By Lucy Piper, medwireNews reporter
medwireNews: A modification to the first titration dose of donanemab treatment could significantly reduce the risk for the amyloid-related imaging abnormality of edema and/or effusion (ARIA-E) in patients with early, symptomatic Alzheimer’s disease (AD), suggests the phase 3b TRAILBLAZER-ALZ 6 study.
Presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain, the results show that the new dosing regimen reduced the relative risk for ARIA-E by a significant 41% compared with the standard regimen.
Specifically, the modification involved one of the two vials of donanemab 350 mg given at the first infusion according to the standard titration instead administered at the third infusion at 8 weeks.
A further two modified regimens were also tested and while they were both associated with reductions in ARIA-E risk, they did not reach statistical significance relative to the standard titration.
In all, 843 patients (mean age 73 years; 58% women) with AD participated in the trial and were randomly assigned to one of the four treatment regimens:
- Standard titration (n=207) – intravenous donanemab every 4 weeks at a dose of 700 mg for the first three infusions and then at 1400 mg for the fourth;
- Modified titration regimen (n=212) – intravenous donanemab 350 mg for the first infusion, 700 mg for the second infusion, 1050 mg for the third infusion, and 1400 mg for the fourth infusion;
- Dose skipping regimen (n=210) – donanemab 700 mg for the first infusion, no second infusion at 4 weeks, and 1400 mg for the third and fourth infusions;
- Cmax regimen (based on the drug concentration; n= 213) – donanemab 350 mg every week for 10 weeks, followed by 700 mg at weeks 12 and 14.
When necessary, the treatment groups received placebo to maintain blinding.
John Sims (Eli Lilly and Company, Indianapolis, Indiana, USA) noted that “cumulative donanemab exposure for the four dosing regimens was the same by week 16,” after which all the treatment groups received monthly donanemab up to week 24.
By week 24 of treatment, the rate of ARIA-E in the patients receiving the modified titration regimen was significantly reduced compared with those in the standard titration arm, at 13.7% versus 23.7%.
The modified titration regimen had a 94% probability of achieving at least a 20% reduction in ARIA-E relative to the standard titration, which met the primary study objective of more than 80%.
This was not the case for the dose skipping and Cmax regimens, however. ARIA-E occurred in 18.6% and 18.3% of patients in these groups, respectively, which was numerically but not significantly lower than the rate for the standard titration group.
On magnetic resonance imaging at 24 weeks, 86% of patients given the modified infusion regimen were free of ARIA-E, compared with 76% of those receiving the standard infusion, with improved distribution across the radiographic severity categories. And symptomatic ARIA-E was reduced by 2.8% and 4.8%, respectively.
The study participants were stratified for apolipoprotein E4 genotype and reductions favoring the modified treatment regimen were seen irrespective of carrier status, with a “dramatic” difference seen for homozygotes, said Sims, at rates of 19% versus 57% in the standard titration group.
The presenter pointed out that differences in ARIA-E between the two treatment regimens were evident from the first dose, adding that the initial engagement of amyloid in the blood vessel “is very likely” to be a “key aspect of ARIA-E.”
There was no significant difference between patients receiving the modified and standard titration regimens regarding the rates of serious adverse events (9.9 vs 8.7%), treatment discontinuations due to adverse events (5.2 vs 3.9%), or treatment-related adverse events (48.6 vs 50.2%). However, Sims reported that one patient with ongoing ARIA-E in the enhanced titration group died due to cerebral intraparenchymal hemorrhage after receiving tissue plasminogen activator treatment for stroke-like symptoms.
He highlighted that the reduction in ARIA-E with the modified treatment regimen did not come at the expense of amyloid reduction. Amyloid-lowering over the 24 weeks was comparable for the two groups, with mean decreases from baseline of 56.3 Centiloids (CL) with the modified titration strategy and 58.8 CL with standard titration, as was the reduction in plasma phosphorylated-tau217.
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