VX-166, a novel potent small molecule caspase inhibitor, as a promising new treatment for sepsis

Introduction

Lymphocyte apoptosis has been identified as an important factor contributing to both the onset of sepsis and to the progression into septic shock and multiple organ failure. Antiapoptotic therapy through caspase inhibition therefore offers a novel and promising approach to the treatment or prevention of sepsis. Significantly, administration of caspase inhibitors has already been shown to be beneficial in animal models of the disease. We have designed VX-166, a novel broad caspase inhibitor that has an advantageous pharmacokinetic and toxicity profile and should be suitable for use in man. The present study was performed to evaluate VX-166 as a therapeutic agent for the treatment of sepsis.

Methods and results

VX-166 demonstrated extremely potent antiapoptotic activity in a variety of cell assays using a number of different apoptotic stimuli. In vivo, VX-166 was tested in a murine model of endotoxic shock and a rat caecal ligation and puncture model (CLP) of peritoneal sepsis. In the first model, male CD-1 mice (n = 28 per group) were administered lipopolysaccharide (LPS) (20 mg/kg i.v.) and their survival monitored for 96 hours. VX-166 administered by repeat i.v. bolus (0, 4, 8 and 12 hours post-LPS) dramatically improved survival in a dose-dependent fashion (P < 0.0001). This result was confirmed in a second study where the optimal dose (30 mg/kg) of VX-166 substantially improved survival from 0% in the vehicle group to 75% in the VX-166 group (P < 0.0001). In the second model, adult male Sprague-Dawley rats (n = 12 per group) underwent CLP. Their necrotic caecum was excised 20 hours later and survival was monitored over 10 days. Continuous administration of VX-166 by mini-osmotic pump immediately following surgery improved survival (P < 0.01) from 38% in the control group to 88% in the compound-treated group. Mode of action studies in this model confirmed that VX-166 reduced thymic atrophy and lymphocyte apoptosis (P < 0.01). This is good evidence of the anti-apoptotic activity of the compound in vivo. In addition, plasma endotoxin levels were reduced (P < 0.05), strongly suggesting that VX-166 can improve clearance of bacteria from the bloodstream in sepsis. Most importantly, we demonstrated that VX-166 fully retained its efficacy when dosed 3 hours after insult (P < 0.01), by improving survival from 42% in the control group to 92% in the dosed group.

Conclusion

These results show that VX-166 substantially improves survival in experimental sepsis. As VX-166 also has an excellent toxicity profile and pharmacokinetic properties that make it suitable for use in man, we believe that VX-166 represents an exciting opportunity as an anti-apoptotic therapy for the prevention and treatment of sepsis.