Modified Donanemab Dosing May Reduce ARIA-E Risk in Early Alzheimer’s

Modified titration of donanemab (Kisunla) for early Alzheimer’s disease significantly reduced the frequency of amyloid-related imaging abnormalities with edema and effusion (ARIA-E) compared to standard dosing, while maintaining sufficient amyloid reduction, according to findings from the TRAILBLAZER-ALZ 6 trial presented at the Clinical Trials on Alzheimer’s Disease conference in Madrid.

In this exclusive MedPage Today video, John R. Sims, MD, senior medical director at Eli Lilly, discusses the study results.

Following is a transcript of his remarks:

TRAILBLAZER-ALZ 6 was designed to increase our understanding of ARIA. Amyloid-related imaging abnormalities occur with amyloid-targeting therapies and some aspects of ARIA are understood, but there’s still a great deal of learning that’s still required in this space.

And so some aspects of this are dose and time and titration. And these are some aspects that we decided to study in TRAILBLAZER-6. In particular, we decided to study three alternative dosing paradigms to see if they could improve on the current standard regimen.

For those other arms, we basically had four randomization arms to go to — standard and the three additional arms — and we randomized participants 1:1:1:1 across those arms. We kept it blinded. People were stratified according to their APOE genotype as well as to amyloid load since these are the key important aspects for both risk and for the pharmacodynamic [PD] effect.

This study was positive. The primary outcome was assessed at 24 weeks, and the primary outcome was to identify a lower, or at least one of the arms that might have lower ARIA-E frequency. This was established at 24 weeks because that’s about when 90% of the prior ARIA-E has occurred from other studies. And this had a Bayesian logistical regression analysis, which stated a posterior probability that at least one arm had 80% probability of 20% or greater risk reduction for ARIA-E.

And this was met by an arm we call modified titration. It met that primary objective and that ARIA-E frequency was 14% for the modified titration versus 24% for the standard dosing. And so this represented a 41% relative risk reduction in that first 24 weeks for ARIA-E for the modified titration, and that achieved that with a probability of 94%.

So in summary, this 24-week data with the change of initiation of just one of the vials, moving it from the first month to the third month of this modified titration, was significantly lowering ARIA-E to 14% compared to the 24% for the standard arm. This had lower ARIA symptomatic ARIA-E, and it had lower radiographic severity. It also had a significantly lower ARIA-E in the homozygous population, comparable PK [pharmacokinetic] profiles, and comparable amyloid-lowering and p-tau217 responses. And all of the PK and the PD and the safety contribute to submitting this to global regulators for a consideration of updating our dosing on label.

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