APOLLOE4 Phase 3 study of oral ALZ‐801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

INTRODUCTION: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid‐related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ‐801/valiltramiprosate, an oral brain‐penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS: This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study of ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old homozygotes with Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug–placebo difference on the Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating–Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION: APOLLOE4 is the first disease‐modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ‐801 has the potential to be the first effective and safe anti‐amyloid treatment for the high‐risk APOE ε4/ε4 population. Highlights: The APOLLOE4 Phase 3, placebo‐controlled, 78‐week study is designed to evaluate the efficacy and safety of ALZ‐801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini‐Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating–Sum of Boxes, Amsterdam‐Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ‐801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects. [ABSTRACT FROM AUTHOR]