Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis

作者：Robert D. Henderson, Jan M. Agosti, Pamela McCombe, Kathryn Thorpe, Susan Heggie, Saman Heshmat, Mark W. Appleby, Brian William Ziegelaar, David Crowe, Garry L. Redlich · 发表于：Medicine · 年份：2021 · DOI：10.1097/md.0000000000027421 · 被引用次数：19 · 研究领域：Amyotrophic Lateral Sclerosis Research、Multiple Sclerosis Research Studies、Cervical and Thoracic Myelopathy

BACKGROUND: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers. METHODS: In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor. RESULTS: IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly ...