Replies to post #84761 on Biotech Values

[drbio45]

mcbio

you have been following ACHN very closely. what is your opinion at the present time.

[DewDiligence]

Perhaps he misspoke?

I wouldn’t call this an outright misstatement, but rather sloppy wording. I’m almost certain he meant that the two prodrugs resolve to the same monophosphate nucleotide. From that point forward, the monophosphate nuke gets converted to a triphosphate nuke in vivo, and hence the two prodrugs eventually produce the same triphosphate.

From a practical standpoint, it wouldn’t make much sense to have the prodrugs resolve to a triphosphate. This would weigh down the parent drugs with extra baggage and would gain little or nothing in terms of PK/PD.

[DewDiligence]

Nucleoside vs Nucleotide: Why Does It Matter?

[Updated for VRUS’ PSI-879/PSI-938; clarified that new-generation
nucleotide prodrugs resolve to the monophosphate nucleotide.]


A nucleotide (right) consists of a nucleoside (left) and 1-3 attached
phosphate groups. The nucleotide depicted below right is a monophosphate.



Why does the distinction between a nucleoside and a nucleotide matter?

The active agent for all nucleoside/nucleotide antiviral drugs is the triphosphate nucleotide, which is three phosphorylation steps removed from the nucleoside.

IDIX found that a major reason for the failure of NM283, a first-generation nucleoside, was the in vivo inefficiency and patient-to-patient variability of the first phosphorylation step, which converts a nucleoside into a monophosphate nucleotide.

IDIX’s IDX184 and VRUS’ PSI-7851, PSI-879, and PSI-938 are prodrugs of the monophosphate nucleotide; these drugs thus sidestep the problem encountered with NM283 by performing the first phosphorylation step ex vivo.

(The new-generation drugs mentioned above perform the second and third phosphorylation steps in vivo, but these steps do not present a practical problem because they are more efficient and less prone to variability than in vivo performance of the first phosphorylation step.)

[DewDiligence]

VRUS: Confirmed on the AASLD webcast that PSI-879 and PSI-938 are prodrugs of the monophosphate nucleotide, as posted in #msg-42335204. Regards, Dew

Link for VRUS AASLD webcast:
http://investor.pharmasset.com/events.cfm

Link for AASLD webcast slides (see slide #39):
http://investor.pharmasset.com/common/download/download.cfm?companyid=VRUS&fileid=329458&filekey=c67362a8-fc76-4ddb-bb0d-3eeeffd2d619&filename=IR%20Event%20Slides%20AASLD%20110209_FINAL.pdf