Pharmasset Nominates PSI-879 as a New Nucleotide Analog Inhibitor of Hepatitis C for Preclinical Development
- IND or foreign regulatory equivalent submission anticipated in fourth quarter of 2010
PRINCETON, N.J., Oct. 6 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS - News) announced today the nomination of PSI-352879 (PSI-879) as a second development candidate from two series of purine analogs for the treatment of chronic hepatitis C virus (HCV) infection. PSI-879 is a proprietary nucleotide analog polymerase inhibitor of HCV that is being advanced into studies required for submission of an Investigational New Drug (IND) application with the FDA or equivalent foreign regulatory application.
"PSI-879 employs a different prodrug technology than our lead purine nucleotide, PSI-938. We plan to submit an IND for PSI-938 in the first quarter of 2010" stated Michael Otto, PhD, Pharmasset's Chief Scientific Officer. "We now are in a position to have two opportunities to develop a purine and pyrimidine nucleoside/tide combination. We believe in addition to being used in combination, our nucleoside/tide analogs also have the potential to be combined with other classes of direct acting antivirals for HCV."
Preclinical data demonstrate that purine nucleotide analogs have many of the benefits of pyrimidine nucleoside/tide analogs, such as RG7128 and PSI-7851, by demonstrating in vitro activity across multiple genotypes, a higher barrier to resistance than other classes of HCV small molecules in development, and the potential to be combined with other direct acting antivirals targeting HCV. In addition, these purine analogs are also active against the S282T resistant variant selected in vitro by the pyrimidine analogs and are metabolized to the active triphosphate form through a different phosphorylation pathway than the pyrimidines. Given these characteristics, purine and pyrimidine analogs have the potential to be combined as part of a future treatment regimen.
[PSI-938 is structurally and mechanistically similar to IDIX’s IDX184, but is about two years behind in development. VRUS’ grand scheme for HCV is to develop a dual-nucleoside regimen where the component nukes have complementary resistance profiles, and this is best accomplished by employing one pyrimidine analog and one purine analog. (The same idea was used by GILD in the HIV market to create Truvada.) RG7128 and PSI-7977, VRUS’ more advanced HCV polymerase inhibitors, are pyrimidine analogs, while PSI-938 (and the follow-on compound, PSI-879) are guanosine (purine) analogs. Of these drugs, only R7128 has been licensed to Roche; the others are wholly owned by VRUS.]
PRINCETON, N.J., April 8 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq:VRUS) announced today that dosing has initiated in a phase 1, single ascending dose (SAD) study in healthy volunteers with PSI-938, a third generation purine nucleotide analog polymerase inhibitor of hepatitis C virus (HCV). Pharmasset recently filed an Investigational New Drug Application (IND) with the Food and Drug Administration (FDA).
"PSI-938 is our first purine nucleotide analog to move into clinical development," stated Dr. Michelle Berrey, Pharmasset's Chief Medical Officer. "As PSI-938's resistance profile is different from other nucleoside/tides in development for HCV and it has a different metabolic pathway from pyrimidine analogs, such as RG7128 and PSI-7977, we believe PSI-938 could be potentially combined with other nucleosides in development to deliver a pan-genotype regimen. We look forward to reporting the first antiviral data with PSI-938 in the third quarter of 2010."
Purine and Pyrimidine Analogs
Purine nucleoside/tide analogs have many of the benefits of pyrimidine nucleoside/tide analogs, such as RG7128 and PSI-7977, in that they have demonstrated in vitro activity across multiple HCV genotypes, have a higher barrier to resistance than other classes of HCV small molecules in development, and have a lower risk of drug interactions when combined with other direct acting antivirals targeting HCV. In addition, Pharmasset's purine analogs retain activity against the S282T mutation associated with in vitro resistance in other nucleoside/tide analogs in development, and are metabolized to the active triphosphate form through a different phosphorylation pathway than the pyrimidine analogs. Given these characteristics, Pharmasset's purine and pyrimidine analogs have the potential to be combined as part of a future treatment regimen.‹
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