Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA

Vere Hodge, R Anthony

The founding culture of Pharmasset included a focus on nucleoside/tide analogues and selecting only those compounds that have a good safety profile. Pharmasset understood that all the drugs, with the highest genetic barriers, were nucleoside/tide analogues (but, of course, not all nucleoside/tide analogues have a high genetic barrier). For all viruses which have high mutation rates (e.g. HIV and HCV), combination therapy needs at least one drug with a high genetic barrier. A good safety profile is just as important as a good activity -at Pharmasset, compounds were assessed in a cascade, which started with a test for activity (an HCV replicon assay), but this assay also included a ribosomal-RNA cytotoxicity test. The next steps in the cascade were all aimed at assessing the safety profilecytotoxicity evaluations in a panel of five cell lines with replicating cells, mitochondrial toxicity and bone marrow toxicity. To my knowledge, it is rare to find a compound-screening strategy giving so much emphasis to the safety profile at such an early stage in the evaluation of a novel compound. This strategy led to PSI-6130, being identified as a compound with potential, when their competitors had compounds which may have had comparable activities but not the same safety profile. The Pharmasset selection strategy had led to a compound having a 'hidden' advantage over all the competitor compounds.