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Donanemab Shows Clinically Meaningful Benefit for Early Alzheimer Disease
Donanemab, a monoclonal antibody designed to clear brain amyloid plaque, significantly slowed clinical progression at 76 weeks in patients with early symptomatic Alzheimer disease and amyloid and tau pathology. Researchers published their findings in JAMA.
“Donanemab treatment resulted in clinically meaningful benefit (considered to be >20% slowing of clinical progression) on the iADRS [integrated Alzheimer Disease Rating Scale] and CDR-SB [change in the sum of boxes of the Clinical Dementia Rating Scale] scales for both the low/medium tau and combined populations, regardless of statistical model,” wrote corresponding author John R. Sims, MD, Eli Lilly and Company, Indianapolis, Indiana, and coauthors. “Additional support for clinical relevance is the 38.6% risk reduction of disease progression as measured on the CDR-G [CDR Global score] score and the 4.4 to 7.5 months saved over the 18-month study (low/medium tau population).”
The global TRAILBLAZER-ALZ 2 phase 3 trial included 1736 patients with early symptomatic Alzheimer disease, defined as mild cognitive impairment or Alzheimer disease with mild dementia. Participants had amyloid and low/medium or high tau pathology based on positron emission tomography imaging.
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The double-blind study randomized 860 participants to receive donanemab and 876 participants to receive placebo intravenously every 4 weeks over 72 weeks. A total 1320 patients completed the trial.
At 76 weeks, the least-squares mean change in score on the iADRS, on which a lower score signals greater impairment, was −6.02 in the donanemab group and −9.27 in the placebo group in the low/medium tau population. In the combined study population, the least-squares mean change in iADRS score was −10.19 with donanemab and −13.11 with placebo, according to the study.
Donanemab also significantly slowed Alzheimer disease progression across numerous secondary clinical outcomes. In fact, 23 of 24 primary, secondary, and exploratory gated outcomes were statistically significant, the study found.
“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,” researchers wrote.
Amyloid-related imaging abnormalities of edema or effusion occurred in nearly a quarter of patients with donanemab compared with 2.1% with the placebo. Three deaths in the donanemab group occurred following 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,” researchers wrote, “in addition to earlier treatment of the disease when less amyloid pathology is present and, theoretically, when amyloid-related imaging abnormalities risk is lower.”
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