AAC Accepts, published online ahead of print on 22 December 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00939-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Debio 025, a cyclophilin binding molecule, is highly efficient in clearing HCV replicon containing cells, alone or when combined with Specifically Targeted Antiviral Therapy for HCV (STAT-C) inhibitors

Lotte Coelmont, Suzanne Kaptein, Jan Paeshuyse, Inge Vliegen, Jean-Maurice Dumont, Grégoire Vuagniaux, and Johan Neyts^*

Rega Institute for Medical Research, KULeuven, 3000 Leuven, Belgium; Debiopharm, CP211-Lausanne, Switzerland

^* To whom correspondence should be addressed. Email: johan.neyts{at}rega.kuleuven.be.

Debio 025 is a potent inhibitor of hepatitis C virus (HCV) replication [Hepatology, 43:761-70]. In phase I clinical studies monotherapy (dose 1200 mg BID of Debio 025) resulted in a mean maximal decrease in viral load of 3.6 log₁₀ [Hepatology, 47: 817-26], whereas a reduction of 4.6 log₁₀ was obtained in phase II studies where Debio 025 was combined with interferon [J Hepatol, 48: S2]. We here report on the particular characteristics of the in vitro anti-HCV activities of Debio 025. The combination of Debio 025 with either ribavirin (RBV) or STAT-C inhibitors [NS3 protease or NS5B (nucleoside and non-nucleoside) polymerase inhibitors] resulted in an additive antiviral activity in short term antiviral assays. Debio 025 has the unique ability to clear hepatoma cells from their HCV replicon when used alone or in combination with interferon and STAT-C inhibitors. Debio 025, at concentrations that have been observed in human plasma (0.1 or 0.5 µM), was able to delay or prevent the development of resistance to HCV protease inhibitors as well as to nucleoside and non-nucleoside polymerase inhibitors. Debio 025 forms an attractive drug candidate for the treatment of HCV infections in combination with standard interferon-based treatment and treatments that directly target the HCV polymerase and/or protease.

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