Phase 1/2 double-blind, placebo-controlled, dose escalation, safety, and pharmacokinetic study of pagibaximab (BSYX-A110), an antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birth-weight neonates

Abstract

Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 +/- 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

FIG. 1.

Plasma anti-LTA antibody concentrations over time by pagibaximab dose group on a semilogarithmic axis. The values shown are means ± standard deviations. Each error bar represents 1 standard deviation. There were seven patients in the 10-mg/kg dose group with data for six patients included on day 56. There were eight patients in the 30-mg/kg dose group with data for seven patients included on day 42 and data for five patients included on day 56. There were eight patients in the 60-mg/kg dose group with data for seven patients included on day 14, day 28, and day 42 and data for six patients included on day 56. There were eight patients in the 90-mg/kg dose group with data for six patients included on day 56. The individual symbols represent positive staphylococcal blood cultures and are plotted as the concentration (Conc) of pagibaximab in serum (as determined by direct measurement by an enzyme-linked immunosorbent assay) versus the time in days when the positive blood culture was drawn. ✹, placebo treatment group; ▾, 10-mg/kg dose group; ▴, 30-mg/kg dose group; ▪, 60-mg/kg dose group; •, 90-mg/kg dose group. All placebo symbols lie on the x axis, since there were no measurable serum antibody concentrations in this group. All staphylococcal infections occurred at an estimated serum anti-LTA concentration of <500 μg/ml.

FIG. 2.

PFGE patterns for genetic relatedness of the 25 CONS isolates. In the far right columns, the patient identification (ID) number and bacterial species identification for each staphylococci were listed for each isolate's dendrogram. The degree of strain relatedness from 40 to 100% is shown by the scale bar.