title: First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P-selectin.
abstract: Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered in an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, and pharmacodynamics. Fifty-six healthy subjects were enrolled in this randomized, double-blind placebo-controlled study. Each dose level (0.03-20 mg/kg) was investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo). Platelet-leukocyte aggregates, free/total soluble P-selectin concentration ratio, drug concentrations, bleeding time, platelet aggregation, antibody formation, and routine laboratory parameters were measured frequently until 32 weeks. Pharmacokinetic profiles were indicative of target-mediated drug disposition. Platelet-leukocyte aggregate inhibition and soluble P-selectin occupancy showed dose dependency and were strongly correlated to inclacumab plasma concentrations, with IC50 of 740 and 4600 ng/mL, respectively. Inclacumab was well tolerated by the majority of subjects and did neither affect bleeding time nor platelet aggregation. These findings allowed the investigation of the potential beneficial therapeutic use of inclacumab in patient study.
authors.affiliation: *F. Hoffmann-La Roche AG, Basel, Switzerland; and †JJG Pharma Consulting, GmbH, Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Schmitt
authors.forename: Markus
authors.initials: M
authors.lastname: Abt
authors.forename: Cornelia
authors.initials: C
authors.lastname: Ciorciaro
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kling
authors.forename: Candice
authors.initials: C
authors.lastname: Jamois
authors.forename: Eginhard
authors.initials: E
authors.lastname: Schick
authors.forename: Corinne
authors.initials: C
authors.lastname: Solier
authors.forename: Renée
authors.initials: R
authors.lastname: Benghozi
authors.forename: Jacques
authors.initials: J
authors.lastname: Gaudreault
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001760:Bleeding Time; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004739:England; D005260:Female; D064368:Healthy Volunteers; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000276:immunology; D010974:Platelet Aggregation / Q000187:drug effects; D011237:Predictive Value of Tests; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D002317:Cardiovascular Agents; D019007:P-Selectin; C546937:SELP protein, human; C000604431:inclacumab