Caspase inhibitors for the treatment of hepatitis C

Abstract

Decreasing hepatocyte injury and death is an attractive therapeutic target in chronic hepatitis C and other liver diseases. Apoptotic cell death is a critical mechanism responsible for liver injury in hepatitis C, and contributes to hepatic fibrogenesis. At the cellular level, apoptosis is executed by a family of cysteine proteases termed caspases. Caspase inhibitors have been developed to inhibit these proteases and attenuate cellular apoptosis in vivo. By reducing hepatocyte apoptosis these agents have the potential to serve as hepatoprotective agents, minimizing liver injury and fibrosis. Studies on a variety of animal models, and time-limited studies in human patients with hepatitis C suggest these are promising therapeutic agents. However, although these agents hold promise, their usefulness requires further studies, especially longer duration studies using hepatic fibrogenesis as the end point before they can be considered further for the treatment of patients infected with the hepatitis C virus.

Fig. 1

The extrinsic pathway is initiated by the engagement of a death receptor by its cognate ligand, which results in initiator caspases 8 and 10. Activated initiator caspases cleave the BH3-only member of the Bcl-2 family Bid, which, in turn, causes mitochondrial dysfunction. The intrinsic pathway can be triggered by different intracellular stresses converging on the mitochondria. Both pathways lead to mitochondrial permeabilization with release of pro-apoptotic mitochondrial proteins, resulting in caspase 9 activation, and, subsequently, through a proteolytic cascade, activation of the effector caspases 3, 6 and 7, responsible for the degradation of numerous cellular components. Inhibition of caspases is an effective tool to block the extrinsic or death receptor pathway of cell death. Blocking caspase 9/3/6/7 will not prevent cell death as mitochondrial dysfunction, a lethal event, has already occurred.

Fig. 2

Patients received IDN-6556 orally once a day at the dose indicated. Changes in serum ALT values are expressed as percent change from baseline. QD dosing indicates once a day drug administration. Data are expressed as the means ± standard error of the mean (SEM). (Reprinted from Pockros PJ, Schiff ER, Shiffman ML, et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 2007;46(2):326; with permission.)

Fig. 3

Four patients with NASH were treated with IDN-6556 at a dose of 100 mg orally twice a day. Changes in the serum ALT values are expressed as a percent change from baseline. Results are the mean ± SEM in 4 patients. (Reprinted from Pockros PJ, Schiff ER, Shiffman ML, et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 2007;46(2):327; with permission.)