Donanemab may delay Alzheimer’s-related cognitive and functional decline
Donanemab reduced cognitive and functional decline in patients with early symptomatic Alzheimer’s disease (AD), according to results of the phase II TRAILBLAZER-ALZ trial.
“[T]reatment with donanemab resulted in modestly less cognitive and functional decline than placebo; however, slowing disease progression by half … was not achieved, and treatment resulted in amyloid-related imaging abnormalities,” the investigators said.
Participants in this multicentre (56 sites in US and Canada), double-blind study were 257 patients aged 60–85 years with early symptomatic AD* with tau and amyloid deposition on positron-emission tomography (PET)** and Mini–Mental State Examination (MMSE) score 20–28. They were randomized 1:1 to receive intravenous donanemab (700 mg for the first three doses, then 1,400 mg; n=131, mean age 75 years, 51.9 percent female) or placebo (mean age 75.4 years, 51.6 percent female) Q4W for ≤72 weeks.
Patients were primarily White (93.1 and 96.0 percent of the donanemab and placebo groups, respectively) and 72.5 and 74.2 percent, respectively, were APOE ε4 carriers. Mean baseline MMSE score was 23.6 and 23.7, respectively, Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score 3.6 and 3.4, global tau load on flortaucipir PET 0.47 and 0.46, and amyloid plaque level on florbetapir PET 107.6 and 101.1 centiloids, respectively.
At 76 weeks, the decline from baseline in Integrated Alzheimer’s Disease Rating Scale (iADRS) score*** (baseline score 106 in both groups) was smaller in the donanemab than the placebo group (-6.86 vs -10.06; difference, 3.20, 95 percent confidence interval, 0.12–6.27; p=0.04), with the smaller decrease suggestive of lower levels of cognitive and functional decline. [N Engl J Med 2021;384:1691-1704]
Change from baseline in CDR-SB score at 76 weeks did not significantly differ between the donanemab and placebo groups (difference, -0.36), nor did change in Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (difference, 1.21) or MMSE scores (difference, 0.64).
At 76 weeks, there was a greater reduction in amyloid plaque levels in the donanemab vs placebo group (-84.13 vs 0.93 centiloids), with a 67.83 centiloid greater reduction with donanemab at 24 weeks. Amyloid-negative status (amyloid plaque level <24.10 centiloids) was noted in 40.0, 59.8, and 67.8 percent of patients in the donanemab group at week 24, 52, and 76, respectively. At week 28 and 52, 27.4 and 54.7 percent of denosumab recipients, respectively, experienced reductions in amyloid levels sufficient to warrant a switch to placebo.
Change in global tau load from baseline to 76 weeks did not significantly differ between groups, nor did volumetric MRI-assessed hippocampal volume.
“[I]t is possible that global tau changes on PET lag as compared with amyloid changes on PET and that an 18-month period is too short to detect global tau changes,” noted the investigators.
However, there were greater reductions in whole-brain volume and greater increases in ventricular volume in the donanemab vs placebo group at weeks 52 and 76, a finding that, according to the investigators, warrants further examination.
Serious adverse events (AEs) did not differ between donanemab and placebo recipients (17.6 percent in each group). There was one death in the donanemab and two in the placebo group. AEs led to discontinuation of the intervention in more donanemab than placebo recipients (30.5 percent vs 7.2 percent)
ARIA-E# occurred more frequently in donanemab than placebo recipients (26.7 percent vs 0.8 percent), with 6.1 percent of all donanemab recipients reporting symptomatic ARIA-E, and serious symptomatic ARIA-E events leading to hospitalization in two donanemab recipients (both resolved).
There were no incidents of brain macrohaemorrhages. Superficial siderosis of the central nervous system (13.7 percent vs 3.2 percent), nausea (10.7 percent vs 3.2 percent), and infusion-related reactions (7.6 percent vs 0) were more common in donanemab than placebo recipients, while contusions were more common with placebo (8.0 percent vs 0). About 90 percent of donanemab recipients had antidrug antibodies.
Although donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living compared with placebo at 76 weeks in patients with early AD, its impact on the secondary outcomes varied, the investigators highlighted. As such, trials with a larger population and longer follow-up period are necessary to examine the efficacy and safety of donanemab in AD.