Biotech Values

[DewDiligence]

Why HCV Nucleotides Are Better than Nucleosides

[Is] IDX184 the lead nucleotide polymerase inhibitor with these results?

IDX184 is neck and neck with VRUS’ PSI-7977 (#msg-49048250) for the honor of being the lead HCV nucleotide polymerase inhibitor in development, while RG7128 from Roche/VRUS is the lead nucleoside polymerase inhibitor. From a practical standpoint, nucleoside drugs may be considered “first-generation nukes,” and nucleotide drugs may be considered “second-generation nukes.”

What is the consequential distinction between first-generation (nucleoside) nukes and second-generation (nucleotide) nukes? The first-generation nukes do not contain a phosphate group, and hence they have to perform in vivo the first phosphorylation step of the process that generates the active triphosphate metabolite. Due to the inefficiency of performing the first phosphorylation step in vivo, first-generation nukes such as RG7128 have to be dosed at much higher levels than second-generation nukes such as IDX184 and PSI-7977, which means that first-generation nukes will inevitably have more problems than second-generation nukes with safety and tolerability.

Let’s frame the above with some hard numbers. The cumulative daily dose of RG7128 being tested in phase-2b is 1000-2000mg (#msg-43836489), while the highest dose of IDX184 tested to date is 100mg, i.e. one-twentieth of the highest tested dose of RG7128.

Please bear in mind that all nukes have efficacy against HCV replication because the mechanism of action—chain termination of the polymerase—is simple, direct, and well understood. Thus, what sets one HCV nuke apart from another is not efficacy per se, but rather is whether the dose required for efficacy is safe and easy to tolerate. On this score, there is no question that the second-generation nukes will outshine the first-generation ones.

p.s. Please see #msg-42396728 for the graphical representation of the molecular structures that underpin the above discussion.