Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer’s Disease Treated with Escalating Doses for up to 133 Weeks

作者：Heather Guthrie, Lawrence S. Honig, Helen H. Lin, Kaycee M. Sink, Kathleen Blondeau, Angelica Linnea Quartino, Michael J. Dolton, Montserrat Carrasco‐Triguero, Qinshu Lian, Tobias Bittner, David Clayton, Jillian P. Smith, Susanne Ostrowitzki · 发表于：Journal of Alzheimer s Disease · 年份：2020 · DOI：10.3233/jad-200134 · 被引用次数：66 · 研究领域：Alzheimer's disease research and treatments、Cholinesterase and Neurodegenerative Diseases、Computational Drug Discovery Methods

BACKGROUND: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. OBJECTIVE: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. METHODS: In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. RESULTS: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations o...