Risk of ARIA-E in Donanemab Attenuated Through New Enhanced Titration Method of Delivery

Mark A. Mintun, MD

New findings from the phase 3b TRAILBLAZER-ALZ-6 trial (NCT05738486), a study of the recently approved antiamyloid treatment donanemab (Kisulna; Eli Lilly), showed that an enhanced titration dosing regimen of the treatment led to significant reductions in the frequency and severity of amyloid-related imaging abnormalities-edema (ARIA-E). In addition to numerically lower ARIA-E at 24 weeks, those on the titrated dosing regimen also maintained sufficient amyloid reduction.¹

In the study, 843 adults with early symptomatic Alzheimer disease (AD) were stratified by apolipoprotein (APOE) genotype and baseline amyloid levels and randomly assigned to the standard dosing arm or 1 of 3 alternative dosing arms in a 1:1:1:1 ratio. By week 24, the frequency of ARIA-E was 23.7% for the standard dosing arm, and 18.6%, 13.7%, and 18.3% for the 3 alternative dosing arms.

These data were presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1 in Madrid, Spain, by several investigators, including Mark A. Mintun, MD, vice president of Pain and Neurodegeneration Research, and Clinical Development Chief Medical Officer at Avid Radiopharmaceuticals, a subsidiary of Eli Lilly. In the trial, the 4 treatment arms varied in donanemab dosage per infusion and frequency of dosing but the total donanemab exposure by week 16 was the same. Bayesian logistic regression models were used to analyze the relative risk reduction of ARIA-E by week 24, comparing each alternative dosing regimen to the standard dosing approach.

Results from the study showed that the enhanced titration dosing regimen with the lowest ARIA-E (13.7%) had a 41% reduction in the relative risk of ARIA-E compared with the standard dosing arm. In addition, the ARIA-E radiographic severity in the enhanced titration arm was significantly less than the standard dosing arm with 4.7%, 9.0%, and 0% of mild, moderate, and severe ARIA-E compared with percentages of 9.2%, 12.6%, and 1.9%, respectively. Furthermore, the enhanced titration arm demonstrated less frequent symptomatic ARIA-E than the standard dosing arm (2.8% vs 4.8%).

Donanemab, an FDA-approved antiamyloid treatment, maintained its effect on amyloid and phosphorylated tau (p-tau)217 even with the new titrated regimen. Overall, at week 24, all arms had significant amyloid reduction, with adjusted mean change of 58.8 (SE, 1.8) centiloids in the standard arm, 56.3 (SE, 1.7) in the enhanced titration arm, and 58.7 (SE, 1.7) and 51.0 (SE, 1.7) centiloids in the other alternative dosing arms. Recorded data on changes in p-tau217 at 24 weeks were similar in all dosing arms as well.

Serious adverse events, discontinuations, and treatment-related adverse events in the alternative dosing arms were generally similar to those in the standard dosing arm. One participant in the titration arm, who had ongoing ARIA-E, experienced stroke-like symptoms and, after receiving tissue plasminogen activator, subsequently died from cerebral intraparenchymal hemorrhage. The frequency of infusion-related reactions was also comparable between the alternative and standard dosing arms.

Donanemab received FDA approval in early July as a treatment for early-stage AD, becoming the first and only medication with evidence to support stopping treatment when amyloid plaques are removed. The therapy is a prescription medicine administered intravenously every 4 weeks, 700 mg for the first 3 doses and 1400 mg thereafter.

The therapy’s approval was supported by data from TRAILBLAZER-ALZ-2 (NCT04437511), a large-scale, phase 3, double-blind, placebo-controlled trial that featured 1736 patients with early-stage AD who received either donanemab (n = 860) or placebo (n = 876) every 4 weeks for up to 72 weeks. Spanning across 277 medical sites in 8 countries, the primary outcome of the study was least-square mean (LSM) change in integrated Alzheimer Disease Rating Scale (iADRS) score, with lower scores indicating greater impairment. In patients with a low or medium amount of tau pathology, LSM change from baseline in the iADRS score at 76 weeks was –6.02 (95% CI, ­–7.01 to –5.03) in the donanemab group and ­–9.27 (95% CI, –10.23 to ­–8.31) in the placebo group, resulting in a 35.1% (95% CI, 19.90-50.23) slowing of disease progression.^2,3

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REFERENCES
1. Wang H, Nery ES, Ardayfio P, et al. The effect of different donanemab dosing regimens on ARIA-E and amyloid lowering in adults with early symptomatic Alzheimer disease: primary outcome results from TRAILBLAZER-ALZ 6. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 29-November 1; Madrid, Spain. ABSTRACT OC01.
2. Lilly's Kisunla™ (donanemab-azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease. News Release. Eli Lilly. Published July 2, 2024. Accessed October 29, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early
3. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.13239