BCRX—Thanks for the confirmation, LOL. To reiterate, nucleoside (as opposed to nucleotide) drugs for HCV have been discredited because there are large patient-to-patent differences in the efficiency of the first phosphorylation step in vivo. This requires high dosing to ensure that the less-efficient phosphorylation patients receive enough of the active triphosphate form of the drug, and the consequence of such high dosing is unacceptable toxicity.
The second and third phosphorylation steps work more reliably in vivo, so it’s sufficient for a nucleotide prodrug to include a single phosphate group.
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