A phase 1 study in healthy participants to characterize the safety and pharmacology of inclacumab, a fully human anti-P-selectin antibody, in development for treatment of sickle cell disease

作者：Christina Lourdes Mayer, Kathleen Köeck, M. Hottmann, Andrew Redfern, Mark M. Davis, Aline Barth, Xin Geng, Carolyn Hoppe, Patrick Yue · 发表于：European Journal of Clinical Pharmacology · 年份：2023 · DOI：10.1007/s00228-023-03514-3 · 被引用次数：13 · 研究领域：Hemoglobinopathies and Related Disorders、Blood groups and transfusion、Platelet Disorders and Treatments

PURPOSE: We evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody in development for the treatment of sickle cell disease, at doses up to and exceeding those previously tested in healthy individuals. METHODS: In this phase 1, open-label, single-ascending-dose study, 15 healthy participants were enrolled into cohorts receiving 20 mg/kg (n = 6) or 40 mg/kg (n = 9) IV inclacumab and observed for up to 29 weeks post-dose. Safety, PK parameters, thrombin receptor-activating peptide (TRAP)-activated platelet-leukocyte aggregate (PLA) formation, P-selectin inhibition, plasma soluble P-selectin, and anti-drug antibodies were characterized. RESULTS: Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Mean TRAP-activated PLA formation decreased within 3 h from the start of infusion, and inhibition was sustained for ~ 23 weeks. Mean P-selectin inhibition > 90% was observed up to 12 weeks post-dose. The mean ratio of free to total soluble P-selectin decreased rapidly from pre-dose to end of infusion, then increased gradually to 78% of the baseline ratio by week 29. Treatment-emergent anti-drug antibodies were observed in 2 of 15 participants (13%), without apparent impact on safety, PK, or PD. ...