Interferon Free Combinations - 2012 Archives

2013 Updates

2012

Dec 19
Hepatitis C - First Interferon-Free Regimens Expected to Launch in 2014 in the United States and Europe

Dec 17
Hepatitis C Update Selected Highlights: Key new HCV drugs

Dec 13
Hepatitis C - Initiation of cohort 2 in the interferon-free phase II trial combining simeprevir (TMC435) with sofosbuvir (GS7977) based on a safety and efficacy

Dual Oral Therapy with Daclatasvir and Asunaprevir for Patients with HCV Genotype 1b
Infection and Limited Treatment Options   -
Dual therapy with daclatasvir and asunaprevir, without peginterferon/ribavirin,
was well tolerated and achieved high SVR rates in two groups of
difficult-to-treat patients with hepatitis C virus genotype 1b infection.

Nov 2012

Nov 15
Many Physicians who Treat HCV Have Begun 'Warehousing' and Preparing HCV Patients for the Next Generation of Interferon-Free Treatments to Become Available, According to a Recent BioTrends Report

Nov 14
Slides Available @ NATAP- High Rate of Sustained Virologic Response With the All-Oral
Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B
Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically
Infected With HCV GT 1, 2, or 3

Daclatasvir and Sofosbuvir: Promising HCV Combo May Not See Light of Day

AASLD- Interferon-Free Regimens Produce High HCV Sustained Response

AASLD - Drug Combos Hit Hep C Virus Hard

Nov 13
Abbott Announces Phase 3 Interferon-free Hepatitis C Regimens to be Studied in Broad Patient Populations 

Gilead May Top Rivals With Hepatitis C Therapy Results

AASLD-Daclatasvir, Asunaprevir and BMS-791325 Achieved SVR12 of 94% in Treatment-Naïve Patients with Geno 1 Chronic Hepatitis C

Nov 10
AASLD-100 Percent Sustained Virologic Response Rate (SVR4) Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and Ribavirin in Treatment-Na ïve Geno 1 Hepatitis C Infected Patients

AASLD-Daclatasvir and Asunaprevir Achieved SVR12 in 78% of  Difficult-to-Treat Genotype 1b Prior Null Responders

AASLD-Achillion Programs: Sovaprevir, ACH-3102 and ACH-2684

AASLD- Abbott hepatitis C oral drugs bring high cure rates in trial

UPDATE: Abbott Hepatitis C Regimen Suppresses Virus in New Study

AASLD- ALS-2200 (VX-135), Vertex's Oral Nucleotide Analogue in Development for Hepatitis C

AASLD-Merck MK-5172  Hepatitis C Drug Shows Promise in Study; Abbott Updates Data

Nov 2
Hepatitis C MK-5172:Merck Will Initiate all-oral, interferon-free combination

Hepatitis C Interferon-free: Late-breaking Abstracts Selected for Oral Presentation at The Liver Meeting®

Nov 1
Vertex Announces Collaboration with Janssen To Initiate Phase 2 All-Oral  Study of VX-135 and Simeprevir (TMC435) for the Treatment of Hepatitis C

Hepatitis C: Vertex Enters Agreement with GlaxoSmithKline - Phase 2 All-Oral Study of VX-135 and GSK2336805

Vertex Joins Glaxo, J&J in Testing Hepatitis C Combos

Oct 2012

On The Blog
AASLD Meeting Updates
The 63rd  Annual  Meeting of the  American Association for the Study of Liver Diseases
(AASLD) will take  place November 9-13 in Boston.

Oct 22
Chronic  hepatitis C: Treat or wait?
At the opera,  the show isn’t over until the  large lady begins her aria. In drug  development,
licensing and effective  treatment of thousands of patients define a successful
launch. Following recent  problems with emerging drugs for HCV, I am reminded of
the difficulties of  turning chemicals into drugs and the importance of waiting
until the development  cycle is complete before claiming success.

Oct 13
Perspectives  and challenges of interferon-free therapy for chronic hepatitis C

Oct 2
NATAP - Vertex Nuke Program ALS-2200

Oct 1
BI 201335 and BI 207127-New Hepatitis C Data from Boehringer Ingelheim to be Presented
at AASLD Annual Meeting

New EASL report highlights hepatitis C protease inhibitors, 
nucleotide agents, Non-nucleoside inhibitors and Cyclophilin inhibitors

A special report provided by EASL of the EASL-AASLD Conference on -
Therapy of  Hepatitis C: Clinical Application and Drug Development is now available 
Download PDF

Other topics in the report include;
Therapy of Hepatitis C: Clinical Application and Drug Development
HCV transmission and therapeutic intervention
One year of triple combination therapy
New HCV drugs in development
Overcoming resistance and treatment  failure
 New ways to search for novel anti-HCV drugs

Sept 2012
ACH-3102-Achillion Announces Positive Proof-of-Concept Data 
*ACH-3102: All-oral, interferon-free pilot Phase 2 12-week trial of ACH-3102
and ribavirin for the treatment of HCV GT 1b

The Next Big Thing in Biotech: Hepatitis Drugs

Vertex Reports New Data On ALS-2200 In Hepatitis C Patients - Supporting Advancement into Phase 2 All-Oral Studies in 2012; Ends Development of ALS-2158

A Phase IIa Interferon Free Combination Hepatitis C Trial of Simeprevir  (TMC435) and
TMC647055 Will Commence Shortly

3 & 4 Oral IFN-Free Roche HCV Regimens Studies, Treatment Naïve or Null  Responders:
setrobuvir+mericitabine+danoprevir/r+rbv. ANNAPURNA Study...

Aug 2012
Is Interferon-Free Treatment for Hepatitis C Just a Dream?

New HCV Drugs: non nucleoside polymerase inhibitors 

July 2012
Gilead Begins Single Pill Hepatitis C Study for 2014 Approval 
July 2012/ Gilead Sciences Inc. (GILD) (GILD) said it plans to start a combination study of  two drugs in a single pill to treat hepatitis C by the end of the year, putting it on track to request U.S. regulatory approval for the medicine in 2014.

HCV  Research: new HCV drugs coming; interferon-free therapy  
 
Geno 1-4: Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch  

June 2012
Recent Successes and  Noteworthy Future Prospects in the Treatment of Chronic Hepatitis C
The advent of interferon-free regimens would represent the fulfillment of an  enormous unmet need in interferon-incapable or intolerant patients, but many  experts are predicting and hoping that such regimens will ultimately supplant  interferon-based therapy for most or all HCV patients, perhaps sooner than any  would have anticipated a  short time ago.

Worth the Wait?  Should chronic hepatitis C patients be treated now or wait for promising
therapies?
DONALD JENSEN, MD; ARCHITA P. DESAI, MD; and Gregory T. Everson, MD, debate the risks and benefits
of initiating therapy now versus waiting for future  treatments.

All-oral hepatitis C combos threaten interferon
Marc  Iskowitz
June 01, 2012

Scientists are getting closer to finding the killer app in treating hepatitis  C, but it may be too soon to pick a winner.

Bristol-Myers Squibb and Gilead say that an all-oral therapy joining  daclatasvir from BMS and Gilead's GS-7977 suppressed the virus in more than 95%  of patients across a broad spectrum of genotypes.

The two drugs reached a 100% sustained virologic response (SVR), or cure  rate, at week four in a common subgroup, genotype 1 patients not previously  treated with interferon.The 100% rate held when ribavirin, another traditional treatment mainstay,  was not in the mix, bettering the roughly 90% SVR rate seen in trials for an  Abbott triple therapy.

The direct-acting antivirals (DAAs) from BMS,Gilead and Abbott showed the  best efficacy and tolerability of those presented at the European Association of  the Study of Liver Disease (EASL) in April.

The findings accelerated momentum in a fast-moving category. Not that there  haven't been speed bumps. In February, Gilead's ‘7977 came under assault when  data showed that six out of six subjects treated with the pipeline
drug, all  prior “null” responders to an interferon-containing regimen, experienced viral  relapse within four weeks of completing an all-oral regimen  of ‘7977 and  ribavirin. Gilead's stock fell after the news.

Several analysts now believe daclatasvir, an NS5a inhibitor, and ‘7977, a  nucleotide analog (or “Nuc”), may form the best treatment “backbone” option  across all genotypes. “The ‘killer app' in HCV is probably an NS5a plus a nuc without ribavirin,”  ISI analyst Mark Schoenebaum  declared.

The newer protease inhibitors—Vertex's Incivek and Merck's Victrelis—appear  vulnerable to the all-oral regimens, but not for a few years.

“These results obviously reinforce the expectation that DAA-only (IFN and  RBV-sparing) regimens will likely quickly supplant current HCV treatments when  they become available in the 2015/2016 timeframe,” wrote Deutsche Bank's Barbara  Ryan in a note.

In a dispatch to investors, Credit Suisse's Catherine Arnold said the data  “takes a little shine off” Abbott's HCV program, “but we still view it as a  competitive presence.” The triple therapy combines the firm's protease
inhibitor  ABT-450 + NS5B inhibitor ABT-333 + ribavirin. Another three-drug regimen  including NS5B inhibitor ABT-072 also showed a high HCV cure rate.

The Gilead/BMS combo “represents the most compelling all-oral, interferon-free data in the highly visible [HCV] marketplace,” noted  Arnold.

Gilead has many HCV compounds to pair its nuc with, including an NS5a like  daclatasvir. That makes a Gilead-BMS partnership far from a given.

Ryan also cautioned that other factors—side effects, dosing convenience and  cost—“will be important onsiderations in determining market  share.”

Results from a mix of  Gilead's ‘7977 and ribavirin hit an SVR rate of  88%—above the 50% the Street had expected, according to Schoenebaum. 

Abbott's  all-oral triple combo may be another good backbone option, while daclatasvir  looks like a solid add-on option and BMS is exploring multiple pairing  options.

Other nucs in development include Vertex's ALS-2200 and  ALS-2158,  and biotech firm Idenix's IDX184, which can be combined with its NS5a  inhibitor,  IDX719.
From the June 2012  Issue of MMM

May 2012

Interferon-free DAA combination trials-Highlights from the 47th Annual Meeting of the European Association for the Study of the Liver.  
Dr. Paul Targett-Adams, Principal Scientist at Medivir AB
 I recently attended the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona,
Spain. The conference was attended by approximately 9000 delegates and offered a valuable opportunity to learn of the latest findings and opinion in all aspects of liver research. Here, I reflect on some of my personal highlights from the conference related to progress in the use of direct-acting antivirals (DAAs) to combat hepatitis C virus (HCV) infection; particularly with reference to the development of all-oral interferon-free combination regimens, together with a few other notable reports/trends in the HCV antiviral research and development field.

A special supplementary issue of Gastroenterology with full text viral hepatitis review articles and commentaries are available through open access.

Don't Miss.......
Will Interferon-Free Regimens Prevail?
Many promising small molecule inhibitors directed against hepatitis C virus (HCV)  proteins (direct-acting antiviral [DAA] agents)  and compounds targeting host cell factors (host-targeting agents [HTAs]) are currently in the drug development and...
Click here to view an index of articles.


April 2012
Summary Of The 47th European Association for the Study of  the Liver EASL

Summary from EASL 2012 for Hepatitis C
Will there be an  interferon-free HCV therapy for all: upcoming reality  or just a vision? 

Vertex Update-Plans enrollment for Phase 2b study all-oral (interferon-free) treatment regimen

EASL:Abbott to Present Positive Phase 2 Results from Multiple Interferon-Free Studies of Combination Regimens for the Treatment of Hepatitis C

EASL-BI 201335 and BI 207127-Viral cure achieved without interferon in up to 82% of hepatitis C patients (GT-1a & -1b*)

EASL:Hepatitis C-NEW DATA SUGGESTS INTERFERON-FREE THERAPY AROUND THE CORNER

EASL-All Oral Combo Daclatasvir and GS-7977=100% SVR Geno 1 and 91% SVR Geno 2 and 3 "SVR=4 weeks after-treatment"

Interferon-free combination GS-7977/Ribavirin Will Displace Telaprevir Combo, According to Findings from Decision Resources

Vertex Study:Interferon-Free (All-Oral) Regimen of INCIVEK®, VX-222/Ribavirin-12-Week On-Treatment Data and SVR4 From Phase 2 Announced

When Will We Have Interferon-Free Treatment for Hepatitis C?
William F. Balistreri, MD
Posted: 02/09/2012

Question:
Is it true that we are close to treatment of patients with chronic hepatitis C virus (HCV)
infection with an interferon-free regimen?

Response from William F. Balistreri, MD

Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician,
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

A New Era of Therapy
Combination therapy with pegylated interferon  (PEG-IFN) and ribavirin long stood
as the standard of care for chronic hepatitisC virus (HCV) infection.
Although effective in achieving high rates of sustained
virologic response (SVR), this combination regimen was associated with
troublesome side effects.[1] Therefore, the development of 2 effective protease
inhibitors -- telaprevir and boceprevir -- was hailed as a new era of therapy
for patients with HCV genotype 1 infection.[2] These direct-acting antiviral
agents act at specific steps in the viral lifecycle and allow more effective
treatment with a shorter duration.

Telaprevir and boceprevir, linear inhibitors of the HCV nonstructural protein 3/4A (NS3/4A)
serine protease, were approved by the US Food and Drug Administration for HCV
treatment in May 2011. However, the recent American Association for the Study of
 Liver Diseases (AASLD) recommendations indicate that these direct-acting
antiviral agents must be used in combination with PEG-IFN and ribavirin.[1] This is far
from the ideal regimen; because of poor tolerability, many treatment candidates will decide not
to pursue treatment or to defer treatment until an IFN-free regimen is available.

An Ideal Strategy for HCV
It is true that an IFN-free regimen is "no longer a dream."[3] It is now viewed as part
of a larger goal: the development and validation of an ideal strategy to treat HCV infection.
The long sought-after therapeutic objective is to define a strategy that would be highly
effective against allHCV genotypes, simple (oral drugs only, low pill burden,
and short duration), and safe and tolerable, with low rates of resistance
emergence. The recommended strategy would also assess each potential treatment
candidate for interleukin 28B genotype, which is a robust pretreatment predictor
of SVR to therapy in patients with genotype 1 chronic HCV infection.[1]

How close are we? Various compounds,encompassing at least 5 distinct drug classes,
are currently under development for the treatment of chronic HCV infection, and the
results of trials of several investigational agents were recently published.[3-5]
Many other drug trials were presented at The Liver Meeting 2011: The AASLD 62nd Annual Meeting.
These drugs bring us one step closer to the long sought-after ideal: the ability to delete
noisome IFN injections from treatment strategies.

Promising Preliminary Results
Let me illustrate by focusing on phase 2
studies presented by 2 groups who reported exciting preliminary results of an
investigational agent (PSI-7977) even in the absence of IFN
coadministration.[6,7] PSI-7977, a uridine nucleotide analog polymerase
inhibitor, is administered orally once daily and has strong antiviral activity
against HCV genotype 1 when used in combination with PEG-IFN and ribavirin. A
double-blind placebo-controlled dose-ranging study of PSI-7977 in patients with
HCV genotype 1 documented a rapid virologic response (RVR) in 98% of patients,
with an end-of-treatment response at 24 weeks in 91%.[6] The RVR in the placebo
group was 19%, and the end-of-treatment response was 50%. Of specific note, all
patients with the difficult-to-treat interleukin 28B single-nucleotide
polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3, and
100% went on to achieve an SVR.

In another phase 2 study, this investigational compound allowed all patients to achieve
an RVR. More than 80% of the treatment group had nondetectable HCV RNA at 2 weeks,
 and all patients had undetectable levels at 3 weeks.[7] All patients achieved
normalization of serum alanine aminotransferase levels. No serious adverse events
were attributable to PSI-7977, and as expected, safety and tolerability were greatest
in the IFN-free treatment group.

Thus, PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes,
 has a high barrier to resistance, and has a reassuring safety profile. This drug also allowed a
shorter duration of therapy for viral clearance. These studies support the
continued exploration of this drug and related compounds -- alone, with other
direct-acting antiviral agents, or with shorter duration of IFN therapy in
patients with all HCV genotypes. Further studies will hopefully confirm the
initial excitement and optimism and, of note, will document the spectrum of
potential adverse effects.

Getting to IFN-Free Regimens
Within the next 5 years, IFN-free regimens may be a reality and available in the clinic.
As Sharma and Lok[3] stated, "[I]t is possible that some of these regimens will also be
ribavirin free. This will be good news for patients who wish to be treated but have to defer
treatment because of contraindications to use of PEG-IFN or ribavirin, or out of concerns
about their ability to tolerate these medications." The ideal strategy is on the horizon.

Feb 2012

Feb 28
GS-7977 Plus Ribavirin Will Displace the Current Proprietary Clinical Gold Standard, Telaprevir in Combination with Peg-IFNa/Ribavirin, According to Findings from Decision Resources

Feb 23
Vertex Announces 12-Week On-Treatment Data and SVR4 From Phase 2 Study of Interferon-Free (All-Oral) Treatment Regimen of INCIVEK®, VX-222 and Ribavirin in People with Genotype 1 Hepatitis C
Interim 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.

GS-7977: Hard-to-Treat Group Trips Up Hepatitis C Drug

Hard-to-Treat Group Trips Up HCV Drug

Related: GS-7977-formally PSI-7977 Viral Relapse Seen Post Treatment In ELECTRON Study

By Michael Smith, North American Correspondent, MedPage Today
Published: February 17, 2012
A promising hepatitis C medication has run into a roadblock in a small group of hard-to-treat patients, according to the drug's maker.

The drug, dubbed GS-7977, was being used with a standard drug, ribavirin, but without the other standby, pegylated interferon, to treat 10 patients with genotype one virus, according to Gilead Sciences.
But after a good early response in eight patients, six of them relapsed within a month of finishing the 12-week therapy. The remaining two have not relapsed but have just finished treatment, the company said.
In a conference call, company officials said the results were unexpected but will not derail the drug, which has been shown to be safe and effective in some groups of hepatitis C patients.

The patients who relapsed were so-called "null responders" who had previously been treated with the standard ribavirin and interferon, but who had not cleared the virus.

They are a "challenging patient population to cure," said Norbert Bischofberger, PhD, Gilead's chief scientific officer.

The drug is also being tested, using the same approach, in patients who have not previously been treated and in patients with genotypes two and three of the virus, who are easier to treat.
Preliminary data in the genotype two and three patients, presented last year, showed that 10 of 10 had been cured. Data on the treatment-naive patients is to be presented next month.

The finding in the null responders has "answered an important question," according to Gilead CEO John Milligan, PhD, and hints that in some patient groups more than one direct-acting agent may be needed for a cure.

Bischofberger told those on the conference call that it's also possible, in his opinion, that the 12-week duration of treatment was simply not long enough to knock the virus down.
The direct-acting agents, which target elements of the virus itself, are a new departure in hepatitis C therapy, which for years has relied on boosting the immune system overall using ribavirin and interferon.
GS-7977 is a nucleotide analog polymerase inhibitor; other drugs, both approved and under development, attack the viral protease enzyme or other targets.

But the advent of the direct-acting agents has sparked a push to stop using interferon, which is difficult for many patients to tolerate, and some studies have suggested that a combination of the new agents would work well without the older drug.

In this case, exactly why such a high percentage of the patients relapsed remains unclear, Milligan said, reminding those on the call that the data are "preliminary results" in only eight patients.

Source-Medpage Today
From Medscape Gastroenterology > Ask the Experts
When Will We Have Interferon-Free Treatment for Hepatitis C?
William F. Balistreri, MD
Posted: 02/09/2012

Question: Is it true that we are close to treatment of patients with chronic hepatitis C virus (HCV) infection with an interferon-free regimen?

Response from William F. Balistreri, MD Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 

A New Era of Therapy
Combination therapy with pegylated interferon (PEG-IFN) and ribavirin long stood as the standard of care for chronic hepatitis C virus (HCV) infection. Although effective in achieving high rates of sustained virologic response (SVR), this combination regimen was associated with troublesome side effects.[1] Therefore, the development of 2 effective protease inhibitors -- telaprevir and boceprevir -- was hailed as a new era of therapy for patients with HCV genotype 1 infection.[2] These direct-acting antiviral agents act at specific steps in the viral lifecycle and allow more effective treatment with a shorter duration. Telaprevir and boceprevir, linear inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease, were approved by the US Food and Drug Administration for HCV treatment in May 2011. However, the recent American Association for the Study of Liver Diseases (AASLD) recommendations indicate that these direct-acting antiviral agents must be used in combination with PEG-IFN and ribavirin.[1] This is far from the ideal regimen; because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until an IFN-free regimen is available. 

An Ideal Strategy for HCV
It is true that an IFN-free regimen is "no longer a dream."[3] It is now viewed as part of a larger goal: the development and validation of an ideal strategy to treat HCV infection. The long sought-after therapeutic objective is to define a strategy that would be highly effective against allHCV genotypes, simple (oral drugs only, low pill burden, and short duration), and safe and tolerable, with low rates of resistance emergence. The recommended strategy would also assess each potential treatment candidate for interleukin 28B genotype, which is a robust pretreatment predictor of SVR to therapy in patients with genotype 1 chronic HCV infection.[1] How close are we? Various compounds, encompassing at least 5 distinct drug classes, are currently under development for the treatment of chronic HCV infection, and the results of trials of several investigational agents were recently published.[3-5] Many other drug trials were presented at The Liver Meeting 2011: The AASLD 62nd Annual Meeting. These drugs bring us one step closer to the long sought-after ideal: the ability to delete noisome IFN injections from treatment strategies. 

Promising Preliminary Results
Let me illustrate by focusing on phase 2 studies presented by 2 groups who reported exciting preliminary results of an investigational agent (PSI-7977) even in the absence of IFN coadministration.[6,7] PSI-7977, a uridine nucleotide analog polymerase inhibitor, is administered orally once daily and has strong antiviral activity against HCV genotype 1 when used in combination with PEG-IFN and ribavirin. A double-blind placebo-controlled dose-ranging study of PSI-7977 in patients with HCV genotype 1 documented a rapid virologic response (RVR) in 98% of patients, with an end-of-treatment response at 24 weeks in 91%.[6] The RVR in the placebo group was 19%, and the end-of-treatment response was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3, and 100% went on to achieve an SVR. In another phase 2 study, this investigational compound allowed all patients to achieve an RVR. More than 80% of the treatment group had nondetectable HCV RNA at 2 weeks, and all patients had undetectable levels at 3 weeks.[7] All patients achieved normalization of serum alanine aminotransferase levels. No serious adverse events were attributable to PSI-7977, and as expected, safety and tolerability were greatest in the IFN-free treatment group. Thus, PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes, has a high barrier to resistance, and has a reassuring safety profile. This drug also allowed a shorter duration of therapy for viral clearance. These studies support the continued exploration of this drug and related compounds -- alone, with other direct-acting antiviral agents, or with shorter duration of IFN therapy in patients with all HCV genotypes. Further studies will hopefully confirm the initial excitement and optimism and, of note, will document the spectrum of potential adverse effects. 

Getting to IFN-Free Regimens
Within the next 5 years, IFN-free regimens may be a reality and available in the clinic. As Sharma and Lok[3] stated, "[I]t is possible that some of these regimens will also be ribavirin free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or ribavirin, or out of concerns about their ability to tolerate these medications." The ideal strategy is on the horizon.

Video
New and experimental oral drugs to treat hepatitis C

Jan 2012

The end of the beginning for hepatitis C treatment    
Download the PDF here 

1. Douglas Dieterich Mt Sinai Hosp NYC

Hepatology Jan 2012

Accepted Article (Accepted, unedited articles published online for future issues)

THE END OF THE BEGINNING FOR HEPATITIS C TREATMENT

"Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning." Winston Churchill.

These are extraordinary times in the history of HCV drug development. We waited 13 years between the approval of ribavirin in 1998 and the approval of telaprevir and boceprevir in 2011. The trajectory of drug discovery and clinical trials has gone from exponential to warp speed since the EASL meeting in April 2011, and these two articles are perfect examples of what has changed the world of hepatitis C; interferon-free combination therapy and in one of the trials, leading to eradication of the virus. The first demonstration in man of IFN-free combination therapy with direct acting antivirals (DAA's) was the INFORM-1 trial presented first at EASL 2009 and published in 2010(1) It showed that a nucleoside analogue polymerase inhibitor (now known as mericitabine) and a protease inhibitor (now known as danoprevir (now boosted with ritonavir) together without PEG or RBV could reduce HCV viral load by 5·1 log10 IU/mL in 14 days with no sign of resistant virus. This was the proof of principle that two DAA's by themselves could render most patients undetectable without PEG or RBV. This combination hit a snag with some danoprevir toxicity issues, and development has slowed. Those issues were successfully resolved with ritonavir boosting and the follow up study to INFORM is now proceeding apace and data will be forthcoming from that trial in 2012 or 2013.

The Zeuzem study published in this journal (2) compared an all-oral combination of tegobuvir a nonnucleoside polymerase inhibitor given twice daily plus GS 9256 an NS3 serine protease inhibitor with and without ribavirin in two arms for 28 days, at which point they received peginterferon and ribavirin standard of care. The third arm used quadruple therapy with both DAA's plus peginterferon and ribavirin for 28 days and then peginterferon and ribavirin alone. All patients with viral rebound of >.5 log10 from nadir or non response defined as < 2.0 log10 decline at day 5 received peginterferon and ribavirin immediately. Median maximal reductions in HCV RNA were -4.1log10 IU/ml, -5,1 log10 IU/ml and -5.7 log10 IU/ml for tegobuvir plus GS 9256, tegobuvir , GS9256 plus ribavirin and the tegobuvir, GS9256, peg and ribavirin arms. The results were quite instructive. RVR for the two DAA's alone was 7%, for the two DAA's plus ribavirin 38% and for the quadruple therapy arm 100%. The importance of ribavirin in preventing resistance is very clear with this combination and reemphasizes the continuing value of using ribavirin in all oral regimens of DAA's. It also demonstrates the real, but weak antiviral activity of ribavirin (3). Why was this result so much different than that of INFORM where virtually all patients were undetectable at 14 days of dual therapy? The answer lies in the barrier to resistance (4). The nucleoside/nucleotide analogues in general have a very high barrier to resistance and the INFORM study used the nucleoside mericitabine. The barrier to resistance for protease inhibitors is relatively low, and lower still for genotype 1a as opposed to genotype 1b, since the 1a virus only requires one mutation to generate resistance to protease inhibitors, while the 1b virus requires two. Most nonnucleoside polymerase inhibitors have a relatively low barrier to resistance. When you combine two DAA's with relatively low barriers to resistance, it is easy for the virus to produce the double mutants that are resistant to both drugs. Ribavirin slows this down somewhat, but does not add enough antiviral activity to prevent resistance over 60% of the time with tegobuvir and GS 9256. There is one other factor involved in preventing resistance and that is the activity of the DAA. Extremely potent agents, which drop the viral load down to undetectable rapidly, also prevent resistance. A good example of this is the combination study of BI 201335 and BI 207127 (5). This study compared two groups: BI201727 400 mg or 600 mg given thrice daily plus BI 201335 and ribavirin 1000-1200 mg for 4 weeks. In the 400 mg group, the RVR was 73 %( with better response in genotype 1b than 1a, as one would expect with a protease inhibitor in the regimen). In the 600 mg group, the RVR was 100% and did not differ between genotype 1a and 1b. From this data one can infer that the potency of either the protease inhibitor or the nonnucleoside polymerase inhibitor was different, since the same two classes of drugs, plus ribavirin yielded a much higher RVR. To be fair, there was no arm without ribavirin in this study and, of course, it is hard to compare results between studies. The designs of both studies are elegant, simple and easy to understand and advance the field enormously. Gilead is now aggressively addressing the issue of potency by adding a third DAA to tegobuvir and GS 9256 with and without ribavirin. (6)

The other study in this issue of Hepatology (7) advances the field dramatically further. Not only does it move us from RVR without interferon to SVR, but it does it in null responders! This represents a giant step towards the "Holy Grail" of HCV therapy: once daily, oral interferon-free treatment. The world of HCV treatment changed forever in April of 2011 when the first interferon-free SVR's were presented using an NS5A inhibitor and a protease inhibitor, the same two drugs used in the Chayama paper. (8) The 100% SVR with quadruple therapy was overshadowed by the all-oral double DAA combination, without ribavirin that resulted in a 36% SVR. This was the long awaited proof of principle that HCV could be eradicated without interferon. Of note in the all-oral arm was that both of the genotype 1b patients achieved an SVR, but only 2/9 of the genotype 1a patients achieved an SVR demonstrating the differences in activity of protease inhibitors in genotypes 1a and 1b.

The Chayama study in this issue examined the combination of the NS5A BMS-790052 60 mg qd ( now called daclatasvir) and the protease inhibitor BMS-650032 600mg (now called asunaprevir) in null responders, but only in genotype 1b, the most common genotype in Japan. Ten patients received both drugs for 24 weeks. Of the nine patients who completed the study, all achieved an SVR. HCV RNA remained undetectable in the patient who discontinued treatment after two weeks. This is truly a remarkable achievement in the field of HCV treatment. It is only partially applicable to genotype 1a patients around the world, but nonetheless brings us closer to what we seek in HCV therapy: all oral highly effective treatment. This publication marks a turning point in the HCV drug development world. It demonstrates that a protease and an NS5A inhibitor together can achieve an extremely high SVR in null responders, at least in genotype 1b. It is the second trial to show that an SVR is possible without either interferon or ribavirin in null responders.

In the patois of HCV drug development, we often speak of an all-oral regimen as the "Holy Grail" we all seek. In history that term has had many meanings, particularly in Arthurian legends beginning in the late 12th century. The meaning that comes closest, though to what we really intend, is in Wolfram von Eschenbach's Parzival. In it he portrays the grail as a stone that prevents anyone who sees it from dying. The development of an oral regimen of DAA's that can produce SVR in a high proportion of patients is the grail that we seek. It will prolong life and prevent death from liver disease, just as the epidemic reaches crisis proportions. The two studies in this issue of Hepatology bring us much closer to providing the answer to the epidemic.

New targets for antiviral therapy of chronic hepatitis C
February 2012
The ideal future therapy of chronic hepatitis C should fulfil at least four criteria. First, it should be IFN-free to reduce side effects and contraindications; second, it should impose a high barrier of drug resistance; third, it should require only short treatment duration; forth, SVR should be as high as possible, ideally greater than 90%. Initial clinical studies have shown that IFN-free therapy is possible in principle [62, 63]. Gane and colleagues have conducted a clinical trial (INFORM-1) based on a combination of two DAA: [1] RG7128, a NI with a high resistance barrier and [2] Danoprevir, a protease inhibitor with a low resistance barrier [62]. Patients infected with genotype 1 viruses were treated for 14 days and showed a marked decrease in viral load. Viral breakthrough could not be detected. The combination therapy was well-tolerated by patients and discontinuation was not observed. Together with other clinical data this study shows great promise that IFN-free therapy of chronic hepatitis C is not a fiction, but might become reality in the not too distant future.
Continue Reading

Hepatitis C - Looking Ahead to 2012
There's been real concern that we might never be able to get away from interferon entirely, but now we're starting to get an inkling that that might not be the case,” says Gary Davis, director of the general and transplant hepatology unit at the Baylor University Medical Center in Dallas.


Dec  2011

Experimental Hepatitis C Drug PSI-938 Halted In Clinical Trial
--Use of PSI-938 halted in clinical trial due to liver-related abnormalities
--Studies of lead hepatitis C candidate, PSI-7977, continue

During routine safety monitoring, the company detected laboratory abnormalities associated with liver function in subjects receiving PSI-938 300 mg once daily. These laboratory abnormalities have not been observed in patients receiving PSI-7977 and ribavirin in the QUANTUM study or in other trials evaluating PSI-7977. Both the 12 and 24-week PSI-7977 and ribavirin arms will continue unchanged, data from which will support NEUTRINO, an interferon free, 12-week Phase 3 study of PSI-7977 and ribavirin in patients with HCV genotype 1 (GT-1).

New In Mulimedia
Interferon-Free Treatment Regimens for Hepatitis C: Are We There Yet?
Text Available Here

Initiation of ALS-2200/ALS-2158 in clinical studies this data may enable initiation study of interferon-free combination by Vertex and Alios BioPharma
Vertex Pharmaceuticals Inc. has launched two clinical studies with California biotech Alios BioPharma Inc. to test treatments for hepatitis C virus.

-Studies to evaluate safety and effects on viral kinetics in people with chronic genotype-1 hepatitis C-

-Data expected in second quarter of 2012 could enable initiation of interferon-free, nucleotide-based combination studies in the second half of 2012-

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) andAlios BioPharma, Inc.today announced the initiation of two clinical studies for the nucleotide analogues ALS-2200 and ALS-2158, which are inhibitors of the hepatitis C NS5B polymerase. The studies will evaluate the safety and tolerability of ALS-2200 and ALS-2158 in healthy volunteers followed by a seven-day evaluation to observe the effects on viral kinetics in people with chronic genotype-1 hepatitis C. Data are expected in the second quarter of 2012, which could enable the initiation of studies to evaluate multiple all-oral, interferon-free combination regimens for chronic hepatitis C in the second half of 2012. Vertex has worldwide development and commercialization rights for ALS-2200 and ALS-2158, which were discovered by Alios BioPharma. Alios and Vertex are jointly conducting the Phase 1 studies announced today......


Bristol-Myers Squibb announced on Dec 2 that it has entered into a clinical collaboration agreement with Tibotec Pharmaceuticals, to evaluate the utility of daclatasvir (BMS-790052), Bristol-Myers Squibb’s investigational NS5A replication complex inhibitor, in combination with Tibotec Pharmaceuticals' investigational NS3 protease inhibitor, TMC435, for the treatment of chronic hepatitis C virus (HCV).

Medivir - TMC435 will be evaluated in a phase II combination study with daclatasvir (BMS 790052) for HCV genotype-1 patients

Under the agreement the companies will evaluate the potential to achieve sustained viral response 12 and 24 weeks post treatment in patients with HCV genotype 1 in a study with three treatment regimens:

1-An oral, once-daily treatment regimen of daclatasvir and TMC435 with pegylated-interferon alpha plus ribavirin
2-An oral, once-daily treatment regimen of daclatasvir and TMC435 with ribavirin
3-An oral, once-daily treatment regimen of daclatasvir and TMC435 alone.

The study is planned to start in the first half of 2012.

Bristol-Myers Squibb Enters Clinical Collaboration Agreement with Tibotec Pharmaceuticals for Phase II Combination Study in Patients Chronically Infected with Hepatitis C

(NEW YORK, December 2, 2011) – Bristol-Myers Squibb Company (NYSE:BMY) announced today that it has entered into a clinical collaboration agreement with Tibotec Pharmaceuticals, one of the Janssen Pharmaceutical Companies, to evaluate the utility of daclatasvir (BMS-790052), Bristol-Myers Squibb’s investigational NS5A replication complex inhibitor, in combination with Tibotec Pharmaceuticals' investigational NS3 protease inhibitor, TMC435, for the treatment of chronic hepatitis C virus (HCV).

Under the agreement the companies will evaluate the potential to achieve sustained viral response 12 and 24 weeks post treatment in patients with HCV genotype 1 in a study with three treatment regimens:

An oral, once-daily treatment regimen of daclatasvir and TMC435 with pegylated-interferon alpha plus ribavirin
An oral, once-daily treatment regimen of daclatasvir and TMC435 with ribavirin
An oral, once-daily treatment regimen of daclatasvir and TMC435 alone.
The study is planned to start in the first half of 2012.

“Bristol-Myers Squibb is dedicated to developing innovative treatment options for patients with serious diseases like HCV,” said Brian Daniels, senior vice president, Development. “We are pleased to work with Tibotec to advance the scientific understanding for the potential for an all-oral regimen of direct acting antivirals, which would be an important advancement for patients with HCV. This is a continuation of our leadership in forging partnerships to advance combination antiviral therapy.”

-End-

VIDEO-Hepatitis C : Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127 and Ribavirin
Dr. Stefan Zeuzem discusses his manuscript "Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV Infection."


Nov 2011

AASLD-Novartis’ alisporivir-(DEB025) may become first interferon-free oral for hepatitis C G2/G3
The clear conclusion from a clinical trial of alisporivir (DEB025, from Swiss drug major Novartis [NOVN: VX]), an oral host-targeting cyclophilin inhibitor, is that treatment based on it may be an effective, interferon (IFN)-free alternative for individuals with genotype 2 or 3 (G2/G3) hepatitis C virus (HCV) infections. The finding was presented by Jean-Michel Pawlotsky, a professor at the Henri Mondor Hospital, University of Paris-Est, Creteil, France, at a late-breaking poster session on November 7, 2011 at the 62nd annual meeting of the American Association for the Study of Liver Diseases (AASLD) held last week in San Francisco.

AASLD-BI 201335 plus BI 207127 and ribavirin-76% virological response at week 12, and 59% achieve SVR12 with 16 weeks treatment
Hepatitis C: Interferon-free combination of BI 201335 plus BI 207127 and ribavirin shows up to 76% of patients achieve a virological response at week 12, and 59% achieve SVR12 with 16 weeks treatment Data from pre-specified interim analysis of Phase IIb SOUND-C21 trial with Boehringer Ingelheim’s two investigational HCV direct-acting antivirals presented at AASLD

On a roll, Pharmasset outlines 100% cure rate for hot hep C program - FierceBiotech
Pharmasset is on a roll. The biotech reported yesterday that all 40 hepatitis C patients receiving its closely-watched drug PSI-7977 were essentially cured in the course of the small 12-week study, offering another glimpse at what is shaping up as the next big step forward in treating hepatitis C.

Significantly, the study had set out to see just how little interferon would be needed for PSI-7977 to work against the virus. Investigators split the 40 patients into four groups. One group received no interferon while the other three groups received either four weeks, 8 weeks or 12 weeks of combined treatment. All patients were also treated with ribavirin, a standard therapy.

"Although patient numbers are small, we believe the results are extremely impressive," noted Wells Fargo Securities, according to a report in Bloomberg.

Pharmasset's shares, which have been rising swiftly this year, swelled an additional 8% early this morning as investors got a chance to look over fresh evidence that PSI-7977 could emerge from late-stage studies as the first interferon-free, oral hep C drug on the market.

"VRUS impressed a packed house of AASLD attendees by showing a 100% SVR rate in genotype 2/3 patients receiving PSI-7977 and ribavirin but no interferon," stated analysts at Brean Murray Carret. "We believe this validates the company's decision to move into Phase III program with this combination and supports a new front line standard of care in these patients. Given the substantially better safety profile, we believe it will be unethical to use interferon in untreated Gt. 2/3 patients once PSI-7977 is approved."

- read the Bloomberg report
- see the StreetInsider post


Twelve Weeks Interferon-Free PSI-7977 Regimen Cures 100 Percent Hep C Genotype 2/3
A twelve-week course of Pharmasset’s once-daily experimental nucleotide analog PSI-7977, combined with ribavirin, cured 10 of 10 people living with genotype 2/3 hepatitis C virus (HCV) who used the regimen—without pegylated interferon—in a Phase II clinical trial. The highly encouraging results were reported Sunday, November 6, at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco.

Compared with the three other groups included in the study, which involved taking PSI-7977 plus ribavirin with either four, eight or 12 weeks of pegylated interferon, significant improvements in safety and tolerability were also documented among those using PSI-7977 plus ribavirin alone, according to Edward Gane, MD, of the Auckland City Hospital in Auckland, New Zealand, and his ELECTRON study colleagues.
Continue Reading...


HCV Snapshots: A Summary of AASLD 2011
—Alan Franciscus, Editor-in-Chief
The 2011 meeting of the American Association for the Study of Liver Diseases is an important event for patients with chronic hepatitis C virus (HCV) infection and other liver diseases.  This year, Alan Franciscus (AF) and Lucinda K. Porter, RN (LKP) provide highlights on some of the presentations and posters.

Important note:The research results presented here are gathered from conference posters, presentations and abstracts.  They represent part of the story, particularly data presented about current HCV medications and medications being developed to treat hepatitis C.  There are many factors that influence treatment outcomes such as the number of patients in the study, and the patient demographics (genotypes including subtypes, age, placebo vs. open label, ethnicity, etc.) to name a few.  Unless and until these studies are published in a peer-reviewed journal, these data and conclusions are considered preliminary.
Click Here For Summary


PSI-7977 and Daclatasvir (BMS-790052) 12 wk Interferon-Free Tx Arms Added-Genotype 1
New 12 Week, Interferon-Free Treatment Arms Added to All-Oral Combination Study of PSI-7977 and Daclatasvir (BMS-790052) for HCV Genotype 1

PRINCETON, N.J., Nov. 4, 2011

PRINCETON, N.J., Nov. 4, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) and Bristol-Myers Squibb Company (NYSE: BMY) announced today the addition of four treatment arms to the ongoing Phase IIa trial evaluating the combination of Pharmasset's PSI-7977, a nucleotide polymerase inhibitor, and Bristol-Myers Squibb Company's daclatasvir (BMS-790052), an investigational NS5A replication complex inhibitor, for the treatment of chronic hepatitis C (HCV). This trial is the result of a clinical collaboration agreement between Pharmasset and Bristol-Myers Squibb announced in January 2011.

"Recent data from Pharmasset's ELECTRON trial as well as other all-oral DAA combination studies have demonstrated the potential of 12 week treatment regimens," stated William Symonds, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine. "This study will evaluate whether the potent antiviral activity and high barrier to resistance seen in Phase II studies of PSI-7977 may enable shorter treatment durations with an interferon-free regimen than the current standard of care."

"Hepatitis C is a rapidly evolving field of research. As the science evolves, we are evolving our clinical development programs to continue to drive advances in HCV research," said Brian Daniels, senior vice president, Development, Bristol-Myers Squibb. "Shorter duration, all-oral therapy and effective treatment options for patients who have failed approved triple therapy regimens are clear unmet medical needs in HCV. With this study, we aim to understand the potential for daclatasvir to help address these needs, as part of a novel combination treatment regimen."

About the Trial

This Phase IIa trial completed enrollment in September 2011 with approximately 84 subjects with chronic HCV genotypes 1, 2 or 3 who have not been treated previously. The primary endpoint of the trial is sustained virologic response (SVR). Subjects were randomized equally across each of the following arms:

* PSI-7977 400mg QD for 7 days, then add daclatasvir 60mg QD for a further 23 weeks in genotype 1 subjects;
* PSI-7977 400mg QD for 7 days, then add daclatasvir 60mg QD for a further 23 weeks in genotype 2 or 3 subjects;
* PSI-7977 400mg QD and daclatasvir 60mg QD for 24 weeks in genotype 1 subjects;
* PSI-7977 400mg QD and daclatasvir 60mg QD for 24 weeks in genotype 2 or 3 subjects;
* PSI-7977 400mg QD, daclatasvir 60mg QD and ribavirin for 24 weeks in genotype 1 subjects;
* PSI-7977 400mg QD, daclatasvir 60mg QD and ribavirin for 24 weeks in genotype 2 or 3 subjects.


Four new treatment arms are now being added to the study; two in genotype 1 treatment-naïve subjects and two in subjects who have failed therapy with pegylated interferon and ribavirin in combination with telaprevir or boceprevir. One hundred and twenty patients will be enrolled in the following four arms (2:2:1:1):

* PSI-7977 400mg QD and daclatasvir 60mg QD for 12 weeks in HCV genotype 1 treatment-naïve patients;
* PSI-7977 400mg QD, daclatasvir 60mg QD and ribavirin for 12 weeks in HCV genotype 1 treatment-naive patients;
* PSI-7977 400mg QD and daclatasvir 60mg QD for 12 weeks in genotype 1 HCV patients who have previously failed telaprevir or boceprevir treatment;
* PSI-7977 400mg QD, daclatasvir 60mg QD and ribavirin for 12 weeks in HCV genotype 1 patients who have previously failed telaprevir or boceprevir treatment.

Additional details can be found at www.clinicaltrials.gov.

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 initiating an interferon-free, Phase III program in patients with HCV genotypes 1, 2 and 3 and continues to be evaluated in five Phase IIb trials in patients with all HCV genotypes. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, is being studied in QUANTUM, a Phase IIb interferon-free trial of PSI-7977 and PSI-938 in subjects with all HCV genotypes. Mericitabine (RG7128) continues in development through a strategic collaboration with Roche.

Pharmasset All-Oral Therapy By 2013?

Oct 2011

A Cure For Hepatitis C-The Pharmaceutical Companies and Us
This review covers the newly approved HCV protease inhibitors boceprevir and telaprevir, along with the promise of interferon free therapies.

Oct 10

ELECTRON Trial - Pharmasset Adds New Study Arm-PSI-7977

Oct 5

Interferon Free Combo-PSI-7977/riba"Two HCV Meds are Better than One For Pharmasset "

AASLD-protease inhibitor BI 201335 and polymerase inhibitor BI 207127 Interferon Free Combo-New Data to be presented by Boehringer

Sept

Pharmasset Initiates QUANTUM, a Phase 2b Interferon-Free Trial of PSI-7977 and PSI-938 for All HCV Genotypes

PRINCETON, N.J., Sept. 13, 2011 /PRNewswire via COMTEX/ -- Pharmasset, Inc. announced today that screening has begun in a Phase 2b, international study of PSI-7977 and PSI-938, two nucleotide analog polymerase inhibitors for the treatment of chronic hepatitis C (HCV). The QUANTUM trial will evaluate interferon-free regimens of PSI-7977 400mg QD and PSI-938 300mg QD with and without ribavirin over 12 or 24 weeks in patients with HCV who have not been treated previously. The trial will also evaluate the use of PSI-938 monotherapy.
"We are encouraged by the early efficacy and safety data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "The QUANTUM trial is the first interferon-free, all-nucleotide study with an SVR endpoint. The ability to include all HCV genotypes was supported by data from the NUCLEAR study and the interferon free arms of the ELECTRON trial. Data from ELECTRON are expected later this year."

About the Phase 2b QUANTUM Trial
This study is designed to enroll approximately 450 patients with chronic HCV of all viral genotypes who have not been treated previously. The primary endpoint of the trial will be sustained virological response (SVR24). Patients will be equally randomized across the following arms:
PSI-938 only
PSI-938 and PSI-7977
PSI-7977 and ribavirin
PSI-938, PSI-7977, and ribavirin
All arms will be study for both 12 and 24 weeks with a placebo control of 24 weeks.
Placebo for 24 weeks

HCV patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. Cirrhotic and non-cirrhotic patients will be enrolled in the study.
Additional details on this and all ongoing Pharmasset sponsored trials can be found at www.clinicaltrials.gov .

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 five Phase 2b trials, including abbreviated duration interferon and interferon-free regimens, in subjects with all HCV genotypes. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, is in QUANTUM, a Phase 2b interferon-free trial of PSI-7977 and PSI-938 in subjects with all HCV genotypes. Mericitabine (RG7128) continues in three 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.

Dramatic Changes in Hepatitis C Treatment Expected to Continue
Excerpted;

Companies that believe in the importance of antiviral combinations for future commercial relevance in hepatitis C are likely to have opinions as to how many drugs they believe will be needed in antiviral combination regimens, and are likely to pursue strategies directed at accessing at least that number of compounds if not a greater number as insurance against attrition. Mathematical modeling from Perelson and colleagues suggests that interferon-free regimens will need to contain three or four distinct antiviral mechanisms to result in viral eradication (SVR) prior to emergence of resistance. To access the required number of drugs, companies have several business alternatives available. They can rely on maturation of their internal pipelines, although few if any companies appear today to have sufficiently robust internal pipelines to rely exclusively on this approach. Companies can rely on cross-company clinical collaboration agreements to gain initial data on particular antiviral combinations, although this approach doesn’t directly answer the question of how to seek approval and launch effective marketing efforts for the individual components studied in a cross-company antiviral drug combination trial. Companies with antiviral drugs other than protease inhibitors can look to utilize one of the approved protease inhibitors as one other mechanism, analogous to the use of interferon and ribavirin in the development of the protease inhibitors to date, but this will only be a partial solution if three or more DAAs are required. Lastly, companies can gain exclusive access to antiviral drugs outside their current pipelines through a variety of business deals, allowing them to quickly assemble a pipeline with sufficient depth to increase the chances of being early to market with a successful combination regimen. To date, examples of all these strategies except combination with one of the approved protease inhibitors have been pursued by one or more companies. Going forward, these efforts across the industry are likely to culminate in approval of direct acting antiviral combination regimens, with the ultimate goal of assembling combinations powerful enough to eliminate interferon and perhaps ribavirin from hepatitis C therapy. These advancements may occur within the next few years, and if realized, would represent yet another dramatic improvement in hepatitis C therapy, at least as dramatic as the advances recently realized with the approval of the first protease inhibitors.
Read Full Article Here...............


Gilead Amends Study Design for Ongoing Hepatitis C Clinical Trials That Include GS 9190, Pegylated Interferon and Ribavirin, and Another Direct-Acting Antiviral Agent

Change Does Not Affect Ongoing "All Oral" Clinical Trials Evaluating Multiple Direct-Acting Antivirals in Combination

FOSTER CITY, Calif., Sep 04, 2011 (BUSINESS WIRE) -- Gilead Sciences, Inc. today announced that, in consultation with the U.S. Food and Drug Administration (FDA), the company will amend the design of ongoing clinical trials to discontinue dosing of GS 9190 in hepatitis C-infected patients who are receiving that compound in combination with pegylated interferon and ribavirin, and another direct-acting antiviral agent.

This decision follows reports of two serious adverse events in patients enrolled in two separate studies who were receiving a four-drug regimen of GS 9190, an investigational HCV NS5B polymerase inhibitor; pegylated interferon and ribavirin; and one of two protease inhibitors (GS 9451 in one study and GS 9256 in the second study). Patient safety is Gilead's top priority, and the company will therefore immediately halt the dosing of GS 9190 in patients receiving this combination of medications.

Pegylated interferon in combination with ribavirin is currently part of the standard of care treatment for patients with chronic hepatitis C. Because of the side effects that can be associated with interferon, Gilead is working to develop multiple oral antivirals that, when used in combination, may be able to reduce or eliminate the need for interferon.

Gilead does not anticipate any impact on the timelines for or goals of its planned and ongoing clinical studies evaluating an "all oral" regimen for the treatment of chronic hepatitis C. Studies that include GS 9190 but do not include pegylated interferon will continue as planned. Similarly, studies that include the combination of GS 9451 (an investigational protease inhibitor), GS 5885 (an investigational NS5A) and pegylated interferon and ribavirin will continue.

About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in the forward-looking statements, including the risk that further analysis of the laboratory abnormalities, adverse events and other data obtained to date may not support the continued development of GS 9190 and the risk that further clinical testing of Gilead's developmental compounds (including GS 9190, GS 9451, GS 5885 and GS 9256) and all oral regimens containing such compounds result in laboratory abnormalities, adverse events and other clinical data that may not support the continued development of such compounds or regimens. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2011, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
SOURCE: Gilead Sciences, Inc.


Aug 2011

Hepatitis C-TMC435 ;MedivirAB Completed Enrollment of Three Global Phase 3 Trials
08/31/2011 07:20 am

TMC435 is being developed both in combination with PegIFN/RBV and in combination with Direct-acting Antiviral (DAA) agents without peginterferon and with or without ribavirin (RBV).

Medivir AB : Completed Enrollment of Three Global Phase 3 Trials for TMC435 in Chronic Hepatitis C Genotype-1 Infected Patients

Press release
31-Aug-11 Huddinge, Sweden – MedivirAB (OMX: MVIR) is an emerging researchbased specialty pharmaceutical company focused on infectious diseases.

Medivir today announced that its investigational protease inhibitor TMC435, developed by Tibotec Pharmaceuticals, has successfully completed enrollment of three ongoing global phase 3 trials and further reports that all patients are now on TMC435 or active control treatment. The trials are QUEST 1 and QUEST 2, in treatment naive patients, and PROMISE in the treatment experienced relapser patient population. In all three trials, the duration of total treatment is response guided and patients in the TMC435 arms are eligible to stop all treatment at week 24 if predefined response-guided criteria are met.

Medivir recently announced that TMC435 had received “Fast Track” designation by the U.S. Food and Drug Administration (“FDA”) for the treatment of chronic hepatitis C (CHC) genotype-1 infection. This is based on TMC435’s potential to address unmet medical needs in the treatment of chronic HCV infection.

In parallel to these trials, phase 3 studies for TMC435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, have also completed enrollment.

Global Phase 3 Program in brief:
· TMC435-C208 or QUEST-1 includes approximately 375 treatment-naïve patients
· TMC435-C216 or QUEST-2 includes approximately 375 treatment-naïve patients
· TMC435-C3007 or PROMISE includes approximately 375 who have relapsed after prior interferon-based treatment

Bertil Samuelsson, Chief Scientific Advisor at Medivir, comments - "We are extremely excited to have completed the enrollment and patient dosing in three large global phase 3 trials. It is a monumental milestone step for Medivir as a company and for TMC435 progress towards market registration. The completed enrollment of phase 3 studies for TMC435


PSI-938 Receives Fast Track from the FDA for Hepatitis C
Pharmasset, Inc.
PRINCETON, N.J., Aug. 24, 2011 --
/PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) 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.

ContactRichard E. T. Smith, Ph.D. VP, Investor Relations and Corporate Communications richard.smith@pharmasset.comOffice: +1 (609) 613-4181


Related; July 8 2011- All Oral Combo; Study to evaluate the combination of PSI-7977 and TMC435 with and without ribavirin in prior null responder, genotype 1 HCV patients

Updated on June 8 2011

For far too many years, the standard hepatitis C treatment was a combination of interferon and the oral antiviral drug ribavirin. Hepatitis C therapies have evolved since 1991 when the FDA approved that first alfa interferon (Schering’sIntron A) to treat hepatitis C. If you're interested in viewing the timeline and the origin of Hepatitis click  here.

Flash back to over a decade ago to Interferon, which is a manufactured version of certain natural proteins that fight viruses. We had to inject three times a week, the side effects and SVR stats were to be desired, until  pegylated interferon entered the scene, which became the standard of care. At the time it was a significant step towards better treatment. The drug is modified so that it stays in the body longer hence only one injection a week. We were elated, because patients knew that with pegylated interferon those peaks and valley were no more, and the side effects would be less. But the real news was that the SVR rates were getting better, much better then Alfa interferon. We were on our way, and the HCV community thought this was the golden ticket. The excitement for many of us only lasted for a short time, or until we relasped or never responded, SVR didn't  happen for everyone. The stats for genotype 1 patients were at only 40 percent, and some genotype 1, 4 and 3  patients were left behind.

Fast forward to May 2011, and the  FDA approval of  Telaprevir/ Incivek and  Vicrelis/Boceprevir . Will it get any better ? Yes, with the promise of  inteferon-sparing combinations. Today the blog will touch on a few of these promising drugs. For those readers who are newly diagnosed or are just starting to consider therapy here a few beneficial links on the recent new FDA approved drugs to get you started.

The FDA transcript of the May 23 teleconference briefing on both drugs is available  here.The medication guide, and prescribing information for boceprevir can be viewed here and here. As for telaprevir you can read those inserts here and here .The good news is that both drug companies are offering patient assistance programs. The SVR stats on both drugs are available in this months newsletter over at  HCV Advocate, check out the newsletter here. Today CVS Caremark announced it has put in place a Hepatitis C Support Program to Help Patients Manage New Triple Therapy Regimen, good move by the pharmacy.
Last but not least a short entry on Victrelis and Incivek can be viewed by clicking here.

This brings us to the exciting pipeline of a few new investigational drugs, including inteferon-sparing combinations. We had some big news coming from the EASL in March 2011 on Bristol-Myers interferon free combination: BMS-790052 + BMS-650032 and Pharmasset's  PSI-938 and PSI-7977 (Monotherapy) without pegylated-interferon and ribavirin. Also included in this post will be Boerhinger Ingelheim's interferon free combination BI 201335 + BI 207127 and Pharmasset’s PSI-7977 + Bristol-Myers  BMS-790052 interferon-sparing combo.

Today the buzz over at Forbes was about Pharmassets drug PSI-7977

Analyst Yaron Werber said the drug candidate, which is designated PSI-7977, could be approved as soon as mid-2014 to treat two relatively rare types of hepatitis C. Werber said PSI-7977 could get to the market sooner if it is approved to treat hepatitis C genotypes 2 and 3, which make up a minority of cases. In late May, Pharmasset started a mid-stage clinical trial of PSI-7977 as a treatment for hepatitis C genotypes 1, 2, and 3. Genotype 1 makes up about 70 percent of hepatitis C diagnoses. Werber said he thinks the drug "will have solid data and will be one of the dominant drugs in hepatitis C." The analyst said Pharmasset should present study data in November and should start late-stage studies in early 2012.

On June 8th
Pharmasset Announced The  Expansion of the ELECTRON trial of PSI-7977 For Hepatitis C 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.

April 2011

We start with Boehringer Ingelheim which has completed Phase I trials using their two oral drugs BI 207127 and BI 201335. The Phase II trial evaluating BI 207127 plus BI 201335 in PegIFN-free regimens, both with and without ribavirin, are currently underway.
Click Here For Trial Information ; Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection

Excerpted From The Press Release;
Boehringer Ingelheim announced the study outline for the pivotal Phase III clinical trials designed to evaluate BI 201335, its investigational once-daily oral protease inhibitor, in both treatment-naïve and -experienced patients with chronic genotype-1 hepatitis C virus (HCV), the most challenging genotype to treat.

In parallel, the U.S. Food and Drug Administration (FDA) has granted Fast Track designations for BI 201335 plus standard-of care (SOC), and as part of the interferon-free combination with the polymerase inhibitor, BI 207127, in chronic genotype-1 HCV patients.

“We are delighted to receive the FDA’s Fast Track designation for both, our BI 201335 plus SOC, and interferon-free combination treatment approaches. If successful, the combination therapy carries the potential for patients to live without the burden of interferon’s side effects,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim. Read The Press Release Here


EASL March 2011

Bristol-Myers Interferon-Free Combo Cured Hepatitis Patients
Data Presented at the March 2011 EASL showed that Bristol-Myers two investigational oral hepatitis C drugs BMS-790052 and BMS-650032, cured 4/11 people without interferon and ribavirin. These patients failed prior HCV therapy deemed as null-responders (the most difficult to treat).

In the 21-person trial, ten patients got the two drugs together with interferon and generic ribavirin. All showed no sign of the virus 12 weeks after the treatment was over. One patient had signs of virus at 24 weeks and was again virus-free in another follow-up test 35 days later.

Of 11 patients who took the Bristol-Myers combination alone, five had cleared the virus from their bodies at the end of treatment. Four remained virus-free after 24 weeks.

See Slides From NATAP

HCV Cured With out Peginterferon/ribavirin with 2 oral HCV drugs BMS790052+BMS650032: Quadruple Therapy With BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 Weeks Results in 100% SVR12 in HCV Genotype 1 Null Responders: "HCV infection can be cured without interferon & ribavirin: 2 orals BMS790052+BMS650032"  - (04/02/11)

EASL
PSI-938 and PSI-7977 combination
Other remarkable news from the EASL came from the drug company Pharmasset which presented studies on the PSI-938 and PSI-7977 combination. The study was in treatment-naive, non-cirrhotic patients with genotype 1, these patients were treated with PSI-938 and PSI-7977 (Monotherapy) without pegylated-interferon and ribavirin.  Patients in the study "all" achieved undetectable in short-term followup . The drugs have high barriers to resistance, and broad genotype coverage.

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 by the EASL.

The early data on  the two Pharmasset drugs PSI-938 and PSI-7977 is impressive, thus far the best data we have seen in all-oral therapy . 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.

See CCO for Capsule Summary
,
Slides From NATAP
ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 AND PSI-7977 PROVIDES 94% HCV RNA < LOD AT DAY 14: FIRST PURINE/PYRIMIDINE CLINICAL COMBINATION DATA (THE NUCLEAR STUDY) -

The Other Pharmasset Trial; PSI-7977 and RBV With and Without PEG-IFN Genotypes 2 and 3
.First Received on December 13, 2010.   Last Updated on December 21, 2010
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
To assess safety and tolerability of PSI-7977 400 mg and ribavirin (RBV) with and without pegylated interferon alfa 2a (PEG-IFN) in treatment naive subjects with hepatitis C (HCV) genotypes 2 or 3
Click Here For Trial Information 


January 2011
Other significant news was the clinical collaboration announcement made in January 2011 by the two pharmaceutical companies Pharmasset and Bristol Myers to evaluate the utility of BMS-790052, Bristol-Myers Squibb , in combination with Pharmasset’s-PSI-7977 for the treatment of  hepatitis C . This collaboration will speed up the process of testing medications with the end result leading to improved drugs to treat HCV. The FDA has encouraged these collaborations, and we can only hope other pharmaceutical companies will follow suit.

The Collaboration;  Pharmasset’s PSI-7977, and Bristol-Myers  BMS-790052
Pharmasset and Bristol-Myers Squibb announced  that the companies have entered into a clinical collaboration agreement to evaluate the utility of BMS-790052, Bristol-Myers Squibb’s NS5A replication complex inhibitor, in combination with PSI-7977, Pharmasset’s nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus (HCV). This proof of concept study will evaluate the potential to achieve sustained viral response 24 weeks post treatment with an oral, once-daily treatment regimen in patients across HCV genotypes. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of BMS-790052 in combination with PSI-7977, with and without ribavirin, in treatment-naïve patients chronically infected with HCV genotypes 1, 2, and 3. The study is planned to start in the first half of 2011. This collaboration represents the first cross-company collaboration combining two oral agents to address a significant unmet medical need in the treatment of HCV.

The January Press Release; Pharmasset and Bristol-Myers Squibb  clinical collaboration agreement
.
May 2011.
On May 26, 2011 Pharmasset and Bristol-Myers initiated a Phase 2a trial investigating the combination of Pharmasset's PSI-7977, and Bristol-Myers Squibb's  BMS-790052.  The primary endpoint of the trial is sustained virologic response.

About the Trial
This Phase 2a trial is planned to enroll approximately 84 patients with chronic HCV genotypes 1, 2 or 3 who have not been treated previously. The primary endpoint of the trial is sustained virologic response (SVR). The trial will be conducted in the U.S. Subjects will be randomized equally across each of the following arms:

• PSI-7977 400mg QD for 7 days, then add BMS-790052 60mg QD for further 23 weeks in genotype 1 subjects;
• PSI-7977 400mg QD for 7 days, then add BMS-790052 60mg QD for further 23 weeks in genotype 2 or 3 subjects;
• PSI-7977 400mg QD and BMS-790052 60mg QD for 24 weeks in genotype 1 subjects;
• PSI-7977 400mg QD and BMS-790052 60mg QD for 24 weeks in genotype 2 or 3 subjects;
• PSI-7977 400mg QD, BMS-790052 60mg QD and ribavirin for 24 weeks in genotype 1 subjects;
• PSI-7977 400mg QD, BMS-790052 60mg QD and ribavirin for 24 weeks in genotype 2 or 3 subjects.

About PSI-7977
PSI-7977 is a uracil nucleotide analog inhibitor of the NS5B polymerase being developed for the treatment of chronic HCV infection. Nucleotide analog polymerase inhibitors work by acting as alternative substrates that block the synthesis of HCV RNA, which is essential for the virus to replicate. PSI-7977 has been studied in combination with peginterferon and ribavirin for up to 12 weeks in genotype 1, 2 or 3 patients and is currently in two Phase 2b studies, one of which is investigating an interferon sparing regimen in genotype 2 or 3 patients. PSI-7977 is also being investigated in a 14-day combination study with PSI-938, a guanine nucleotide analog.

Click here for trial information;
Parallel, Open-Label, Randomized Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of PSI-7977 in Combination With BMS-790052 With or Without Ribavirin in Treatment Naive Subjects Chronically Infected With Hepatitis C Virus Genotypes 1, 2, or 3
,
View The Press Release Here; PSI-7977 and BMS-790052 interferon-free trial for Geno 1,2 and 3 initiated

Recap and Other Trials Making The News;
,
.Press Release; Medivir - The Phase 3 Program for TMC435 in Treatment-Naive Patients and Patients who Have Relapsed After Prior Interferon-Based Treatment
Click Here For Trial Information

From The March EASL

More On TMC435 - The ASPIRE Study
Medivir is a Sweden-based with the companies key pipeline asset, TMC435, a protease inhibitor, is in phase 2b clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals, a Johnson & Johnson group company,.

TMC435 is a potent, once-daily, oral hepatitis C virus protease inhibitor which recently entered clinical phase 3 studies. The study enrolled patients chronically infected with genotype-1 hepatitis C virus (HCV) that had previously failed treatment with standard of care therapy (peginterferon and ribavarin). TMC435 is being jointly developed by Medivir and its partner Tibotec.

In this Week 24 interim analysis, treatment-experienced patients who failed peginterferon and ribavarin treatment achieved significantly greater virologic response rates following treatment with TMC435-containing regimen at all doses, compared with placebo. Results demonstrated that the TMC435 150 mg dose group showed the highest response, particularly in prior null responders. In this 150 mg dose group, HCV RNA levels were undetectable at week 24 for between 82% and 91% of the patients. Results also showed that there was no statistically relevant difference in safety and tolerability between the TMC435 and placebo treated groups.

Slides From Natap; The ASPIRE Trial: TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment: Week 24 interim analysis -

PSI-7977 Genotypes 1,4,5,6
PSI-7977 administered in combination with pegylated interferon and ribavirin (PEG/RBV) in treatment naive patients with HCV genotypes 1,4,5,6, or indeterminate genotype.
Press Release;
Hepatitis C Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes
Click here for Locations and Trial Information


PSI-7977 Genotypes 2 and 3
Click Here For Trial Information;
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
,
/The Phase II trial evaluating BI 207127 plus BI 201335 in PegIFN-free regimens, both with and without ribavirin
,Click Here For Trial Information ;
Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection

___________________________________

,
BMS Phase 2B Study including 4 drug regimen of NS5A BMS-790052 + protease BMS-650032 + Peglambda/Rbv 
Click Here For Trial Information;
Safety Study of Pegylated Interferon Lambda Plus Single or 2 Direct Antiviral Agents With Ribavirin
Additional clinical trials can be found at  http://clinicaltrials.gov/

Related; Investigational Compound PEG-Interferon Lambda Achieved Higher Response Rates with Fewer Flu-Like and Musculoskeletal Symptoms and Cytopenias Than PEG-Interferon Alfa in Phase IIb Study of 526 Treatment-Naive Hepatitis C Patients


From The EASL In March;
More On The Four Drug Combo
.
 4-Drug Combo BMS-650032, BMS-790052 pegylated Interferon-alpha (PegIFN-alpha); ribavirin (RBV)
,
Quadruple therapy shows 100 percent SVR for HCV patients previously unresponsive to treatment

Is this treatment approach the next HCV therapy frontier?

Berlin, Germany, Saturday 02 April 2011: Exciting new data presented today at the International Liver CongressTM 2011 show that quadruple therapy in chronic hepatitis C (HCV) patients suppressed the emergence of resistant variants and resulted in a 100% rate of sustained virological response - undetectable HCV RNA - 12 weeks after treatment (SVR12).1

In the quadruple therapy study, HCV patients were given four drugs in combination; pegylated Interferon-alpha (PegIFN-alpha); ribavirin (RBV); and two different direct-acting antivirals (DAAs) BMS-650032 (an HCV NS3 protease inhibitor) and BMS-790052 (an HCV NS5A replication complex inhibitor).

The current standard of care (SoC) for HCV therapy is PegIFN-alpha plus RBV – a dual therapy. The addition of DAAs (currently in phase-III clinical trials) marks the next step in treatment evolution – a triple therapy. However, the new data presented today suggests that quadruple therapy could be the next generation of treatment for chronic HCV patients.

Professor Heiner Wedemeyer, EASL'S Secretary General, said: "Quadruple therapy is possibly the future of HCV treatment; this study goes a way to confirming that. While it's expected that the first DAAs and triple therapy will be approved for use later this year, quadruple therapy appears to have a more profound effect on virological response, with less of a resistance problem."

The study may also provide new hope for a growing number of HCV patients who cannot be effectively treated for chronic hepatitis with current treatments.
http://www1.easl.eu/easl2011/program/Orals/418.htm

Links;Click Here For Clinical Connections; International Search

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