The drug programs in question originated from Bristol-Myers Squibb (BMS) and Inhibitex, which the former company bought for $2.5 billion last February, and were part of the heavily hyped 'race' to develop tolerable, interferon-alpha-free treatments for HCV. BMS-986094 moved rapidly through preclinical development, a fact that its developers have themselves drawn attention to. “We first made this in the labs in Cardiff in November 2008, and it progressed into man, first-in-man, by May 2010. That's 18 months, and that's incredibly quick. Industry normally takes about three years to do that,” Chris McGuigan, professor of medicinal chemistry at Cardiff University in Wales, stated in a promotional video posted on the university's website (http://www.cardiff.ac.uk/news/articles/business-innovation-9031.html, accessed 4 October, 2012). McGuigan is a research collaborator and former director of Alpharetta, Georgia–based Inhibitex, and BMS acquired Inhibitex largely on the strength of McGuigan's work with BMS-986094.
The BMS-986094 molecule, an inhibitor of the HCV RNA polymerase nonstructural protein 5B (NS5B), is an aryl-phosphoramidate prodrug of 6-O-methyl-2′-C-methyl guanosine, which blocks HCV replication by terminating synthesis of the viral RNA chain. Daclatasvir is a first-in-class molecule, which New York-based BMS describes as a replication complex inhibitor, although its precise mechanism of action is not fully understood. Its molecular target, a multifunctional regulatory protein called NS5A, is essential to HCV replication but its specific role in the process has yet to be elucidated. Neither exhibited any major cause for concern in earlier studies, which suggests that the combination may have contributed to the devastating cardiotoxicity seen in the trial.
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