Donanemab in early symptomatic Alzheimer disease

Donanemab in Early Symptomatic Alzheimer Disease

• RCT (n=1736) found donanemab slowed clinical progression at 76 weeks vs. placebo, with mean change in integrated Alzheimer Disease Rating Scale score of -6.02 vs -9.27 (p<0.001), respectively for low/medium tau population & -10.10 vs -13.11 in combined study population (p<0.001)
  • study authors concluded:
    • among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population
• commentary:
  • an editorial suggests that although donanemab was effective at eliminating cerebral amyloid (cleared in 80% of the treatment group), the clinical effect was comparatively weak and cognition/daily function continued to decline in all participants (2)
    • notes that several important subgroup analyses were not adequately powered and the study does not provide sufficient evidence of safety/efficacy among other races as 72% of participants were US-based, of those, 96.2% were White
    • also notes that treatment with donanemab was associated with significant safety risks - among participants who developed serious amyloid-related imaging abnormalities (ARIA) or brain bleeding and swelling, 3 deaths were determined to be drug-related. Donanemab decreased whole-brain volume and increased ventricular volume and amyloid-related imaging abnormalities were seen in about 37% donanemab-treated patients vs 15% placebo-treated patients
  • safety concerns are cited in a second editorial (3)
    • suggests it will be important to replicate the risk-mitigating measures incorporated into trials, such as excluding patients with evidence of significant cerebral amyloid angiopathy on baseline MRI, conducting surveillance MRIs at regular intervals during treatment, and incorporating conservative algorithms for suspending or stopping treatment when ARIA occurs

Reference:

• Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239
• Manly JJ, Deters KD. Donanemab for Alzheimer Disease-Who Benefits and Who Is Harmed? JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.11704
• Rabinovici GD, La Joie R. Amyloid-Targeting Monoclonal Antibodies for Alzheimer Disease. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.11703