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Multiple dose safety and pharmacokinetic study of bavituximab in patients with chronic hepatitis C virus (HCV) infection
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Reported by Jules Levin
AASLD Nov 2007
E. J. Lawitz1; E. W. Godofsky2; J. S. Shan3
1. Alamo Medical Research, San Antonio, TX, USA.
2. University Hepatitis Center at Bach and Godofsky, Sarasota, FL, USA.
3. Peregrine Pharmaceuticals, Tustin, CA, USA.
Background: Bavituximab, an investigational monoclonal antibody targeting phosphatidylserine (PS) located on the surface of virus infected cells and enveloped viruses, is being developed as an anti-HCV agent. It has immunostimulatory effects in preclinical viral models. Single intravenous (IV) infusions of bavituximab up to 6 mg/kg were well-tolerated and showed transient antiviral activity in chronic HCV patients.
Methods: To determine the safety, tolerability and pharmacokinetics of multiple IV infusions of bavituximab, sequential cohorts of 6 patients were given twice weekly 90 min IV infusions for two weeks at 0.3, 1, 3 or 6 mg/kg and followed until week 12. Vital signs, physical exams, safety laboratory parameters, serum bavituximab levels and serum HCV RNA levels were measured.
Results: Twenty-four patients (15 male, mean age 49) were enrolled. Eleven were non-responders, 8 were relapsers and 5 were treatment-naïve. Mean baseline viral load was 5,000,000 copies/mL and 15 were infected with genotype 1, 8 with genotype 3 and 1 with genotype 2. The infusions were well-tolerated. No serious adverse events (SAEs) or early discontinuations were reported. There was no dose-related increase in incidence or severity of adverse events (AEs). All AEs were mild or moderate and transient, except for grade 3 neck pain and arthralgia (drug-related) in a patient with a history of joint pain at 3 mg/kg bavituximab and grade 3 elevated blood glucose (unrelated) in another patient with diabetes at 0.3 mg/kg bavituximab. All other drug-related AEs were mild: hypertension in 1 patient at 0.3 mg/kg, headache in 1 patient and headache and pruritis in 1 patient at 1 mg/kg and flu-like illness/symptoms in 2 patients at 6 mg/kg after the first infusion. Bavituximab reaches Cmax at 2-3 h postdose with a mean elimination half-life of ~34 h. Bavituximab exhibited dose-proportional increases in Cmax and AUC in single and multiple dosing and did not lead to significant accumulation. All dose levels exhibited on therapy antiviral activity (decline of >0.5 log10 reduction in HCV RNA). The 3mg/kg cohort had the largest number of patients showing antiviral activity, as 5 of 6 subjects achieved >0.5 log decline in HCV RNA.
Conclusions: Twice weekly IV doses of bavituximab up to 6 mg/kg were safe and well-tolerated. Single-dose and multiple dose pharmacokinetics of bavituximab are linear, predictable and no accumulation appears to occur over time. Two weeks of dosing is indicative of antiviral effect in a proportion of patients. Future studies designed to optimize the dosing schedule and investigate combining bavituximab with current standard therapy are planned.
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