An alternate dosing plan for the anti-amyloid drug donanemab (Kisunla) reduced the risk of brain edema and effusion but still maintained sufficient amyloid reduction in early Alzheimer's disease, the phase IIIb TRAILBLAZER-ALZ 6 study showed.
At week 24, the frequency of amyloid-related imaging abnormalities with edema and effusion (ARIA-E) was 23.7% for the standard dosing arm, and 18.6%, 18.3%, and 13.7% for each of three alternative dosing arms, reported John Sims, MD, of drugmaker Eli Lilly in Indianapolis, at the annual Clinical Trials on Alzheimer's Disease meeting.
The standard dosing regimen was 700 mg of donanemab for the first three infusions, then 1,400 mg for each infusion after that. The modified titration arm with the lowest ARIA-E frequency (13.7%) was 350 mg for the first infusion, 700 mg for the second infusion, 1,050 mg for the third infusion, and 1,400 mg for each infusion after that.
The posterior probability of the modified titration arm achieving at least a 20% relative risk reduction in ARIA-E versus the standard arm was 94.1%.
"We were able to demonstrate that one of the dosing paradigms -- the modified titration arm -- did achieve success in lowering ARIA-E rates," Sims said. "That was accompanied by lower symptomatic frequencies, lower radiographic severities, and a fairly dramatic impact on the [APOE4] homozygous population."
The modified titration and standard dosing regimens had comparable pharmacokinetic profiles and a comparable pharmacodynamic effect on amyloid and plasma p-tau217, he added.
TRAILBLAZER-ALZ 6 is still ongoing but "given the clinical implications and the safety findings of this, we plan to submit and discuss this with global regulators for a possible update to labels," Sims said.
Donanemab was approved by the FDA in July to treat adults with early symptomatic Alzheimer's disease with confirmed amyloid pathology. The agency's decision was based on results of the phase III TRAILBLAZER-ALZ 2 trial, in which donanemab slowed clinical progression relative to placebo (P<0.001).
In the pivotal trial, 24% of donanemab-treated participants had ARIA-E and 31.4% had ARIA with cerebral microhemorrhages and hemosiderin deposits (ARIA-H). Two ARIA-related deaths were attributed to donanemab in that study. ARIA occurred more frequently in APOE4 homozygotes than in heterozygotes or noncarriers.
The prescribing information for donanemab includes a for ARIA and says APOE4 testing should be performed before starting treatment. The warning cautions that serious intracerebral hemorrhages, including fatal hemorrhages, have been seen with this class of medications.
, which was triggered before the pivotal trial was completed, aimed to assess the effect of different donanemab dosing regimens on the frequency of ARIA relative to amyloid reduction. It was a randomized, double-blind study of 843 adults with early symptomatic Alzheimer's and amyloid pathology.
Participants were randomly assigned to the standard donanemab dosing arm or one of three alternative dosing arms in a 1:1:1:1 ratio. The four treatment arms varied in dose per infusion and frequency of dosing, but by week 16, the total donanemab exposure was the same.
The severity of ARIA-E was less in the modified titration arm than with standard dosing, Sims said. The frequency of symptomatic ARIA-E was 2.8% in the modified titration arm, compared with 4.8% in the standard dosing arm.
The modified titration arm showed no significant difference in overall ARIA-H including cerebral microhemorrhages, but superficial siderosis was seen less frequently.
Serious adverse events, discontinuations, or treatment-related adverse events in the two arms were largely comparable. Frequencies of infusion-related reactions also were similar.
One participant in the modified titration arm, an APOE4 homozygote with ongoing ARIA-E, had stroke-like symptoms and, after receiving tissue plasminogen activator treatment, died due to cerebral intraparenchymal hemorrhage.
In both arms, participants had significant amyloid reduction from baseline to 24 weeks, Sims noted. Adjusted mean change was 58.8 centiloids in the standard arm and 56.3 centiloids in the modified titration arm. Plasma p-tau217 reductions at 24 weeks were similar in both arms.
About 10% of participants (21 people in each dosing group) were APOE4 homozygotes. At 24 weeks, 19% of APOE4 homozygotes on the modified titration regimen had ARIA-E, compared with 57% on standard dosing.
Disclosures
This study was funded by Eli Lilly and Company.
Sims is an employee of Eli Lilly and a minor shareholder.
Primary Source
Clinical Trials on Alzheimer's Disease
Wang H "The effect of different donanemab dosing regimens on ARIA-E and amyloid lowering in adults with early symptomatic Alzheimer's disease: primary outcome results from TRAILBLAZER-ALZ 6" CTAD 2024.