143 Efficacy and Safety of Increasing Doses of the Cyclophilin Inhibitor Debio 025 in Combination With Pegylated Interferon Alpha-2a in Treatment Naive Chronic HCV Patients

Flisiak, Robert; Feinman, S.V.; Jabłkowski, Maciej; Horban, Andrzéj; Kryczka, Wiesław; Halota, Waldemar; Heathcote, Jenny; Mazzella, Giuseppe; Vandelli, C.; Liz, Jorge S.; Crabbé, R.; Scalfaro, Piétro; Porchet, Hervé

doi:10.1016/s0168-8278(08)60145-2

Cited by 23 publications

(16 citation statements)

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“…52 In a dose-ranging study of 90 treatment-naïve patients with varying genotypes, the combination of DEBIO-025 (1,000 mg/day) plus PEG-IFN ␣-2a led to greater declines in HCV RNA (Ͼ4 log) compared to DEBIO-025 alone (Ͼ2 log). 53 Future studies will be carried out with 600 mg daily because higher dosages have been associated with isolated conjugated hyperbilirubinemia. 51,53 The proposed mechanism of this effect is competitive inhibition of biliary canalicular transporters.…”

Section: Inhibitors Of Host Cofactors: Cyclophilin Inhibitorsmentioning

confidence: 99%

Avoiding therapeutic pitfalls: The rational use of specifically targeted agents against hepatitis C infection

2008

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The development of specifically targeted antiviral agents against hepatitis C is a major therapeutic advance that promises to markedly improve treatment response rates in patients with chronic infection. However, rapid emergence of drug resistance has already been described, the consequences of which are not yet understood. Although there are important differences between hepatitis C (HCV) and human immunodeficiency virus (HIV) infection, the judicious use of candidate agents against HCV should be guided by principles that have been established in the HIV therapeutic arena. In this review, we attempt to draw useful parallels between the development of antiretroviral therapy for HIV and preliminary data on antiviral agents for hepatitis C virus infection. Applying concepts learned in HIV therapeutics will hopefully lead to a prudent and cautious path in HCV treatment paradigms, particularly with respect to drug resistance. (HEPATOLOGY 2008;48:1700-1712

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Section: Inhibitors Of Host Cofactors: Cyclophilin Inhibitorsmentioning

confidence: 99%

Avoiding therapeutic pitfalls: The rational use of specifically targeted agents against hepatitis C infection

2008

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“…Both compounds inhibit HCVspecific RNA replication in vitro (17,19). Clinical studies indicate that Debio-025 suppresses HCV plasma viremia when it is given as monotherapy for 14 days to patients coinfected with HIV-1 and HCV and when it is given as a component of a two-drug combination regimen with pegylated interferon for 28 days to HCV-monoinfected patients (8,9). This report describes the preclinical profile of SCY-635, a 3,4-disubstituted nonimmunosuppressive CsA analog that exhibits potent suppression of HCV RNA replication in vitro.…”

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confidence: 99%

SCY-635, a Novel Nonimmunosuppressive Analog of Cyclosporine That Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication In Vitro

Hopkins

Scorneaux

Huang

et al. 2010

Antimicrob Agents Chemother

136

125

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SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 M. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.Hepatitis C virus (HCV) is a member of the Flaviviridae family, which comprises three distinct genera, including the flaviviruses (such as yellow fever virus, dengue virus, West Nile virus, and Japanese encephalitis virus), the pestiviruses (bovine viral diarrhea virus and classical swine fever virus), and the hepaciviruses (of which HCV is the only member) (16). HCV is highly polymorphic, and current taxonomic schemes recognize six major genotypes and several subtypes. Although no strict relationship exists between the genotype and the severity of HCV disease or the clinical outcome, numerous clinical studies indicate that patients who are infected with genotype 1 viruses are less responsive to antiviral therapy than individuals who are infected with genotypes 2 through 6 (10, 11). Chronic infection with HCV now represents a major global health problem, with approximately 170 million people worldwide being infected (26). The current standard of care for chronic hepatitis C virus infection involves treatment for up to 1 year with combination chemotherapy of pegylated alpha interferon coadministered with ribavirin. At this time, there are no approved drugs specifically indicated for the treatment of patients who do not respond to first-line therapy. Complete clearance of the virus is achieved in approximately 50% of all HCV-infected patients who initiate therapy (10, 11), and the response rates are related to viral factors (the genotype and the viral load), as well as multiple host factors (the presence of liver fibrosis, cirrhosis, ethnicity, coinfection with HIV type 1 [HIV-1], alcohol consumption, and metabolic disorders).At this time, the combined action of interferon and ribavirin against HCV infection is poorly understood. The e...

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“…During a 15-day phase 1b study in which patients coinfected with human immunodeficiency virus (HIV) and HCV received 1,200 mg of Debio 025 or placebo twice daily, Debio 025 resulted in a mean maximal decrease in the viral load of 3.6 log 10 units (19). When Debio 025 was combined with pegylated IFN alpha 2a during phase IIa studies, a reduction in the viral load of 4.6 log units was obtained (17). NIM811 (37) and SCY-635 (23), two other nonimmunosuppressive Cs analogues, have also been shown to specifically inhibit HCV replication.…”

mentioning

confidence: 99%

Debio 025, a Cyclophilin Binding Molecule, Is Highly Efficient in Clearing Hepatitis C Virus (HCV) Replicon-Containing Cells When Used Alone or in Combination with Specifically Targeted Antiviral Therapy for HCV (STAT-C) Inhibitors

Coelmont

Kaptein

Paeshuyse

et al. 2009

Antimicrob Agents Chemother

120

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Hepatitis C virus (HCV) represents a major health burden. An estimated 170 million to 180 million people worldwide are chronically infected with this virus and are at increased risk of developing liver cirrhosis and/or hepatocellular carcinoma (64). The current standard of care for chronic hepatitis C consists of pegylated alpha interferon (IFN) in combination with ribavirin (RBV) (12). This therapy is, however, associated with serious side effects and results in a sustained virological response in only 50 to 60% of patients (depending on the genotype). There is thus an urgent need for more effective and better-tolerated drugs.Selective inhibitors of HCV replication that target the NS3 protease and the NS5B RNA-dependent RNA polymerase (RdRp) in particular have been pursued as potential new therapies (38). BILN 2061 (culprivir), a peptidomimetic inhibitor of the HCV NS3 protease (the first selective inhibitor of HCV to be administered to patients), resulted in a rapid and pronounced decline in the level of viral replication in patients chronically infected with HCV genotype 1. Its clinical development was, however, halted because of cardiotoxicity (22,31). Currently, four NS3 protease inhibitors are in clinical development, i.e., VX-950 (telaprevir), SCH-503034 (boceprevir), and TMC435350 (2,51,56). Telaprevir and boceprevir are at the most advanced stages of development and are being evaluated in combination with the standard therapy in phase III and phase II clinical trials, respectively (3,39,45,50). Several nucleoside polymerase inhibitors (NIs) and nonnucleoside polymerase inhibitors (NNIs) are or have been in development. Nucleoside analogue inhibitors of HCV replication basically act as chain terminators of the polymerization process once they have been phosphorylated to their 5Ј-triphosphate metabolite (13).

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143 Efficacy and Safety of Increasing Doses of the Cyclophilin Inhibitor Debio 025 in Combination With Pegylated Interferon Alpha-2a in Treatment Naive Chronic HCV Patients

Cited by 23 publications

References 0 publications

Avoiding therapeutic pitfalls: The rational use of specifically targeted agents against hepatitis C infection

Avoiding therapeutic pitfalls: The rational use of specifically targeted agents against hepatitis C infection

SCY-635, a Novel Nonimmunosuppressive Analog of Cyclosporine That Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication In Vitro

Debio 025, a Cyclophilin Binding Molecule, Is Highly Efficient in Clearing Hepatitis C Virus (HCV) Replicon-Containing Cells When Used Alone or in Combination with Specifically Targeted Antiviral Therapy for HCV (STAT-C) Inhibitors

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