How do the TRAILBLAZER-ALZ 2 trial results for donanemab translate to the clinic?

medwireNews: An insightful session at the Alzheimer’s Association International Conference 2024 looked at how the TRAILBLAZER-ALZ 2 data relate to the use of donanemab in clinical practice, including efficacy, ARIA risk, and dose limiting duration. Starting with an overview of the clinical efficacy of donanemab in TRAILBLAZER-ALZ 2, Jennifer Zimmer (Eli Lilly and Company) reminded delegates in Philadelphia, Pennsylvania about the key highlights. These included a 37% reduced risk for progression to the next stage of Alzheimer’s disease (AD) with donanemab versus placebo at 76 weeks, as assessed by Clinical Dementia Rating–global score (CDR-GS) every 3 months, and a 50% reduction in patients progressing from mild cognitive impairment (CDR-GS=0.5) to moderate AD (CDR-GS≥2). Efficacy was consistent across patients with low-to-medium and high tau positron emission tomography (PET) levels at baseline, with respective risk reductions in AD progression versus placebo at 18 months of 39% and 38%, respectively. Superior clinical efficacy with donanemab treatment versus placebo was seen across subgroup analyses by age, sex, clinical stage, tau PET category, apolipoprotein (APO)E Ɛ4 genotype, and race, although Zimmer pointed out that “some subgroups were quite small and this limits the ability to make statistical comparisons.” She also pointed out post-treatment reductions in amyloid PET, plasma phosphorylated (p)-tau 217, and plasma glial fibrillary associated protein (GFAP) supported donanemab treatment and were seen in the population as a whole as well as in under-represented populations, such as Hispanic/Latino participants and Black/African American participants. Managing ARIA risk Alessandro Biffi (Eli Lilly and Company) discussed the risk for amyloid-related imaging abnormalities (ARIA), which he said is a “class-related safety risk associated with amyloid removal,” but one that “can be managed.” The most frequent symptoms are headache, confusion, nausea/dizziness, with less frequent symptoms of gait disturbance, and neuropsychiatric and visual impairment. Rare symptoms include seizure, focal deficits, which can mimic ischemic stroke, Biffi noted, and encephalopathy. Among 853 patients treated with donanemab in TRAILBLAZER-ALZ 2, ARIA-E (edema) developed in 24.0% of patients and ARIA-H (microhemorrhages) developed in 31.4%. This compared with 2.1% and 13.6% of patients treated with placebo. Biffi pointed out that ARIA-E events were predominantly (93%) mild-to-moderate radiographically, and they were asymptomatic or symptomatic in 18% and 6% of donanemab-treated patients, respectively. However, serious ARIA-E events occurred in 1.5% of patients and three (0.4%) patients with serious ARIA-E died. When the research team looked at ARIA events across TRAILBLAZER-ALZ 2, the TRAILBLAZER-ALZ 2 addendum, TRAILBLAZER-ALZ, and additional donanemab-treated patients from other ongoing trials, they found that most patients only had one episode of ARIA-E, and it did not tend to reoccur when donanemab was reintroduced and was primarily asymptomatic in the minority for whom it did. To understand potential ARIA risk factors, the investigators applied machine learning models that included 42 variables. The greatest risk factors for ARIA-E were being APOE Ɛ4 homozygous, having 2–4 microhemorrhages, and baseline superficial siderosis, which increased the risk 4.6-fold, 2.5-fold, and 2.2-fold relative to being a noncarrier of APOE Ɛ4 and not having microhemorrhages or superficial siderosis, respectively. For ARIA-H, the greatest risk factors were having an APOE Ɛ4 genotype and baseline superficial siderosis. Antithrombotic use did not increase the risk for ARIA and there was no interaction between antithrombotic use and APOE Ɛ4 genotype, Biffi commented. There was also little impact of baseline amyloid level and mean arterial pressure on ARIA risk-. He concluded that identification of high-risk patients prior to treatment “represents the first cornerstone of ARIA risk management, followed by strict adherence with the MRI [magnetic resonance imaging] monitoring schedule, dose titration, interruption, or discontinuation if warranted, and the use of corticosteroids for serious or symptomatic ARIA.” Limited duration dosing Emily Collins (Eli Lilly and Company) discussed the fact that the TRAILBLAZER-ALZ 2 data support limited duration dosing. This is based on the finding that when patients met the dose cessation criteria of a mean amyloid PET level of 24.1 centiloids (CL), levels remained low. This was seen from week 24 as well as from week 52. Also, that the difference in scores on the CDR-sum of boxes between the placebo- and donanemab-treated groups continued to widen after treatment completion. In terms of knowing when to stop treatment, Collins said that a visually negative MRI scan may be feasible to determine this, showing brain scans of donanemab-treated patients 6 months after treatment that were similar to those of amyloid-negative patients. She also pointed out that approximately two-thirds of participants treated with donanemab reached amyloid PET <24.1 CL by 12 months and so this might be the point at which to scan, adding that a high baseline amyloid level corresponded with the time to achieve the amyloid threshold of below 24.1 CL. Collins concluded, however, that the current evidence “does not support the use of plasma p-tau217 for determining donanemab amyloid removal.” She explained that this is because p-tau217 correlates with both amyloid and tau, and so it continues to reflect tau pathology after amyloid removal. medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group This content was originally published on Journey to a New Era for Alzheimer’s Disease; an independent education program developed by Springer Healthcare IME. This program is supported by an educational grant from Lilly. This content is intended for healthcare professionals outside of the UK. AAIC24; Philadelphia, Pennsylvania, USA: July 28–Aug 1

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How do the TRAILBLAZER-ALZ 2 trial results for donanemab translate to the clinic?

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