Review Resistance to Mericitabine, a Nucleoside Analogue Inhibitor of HCV RNA-Dependent RNA Polymerase
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Antiviral Therapy 2012; 17:411–423 (doi: 10.3851/IMP2088) Review Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase Jean-Michel Pawlotsky1,2*, Isabel Najera3, Ira Jacobson4 1National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France 2INSERM U955, Créteil, France 3Roche, Nutley, NJ, USA 4Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA *Corresponding author e-mail: [email protected] Mericitabine (RG7128), an orally administered prodrug passage experiments. To date, no evidence of genotypic of PSI-6130, is the most clinically advanced nucleoside resistance to mericitabine has been detected by popula- analogue inhibitor of the RNA-dependent RNA poly- tion or clonal sequence analysis in any baseline or on- merase (RdRp) of HCV. This review describes what has treatment samples collected from >600 patients enrolled been learnt so far about the resistance profile of mericit- in Phase I/II trials of mericitabine administered as mon- abine. A serine to threonine substitution at position 282 otherapy, in combination with pegylated interferon/ (S282T) of the RdRp that reduces its replication capacity ribavirin, or in combination with the protease inhibitor, to approximately 15% of wild-type is the only variant danoprevir, for 14 days in the proof-of-concept study of that has been consistently generated in serial in vitro interferon-free therapy. Introduction The approval of boceprevir and telaprevir [1,2], the first HCV variants are selected and grow when the inter- inhibitors of the non-structural (NS) 3/4A (NS3/4A) feron response is inadequate [3,4,6]. Among patients serine protease of HCV, for use in combination with who did not achieve a sustained virological response pegylated interferon-a and ribavirin (triple therapy), (SVR) during clinical development trials of triple has ushered in a new era of direct acting antiviral therapy, 53% of patients treated with boceprevir and agents (DAAs) for the treatment of chronic hepatitis 62% of patients treated with telaprevir had protease- C. Triple therapy significantly increases viral eradica- inhibitor-resistant viral variants detected by popula- tion rates in both treatment-naive and previous non- tion sequencing (or direct sequencing) as the dominant sustained virological responders to interferon-based population at the time of treatment failure [16,17]. therapy while also decreasing the required duration of Long-term follow-up studies have shown that the wild- treatment for many patients [3–10]. These advances type viral population becomes dominant within 1–2 do, however, have limitations: the side-effect bur- years in the majority of patients [18,19]. However, the den is increased and the available protease inhibitors resistant variants may not have cleared completely and (boceprevir and telaprevir) are only approved for treat- could continue to replicate at low levels. ment of HCV genotype 1 infection. In addition, these Mericitabine (RG7128) is an orally administered first-generation protease inhibitors have a low barrier prodrug of PSI-6130 (b-d-2′-deoxy-2′-fluoro-2′-C- to antiviral resistance. As a result, resistance to pro- methylcytidine), a potent and selective nucleoside tease inhibitors develops rapidly in most patients when analogue inhibitor of the NS5B protein-encoded these agents are administered alone [11–13]. Resistance RNA-dependent RNA polymerase (RdRp) of HCV to DAAs appears to be characterized by outgrowth (Figure 1). The objective of this review is to describe of pre-existing minor viral populations with amino what has been learnt so far about the resistance pro- acid substitutions that confer reduced susceptibility file of mericitabine, the nucleoside analogue RdRp to the drug [14,15]. In combination with pegylated inhibitor that is furthest advanced in terms of clinical interferon-a and ribavirin, protease-inhibitor-resistant phase development. ©2012 International Medical Press 1359-6535 (print) 2040-2058 (online) 411 AVT-11-RV-2317_Pawlotsky.indd 411 10/04/2012 11:22:04 J-M Pawlotsky et al. HCV lifecycle and DAA targets particles in the circulation of infected patients. The lifecycle of HCV is shown in Figure 2. The virus gains HCV is an enveloped, single-stranded positive RNA entry into hepatocytes through a complex interac- hepatotropic virus that associates with lipoprotein tion between HCV envelope glycoproteins E1 and Figure 1. Structures of mericitabinea and its active metabolites, PSI-6130 and RO2433 O NH2 O O NH2 O N N O O HO N N HO N NH O O O F O O HO F HO F PSI-6130 RO2433 Mericitabine (RG7128; (nucleoside analogue (deaminated form orally administered prodrug) inhibitor of HCV NS5B) of PSI-6130) aRG7128. Figure 2. Lifecycle of HCV and potential drug targets 1. Receptor binding 7. Transport and release and endocytosis Entry inhibitors 6. Viral assembly 2. Fusion and uncoating RNA 3. Translation of RNA into polyprotein 5. RNA replication by polymerase Inhibitors of NS3 Inhibitors of and NS3/4A NS5A, NS5B and cyclophilin 4. Polyprotein cleaved into mature viral proteins by host cell and viral proteases Reprinted by permission from MacMillan Publishers Ltd: Nature [62], 2011. 412 ©2012 International Medical Press AVT-11-RV-2317_Pawlotsky.indd 412 10/04/2012 11:22:08 Mericitabine resistance profile E2 and several essential host cell surface components the presence of the drug. Sustained antiviral pressure (glycosaminoglycans, the tetraspanin CD81, the scav- on the majority wild-type virus creates vacant replica- enger receptor class B type-I and the tight junction tion space for the resistant variant, which can subse- proteins claudin-1 and occludin). Entry is followed by quently grow and fill in this space [15]. clathrin-mediated endocytosis [20]. Resistance profiles vary greatly between classes of Viral protein synthesis and replication are cyto- DAAs but less so between drugs in the same class. plasmic processes [21]. Membrane-associated HCV The binding site of a particular DAA is important in replication complexes generate new HCV RNA mol- determining the potential for cross-resistance. Two ecules while translation of RNA genomes produces a different drugs that bind to different ‘pockets’ on the polyprotein comprising approximately 3,000 amino same molecule or to two entirely different proteins acids that is subsequently cleaved by host and viral (‘targets’) are unlikely to show cross-resistance. By proteases into 10 structural and NS proteins. Capsid contrast, two different compounds that bind to the proteins and genomic RNA are assembled into nucle- same pocket on the same target are likely to exhibit ocapsids that bud into the lumen of the endoplasmic cross-resistance. reticulum. Newly formed virions mature in the Golgi Viral replication is suppressed when the serum drug apparatus before exiting the cell through the secre- concentration remains above a threshold. Thus, drug tory pathway [21]. exposure, which reflects the amount of drug absorbed The lifecycle of HCV presents a number of poten- into the blood and the concentration that is sustained tial targets against which many DAA drugs are cur- during the dosing interval, is an important factor in rently being developed [15,22]. The most advanced the prevention of resistance to a DAA. drug development programmes to date have targeted The frequency and speed at which resistance devel- polyprotein processing (by inhibiting the NS3/4A ser- ops when a given patient is treated with a DAA ine protease) and HCV replication (through different depends on the genetic barrier to resistance (num- mechanisms). Two NS3/4A serine protease inhibitors ber of amino acid substitutions required to generate (boceprevir and telaprevir) that target polyprotein resistance to the drug), the fitness of resistant vari- processing and, as a result, HCV production have ants, the level of resistance the mutant(s) confers and now been approved for the treatment of HCV infec- exposure to the drug. Altogether, these parameters tion in both the USA and Europe. In addition, at least account for the so-called ‘barrier to resistance’ of 10 other molecules in this class have been and/or are the drug [15,23,24]. When resistance does develop, being investigated in humans and at least 4 other it generally manifests as a virological breakthrough, classes of drugs that inhibit HCV replication are that is, a re-increase in the HCV RNA level. Several currently in clinical trials. These include nucleoside/ different breakthrough patterns associated with anti- nucleotide analogue inhibitors and non-nucleoside viral resistance have been characterized. For example, inhibitors of RdRp, inhibitors of NS5A, a viral pro- if a high degree of resistance is conferred by an amino tein involved in the regulation of HCV replication, acid substitution and the fitness of the virus is only and inhibitors of cyclophilin A, a host cell protein modestly affected, then the escape pattern will be required for HCV replication [15,22]. characterized by a rapid increase in HCV RNA level despite ongoing DAA administration. Conversely, if HCV resistance to DAAs the degree of resistance is lower and/or the fitness of the resistant virus is impaired, the slope of the HCV DAAs provide not only an opportunity to improve RNA level rebound will be less steep [15,23,24]. cure rates for patients with chronic hepatitis C, but If a drug is highly efficacious against wild-type also a challenge because