JAMA, Published 7/17/23
This article updated July 17, 2023; was first published May 3, 2023 (excerpts)
Question Does Donanemab, a monoclonal antibody designed to clear brain amyloid plaque, provide clinical benefit in early symptomatic Alzheimer disease?
Objective To assess efficacy and adverse events of Donanemab, an antibody designed to clear brain amyloid plaque.
TRAILBLAZER-ALZ 2 was a 76-week, Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants aged 60 to 85 years with early symptomatic Alzheimer disease (mild cognitive impairment or Alzheimer disease with mild dementia) with amyloid and low/medium or high tau pathology. The trial included participants aged 60 to 85 years with early symptomatic Alzheimer disease (mild cognitive impairment or Alzheimer disease with mild dementia).
Adverse events
Treatment-emergent adverse events were reported by 759 of 853 participants (89.0%) receiving donanemab and 718 of 874 participants (82.2%) receiving placebo. Treatment discontinuation due to adverse events was reported in 112 participants receiving donanemab and 38 participants receiving placebo. The most common adverse events that led to treatment discontinuation were infusion-related reactions. There were three deaths (0.4% of participants) in the trial related to brain swelling and 1.6% of participants had serious symptoms relating to brain swelling.
Similar to other amyloid-lowering drugs, and the phase 2 TRAILBLAZER-ALZ trial, amyloid-related imaging abnormalities are an associated adverse event. When amyloid-related imaging abnormalities occur, they are mostly asymptomatic and resolve in approximately 10 weeks. When symptoms occur, they are usually mild, consisting of a headache or increase in confusion, but can have more severe symptoms such as seizures. In some instances, these events can be life-threatening and result in, or lead to, death. For 1.6% of participants in the donanemab treatment group, amyloid-related imaging abnormalities led to serious outcomes, such as hospitalization, and required supportive care and/or corticosteroid use. It is also important to note that 3 deaths in TRAILBLAZER-ALZ 2 occurred after serious amyloid-related imaging abnormalities. Further evaluation of the risks associated with serious and life-threatening amyloid-related imaging abnormalities will be important to identify the best approaches for managing risks and maximizing benefit, in addition to earlier treatment of the disease when less amyloid pathology is present and, theoretically, when amyloid-related imaging abnormalities risk is lower.
(All adverse events are discussed in detail in the full Updated Report.)
Conclusions
Donanemab treatment resulted in clinically meaningful benefit.
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.
Furthermore, an estimated 47% of participants receiving Donanemab had no change in the CDR-SB at 1 year (no disease progression), compared with 29% of participants receiving placebo.
The general belief is that treating Alzheimer disease at the earliest disease stage is likely to result in more clinically meaningful effects.
Almost half of the people taking it had no decline in memory and thinking skills after one year on Donanemab.
For the full Published Online: July 17, 2023. doi:10.1001/jama.2023.13239
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