IDX184 suffers setback in clinical trial....

Posted 8/16/12 on MarketWatch.com. Ouch. This makes Novartis look almost prescient in it's restructuring of it's relationship to Idenix. BMS-094, PSI-938 and IDX184 all share the same chemical structure - even if the cardiac event is unrelated to BMS-094 (hard to tell) I think the market will be wary regarding nucs sharing this structure.  

Idenix plunges 30% on HCV drug setback       08/16 10:43 AM

 BOSTON (MarketWatch) -- Shares of Idenix Pharmaceuticals (IDIX:$5.93,00$-2.38,00-28.64%) plunged 30% to $5.96 Thursday on news that the U.S. Food and Drug Administration has partially halted a Phase II clinical trial for its drug IDX184 over safety concerns. Idenix has been testing the product for the treatment of the hepatitis C virus, or HCV. The FDA placed a 'partial hold' on the trial pending the evaluation of reports that one of the patients taking the treatment had suffered a severe cardiac event. The FDA has also requested that Idenix provide additional patient data to help the agency with its evaluation. IDX184 belongs to a newer class of HCV drugs known as nucleotides. Earlier this month, shares of rival Bristol-Myers Squibb (BMY:$31.95,00$0.07,000.22%) slid almost 10% after the company announced it had suspended a Phase II study of its HCV nucleotide agent due to concerns that a patient had developed heart failure.

Seeking Alpha: Addressing Vertex/Gilead Confusion...

Posted 3-1-2012 on Seeking Alpha.com: More on HCV drug development investment 'irrational exuberance', the author making a case that investors have given Vertex the bum's rush and should take another look. 

Addressing Vertex / Gilead Confusion
March 1, 2012
Contributor: Prohost Biotech

Hepatitis C virus (HCV) treatments are moving stocks of HCV developers up and down in a chaotic way that makes no sense. While Vertex’ (VRTX) Incivek sales have been breaking the record of drug sales, investors who have been fed immature and unconfirmed knowledge that Pharmasset’s oral HCV therapeutics combination will render Incivek obsolete caused a sell-off in VRTX. Investor logic that patients would definitely prefer all oral drugs over a combination that has injectable alfa interferon is undisputable, that’s we too are waiting for a successful all oral HCV treatment, which has yet to emerge.

With the media stressing that Pharmasset was the firm that will put the magic combination on the market, Pharmasset's stock doubled from over $20 in January 2010, to around $45 at the end of December. In 2011, the stock rallied again from $45 in January to $135 in August, split 2 to 1 and started climbing back from around $66 to $72. The firm was then acquired by Gilead (GILD), which paid an additional 67% premium over its obese market price, i.e., around over $130 per share.

This scenario does not make sense to us. Contrary to the market’s culture, investors, for one reason or another, sold a real present to buy a future designed on mere speculation. They sold VRTX, a company that had a marketed HCV drug, which is the first ever to represent a cure for the life-threatening HCV infection and whose sales have been actually generating record revenues to buy into Pharmasset’s oral combination while still in mid-trial and requires more lengthy experimentation before confirming the all-oral combination’s safety and long-term efficacy.

Just before concluding the acquisition deal, on December 16, 2011, Pharmasset surprisingly announced its decision to discontinue all treatment arms with a regimen containing its drug PSI-938 because of laboratory abnormalities associated with liver function in subjects receiving the drug at a dose of 300 mg/day. This news surprised investors, especially Gilead’s shareholders who began to question the value of the deal with Pharmasset. The news did not alter Gillead’s decision to acquire the company. After the acquisition, Gilead’s stock experienced a temporary retreat. Many investors believed that $11 billion was an unprecedented high amount of money to be paid for molecules that have yet to complete clinical trials, confirming their superiority as described by the media since 2009. Investors’ temporary negative reaction toward the deal was the only understandable action in this story.

It did not take time for GILD to fiercely rebound after the firm announced its financial results. The stock was up to $56, matching its new high for the past three years. Less than two months later, though, other trial results with Pharmasset’s combination on HCV genotype 1 patients with a prior “null” response to an interferon-containing regimen demonstrated that the majority of patients experienced viral relapse within four weeks of completing 12 weeks of treatment with what has become Gilead’s combination of GS-7977 plus ribavirin (RBV). GILD tumbled, trading now at around $45, after loosing around 15% of its value.

In the mean time, Vertex is generating millions of dollars selling its selective HCV protease inhibitor. Its stock, though, remained boxed - sold every time it makes an attempt to rally even though Vertex is also trying its own all-oral combination. The stock remained boxed even after data from two treatment arms of the Phase 2 ZENITH study evaluating an interferon-free (all-oral) treatment regimen of the non-nucleoside polymerase inhibitor VX-222 in combination with INCIVEK (telaprevir) tablets and ribavirin in people with genotype 1a or 1b hepatitis C who were new to treatment have demonstrated promising safety and efficacy and after learning that the data from this study will be used to design a Phase 3 program with the goal of submitting a New Drug Application (NDA) to the FDA for the first interferon-free regimen for genotype 1 (1a and 1b) patients by the end of 2014 or beginning of 2015.

Investors didn’t even bother considering the fact that Vertex and its collaborator Alios BioPharma are conducting Phase 1 studies of two structurally-distinct nucleotide polymerase inhibitors, ALS-2200 and ALS-2158. Vertex has begun the first seven-day viral kinetic studies of ALS-2200 and ALS-2158 in people with genotype 1 hepatitis C, whose safety and viral kinetic data expected in the second quarter of 2012. Positive results would enable the initiation of Phase 2 studies in the second half of 2012 to evaluate multiple interferon-free combination regimens of ALS-2200, ALS-2158, INCIVEK, VX-222 and/or ribavirin.

What continued to make no sense at this stage is that investor pessimism with Gilead's all-oral combination that erased 15% of GILD price, did not transform into optimism for VRTX, which was cremated by the enthusiasm for Gilead’s drug that investors are now experiencing doubt about. It looks as if investors are sensitized to not appreciate the firm that introduced the first HCV cure and the first approved cystic fibrosis drug that works at the root cause of the disease, knowing in fact that Vertex has plans ready to bring breakthrough treatments to all cystic fibrosis patients.

Gilead is a great firm and at the end of the day it will probably succeed in bringing an HCV breakthrough treatment to the market. But this does not mean that Vertex will not succeed reaching the same goal. Vertex is also a great firm that has already changed the way chronic life-threatening diseases have been treated. Gilead has a lot of current and upcoming good news and so does Vertex. The HCV market is huge. It requires more than one, or two treatments to satisfy its needs.

Disclosure: We are long both firms.

The Motley Fool - Investors flee Inhibitex and Idenix stock on Pharmasset PSI-938 news...

Idenix Shares Plunged: What You Need to Know
By Evan Niu, The Motley Fool
Posted 3:59PM 12/16/11 Investing

Although we don't believe in timing the market or panicking over market movements, we do like to keep an eye on big changes -- just in case they're material to our investing thesis.

What: Shares of Idenix (NAS: IDIX) are plunging today, down by 16% at the low, after competitor Pharmasset (NAS: VRUS) discontinued use of one of its experimental drugs due to safety concerns.

So what: Pharmasset's experimental hepatitis C drug PSI-938 reported complications with liver function, although the developments aren't expected to interfere with Gilead Sciences' (NAS: GILD) planned acquisition of the company. Idenix also has a hepatitis C drug in its pipeline, which is the company's current focus.

Now what: The news is causing concern among some hepatitis C drugmakers, including Inhibitex (NAS: INHX) , which is also seeing downside today. Interestingly, rival Vertex Pharmaceuticals (NAS: VRTX) is seeing healthy gains, with setbacks for PSI-938 considered positive for Vertex. Idenix's and Inhibitex's hepatitis C drugs are more similar to Pharmassets, which is causing investors to flee for cover.

Pharmasset awarded fast track status for polymerase inhibitor PSI-938...

(Good news for Pharmasset, as the FDA awards it's polymerase inhibitor PSI-938 fast track status, which would shorten the review period from 10 months to six months. Pharmasset also announces the start of an interferon-free, dual polymerase inhibitor trial of PSI-938 in combination with it's PSI-7977 compound in the Q3 of this year)

PSI-938 Receives Fast Track Designation from the FDA for the Treatment of Chronic Hepatitis C Infection

PRINCETON, N.J., Aug. 24, 2011 /PRNewswire via COMTEX/ -- Pharmasset, Inc. /quotes/zigman/101019/quotes/nls/vrus VRUS +0.02% has received fast track designation from the U.S. Food and Drug Administration (FDA) for PSI-938 for the treatment of chronic hepatitis C virus (HCV) infection. PSI-938 is an oral guanosine nucleotide analog polymerase inhibitor of HCV.

In March 2011, Pharmasset presented data from the NUCLEAR study demonstrating that PSI-938 has potent antiviral activity and is generally safe and well tolerated, both as monotherapy and in combination with Pharmasset's lead nucleotide analog, PSI-7977. The NUCLEAR study was conducted in treatment naive subjects with genotype 1 HCV who were treated for 14 days with either PSI-938 or a combination of PSI-938 and PSI-7977 with 92% achieving HCV RNA <15IU/mL, the limit of detection, in the combination arms. Pharmasset plans to initiate QUANTUM, an interferon-free combination trial with PSI-938 and PSI-7977 in the third quarter of 2011.

Under the FDA Modernization Act of 1997, fast track designation may facilitate the development and expedite the review of a drug candidate that is intended for the treatment of a serious and life-threatening condition and demonstrates the potential to address an unmet medical need for such a condition. PSI-938 was granted the fast track designation primarily due to the need for HCV treatments with improved tolerability, safety and efficacy over the existing standard of care for both treatment-naive and treatment-experienced patients.

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in four Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in three Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.

For full press release, click on the attached link.

Pharmasset Announces the Expansion of the ELECTRON Trial in Chronic Hepatitis C

Pharmasset adding arms to it's genotype 2/3 ELECTRON trial looking at shorter durations of therapy in addition to inteferon-free monotherapy for it's PSI-7977 nucleotide analog. Nucs traditionally have a very high barrier to resistance in comparison to non-nucs, but with a virus capable of making every possibly mutation of itself in the course of a day, is nuc monotherapy without an immune system modulator or another viral life cycle-specific inhibitor enough, even in the relatively easy-to-treat G2 and 3 virus? If it's not, what are the odds of a PSI-7977 resistant quasispecies developing and the corresponding fitness level compared to wild type of those variants? Guess we'll find out soon enough. If anyone can shed further enlightenment, please do.

PRINCETON, N.J., June 8, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the addition of three treatment cohorts to the ELECTRON trial of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The rapid and consistent antiviral effects and high barrier to resistance demonstrated with PSI-7977 to date provide the rationale for additional exploratory regimens in this setting. This amendment will add one arm exploring 12 weeks of PSI-7977 monotherapy (without peginterferon and ribavirin) and two arms of interferon-sparing therapy: one for 8 weeks of PSI-7977 plus peginterferon and ribavirin (Peg-IFN/RBV) in patients with HCV genotype 2 (GT2) or 3 (GT3) and one for 12 weeks of PSI-7977 plus Peg-IFN/RBV in patients with HCV genotype 1 (GT1) prior null responses.

"The combination data reported at EASL demonstrated that SVRs were achievable with two oral DAAs in the absence of peginterferon and ribavirin," stated Bill Symonds, PharmD, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine, "We continue to explore the potential for removing peginterferon and ribavirin from the HCV treatment regimen. Given the encouraging data we are seeing in ELECTRON, we have decided to expand the study to investigate PSI-7977 monotherapy, as well as shorter treatment regimens based on the promising data we reported at EASL from PROTON."

Pharmasset anticipates reporting results from the first four arms of the trial (n=40) during the second half of 2011. We have submitted a number of abstracts to the 2011 American Association for the Study of Liver Diseases (AASLD) meeting, including data from the ELECTRON and PROTON trials.

About the Trial

The ELECTRON trial is an exploratory study of PSI-7977 for the treatment of chronic HCV infection. Part 1 of the trial is evaluating 12-week regimens of PSI-7977 400mg QD in combination with ribavirin (RBV) only, and in separate arms with abbreviated durations of Peg-IFN for 4, 8, or 12 weeks in treatment-naive patients with HCV GT2 or GT3. The primary endpoint of the trial is the safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without Peg-IFN. On May 11, 2011, Pharmasset announced the completed enrollment of Part 1 of ELECTRON in patients with HCV GT 2 or GT 3:

* PSI-7977 400mg with RBV for 12 weeks (no peginterferon);
* PSI-7977 400mg with RBV for 12 weeks; Peg-IFN weeks 1-4 only;
* PSI-7977 400mg with RBV for 12 weeks, Peg-IFN weeks 1-8 only;
* PSI-7977 400mg with Peg-IFN and RBV for 12 weeks.


In Part 2 of ELECTRON, Pharmasset will enroll an additional 30 patients into exploratory regimens of monotherapy and abbreviated durations of total therapy. Following on the first four Cohorts of ELECTRON a 5th cohort will be added to explore 7977 400mg monotherapy in treatment-naive patients with HCV GT2 or GT3:

* PSI-7977 400mg monotherapy for 12 weeks.


With the previously reported 100% SVR12 in naive GT2/3 subjects in PROTON, a 6th and 7th cohort will be added to ELECTRON to explore shorter treatment durations in both GT2/3 naive subjects and HCV GT1 subjects who have documented null responses (less than 2 log(10) IU/mL reduction in HCV RNA after 12 weeks of Peg-IFN/RBV):

* PSI-7977 400mg with Peg-IFN/RBV for 8 weeks
* PSI-7977 400mg QD with Peg-IFN/RBV for 12 weeks.


About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in three Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in two Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.

Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 865-0693

Forward-Looking Statements

Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 and our Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.

SOURCE Pharmasset, Inc.

Could an all-oral agent to treat HCV be on the way?

Two week interim data for Pharmasset's Interferon/Ribavirin-free nuc-nuc combo is a long way from an SVR, but so far the company has earned bragging rights by having 15/16 subjects in this early phase trial go undetectable after two weeks. This is seemingly a pretty potent combo in comparison to Vertex's data with it's nuc VX-222 + Telaprevir + Peg Interferon + Ribavirin. Depending on the arm, that data topped out at 38-57% undetectability after 14 days in comparison to 94% with PSI-938 and PSI-7977. Pharmasset’s new landmark was enough for investors to spin like tops and goose the stock to new heights. Keep in mind that investors don’t always act rationally and It’s difficult to predict outcomes as all we know regarding viral kinetics and positive/negative predictive values comes from regimens that contain peg-inf plus ribavirin as its therapeutic backbone. If PSI-938 and PSI-7977 can retain 94% undetectable at four weeks, I’ll be proportionally reassured regarding this combo’s future. It will be interesting how the company defines when it’s time to stop therapy given that there isn’t an immunomodulator aboard. At what time points will the company declare EOT and SVR? An all oral combo would be an amazing paradigm shift for this disease state and will set the bar extremely high for drug developers looking to get into the HCV therapeutic category, but there’s a long road ahead.

Pharmasset Hep C Data Wows Investors

Adam Feuerstein
03/08/11 - 11:46 AM EST
PRINCETON, N.J. (TheStreet) -- Pharmasset(VRUS) shares are soaring on the release of new but very preliminary data that hints at a breakthrough, all-oral cure for hepatitis C.

Treatment with two oral drugs developed by Pharmasset resulted in 15 of 16, or 94%, of patients reporting undetectable levels of the hepatitis C virus after 14 days, according to interim results from a study released Monday.

These early data on the two Pharmasset drugs -- PSI-938 and PSI-7977 are the best reported to date by any company seeking to develop a new, all-oral therapy for hepatitis C. This Pharmasset effort is drawing even more attention because it potentially eliminates the need for patients to be treated with long-acting interferon, one of two drugs currently used to treat hepatitis C but which is difficult for patients to tolerate and causes many side effects.

Pharmasset shares rose 24% on Monday and were up another 8% to $66.92 on Tuesday.

The PSI-938 and PSI-7977 combination data were released Monday in a research abstract released online by the European Association for the Study of the Liver (EASL), which holds its annual meeting March 30 through April 3.

EASL makes research abstracts for its annual meeting freely available to the public but prohibits journalists from writing about the data contained in the research abstracts until they are presented at the annual meeting. TheStreet refuses to adhere to EASL's media embargo since these hepatitis C data are freely available online now and are impacting the stock prices of publicly traded companies developing hepatitis C drugs.

While investors are displaying great enthusiasm for the Pharmasset all-oral drug combination, the data from the study are very early. One particular risk seen in other, similar studies that omit long-acting interferon is the development of mutated hepatitis C virus that can quickly become resistant to drug treatment.

None of the patients treated in the Pharmasset study have reported rebounding levels of hepatitis C virus, according to the research abstract, but so-called viral rebound may emerge as patients are treated longer, or when treatment is stopped and these patients are followed long-term to determine if they are truly cured.
Pharmasset owns full rights to both PSI-938 and PSI-7977. The company is developing another hepatitis C drug, RG7128, in partnership with Roche.

"We believe the full data of a 14-day combination of PSI-7977 / PSI-938 to be presented at the upcoming EASL could show proof of principle for a nuc-nuc combination and position Pharmasset as one of the front runners in the race to develop an interferon-free regimen, which is considered a Holy Grail in hepatitis C treatment," said Leerink Swann analyst Howard Liang in a note to clients Tuesday.

The EASL meeting at the end of the month will also feature data from other companies seeking to develop various combination treatments for hepatitis C.

Vertex Pharmaceuticals(VRTX) is studying a "quad" regimen consisting of two experimental drugs, VX-222 and telaprevir, combined with the current standard of care, long-acting interferon and ribavirin. An EASL research abstract released Monday reported treatment with Vertex's "quad" therapy resulted in 38-57% of patients with undetectable virus after two weeks and 86-87% undetectable after four weeks.

One potential competitive disadvantage to the Vertex quad is that patients still need to be treated with long-acting interferon, which requires weekly injections. Vertex previously reported disappointing results from an all-oral Hep C drug regimen that eliminated interferon.

Telaprevir is currently under review by regulators in the U.S. and Europe. The U.S. Food and Drug Administration is expected to make an approval decision on or before May 23.

Gilead Sciences(GILD) and Bristol-Myers Squibb(BMY) will also be presenting new data from Hep C combination drug studies at the EASL meeting later this month.

--Written by Adam Feuerstein in Boston.

Update on Pharmasset's PSI-7977 and PSI-938....

UPDATE 1-Pharmasset says HCV drugs show promise
7:48am EST

* PSI-7977 shows rapid viral suppression

* PSI-938 found to be well tolerated

Jan 6 (Reuters) - Pharmasset Inc (VRUS.O: Quote, Profile, Research, Stock Buzz) said interim analyses of clinical studies of its two drugs for chronic hepatitis C showed promise.

A mid-stage study of the drug, codenamed PSI-7977, showed rapid viral suppression with all patients remaining below limit of detection at the end of treatment. No serious adverse events were reported.

The drug was granted "fast track" designation in August. Fast-track status is designed to expedite the review of drugs to treat serious diseases and fill unmet medical needs. [id:nSGE67B0JZ]

The company said it expects to start a 24-week mid-stage study of the drug in the second quarter of 2011.

An early-stage study of the drug, codenamed PSI-938, as a monotherapy was found to be safe and well-tolerated, Pharmasset said.

The Princeton, New Jersey-based company's shares, which have risen 50 percent in the last three months, closed at $46.59 on Wednesday on Nasdaq. (Reporting by Shravya Jain in Bangalore; Editing by Sriraj Kalluvila)

Pharmasset Initiates Dosing in a Combination Study of PSI-7977 and PSI-938 for Chronic Hepatitis C...

First study to look at a combination of of a purine and a pyrimidine nucleotide analog (PSI-938 and PSI-7977 respectively). Pharmasset believes the combination of two 'nucs' has a potential higher barrier to resistance, making it attractive to use in combo with other STAT-C/DAA drugs. The company plans a Phase II trail looking at the combination without interferon mid-2011 - Chris

- Phase 1 combination study of a pyrimidine (PSI-7977) and purine (PSI-938) nucleotide analog in patients with chronic hepatitis C

- Interim data expected in first quarter of 2011

PRINCETON, N.J., Nov. 30, 2010 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in Part 2 of a Phase 1 study. This is the first clinical study combining a purine (PSI-938) and a pyrimidine (PSI-7977) nucleotide analog for HCV, and is designed to evaluate once daily doses of PSI-7977 and PSI-938 in patients with HCV who have not been treated previously.

"We are excited to be initiating this combination study with two proprietary nucleotide analogs for HCV," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "Based on our in vitro data, we believe the combination of two nucleotide analogs could provide potent antiviral activity across multiple HCV genotypes and could also have a higher barrier to resistance compared to other DAA combinations. We believe nucleotide analogs have a number of key attributes that may make them ideal partners for other DAA combinations, in addition to a 'nuc-nuc' combination."

About the Phase 1 Trial

In Part 1 of the Phase 1 multiple ascending dose study of PSI-938, suppression of HCV RNA below the limit of detection (LOD, <15 IU/mL) was observed in over half of the patients who received PSI-938 at daily doses of 200 mg or 300 mg for seven days. Part 2 of the study is designed to evaluate the combination of PSI-938 and PSI-7977. The primary objective is to assess the safety, tolerability and pharmacokinetics of PSI-938 administered alone for 14 days, and in combination with PSI-7977 for 7 to 14 days. The secondary objective is to evaluate viral kinetics of HCV RNA during monotherapy and combination nucleotide dosing. Approximately forty patients are expected to be enrolled into four cohorts as follows:

* PSI-938 QD administered as monotherapy for 14 days, followed by;
* PSI-938 QD for 7 days followed by PSI-938 plus PSI-7977 QD for 7 days and
* PSI-7977 QD for 7 days followed by PSI-938 plus PSI-7977 QD for 7 days, followed by;
* PSI-938 plus PSI-7977 QD for 14 days


We expect to report preliminary results from Part 2 of this Phase 1 study during the first quarter of calendar year 2011. We also expect to initiate a Phase 2 study of PSI-938 in combination with PSI-7977 during mid-2011. This Phase 2 study proposes to explore durations of PSI-938 and PSI-7977 in interferon-free combinations with an SVR endpoint.

Pharmasset releases Phase 1 data on HCV nucleotide inhibitor PSI-938

Reports Positive Preliminary Antiviral Data with PSI-938 for the Treatment of Hepatitis C 
10/28/2010

PRINCETON, N.J., Oct. 28 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (Nasdaq: VRUS) reported positive preliminary results today from its phase I monotherapy trial of PSI-352938 ("PSI-938") for the treatment of chronic hepatitis C (HCV). PSI-938 is a guanosine nucleotide analog polymerase inhibitor in development for the treatment of chronic HCV infection.

PSI-938 Phase 1 Multiple Ascending Dose Study Overview

In August 2010, Pharmasset initiated a phase 1 multiple ascending dose study with PSI-938 administered once daily (QD) or twice daily (BID) for 7 days. The trial was conducted at two US centers as a blinded, randomized, and placebo-controlled study in 40 patients chronically infected with HCV genotype 1. The primary objective was to assess the safety, tolerability, and pharmacokinetics of PSI-938 administered over 7 days. The secondary objective was to assess antiviral activity by measuring the change in HCV RNA. Patients were randomized within each cohort to receive either PSI-938 (8 patients per cohort) or placebo (2 patients per cohort). Four dose cohorts of PSI-938 (100 mg QD, 200 mg QD, 300 mg QD and 100 mg BID) have been completed.

PSI-938 Antiviral Activity Summary

Preliminary Antiviral Response Observed Following PSI-938 Administered as Monotherapy for 7 Days
Dose	n	Median Change in HCV RNA at Day 8	Range	Number of Subjects with HCV RNA
		(log10 IU/mL)	(log10 IU/mL)
100 mg QD	8	-4.31	-2.66 to -5.12	1	3
200 mg QD	8	-4.64	-3.49 to -5.35	5	7
300 mg QD	8	-3.94	-3.43 to -5.29	4	4
100 mg BID	8	-4.59	-3.94 to -5.08	2	3
Placebo	8	-0.05	+0.17 to -0.29	0	0
LOD = limit of detection (<15 IU/mL) LOQ = limit of quantification (<43 IU/mL)

PSI-938 demonstrated potent antiviral activity with a mean HCV RNA change from baseline of 4.31 log10 IU/mL, 4.64 log10 IU/mL, 3.94 log10 IU/mL and 4.59 log10 IU/mL in patients receiving 100 mg QD, 200 mg QD, 300 mg QD and 100 mg BID for seven days, respectively. HCV RNA declined consistently throughout the 7-day dosing period, with no viral breakthrough. For the 16 subjects who received PSI-938 200 mg QD or 300 mg QD for 7 days, more than half (9 of 16) of the subjects on PSI-938 monotherapy achieved HCV RNA below the limit of detection (15 IU/mL) and 11 out of 16 patients achieved HCV RNA below the limit of quantification (43 IU/mL).

PSI-938 Pharmacokinetic and Safety Summary

Pharmacokinetics parameters were similar between healthy subjects in the single ascending dose study and HCV infected patients in the seven-day multiple ascending dose study. PSI-938 at all doses provided good systemic exposure and continue to support once-daily administration.

PSI-938 was generally safe and well tolerated across all doses studied to date with no serious adverse events and no discontinuations. There were no dose-related trends in adverse events through the dose escalations, no grade 4 treatment emergent laboratory changes, and no trends in clinical laboratory abnormalities.

PSI-938 SAD and preclinical data

The Phase 1a single ascending dose study conducted earlier this year assessed single doses of PSI-938 ranging from 100 mg to 1600 mg or matching placebo in healthy male and female volunteers. No dose-limiting toxicity was identified. Safety and pharmacokinetic data supported progression of PSI-938 to the 7-day monotherapy trial. Full data from the SAD trial will be presented at the upcoming AASLD Annual Liver Meeting in Boston, MA, October 29-November 3, 2010 (poster #1890).

Preclinically, both PSI-938 and Pharmasset's other guanosine analog, PSI-661, which is in late preclinical development, have demonstrated similar potency against wild-type HCV or HCV with the S282T mutation, which can be selected by RG7128 and PSI-7977 in vitro. Although the S282T has not been detected in treatment-naive individuals with HCV, nor selected in clinical trials with any of Pharmasset's nucleoside/tide analogs, the potential for interferon-sparing regimens may increase the focus on antivirals with complementary resistance profiles.

"We are very encouraged by the preliminary efficacy and safety data with PSI-938, our purine nucleotide analog for HCV," said Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "These data provide the first confirmatory evidence that a nucleoside/tide analog can exhibit substantial early antiviral activity in monotherapy as has been observed with compounds in other DAA classes. Unlike other classes of DAAs to date, our nucleotide analogs also provide a higher barrier to resistance and clinically-validated antiviral activity across a broad range of HCV genotypes, characteristics not yet demonstrated with other classes of DAA. We continue to believe that nucleoside/tide analogs will become the backbone of HCV therapy. In addition, similar to HIV, the combination of two complementary nucleoside/tide analogs could provide a differentiated therapy for HCV patients in the future."

PSI-938 and PSI-7977 Combination Study

In this quarter, Pharmasset plans to initiate a short-term study to assess the combination of PSI-938 and PSI-7977. The trial will be conducted in the US, as a blinded, randomized, placebo-controlled study in approximately 50 patients chronically infected with HCV genotype 1. The primary objective will be to assess the safety, tolerability, and pharmacokinetics of PSI-938 and PSI-7977 alone and in combination. Preliminary results are expected in the first half of 2011.

Conference Call and Webcast

Members of Pharmasset's management team will host a conference call today, October 28, 2010, at 8:00 a.m. ET to discuss the preliminary results of the multiple ascending dose trial with PSI-938. Investors may listen to the webcast of the conference call live on the "Events & Presentations" section of Pharmasset's website, www.pharmasset.com. Alternatively, investors may listen to the call by dialing 877-771-7028 from locations in the U.S. and 973-200-3092 from outside the U.S. The webcast replay will be available for at least 72 hours following the call.

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog presently in a Phase 2b study, and PSI-938, an unpartnered guanosine nucleotide analog in Phase 1. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development. Racivir, for the treatment of HIV, has completed a Phase 2 clinical study.

Pegasys® and Copegus® are registered trademarks of Roche.

Pharmasset Initiates Phase 1b Multiple Ascending Dose Clinical Trial of PSI-938 in Patients with Chronic Hepatitis C

-- PSI-938 single ascending dose study in healthy volunteers supports progression to 7 day monotherapy study in HCV infected patients -- PSI-938 was generally safe and well tolerated with no dose-limiting toxicity -- Further results from single ascending and multiple ascending dose trials are expected in the third quarter 2010

PRINCETON, N.J., July 28 /PRNewswire-FirstCall/ -- Pharmasset, Inc. (NASDAQ:VRUS) announced today that safety and pharmacokinetic data from the PSI-352938 ("PSI-938") single ascending dose study support progression to a multiple ascending dose trial with PSI-938, which has initiated dosing. PSI-938 is a guanine nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. This study is designed to assess the safety, tolerability and antiviral activity of PSI-938 monotherapy administered over 7 days in HCV-infected individuals.
 

"PSI-938 is the third differentiated nucleoside analog that Pharmasset has advanced into clinical development for HCV," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "As with RG7128 and PSI-7977, PSI-938 demonstrates a high barrier to resistance in vitro; but unlike the cytidine and uridine analogs, PSI-938 retains equivalent potency against the S282T mutant. As the HCV field moves toward IFN-sparing, all-oral DAA combinations, we continue to believe nucleosides could become the backbone of care given these differentiating attributes and have the potential to be combined with all DAA classes."
 

PSI-938 Phase 1 Program Overview
 

The Phase 1 program is investigating the safety, tolerability and pharmacokinetics of PSI-938 in healthy subjects following escalating single doses (Phase 1a), and in patients chronically infected with HCV genotype 1 following repeat dosing for 7 days (Phase 1b). The Phase 1b study will additionally investigate hepatitis C viral dynamics and monitor for the development of drug resistance.
 

Subjects in the Phase 1a single ascending dose study received single doses of PSI-938 ranging from 100 mg to 800 mg or a matching placebo. Preliminary data from the phase 1a single ascending dose study includes:
 

--  No serious adverse events or discontinuations;
  --  No dose-related adverse events or dose-limiting toxicity;
  --  No grade III / IV lab abnormalities;
  --  No clinically significant changes in vital signs or ECGs; and
  --  PK which supports QD dosing.

A Phase 1b multiple ascending dose trial has now been initiated in treatment-naïve patients with chronic HCV genotype 1 infection. Subjects will be enrolled at multiple centers in the US and randomized to PSI-938 or placebo. Based upon the results from the first time in human study, the first dose of PSI-938 to be tested will be 100 mg administered once daily. The primary objectives of this study are to assess the safety, tolerability, pharmacokinetics and viral dynamics of PSI-938 after repeat dosing over 7 days.
 

  Results from both studies are expected in the third quarter of 2010.

  Purine and Pyrimidine Analogs

Pharmasset's purine nucleoside/tide analogs share 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, in spite of the prodrug technology, have no CYP 3A4 liability and thus a lower risk of drug interactions when combined with other direct acting antivirals targeting HCV. In addition, Pharmasset's purine analogs retain equivalent potency against wild type HCV and virus with the S282T mutation associated with in vitro resistance in other nucleoside/tide analogs in development. Furthermore, the purines are metabolized to the active triphosphate form through a different phosphorylation pathway than the pyrimidine analogs, thus decreasing the risk of competition between the two analogs for conversion to the active triphosphate. Given these characteristics, Pharmasset's purine and pyrimidine analogs have the potential to be combined as part of a future treatment regimen, which will be the focus of upcoming trials.