The cyclophilin inhibitor Debio-025 shows potent anti–hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus

Abstract

Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log 10 after a 14-day oral treatment with 1200 mg twice daily (P < 0.0001) with an effect against the 3 genotypes (1, 3, and 4) represented in the study. In addition, the absence of viral rebound during treatment indicates that Debio-025 has a high barrier for the selection of resistance. In Debio-025-treated patients, cyclophilin B (CypB) levels in peripheral blood mononuclear cells decreased from 67 ؎ 6 (standard error) ng/mg protein (baseline) to 5 ؎ 1 ng/mg protein at day 15 (P < 0.01). Conclusion: Debio-025 induced a strong drop in CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti-hepatitis C drugs. (HEPATOLOGY 2008; 47:817-826.)

Hepatitis C Virus NS5A Protein Is a Substrate for the Peptidyl-prolyl cis/trans Isomerase Activity of Cyclophilins A and B

“…These results provided for the first time a molecular mechanism for the early-on observed anti-HCV activity of CsA (18 -20). Although this initial report suggests that only CypB would be involved in the HCV replication proc-ess (17), a growing number of studies have recently pointed out a role for other cyclophilins (21)(22)(23)(24)(25).…”

Cyclophilin A Is a Damage-Associated Molecular Pattern Molecule That Mediates Acetaminophen-Induced Liver Injury

“…Both of these mechanisms are independent of the well-established immunosuppressive action of cyclosporine. Nonimmunosuppressive cyclophilin inhibitors that bind to CypA and CypD are in human trials as treatments for hepatitis C infection (43). Future studies will be needed to confirm that these agents inhibit acetaminophen-induced liver injury, but the absence of immunosuppression has the potential to improve the drug's risk/benefit profile by reducing the risk for sepsis in these critically ill patients.…”

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

“…During a 15-d phase Ib study in which subjects coinfected with HIV and HCV received 1200 mg BID of Debio 025 or placebo, and Debio 025 resulted in a mean decrease in the viral load of 3.6 log 10 IU/ml (Flisiak et al, 2008b). In contrast, a phase I trial of Debio 025 suggested that the drug has a limited effect on HIV-1 replication.…”