An evaluation of the cyclophilin inhibitor Debio 025 and its potential as a treatment for chronic hepatitis C

Crabbé, R.; Vuagniaux, Grégoire; Dumont, Jean-Maurice; Nicolas‐Métral, Valérie; Marfurt, Judith; Novaroli, Laura

doi:10.1517/13543780802651583

Cited by 39 publications

(25 citation statements)

References 28 publications

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“…More importantly, they lack cross-resistance with SOC and the most advanced DAA drugs. This has led to the suggestion that they could form part of future combination therapies for chronic HCV (8).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…It had low levels of activity against HIV but is being investigated in phase 2 and 3 clinical trials with and without PegIFN/RBV in patients with HCV genotypes 1, 2, and 3 [34, 35]. Early studies included patients with HCV/HIV co-infection [35].…”

Section: The Daa Pipeline: Implications For the Hcv/hiv Co-infected Pmentioning

confidence: 99%

Hepatitis C and HIV Co-Infection: New Drugs in Practice and in the Pipeline

Jennings

Sherman

2012

Curr HIV/AIDS Rep

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HCV/HIV coinfection continues to represent a serious health issue with risk of liver disease progression and development of hepatocellular carcinoma. Pegylated interferon with ribavirin is approved for treatment but results are suboptimal and tolerability poor. First-generation HCV protease inhibitors appear to significantly improve HCV treatment response in the setting of HIV infection. Interactions with HIV protease inhibitors have been documented, but the significance of this in terms of adverse reactions and HCV or HIV viral breakthrough remains uncertain. Next generation agents hold the promise of even better efficacy, with improved dosing schedules and perhaps decreased risk of drug:drug interactions.

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“…This may be due to the inhibition of the multidrug resistance protein 2 (MRP2) transporter by alisporivir [56], resulting in reduced elimination of conjugated bilirubin. Hyperbilirubinaemia has also been observed in phase II studies of another cyclophilin inhibitor in development, NIM811 [57].…”

Section: Other Directly Acting Antivirals In Developmentmentioning

confidence: 99%

Directly acting antivirals for hepatitis C and antiretrovirals

Seden

Back²

2011

Current Opinion in HIV and AIDS

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As a result of DDIs, the concomitant use of some medicines with DAA will be contraindicated, whereas other combinations may require caution, monitoring, or dose modification of the co-administered drug. Management of DDIs with these novel agents will pose a new challenge, and prescriber awareness of the potential for DDIs is fundamental for safe prescribing. Online resources are likely to play a key role in prescriber education and clinical decision-making.

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An evaluation of the cyclophilin inhibitor Debio 025 and its potential as a treatment for chronic hepatitis C

Cited by 39 publications

References 28 publications

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

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

Hepatitis C and HIV Co-Infection: New Drugs in Practice and in the Pipeline

Directly acting antivirals for hepatitis C and antiretrovirals

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