results of a phase 3 study showed.
“This trial demonstrates that an antiamyloid drug significantly slows the disease and provides meaningful benefit to patients, and we’re hoping that with approval, we will be able to make that drug available,” said Mark Mintun, MD, VP, pain and neurodegeneration research, Eli Lilly.
At a press briefing highlighting the new results, Maria Carrillo, PhD, chief science officer, Alzheimer’s Association, noted the “palpable excitement” surrounding this new study, which follows on the heels of other promising antiamyloid research. “This is the decade of Alzheimer’s disease, and it will get better from here,” she said.
The findings were presented at the Alzheimer’s Association International Conference and were published online in JAMA.
Primary, secondary endpoints met
The TRAILBLAZER-ALZ 2 study included 1,736 patients with mild cognitive impairment (MCI) or mild dementia for whom PET showed evidence of amyloid and tau pathology. The mean age of the participants was 73 years, and most of the participants were White.
Participants were randomly assigned to receive either placebo or donanemab, an investigational IgG1 monoclonal antibody directed against an insoluble, modified, N-terminal, truncated form of beta-amyloid. Donanemab was administered at a dose of 700 mg for the first three doses and 1,400 mg thereafter. The drug was administered intravenously every 4 weeks for up to 72 weeks.
Researchers stratified patients on the basis of the amount of tau, a biomarker for Alzheimer’s disease progression, into a low/medium tau group and a combined tau group (low/medium and high tau).
The primary endpoint was change from baseline to 76 weeks on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures cognition and activities of daily living.
In those with low/medium tau levels, the least squares mean (LSM) change in iADRS score was −6.02 (95% confidence interval, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25; 95% CI, 1.88 – 4.62; P < .001), representing a 35.1% slowing of disease progression.
In the combined (tau) population, LSM change in iADRS was −10.19 (95% CI, −11.22 to −9.16) in the donanemab group and −13.11 (95% CI, −14.10 to −12.13) in the placebo group (difference, 2.92; 95% CI, 1.51 – 4.33; P < .001), representing a 22.3% slowing of disease progression.
The study also met all secondary endpoints regarding measurements of cognitive and functional decline, including the Clinical Dementia Rating–Sum of Boxes (CDR-SB), which showed 36% slowing of decline (P < .0001) over 18 months.
The authors noted that the changes on these scales were clinically meaningful (considered to be > 20% slowing of clinical progression) for both the low/medium tau and combined populations.
Greater benefit with lower tau
However, patients with low/medium tau generally demonstrated effect size estimates that were larger than those of the overall population, which suggests there’s greater benefit when amyloid-lowering therapies are initiated at an earlier disease stage, the investigators noted.
Additional support for clinical relevance was a 38.6% risk reduction of disease progression, as measured on the CDR–Global Score.
In addition, participants who received the active drug benefited in terms of activities of daily living, as demonstrated by 40% less decline (P < .0001) on the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory.
Donanemab significantly reduced brain amyloid plaque: 80% (low/medium tau population) and 76% (combined population) of participants achieved amyloid clearance at 76 weeks. The intervention was also associated with a greater decrease in whole-brain volume.
The treatment effect continued to widen after patients were switched to placebo, as evidenced on PET scan at 6 or 12 months, said Dr. Mintun.
The effects of the drug were similar among men and women but were especially pronounced among younger participants, with a 48% slowing on iADRS and a 45% slowing on CDR-SB in those younger than 75 years.