Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia

Abstract

Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 g/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.Staphylococcus aureus is a leading cause of healthcare-associated and community-onset bacteremia in the United States and abroad (15,23,24). A recent study showed that S. aureus infection was reported as a discharge diagnosis for 0.8% of all hospital inpatients, or an average of 292,045 inpatients per year (19). Infections caused by methicillin-resistant S. aureus (MRSA) in hospitalized patients as well as in otherwise healthy patients with no obvious risk factors are an emerging problem (3,8,18). Current therapy for S. aureus bacteremia (SAB), particularly for MRSA bacteremia, is less than adequate. This fact is supported by the high rates of complications, including mortality, relapsing infection, and metastatic infections (infective endocarditis, bone and joint infections, and suppurative abscesses), associated with SAB (1,2,6,7,11,14,22). Taken together, these observations indicate that novel therapies for SAB are urgently needed.One potential strategy to improve clinical outcomes of SAB is adjunctive therapy using passive immunization with monoclonal antibodies that target S. aureus. Tefibazumab (Aurexis) is a humanized immunoglobulin G1 monoclonal antibody that specifically recognizes clumping factor A (ClfA) with a high affinity. ClfA, a surface adhesin protein found on virtually all strains of S. aureus, is an MSCRAMM (microbial surface components recognizing adhesive matrix molecules) protein that mediates the adhesion of S. aureus to fibrinogen (10,16,17). In preclinic...

A Recombinant Clumping Factor A-Containing Vaccine Induces Functional Antibodies to Staphylococcus aureus That Are Not Observed after Natural Exposure

“…The clinical efficacy of Aurexis remains to be determined. Results of a phase IIa dose escalation study of Aurexis in S. aureus bacteremia patients undergoing vancomycin therapy were inconclusive with respect to the clinical outcome because of the small size of the patient population (n ϭ 60) (38).…”

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

“…Unfortunately, efforts to develop vaccines targeting S. aureus capsular polysaccharide type 5 or 8 conjugates, or the ironregulated surface determinant B protein, have not been successful thus far (38,39). Likewise, passive immunization using monoclonal antibodies targeting the S. aureus adhesin clumping factor A (ClfA, tefibazumab) (40) or lipoteichoic acid (pagibaximab) (41) have not shown efficacy against invasive infections in human clinical studies to date. Moreover, the striking recurrence rates of SSSI due to MRSA imply that natural exposure does not induce optimal preventive immunity or durable anamnestic response to infection or reinfection.…”

Vaccine Protection of Leukopenic Mice against Staphylococcus aureus Bloodstream Infection

“…However, clinical trials with whole-cell killed (82) or subunit vaccines formulated from secreted virulence factors, ␣-hemolysin (Hla) and coagulase, did not protect against recurrent SSTI (29). Immunotherapy with antibodies neutralizing Hla (30,83) or ClfA, the fibrinogen binding surface protein and agglutinin (40,58), also did not protect against S. aureus infection (84,85). Conjugates of S. aureus type 5/8 capsular polysaccharide (CP5/CP8) with Pseudomonas exotoxin A raise opsonophagocytic antibodies (23,86); however, the vaccine did not protect hemodialysis patients from S. aureus infection (28).…”