Amyloid‐Related Imaging Abnormalities in the DIAN‐TU‐001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease

Abstract

Objective To determine the characteristics of participants with amyloid‐related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β‐amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross‐sectional and longitudinal analyses evaluated potential ARIA‐related risk factors. Results Eleven participants developed ARIA‐E, including 3 with mild symptoms. No ARIA‐E was reported under solanezumab while gantenerumab was associated with ARIA‐E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE‐ɛ4 carriers were more likely to develop ARIA‐E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA‐E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA‐E occurrence, all ARIA‐E participants were amyloid‐PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA‐H. Most ARIA‐E radiologically resolved after dose adjustment and developing ARIA‐E did not significantly increase odds of trial discontinuation. ARIA‐E was more frequently observed in the occipital lobe (90%). ARIA‐E severity was associated with age at time of ARIA‐E. Interpretation In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA‐E risk, with additional risk for individuals APOE‐ɛ4(+) or with microhemorrhage. ARIA‐E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744

Presenilin‐1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage

“…This finding has implications for clinical trial enrollment since total microhemorrhage count is a strong risk factor for the development of Aβ-related imaging abnormalities (ARIA) in individuals with DIAD treated with anti-amyloid antibodies. 49 Vascular risk factors may influence the development of these markers of SVD, but in our cohort no difference between pre-and post-200 PSEN1 carriers was observed in the prevalence of hypercholesterolemia, diabetes, or stroke. However, the prevalence of clinically confirmed hypertension was lower in the pre-200 group.…”

“…Regarding microhemorrhages, while we confirmed our previous report that mutation position does not significantly affect the odds of developing them generally 28 or in any specific lobe, we did find an influence on the total count of microhemorrhages, including a trend toward occipital count, with post‐200 carriers showing higher counts starting at preclinical stages. This finding has implications for clinical trial enrollment since total microhemorrhage count is a strong risk factor for the development of Aβ‐related imaging abnormalities (ARIA) in individuals with DIAD treated with anti‐amyloid antibodies 49 …”

Tailoring MAPK Pathways: New Therapeutics Avenues for Managing Alzheimer’s Diseases

“…DIAN-TU, a phase 2/3 trial, focused on primary prevention for the autosomal dominant form of AD, which has a known link to Aβ dysfunction and early cognitive decline 29 . Regrettably, a preliminary analysis of the trial revealed that both investigational anti-amyloid drugs, Roche's gantenerumab and Lilly's solanezumab, did not meet the primary endpoint criteria (DIAN-Multivariate Cognitive Endpoint) 30 . In October 2019, phase 3 study was conducted using aducanumab's which also could not offer clinical advantage and could not modify the diseases severity 31 .…”

Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities

“…Different incidences of ARIA have been observed in clinical trials, with ARIA-E rates of 30% or greater for aducanumab 14 , 25 , 26.7% for bapineuzumab 15 , 25% for gantenerumab 26 – 28 , 24% for donanemab 16 , and 12.6% for lecanemab 17 , while solanezumab and crenezumab have no reported cases of ARIA-E 29 – 32 . Although the molecular mechanisms underlying these differences are unclear, they are likely to relate to the profiles of antibody binding to different forms of Aβ, and to the ability of the antibody to mobilize vascular amyloid and trigger microglial effector function.…”