Modified Kisunla dosing shown to lower risk of ARIA-E in Alzheimer’s
Shifting 1 vial from first to third infusion reduces risk in Phase 3 trial
Being started on a smaller dose of the approved early Alzheimer’s disease therapy Kisunla (donanemab) — by shifting one vial from the first to the third infusion treatment — reduces the risk of ARIA-E, or amyloid-related imaging abnormalities associated with brain swelling, among adults with the neurodegenerative condition.
That’s according to the findings of an ongoing Phase 3 clinical study, dubbed TRAILBLAZER-ALZ 6 (NCT05738486), that’s testing the safety of different dosing regimens of Kisunla in adults with early Alzheimer’s. The participants are administered one of four dosing regimens of Eli Lilly’s Kisunla, interspersed with periods in which they receive a placebo, over 24 weeks, or nearly six months.
Based on these data, Eli Lilly plans to file with global regulators for a potential label update for Kisunla, according to a company press release.
“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 the company’s wholly-owned subsidiary Avid Radiopharmaceuticals.
Mintun added that “modified titration could offer continued convenience of once-monthly dosing and limited duration treatment while also reducing ARIA-E and maintaining similar amyloid plaque removal.”
Dosing change resulted in 40% lower risk of ARIA-E vs. earlier trial
Shifting one vial of Kisunla from the first to the third infusion reduced the proportion of patients with any occurrence of ARIA-E as observed with the standard dosing regimen used in the pivotal Phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511).
The dosing change resulted in that occurrence dropping from 24% in TRAILBLAZER to 14% — a 41% lower relative risk.
The modified dosing regimen reduced ARIA-E the most in patients with two copies of the ApoE4 gene variant, which is known to have a high genetic risk for Alzheimer’s. With the modification, 19% of these patients experienced ARIA-E compared with 57% on the standard dosing regimen, lowering their relative risk by 67%, according to Eli Lilly.
Like other antibody-based treatments designed to target amyloid — a protein that forms toxic plaques in the brain and contributes to how Alzheimer’s develops and progresses — Kisunla carries a risk of ARIA-E. This side effect typically occurs early and is asymptomatic, but seizures and other symptoms may occur.
Given as a monthly infusion into the vein, Kisunla’s standard dosing regimen consists of two vials (700 mg) for the first three infusions, and four vials (1,400 mg) thereafter. In addition to this regimen, the TRAILBLAZER-ALZ 6 study is testing three other dosing regimens with the same total amount of Kisunla.
The results at 24 weeks showed that a modified dosing regimen consisting 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, resulted in the greatest reduction of ARIA-E compared with the other alternatives.
Patients on the modified dosing regimen had similar reductions in amyloid plaques as those on the standard dosing regimen. By 24 weeks, amyloid plaques were reduced by 67% in the patients on the modified dosing regimen, nearly matching the 69% reduction in those on the standard one.
Data on the risk of ARIA-E in adults with early Alzheimer’s, including those with mild cognitive impairment and mild dementia, after 52 weeks, or one year, are expected early next year.
Both dosing regimens showed similar safety profiles, with no new safety issues. Infusion reactions occurred at the same rate in both groups. 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 Kisunla.
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