Following the launch of the first disease-modifying therapies (DMTs) for Alzheimer’s disease (AD), a key theme at the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Diseases has been their safety profile, focusing on the issue of amyloid-related imaging abnormalities (ARIA), a significant side effect of the anti-amyloid-beta (Aβ) monoclonal antibody (mAb) drug class.
During a symposium on Aβ-targeting therapies, held on April 3, Eli Lilly presented 12-month data from its TRAILBLAZER-ALZ 6 study (NCT05738486) evaluating a modified titration dosing regimen for Kisunla (donanemab). The 12-month data showed that the previously reported significant reduction in ARIA-E (ARIA related to underlying vasogenic oedema) at 24 weeks was maintained at 12 months, with a rate of ARIA-E of 15.6% and symptomatic ARIA-E of 2.8%. This is compared with rates of ARIA-E and symptomatic ARIA-E of 24.0% and 6.1%, respectively, with the standard dosing regimen tested in the TRAILBLAZER-ALZ 2 trial (NCT04437511) that was used to approve Kisunla. Importantly, TRAILBLAZER-ALZ 6 also showed that the modified titration dosing regimen did not affect amyloid reduction when compared with the standard regimen. Further, the reduction in ARIA-E rates in TRAILBLAZER-ALZ 6 was seen across all APOE4 genotypes, with the largest reduction in rate occurring in the APOE4 homozygote group, the patient population that is particularly at risk of developing ARIA.
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A key concern for regulators is the risk-benefit of the anti-Aβ mAbs, and the modified titration regimen is currently under priority review in the US. An updated prescribing label could help increase the uptake of Kisunla, with the reduced ARIA risk more in line with Eisai/Biogen’s Leqembi (lecanemab). In other regions, such as Europe, where Kisunla received a negative opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) due to its adverse side-effect profile in March 2025, a modified titration regimen reducing the risk of ARIA could increase the likelihood of an approval of the drug, with Lilly set to seek a re-examination of the decision.
In the same symposium on Aβ-targeting therapies in AD, real-world data of Leqembi use in the Tel Aviv Medical Center was presented. On a positive note, out of the 86 patients who had initiated Leqembi treatment, only three experienced ARIA-E, with two of the cases mild and asymptomatic in nature, and the other case moderate and symptomatic. While the low rate of ARIA-E in this non-clinical-trial population is promising for increasing the clinical use of Leqembi, it was a small cohort, and more extensive real-world data will be required for physicians to become comfortable with the risks of prescribing anti-Aβ mAbs such as Leqembi. Further, the Tel Aviv Medical Center decided to not prescribe Leqembi to APOE4 homozygotes, which likely also contributed to the lower rates of ARIA seen. This preliminary evidence appears to support the various regulatory agency decisions, including in the UK, to exclude the APOE4 homozygous patient population from their approval label and highlight the unmet need for safer treatment options for all patients with AD.
Due to the risks of ARIA, a magnetic resonance imaging (MRI) scan is required before anti-Aβ mAb treatment, with further MRIs recommended before subsequent infusions. Access to MRI scans is a key economical and operational limiting factor for the uptake of these drugs as healthcare systems adjust to the addition of these DMTs to the treatment paradigm. A further presentation during the same symposium at AD/PD 2025 focused on how MRI methods could be accelerated to improve access. Focused protocols that reduced the amount of time a patient spent in the MRI by around two-thirds would not only make the MRI process more cost-effective per patient but it would also enable more patients to access MRIs and enhance patient comfort during the process.
The various presentations in this symposium highlight the significant impact that ARIA is having on the DMT landscape for AD, as well as showing that there is a broader community focus on how to best tackle ARIA. While still in early days, the ARIA-focused treatment optimisation strategies provide new hope for a wider adoption of the amyloid beta mAbs.
