Donanemab—an investigational antibody that targets a modified form of beta amyloid present only in established plaques—appeared to slow decline of a composite measure of cognition and daily function in patients with early symptomatic Alzheimer’s disease, according to results from the phase II TRAILBLAZER-ALZ trial.
Change from baseline in the Integrated Alzheimer’s Disease Rating Scale (iADRS) score at 76 weeks was −6.86 with donanemab compared with −10.06 with placebo (difference: 3.20, 95% CI, 0.12-6.27; P=0.04), reported Mark Mintun, MD, of Eli Lilly in Indianapolis, and co-authors in New England Journal of Medicine.
“This randomized phase II trial showed that, in patients with early symptomatic Alzheimer’s disease, treatment with donanemab resulted in modestly less cognitive and functional decline than placebo; however, slowing disease progression by half (an assumption on which the power calculation was based) was not achieved, and treatment resulted in amyloid-related imaging abnormalities,” Mintun and colleagues wrote.
“Longer and larger trials are required to study the efficacy and safety of donanemab in early Alzheimer’s disease. TRAILBLAZER-EXT, a follow-on study for those who participated in TRAILBLAZER-ALZ, is currently enrolling participants,” they noted. In addition, TRAILBLAZER-ALZ2, a larger phase II study, is underway.
Researchers of the double-blind TRAILBLAZER-ALZ study enrolled 272 patients with early symptomatic Alzheimer’s disease who had both amyloid and tau positive PET scans. The primary outcome compared patients randomized to placebo (n=126) versus donanemab (n=131) at 76 weeks on the Integrated Alzheimer’s Disease Rating Scale (iADRS), a recently introduced composite measure of cognition and daily function.
The iADRS combines a measure of cognition (the Alzheimer’s Disease Assessment Scale-Cognitive subscale, or ADAS-Cog) and a measure of daily function (the Alzheimer’s Disease Cooperative Study – Instrumental Activities of Daily Living, or ADCS-iADL). These two components individually also were secondary endpoints, along with the Mini–Mental State Examination (MMSE) and changes in amyloid and tau burden on PET.
Active and passive immunization approaches to Alzheimer’s disease treatment targeting both amyloid and tau have been reviewed recently, and an FDA decision regarding approval of amyloid-targeting aducanumab is expected in 2021 after a widely-debated review process.
Donanemab also targets amyloid, but is specific for the amyloid beta protein species with an N-terminal pyroglutamate residue present in plaques as an insoluble form. This species is toxic, resistant to degradation, and is thought to act as a seed promoting faster aggregation and amyloid beta sheet stabilization. Prior work suggested that doses of donanemab up to 10 mg/kg were tolerated but only the 10 mg/kg dose changed amyloid imaging findings, with reductions of up to 50%.
Mintun and co-investigators included patients 60 to 85 years old who met diagnostic criteria for mild cognitive impairment or mild dementia with MMSE scores of 20-28 (mean score about 24). Mean age was 75 years, and about 52% were women. While all participants were both amyloid and tau positive on PET scan, those with the highest levels of tau were excluded.
Mean baseline iADRS was about 106 for both groups. For the donanemab and placebo groups, respectively, baseline global tau loads on flortaucipir PET were 0.47 and 0.46 centiloids, and amyloid plaque levels on florbetapir PET were 107.6 and 101.1 centiloids.
Treatment was given as an intravenous infusion once every 4 weeks for 72 weeks, with final assessment 4 weeks after the final infusion. If the first three donanemab doses (700 mg each) did not result in ARIA-E on imaging, the dose was increased to 1,400 mg. Dose adjustments were based on amyloid imaging at weeks 24 and 52: if florbetapir PET amyloid level was 11 to 24 centiloids, the dose was lowered to 700 mg. If the level was in this range on two consecutive scans, or if it was less than 11 on any scan, donanemab was switched to placebo. (Less than 24 centiloids was considered an amyloid-negative scan.)
In 76 weeks, donanemab reduced amyloid plaque level by a mean 85 centiloids. “The donanemab dosing regimen was selected to facilitate aggressive removal of amyloid plaques early in the trial, and almost 60% of participants had amyloid-negative status by 52 weeks,” Mintun and colleagues observed.
Neither global tau load nor hippocampal volume differed substantially between groups. “It 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,” the researchers suggested.
Results for other secondary outcomes were mixed. “No definite conclusions can be drawn from data regarding the difference between groups in the change in the ADAS-Cog13 score,” the authors wrote. “The results for the ADCS-iADL and MMSE scores showed no substantial difference between groups.”
The safety profile of donanemab was consistent with observations from phase I data, including amyloid-related imaging abnormalities (ARIA). Among treated participants, ARIA with edema (ARIA-E) occurred in 27% and was symptomatic in 6%.
Most cases of ARIA-E (n=35 for donanemab, n=1 for placebo) occurred by week 12, with two participants in the donanemab group requiring hospitalization. Both had confusion, but symptoms resolved in both over a mean of 18 weeks.
Incidence of death or serious adverse events did not differ between the groups, with at least one adverse event reported by 90.8% in the donanemab group and 90.4% in the placebo group. No macro hemorrhage was seen in either group, but microhemorrhage was seen in about 20% of the donanemab group and in about 5% in the placebo group.
Limitations of the trial include a small sample size of a mostly white cohort, limiting generalizability. In addition, trial discontinuation due to adverse events was higher for those receiving donanemab, introducing survivor bias.
-
Donanemab, an investigational antibody that targets a modified form of beta amyloid present only in established plaques, appeared to slow decline on a composite measure of cognition and daily function in patients with early symptomatic Alzheimer’s disease, the phase II TRAILBLAZER-ALZ trial found.
-
Change from baseline in the Integrated Alzheimer’s Disease Rating Scale (iADRS) score at 76 weeks was −6.86 with donanemab and −10.06 with placebo (difference 3.20, 95% CI 0.12-6.27; P=0.04).
Paul Smyth, MD, Contributing Writer, BreakingMED™
The study was funded by Eli Lilly.
Mintun is an employee of Eli Lilly.
Cat ID: 33
Topic ID: 82,33,730,33,192,925
