseline levels of tau on PET imaging, where change in iADRS was -6.02 in the treatment group, and -9.27 in the placebo group. This represented a 35.1% slowing of disease progression. Serial PET imaging confirmed that treatment also significantly reduced cerebral amyloid but not concentrations of tau in the frontal lobe. Despite a lack of change in cereberal levels of tau however, there was a significant decrease in plasma levels of phospholyrated tau.
Sixteen deaths were reported on donanemab vs. 10 on placebo. 112 patients (13%) on treatment discontinued treatment on donanemab vs. 38 (4.3%) on placebo. The most common adverse events leading to treatment discontinuation were: Infusion related reactions (3.6% vs. 0%) and amyloid-related imaging abnormalities including effusions/oedema/microhaemorrhages (3.3% vs. 0.5%).
Key Points:
- In patients with early Alzheimer’s disease, donanemab significantly slows down cognitive decline compared to placebo over 76 weeks
- This effect is more pronounced in patients with lower levels of tau pathology, as measured by PET imaging, at baseline
- Donanemab significantly reduced levels of amyloid plaques and plasma tau, but not cerebral tau in the frontal lobes.
- Adverse events were more common in the treatment group, specifically emergent adverse effects leading to discontinuation of treatment.
References:
- Sims JR, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512-527. doi: 10.1001/jama.2023.13239. PMID: 37459141; PMCID: PMC10352931.
Publish on behalf of the Scientific Panel Dementia and Cognitive Disorders