The investigational anti-amyloid drug donanemab (Eli Lilly) has similar clinical efficacy in apolipoprotein E ε4 (APOE4) heterozygous and homozygous carriers and noncarriers at high risk of Alzheimer’s disease (AD), new data from the TRAILBLAZER-ALZ 2 study show.
“It’s important to understand whether APOE genotype affects rates of clinical decline in our clinical trial populations and if it affects efficacy of amyloid-targeting therapies,” said Cynthia Evans, PhD, a neuroscientist with Eli Lilly, Indianapolis, Indiana.
In TRAILBLAZER-ALZ 2, “we saw robust amyloid clearance in all participant groups,” said Evans, which translated into clinically meaningful cognitive benefits for patients.
The findings were presented at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
New Insights
The TRAILBLAZER-ALZ 2 study included 1736 patients (mean age, 73) with mild cognitive impairment or mild dementia with evidence of amyloid and tau pathology on PET scan randomly assigned to receive donanemab or placebo.
Donanemab was administered at a dose of 700 mg for the first three doses and 1400 mg thereafter administered intravenously every 4 weeks for up to 72 weeks.
Participants were stratified based on tau levels, a biomarker for AD 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. A key secondary outcome was the Clinical Dementia Rating scale–Sum of Boxes (CDR-SB).
As previously reported by Medscape Medical News, treatment with donanemab cleared brain amyloid plaque and significantly slowed disease progression in early symptomatic AD.
At the CTAD conference, Evans presented data on the efficacy of donanemab by APOE4 carrier status as well as by tau pathology burden and in the overall population.
In the low-medium tau pathology group, over 76 weeks, donanemab slowed clinical decline in APOE4 carriers and noncarriers by a similar percentage, 35% to 38% on the iADRS and CDR-SB, she reported.
There was “significant slowing of cognitive decline” in both the low-medium tau population and the overall population across all cognitive scales, including the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), she told conference attendees.
Homozygous APOE4 carriers, the smallest group in the trial, had “numerically smaller” treatment effects than heterozygotes or noncarriers, likely due to dose pauses or discontinuation due to amyloid-related imaging abnormalities (ARIA), but the data still favored treatment with donanemab.
“In estimating the Bayesian probability that the treatment difference versus placebo is greater for carriers versus noncarriers — it’s about the toss of a coin. In both the carriers and noncarriers, the probability that the treatment difference favors treatment with amyloid-targeted therapies is very high,” Evans said.
Clinically Meaningful Benefit
In a related presentation, Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix, Arizona, reported data from exploratory post-hoc analyses on the clinical relevance of donanemab treatment.
Surveys have shown that what matters most to patients, care partners, and clinicians is slowing disease progression to maintain independence and the ability to participate in activities longer, Atri told attendees.
Patients want to maintain the ability to do day-to-day things such as “writing things down, performing pastimes, talking about what they’ve read or what they’ve seen on TV, keeping appointments,” he explained.
Post-hoc analyses from TRAILBLAZER-ALZ 2 show that donanemab treatment “translates into meaningful benefits by mitigating the risk of progression and dependency,” Atri reported.
Eli Lilly has filed a submission to the US Food and Drug Administration. A decision is expected by the end of the year.
If approved, donanemab will be the third anti-amyloid monoclonal antibody to be approved in the United States, following aducanumab (Aduhelm) and lecanemab (Leqembi).
The TRAILBLAZER-ALZ 2 trial was funded by Eli Lilly. Evans has reported being an employee of Eli Lilly. Atri has reported receiving consulting-related honoraria or travel years from AbbVie, Acadia, Allergan, Axovant, AZ Therapies, Biogen, Eisai, Grifols, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Prothena, Qynapse, Sunovion, Suven, and Synexus.
16th Clinical Trials on Alzheimer’s Disease (CTAD) conference. Abstrat LB08. Presented October 25, 2023.
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