Replies to post #79281 on Biotech Values

[dewophile]

PSI-7851 has demonstrated potent in vitro anti-HCV activity with EC50 values of 90 +/- 60 nM, which is approximately 15- to 20-fold more potent than Pharmasset's first generation nucleoside polymerase inhibitor, R7128

I believe IDX-184 has a lower (better) EC50 compared to R7128. however both are plenty potent, so this disparity is unlikely to be clinically meaningful unless the lower dose of the idenix compound translates into a better SE profile

[mcbio]

Re: VRUS Phase 1a data/use of "generally"

From the release:

- PSI-7851 was generally safe and well tolerated in Phase 1a single ascending dose trial

Perhaps I'm reading too much into this, but I'm a little skeptical of the use of the word "generally" here. Although they later indicate in the release that there were no adverse events, among other things, I wonder if the use of "generally" implies there may have been other potential safety signals noted in the trial that just didn't arise to a level of signficance due to the fact that this was such a short duration trial.

Note that IDIX did not use the term "generally" in their PR about the initial safety trial of IDX184. See: http://finance.yahoo.com/news/Idenix-Pharmaceuticals-prnews-15008332.html?.v=1

An additional presentation on IDX184 detailed results of the double-blind, placebo-controlled, single dose-escalation study that evaluated the safety and pharmacokinetics of IDX184 in healthy volunteers. Eight subjects (randomized 6:2, active:placebo) in each dosing cohort were administered a single dose of IDX184, ranging from 5 mg to 100 mg, or placebo. IDX184 was safe and well-tolerated in this study; the most common adverse event reported was dizziness and it was more frequently reported in subjects receiving placebo. In this study, the pharmacokinetics of IDX184 and the nucleoside metabolite were consistent with a liver-targeted drug. Systemic exposures and plasma half-life of the nucleoside metabolite were similar to that of its active triphosphate measured in vitro in human hepatocytes. In this healthy volunteer study, IDX184 doses of 50 mg/day and higher led to serum NM levels greater than 2 ng/mL 24 hours post-dose.

[DewDiligence]

VRUS Selects Lead Purine Analog for HCV

[VRUS’ plan 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 the colossally successful Truvada.) R7128 and PSI-7851, VRUS’ HCV polymerase inhibitors already in the clinic, are pyrimidine analogs while the new drug, PSI-938, is a purine. (Of these three drugs, only R7128 has been licensed to Roche; the other two are wholly owned by VRUS.)]

http://finance.yahoo.com/news/Pharmasset-Nominates-PSI938-prnews-1350115973.html?x=0&.v=1

›IND or foreign regulatory equivalent submission anticipated in first half 2010

Tuesday July 7, 2009, 7:00 am EDT

PRINCETON, N.J., July 7 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS ) announced today the nomination of PSI-352938 ("PSI-938") as a lead development candidate from two series of purine analogs for the treatment of chronic hepatitis C virus (HCV) infection. PSI-938 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-938 is particularly interesting to us since it differs from our pyrimidine analogs, R7128 and PSI-7851, because it has a complementary resistance profile and is metabolized through a different phosphorylation pathway," stated Michael Otto, PhD, Pharmasset's Chief Scientific Officer. "These differences may prove to be particularly important as we explore combinations of nucleos(t)ides in clinical development in the future."

Purine nucleos(t)ide analogs have many of the benefits of pyrimidine nucleos(t)ide analogs, like R7128 and PSI-7851, in that they have demonstrated 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.‹