With excellent early markers of efficacy, the main targets of interest became the viral replication systems.\u00a0 The products of NS5B, NS3\/4A, and NS5A \u2013 in that sequence \u2013 were found to be useful drugable\u00a0 targets.\u00a0 In the absence of in-vitro or animal models of HCV replication, the Bartenschlager replicon assay proved invaluable in the early days.\u00a0 It was eventually replaced by even better cell culture systems that allowed in-vitro selection of drug candidates [5]<\/a>, [6]<\/a>.<\/p>\n Similar to HIV, there was always concern that HCV a rapidly mutating a ssRNA virus lacking any proof-reading mechanism for its polymerase, would need a multi-drug approach to prevent early relapse.\u00a0 Viral polymerase was an attractive target given its essential function and both nukes and non-nuke drugs were advanced into\u00a0development but early compounds often proved too toxic or had weak effects on viral\u00a0kinetics.\u00a0 The advent of protease inhibitors was delayed as the shallow enzymatic binding site proved\u00a0a difficult target to latch on and challenging chemists from many companies. When telaprevir (Incivek) and boceprevir (Victrelis) were approved, in 2011, they were rightly considered a break-through in HCV therapy.\u00a0 For the first time, SVR rates around 80% became achievable even in GT1 patients, a monumentous improvement over the prior standard which \u2013 at best- delivered an SVR around 45-55%. \u00a0Thus, the advent of these protease inhibitors provided an almost 2x improvement over PegIFN+RBV at the time and validated the DAA approach to HIV therapy.\u00a0 This boost in efficacy was \u2018bought\u2019 at a cost:\u00a0 side effects abounded and often were quite severe.\u00a0 Still, proof-of-concept had been established beyond doubt.\u00a0 There was reasonable hope that the next generation of protease inhibitors and DAAs would be better tolerated, replace the PegINF+RBV \u2018gold standard\u2019 and reduce treatment times for patients across all GTs.<\/p>\n Enter 2014, the year which brought such rapid changes to the field that HCV guidelines are outdated often before before the ink is dry.\u00a0 First, sofosbuvir entered the stage, a polymerase inhibitor which was well tolerated and produced SVR rates >95% in GT1 patients in \u226424 week studies, with PegIFN+RBV depending on population.\u00a0 Finally, the combination of sofosbuvir + simeprevir, the latter a protease inhibitor, was introduced without a standard PegIFN+RBV\u00a0backbone, a breakthrough in the long history of HCV trials.\u00a0 In particular, the COSMOS trial showed SVR rates > 90% even in prior non-responders and patients with high METAVIR\u00a0scores, paving the way for a purely DAA based regimen of two DAAs only, a regimen now awaiting FDA approval.<\/p>\n The approval of Harvoni\u00a0[7]<\/a> on Oct. 10, 2014 finally takes us to the promised land of an IFN \/ RBV \u2013 free regimens.\u00a0 The combination of sofosbuvir and ledispavir, a nucleosidic polymerase and a NS5A inhibitor, respectively, in a single pill to be taken once a day for 12 wks is just the latest drug combination with exceptional efficacy data: for all patient groups studied, SVR was >90%, often very close to 100%.\u00a0 Even prior non-responders had excellent SVR responses, only cirrhotics seem to do better with a 24 week treatment regimen which then again achieves SVR >90%.<\/p>\n This remarkable progression in therapeutic options begs the question: what’s left to improve?\u00a0 Clearly, there are still many companies engaged in early HCV research hoping to improve on Harvoni, the new standard in HCV treatment.<\/p>\n NOTE ADDED IN PROOF: On Nov. 5th, FDA approved the combination of sofosbuvir+simeprevir as a 2nd purely DAA regimen for GT1 patients. \u00a0Treatment duration is 12 wks for treatment-naive and non-cirrhotic patients, and 24 wks for cirrhotics. \u00a0Cave: Q80K polymorphism indicates poor response to simeprevir<\/p>\n NOTE: \u00a0Drug candidates that are in Phase 2 or later are listed in a previous blog on this site.<\/p>\n NOTE: Areas of improvement, differentiation and unmet needs will be the topic of a future blog at this site.<\/p>\n Abbreviations<\/strong><\/p>\n DAA\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 direct acting antiviral agents \u00a0References: [1]<\/a> like the Cobas AmpliPrep\/Cobas TaqMan HCV Test, Version 2.0 It was d\u00e9j\u00e0 vu all over again, albeit compressed in time: when the race started to replace PegIFN+RBV\u00a0for the treatment of HCV infection, the learnings from HIV drug development and the lessons with HAART provided an excellent template for quick and efficient development. There was early consensus that a search Continue reading 2014: The Year That Changed The Landscape of HCV Therapy<\/span>![\"All-New-HCV-Menu](\"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/11\/All-New-HCV-Menu-copy.jpg?resize=530%2C508&ssl=1\")
<\/a><\/p>\n
\nHAART\u00a0\u00a0 highly active antiretroviral therapy
\nEOT\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 end of therapy
\nLLOQ\u00a0\u00a0\u00a0\u00a0 lower limit of quantitation
\nLLOD\u00a0\u00a0\u00a0\u00a0 lower limit of detection
\nOI\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 opportunistic infection
\nSVR\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 sustained virological response
\nVL\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 viral load<\/p>\n
\n<\/strong>For pricing information see\u00a0http:\/\/www.hepatitisc.uw.edu\/page\/treatment\/drugs<\/p>\n
\n[2]<\/a> Siemens Versant HCV transcription-mediated amplification assay
\n[3]<\/a> S Pas.\u00a0 J Clin Microbiol. Jan 2013; 51(1): 238
\n[4]<\/a> F Carrat.\u00a0 JAMA. 2004;292(23):2839
\n[5]<\/a> E Steinmann.\u00a0 Cell Culture Systems for Hepatitis C Virus\u00a0\u00a0 Antivir Ther 2013. p 17
\n[6]<\/a> D Taylor. Evolution of cell culture systems for HCV Antivir Ther.<\/a>\u00a02013;18(3 Pt B):523
\n[7]<\/a> So far, for GT1 patients only<\/p>\n","protected":false},"excerpt":{"rendered":"