A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome

Objective: To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha in patients with sepsis. Design: Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial. Setting: Intensive care units of six academic medical centers in the United States. Patients: Forty-eight patients with a clinical diagnosis of sepsis who rece ived standard supportive care and antimicrobial therapy. Interventions: Patients received 0.3, 1.0, or 3.0 mg/kg afelimomab or place bo intravenously over 20 min. Three patients in each dose group received si ngle doses; the remaining nine patients in each group received multiple (ni ne) doses at 8-h intervals over 72 h. Measurements and main results: Afelimomab appeared safe and well tolerated. Single- and multiple-dose kinetics were predictable and dose related. The elimination half-life was 44.7 h. Afelimomab treatment resulted in increase d serum concentrations of TNF (includes TNF-antibody complexes) and decreas ed serum interleukin-6 concentrations, whereas no discernible trends were o bserved in placebo-treated patients. There was no significant treatment eff ect on 28-day mortality as was expected given the small number of patients. However, overall mortality was significantly (p = 0.001) associated with b aseline interleukin-6 concentration. All patients experienced adverse event s, but the vast majority were considered unrelated to the study drug and de monstrated no apparent relationship to afelimomab dose. Although 41% of pat ients developed human anti-murine antibodies, there were no clinical sequel ae. Conclusions: Multidose therapy with afelimomab was safe, well tolerated, an d had predictable linear kinetics. A large randomized trial comparing afeli momab to placebo in patients with well defined sepsis has recently been com pleted.