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Antimicrobial Agents and Chemotherapy, July 2009, p. 2879-2886, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01565-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Leonard E. Weisman,1* Helen M. Thackray,2 Joseph A. Garcia-Prats,1 Mirjana Nesin,3 Joseph H. Schneider,1 Jennifer Fretz,2 John F. Kokai-Kun,2 James J. Mond,2 William G. Kramer,4 and Gerald W. Fischer2

Department of Pediatrics, Baylor College of Medicine, Houston, Texas,1 Biosynexus Incorporated, Gaithersburg, Maryland,2 Division of Neonatology, Weill Medical College, New York, New York,3 Kramer Consulting, LLC, North Potomac, Maryland4

Received 24 November 2008/ Returned for modification 31 December 2008/ Accepted 9 April 2009

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.

* Corresponding author. Mailing address: Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin St., Suite 830.17, Houston, TX 77030-2303. Phone: (832) 824-1375. Fax: (832) 825-8877. E-mail: lweisman{at}bcm.edu

{triangledown} Published ahead of print on 20 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2879-2886, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01565-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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