A modified dosing strategy for donanemab (Kisunla), an approved therapy for early Alzheimer's disease, significantly lowers the risk of amyloid-related imaging abnormalities associated with edema (ARIA-E), according to data from the Phase 3 TRAILBLAZER-ALZ 6 trial (NCT05738486). This change involves shifting one vial of the drug from the first to the third infusion, offering a potentially safer profile without compromising efficacy. Eli Lilly, the drug's manufacturer, plans to submit these findings to global regulatory bodies for a label update.
The TRAILBLAZER-ALZ 6 study is evaluating different dosing regimens of donanemab in adults with early Alzheimer's over a 24-week period. The modified regimen consists of one vial (350 mg) for the first infusion, two vials (700 mg) for the second, three vials (1,050 mg) for the third, and four vials (1,400 mg) for all subsequent infusions. This is compared to the standard dosing regimen of two vials (700 mg) for the first three infusions, and four vials (1,400 mg) thereafter.
Reduction in ARIA-E Risk
The modified dosing regimen demonstrated a notable reduction in ARIA-E. The occurrence of ARIA-E dropped from 24% in the TRAILBLAZER-ALZ 2 study, which used the standard dosing, to 14% in the TRAILBLAZER-ALZ 6 study with the modified dosing — a 41% relative risk reduction.
"We are confident in the benefits of Kisunla’s currently approved dosing regimen and are excited that these results reveal a path to potentially improving on Kisunla’s profile by reducing the risk of ARIA-E," said Mark Mintun, MD, group vice president of neuroscience research and development at Eli Lilly and president of Avid Radiopharmaceuticals.
Impact on ApoE4 Carriers
The benefit was particularly pronounced in patients carrying two copies of the ApoE4 gene variant, a known risk factor for Alzheimer's disease. In this subgroup, the modified dosing reduced the ARIA-E risk from 57% with the standard regimen to 19%, representing a 67% relative risk reduction, according to Eli Lilly.
Amyloid Plaque Removal
Importantly, the modified dosing regimen did not compromise the drug's ability to clear amyloid plaques, a key therapeutic target in Alzheimer's disease. At 24 weeks, patients on the modified regimen experienced a 67% reduction in amyloid plaques, comparable to the 69% reduction observed with the standard dosing regimen.
Safety and Future Data
Both dosing regimens exhibited similar safety profiles, with no new safety concerns identified. Infusion reactions occurred at comparable rates in both groups. Data on ARIA-E risk after 52 weeks of treatment are expected early next year.
It was noted that one patient in the modified group experienced severe symptoms and died after treatment with a tissue-type plasminogen activator to break down blood clots, highlighting the need for caution when using thrombolytics in patients on donanemab.
