Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease

• Published in: Blood 2013-11, Vol.122 (21), p.970-970
• Main Authors: Stocker, Jonathan W., Mandarino, Debra, Kawar, Ziad, Alvarez, Richard, Falconer, David, Rollins, Scott A., Rother, Russell P.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.970.970

SelG1 is a humanized anti-P-selectin monoclonal antibody being developed as a treatment for sickle cell disease (SCD). Extensive data have been published that suggest a pivotal role for P-selectin in the pathophysiology of SCD. Much of this work has been conducted in mice engineered to express human β hemoglobin S (sickle cell hemoglobin). These mice have a remarkably similar disease pathology to that observed in human SCD including vasoocclusion. Using these mice, investigators have demonstrated P-selectin interactions between the endothelium and sickled red blood cells, leukocytes and platelets. Additional studies have demonstrated direct P-selectin mediated binding of leukocytes with platelets. All of these cell-cell interactions have been implicated in SCD vasoocclusion. Further, blockade or genetic absence of P-selectin decreases or eliminates these cell-cell interactions and vasoocclusion. A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SelG1. This was a single-center, double-blind, placebo-controlled, first-in-human, ascending single dose and multiple dose study of intravenous (IV)-administered SelG1 in healthy adult male and female subjects. There were 5 dosing cohorts in the study (A through E): Ascending single dose cohorts: Cohort A:0.2 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort B:0.5 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort C:1.0 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort D:5.0 mg/kg IV dose of SelG1 (n=6) or placebo (n=2). Multi-dose cohort: Cohort E:two 8.0 mg/kg IV doses of SelG1 (n=5) or placebo (n=2); the doses were given 2 weeks apart. In Cohorts A through D, SelG1 was slowly eliminated (mean t1/2 = 75.6 to 500 hours). Mean t1/2 values increased in a dose dependent manner. The exposure to SelG1 (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than proportional manner over the dose range. In Cohort E, SelG1 was slowly eliminated (mean t1/2 = 363 hours for the second infusion). The mean Cmax and AUC0-336values were 1.6- and 1.7-fold higher, respectively, after the second infusion relative to the first infusion. The PD data demonstrate that P-selectin function was completely blocked for a minimum of 28 days in Cohort D and at least 56 days in Cohort E. Twenty-six of the 27 subjects who received study drug completed the study, with 1 placebo subject in Cohort D withdrawing himself from the study due to the required trave