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The critical pathophysiological trigger of sepsis is thought to be a disturbance in the equilibrium between the proinflammatory response and concomitant anti-inflammatory mechanisms. Data show that the proinflammatory cytokine TNFα is a principal mediator of sepsis [1,2]. AZD9773 is a sterile lyophilised powder for solution for i.v. infusion containing ovine immune fragments (Fabs) of IgG that bind to human TNFα. We explored the PD and safety profile of AZD9773 in cynomolgus monkeys. AZD9773 PD data are compared with D-CytoFab (a similar ovine anti-TNFα IgG immune Fab product) that showed clinical benefit in a phase IIb study [3].

TNFα is thought to play a central role in the pathogenesis of sepsis and septic shock. AZD9773 is an ovine polyclonal anti-human TNFα immune Fab comprising TNFα-directed and nonspecific Fab populations. AZD9773 potency and pharmacokinetic attributes such as a shorter half-life distinguish it from anti-TNF monoclonal antibodies, which have been assessed previously in clinical sepsis models. Here we explore the preclinical safety/efficacy of AZD9773 in a mouse cecal ligation puncture (CLP) model. There are currently no reports of anti-TNF agent efficacy in mouse CLP; rather, TNFα neutralization is associated with minimal/no effect or increased mouse mortality. As AZD9773 is differentiated from other anti-TNFα agents based on neutralizing potency and pharmacokinetic attributes, we studied both the safety and efficacy of this product in mouse CLP models.

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.