Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury

Abstract

Cold ischemia/warm reperfusion (CI/WR) injury remains a problem in liver transplantation. The aim of the current study was to assess the utility of the pan-caspase inhibitor IDN-6556 on CI/WR injury during human liver transplantation. This report is a post hoc analysis of a Phase II, multi-center, randomized, placebo-controlled, double-blinded, parallel group study. Subjects were assigned to four treatment groups: Group 1 (Organ storage/flush: Placebo-Recipient: Placebo); Group 2 (Organ storage/flush: 15 lg/mL-Recipient: Placebo); Group 3 (Organ storage/flush: 5 lg/mL-Recipient: 0.5 mg/kg); and Group 4 (Organ storage/flush: 15 lg/mLRecipient: 0.5 mg/kg). Liver cell apoptosis was assessed by serum concentrations of the apoptosisassociated CK18Asp396 ('M30') neo-epitope, TUNEL assay and caspase 3/7 immunohistochemistry. Liver injury was assessed by serum AST/ALT determinations. Serum markers of liver cell apoptosis were reduced in all groups receiving drug as compared to placebo. However, TUNEL, caspase 3/7 positive cells and serum AST/ALT levels were only consistently reduced in Group 2 (drug exposed to organ only). This reduction in serum transaminases was significant and observed across the study. In conclusion, IDN-6556 when administered in cold storage and flush solutions during liver transplantation offers local therapeutic protection against CI/WR-mediated apoptosis and injury. However, larger studies are required to confirm these observations.

The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

“…Indeed, clinical trials of systemic caspase inhibitor therapy using IDN-6556, a pan-caspase inhibitor, have been carried out (39 -41). One of these studies (40) was conducted in the setting of liver transplantation, under the cover of immunosuppression, and no cancers have been reported thus far in these patients. IDN-6556 has been shown to have a similar in vivo potency in mice compared with zVAD, and it has been used clinically at a dose similar to EP1013 in this study (3-10 mg/kg) with very few side effects (injection site inflammation and phlebitis) (39 -42).…”

Mechanisms of Renal Apoptosis in Health and Disease

“…IDN-6556 also reduces liver apoptosis in human liver preservation injury and has received an orphan drug label by the US Food and Drug Administration for solid-organ preservation in transplantation. 109 Other small molecules of interest include the p53 inhibitor pifithrin-␣, which prevents apoptosis and protects renal function in ischemia/reperfusion and cisplatin nephrotoxicity, and nanomolecular inhibitors of Apaf-1. 60,91,110 The kidney may be a particularly favorable organ for specific targeting of antiapoptotic molecules.…”

Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review

“…Indeed, multiple signaling pathways in IRI culminate with apoptosis and organ dysfunction. Recently, IDN-6556, a pan-caspase inhibitor (PCI), was applied in liver transplant patients to evaluate its efficacy to mitigate liver injury during cold and warm IR (107). PCI was administered locally to the donor organ during cold storage and systemically to the transplant recipient for 24-48 h posttransplant.…”