95 Efficacy and Safety of the Cyclophilin Inhibitor Debio 025 in Combination With Pegylated Interferon Alpha-2a and Ribavirin in Previously Null-Responder Genotype 1 HCV Patients

Nelson, David R.; Ghalib, Reem; Sulkowski, Mark S.; Schiff, E.; Rustgi, V.; Pockros, Paul J.; Wang, C.; Kerhuel, G. Decosterd; Grosgurin, Pierre; Porchet, Hervé; Crabbé, R.

doi:10.1016/s0168-8278(09)60097-0

Cited by 19 publications

(10 citation statements)

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“…Proof-of-concept was established for Alisporivir when administered as monotherapy to patients who were co-infected with HIV-1 and HCV [10]. Subsequent phase II studies demonstrated the benefit of combination therapy with Alisporivir and pegylated interferon in patients who were naïve to any form of antiviral treatment [53] and combination therapy with Alisporivir together with pegylated interferon and ribavirin in patients with prior evidence of null response [54]. The results of three large randomized phase II studies have been reported.…”

Section: Resultsmentioning

confidence: 99%

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Hopkins

Gallay

2012

Viruses

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The advent of the replicon system together with advances in cell culture have contributed significantly to our understanding of the function of virally-encoded structural and nonstructural proteins in the replication cycle of the hepatitis C virus. In addition, in vitro systems have been used to identify several host proteins whose expression is critical for supporting such diverse activities as viral entry, RNA replication, particle assembly, and the release of infectious virions. Among all known host proteins that participate in the HCV replication cycle, cyclophilins are unique because they constitute the only host target that has formed the basis of pharmaceutical drug discovery and drug development programs. The introduction of the nonimmunosuppressive cyclophilin inhibitors into clinical testing has confirmed the clinical utility of CsA-based inhibitors for the treatment of individuals with chronic hepatitis C infection and has yielded new insights into their mechanism(s) of action. This review describes the biochemical evidence for the potential roles played by cyclophilins in supporting HCV RNA replication and summarizes clinical trial results obtained with the first generation of nonimmunosuppressive cyclophilin inhibitors.

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Section: Resultsmentioning

confidence: 99%

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Hopkins

Gallay

2012

Viruses

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“…Host-targeting antivirals (HTAs) may have a higher barrier to resistance than (most) DAA inhibitors. A number of cyclophilinbinding molecules such as alisporivir (DEB025), NIM811, and SCY-635 have proven to be potent inhibitors of HCV replication and have shown clinical efficacy (30,47).…”

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confidence: 99%

Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

Delang

Vliegen

Froeyen

et al. 2011

Antimicrob Agents Chemother

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Hepatitis C virus (HCV) inhibitors include direct-acting antivirals (DAAs) such as NS3 serine protease inhibitors, nucleoside and nonnucleoside polymerase inhibitors, and host-targeting antivirals (HTAs) such as cyclophilin inhibitors that have been developed in recent years. Drug-resistant HCV variants have been reported both in vitro and in the clinical setting for most classes of drugs. We report a comparative study in which the genetic barrier to drug resistance of a representative selection of these inhibitors is evaluated employing a number of resistance selection protocols. The NS3 protease inhibitors VX-950 and BILN 2061, the nucleoside polymerase inhibitor 2-C-methylcytidine, three nonnucleoside polymerase inhibitors (thiophene carboxylic acid, benzimidazole, and benzothiadiazine), and DEB025 were included. For each drug and passage in the selection process, the phenotype and genotype of the drug-resistant replicon were determined. For a number of molecules (BILN 2061 and nonnucleoside inhibitors), drug-resistant variants were readily selected when wild-type replicon-containing cells were directly cultured in the presence of high concentrations of the inhibitor. Resistance to DEB025 could be selected only following a lengthy stepwise selection procedure. For some DAAs, the signature mutations that emerged under inhibitor pressure differed depending on the selection protocol that was employed. Replication fitness of resistant mutants revealed that the C445F mutation in the RNA-dependent RNA polymerase can restore loss of fitness caused by a number of unfit resistance mutations. These data provide important insights into the various pathways leading to drug resistance and allow a direct comparison of the genetic barriers of various HCV drugs.Hepatitis C virus (HCV) is a positive single-stranded RNA virus and the only member of the Hepacivirus genus within the Flaviviridae family. An estimated 170 million people are chronically infected worldwide. Three million to four million people become newly infected each year (57). Chronically infected patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. In Western countries, infection with HCV is the most common reason for liver transplantation. The current standard of care for the management of chronic hepatitis C virus infection consists of the combination of pegylated alpha interferon (pegIFN-␣) and ribavirin. This therapy is effective in only 50 to 60% of infected patients and is associated with serious side effects (44). Therefore, more tolerable, highly potent inhibitors of HCV replication are urgently needed and are currently also being developed. Antivirals that specifically target viral proteins are referred to as "direct-acting antivirals" (DAAs) for HCV. A number of NS3/NS4A protease inhibitors are currently in clinical development. The first HCV NS3/4A serine protease inhibitor to enter clinical trials was ciluprevir (BILN 2061) (54), but clinical development was halted because of cardiotoxicity. Other protease inhib...

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“…These compounds are active against multiple HCV genotypes and exhibit a significantly higher hurdle for the selection of resistance (6). However, adverse events, such as hyperbilirubinemia, were seen in a number of patients in early studies, particularly at higher dose levels (i.e., 1,000 mg), leading to treatment discontinuation with the most advanced candidate, alisporivir (15,16 (32,49). Interpatient variability, such as is seen with CsA itself (where careful drug level monitoring is needed to avoid adverse events), is also a concern (27).…”

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confidence: 99%

Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family

Gregory¹,

Bobardt

Obeid

et al. 2011

Antimicrob Agents Chemother

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Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30-to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC 50 s] of 0.070 M and 0.16 M in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F < 4%) and low solubility (<25 M), although the half-lives (t 1/2 ) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t 1/2 > 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.Hepatitis C virus (HCV) is a positive-strand RNA virus and is the major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (39). The World Health Organization (WHO) estimates that there are more than 170 million chronic carriers of HCV, which is approximately 3% of the world population (28,29). In developed countries, 50 to 76% of all cases of liver cancer and two-thirds of all liver transplants are due to chronic HCV infection (37).The current standard of care (SOC) involves subcutaneous injections of pegylated alpha-interferon (peg-IFN-␣) and oral dosing of the nonspecific antiviral drug ribavirin for a period of 24 to 48 weeks (9). Overall, response rates to the SOC depend upon the genotype and the pretreatment HCV RNA levels. Patients with genotypes 2 and 3 are more responsive to the SOC than patients infected with genotype 1 (particularly 1b) (25, 31). A significant number of HCV patients do not respond adequately to the SOC or cannot tolerate it due to side effects, leading to poor compliance and a sustained virological response (SVR) of about 50% (31).Direct-acting antiviral (DAA) drugs are being developed to target viral proteins, such as HCV NS5B polymerase or NS3 protease (35). One concern with the increased use of virustargeted agents is that, as was observed with HIV treatment, drug resistance emerges (47). However, compounds that target human proteins (i.e., cyclophilins), rather than viral targets, are also being developed, which should have higher hurdles for viral breakthrough and incidence of resistance duri...

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95 Efficacy and Safety of the Cyclophilin Inhibitor Debio 025 in Combination With Pegylated Interferon Alpha-2a and Ribavirin in Previously Null-Responder Genotype 1 HCV Patients

Cited by 19 publications

References 0 publications

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family

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