March 2011 - Hepatitis C Blog

OctoPlus’ licensee Biolex presents Phase IIb results at EASL showing reduced rates of depression in HCV patients treated with Locteron

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

Locteron’s next-generation controlled-release mechanism is designed to provide key tolerability and dosing advantages over currently marketed interferons

Locteron may address one of the most significant side effects associated with the use of current interferon products in the treatment of HCV

OctoPlus N.V. (“OctoPlus” or the “Company”) (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data show substantially reduced rates of depression in patients treated with Locteron, compared to current HCV treatments.

Jan Egberts, CEO of OctoPlus, comments: “These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron’s controlled release mechanism and even show a significant advantage in depression related side effects. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression, compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments.“

Source Reuters

The following information was taken directly from Biolex’ press release (see www.biolex.com).

Results demonstrating reduced rates of depression from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. In SELECT-2, patients treated with Locteron within the expected commercial dose range experienced substantially lower rates of depression and depressive symptoms than patients treated with the PEG-Intron® control. Locteron, the only controlled-release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed pegylated interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.

In a survey of hepatitis C patients published in the Journal of Viral Hepatitis in 2010, depression was cited as the number one adverse event impacting patient adherence to treatment, and studies have shown that patients who develop depression during treatment have a reduced chance of achieving a cure. The expected progression of treatment for hepatitis C to triple and quad regimens with potentially shorter durations of treatment are unlikely to eliminate the problem of depression as the SELECT-2 results presented today show that the majority of all episodes of depression occur by the 12th week of treatment.

Locteron is administered once every other week and requires half as many injections as the currently marketed pegylated interferons, each of which are injected once per week. In SELECT-2, three different doses of Locteron were studied (320, 480 and 640 µg). All three doses of Locteron in SELECT-2 demonstrated viral kinetics and sustained virologic response (SVR) rates that were comparable with or exceeded the PEG-Intron control while also achieving a statistically significant reduction in flu-like adverse events and lower use of concomitant medications. The Company expects the commercial dose of Locteron to be in the 320 to 480 µg range as the SVR rates for these two doses were comparable with or exceeded the control, and the tolerability advantages (including lower discontinuation rates due to adverse events) were greatest within this dose range.

In SELECT-2, depression was assessed by two methods, including patient self reporting using a validated instrument and adverse event assessment performed by medical personnel at the clinical sites during weekly visits by the patients. The SELECT-2 results demonstrated that patients experienced depression early in the study, with 75% of cases occurring within the first 12 weeks of the trial under each of the reporting methodologies. Under both reporting methodologies, depression was less frequent for the Locteron doses encompassing the expected commercial dose range compared to the PEG-Intron control.

Throughout the 48 weeks of treatment in SELECT-2, patients self reported their status using the Beck Depression Inventory (BDI), one of the most widely used instruments for measuring the severity of depression. Higher BDI scores indicate more severe depressive symptoms. Mean BDI scores peaked by week 12 of treatment for all Locteron doses and for the PEG-Intron control group. The increase in peak mean BDI scores was substantially less for all three Locteron doses compared to the PEG-Intron group. In addition, the results demonstrated that fewer patients reported scores greater than 16 using the BDI (the threshold for mild depression) in the 320 and 480 µg Locteron dose groups compared to the PEG-Intron group.

Click on the link below for the full press release including tables.

Click here for the press release in PDF format

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Fluvastatin Enhances Chronic Hepatitis C Treatment Response in Combination with Pegylated Interferon-Alpha and Ribavirin

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

Well-known statin could be recycled as HCV therapy supplement

Berlin, Germany, Thursday 31 March 2011: /PRNewswire/ — New data presented today at the International Liver Congress confirm the antiviral activity of fluvastatin – commonly used as a cholesterol-lowering treatment – in patients with chronic hepatitis C (HCV).

Patients had improved early and sustained virological response (EVR and SVR) when treated with the current standard of care – pegylated Interferon-alpha and ribavirin (PegIFNα/RBV) – and fluvastatin. The results show patients receiving fluvastatin and PegIFNα/RBV achieve higher rates of EVR and SVR – 75.96% and 63.46% – to those receiving placebo and PegIFNα/RBV – 61.9% and 49.52% respectively.

EASL’s Secretary General, Professor Heiner Wedemeyer, said: “We know that metabolic syndrome (MS), the main treatment indication for statins, is associated with severe fibrosis and lower treatment responses in chronic HCV patients. The confirmation that the combination of fluvastatin and PegIFNα/RBV could provide better clinical outcomes for those patients with co-morbid chronic HCV and MS is very exciting for clinicians.”

Even in patients without MS, the study shows that responses to treatment are still higher in patients treated with fluvastatin and PegIFNα/RBV (EVR 85.36% versus 71.42% and SVR 74.39% vs. 58.44).
“Today, healthcare professionals have to be mindful when considering health provision and treatment costs. We cannot overlook the importance of opportunities to maximise more affordable drugs’ potential to complement the current standard of care for chronic HCV management,” said Professor Wedemeyer.

This new study concludes that the synergistic effects between fluvastatin and PegIFNα/RBV shows lipid lowering drugs may favour HCV clearance and be useful as a chronic HCV treatment, irrespective of the presence of metabolic syndrome.

About the study
In the double-blind pilot study, 209 treatment naïve HCV genotype 1b patients were given either PegIFNα/RBV and 20 mg of fluvastatin (104 patients) or PegIFNα/RBV and 20 mg of placebo (105 patients) for 48 weeks. Study medication was administered for 72 weeks (48 weeks in association with PegIFN-ribavirin plus 24 weeks in follow-up) in all patients, irrespective their lipid profile.
Both EVR and SVR are makers of a drug’s efficacy as an HCV treatment: EVR is measured by detectable HCV RNA at week 4, but undetectable HCV RNA at week 12, maintained to the end of treatment; SVR is measured by undetectable HCV RNA 24 weeks after the end of treatment.

About fluvastatin
Fluvastatin has previously shown promise as an HCV treatment: a 2008 study of 31 patients found the drug exhibited antiviral activity against HCV, although the authors described the effect as modest, variable, and often short-lived.
Fluvastatin is a statin, a class of drug that improves blood cholesterol levels primarily by inhibiting a liver enzyme called HMG Co-A reductase, thus reducing the liver’s ability to make cholesterol.

About metabolic syndrome
Metabolic syndrome (MS) is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. It is also linked with a higher risk to develop severe fibrosis in chronic HCV patients.

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Novartis first-in-class antiviral DEB025 achieved sustained viral response in 76% of patients with chronic hepatitis C, new phase II study shows

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) showed superior viral cure vs standard of care alone (p=0.008)[1]
A cyclophilin inhibitor, DEB025 belongs to a new class of medicines that limit hepatitis C virus replication and have the potential to reshape hepatitis C therapy
Phase III study with DEB025 commenced recently with previously untreated patients infected by the most common form of hepatitis C virus

Basel, March 31, 2011 – Novartis announced today that a Phase II study with the first-in-class antiviral DEB025 (alisporivir) met its primary endpoint for achieving viral cure (24 weeks after stopping treatment) in 76% of patients with chronic hepatitis C[1]. The study involved nearly 300 previously untreated patients infected with the most common form of hepatitis C virus (HCV), the genotype 1 (G1)[1].

The data were presented today at the European Association for the Study of the Liver (EASL) congress in Berlin, Germany. The findings show that 76% of G1 chronic hepatitis C patients treated with DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) achieved superior viral cure (known as sustained viral response, or SVR) compared to 55% of patients on standard of care alone (p=0.008)[1]. Treatment with DEB025 demonstrated a low incidence of adverse events, with discontinuation rates comparable between treatment groups[1].

“Hepatitis C is difficult to treat and current therapies are only effective in about half of patients infected with the most prevalent genotype of HCV[2],” said Stefan Zeuzem, Professor of Medicine at the Goethe University Hospital in Frankfurt, Germany, and the study’s principal investigator. “These results are exciting because a large majority of patients achieved sustained viral response with DEB025, with some who also benefited from a shorter duration of treatment compared to standard therapy[1].”

DEB025 is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the virus directly, DEB025 is a host targeting antiviral (HTA) that targets so-called host proteins which are essential for the replication of HCV. As these proteins play a key role in the replication of all types of HCV, DEB025 may offer an effective treatment option for a broad range of HCV forms. In other clinical trials, DEB025 has also shown effective antiviral activity against other common HCV genotypes (G2, G3 and G4)[3].

“There is a critical need for more effective drugs to treat chronic hepatitis C, and Novartis is dedicated to developing medicines that will reduce the burden of this disease for patients and physicians,” said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. “DEB025 has a new mode of action that may stop the virus from replicating and could reshape the future approach to treatment of hepatitis C.”

More than 170 million people worldwide are infected with HCV, which can cause serious liver disease leading to cirrhosis, liver cancer, and in some cases death. HCV is a blood borne virus that predominantly affects the liver[4],[5]. As an RNA (ribonucleic acid) virus, it mutates much more than DNA (deoxyribonucleic acid) viruses. This ability to change makes it harder for the immune system to clear (or eliminate) the virus. There are six major variations of HCV, known as genotypes and labelled from G1 to G6[5].

The study presented at EASL was a 48-week, global, double-blind, randomized, placebo-controlled trial in G1 treatment-naïve chronic hepatitis C patients. It evaluated the efficacy and safety of DEB025 combined with pegylated-interferon alfa 2a/ribavirin (PegIFN/RBV) vs. PegIFN/RBV alone. The primary endpoint was sustained viral response after 24 weeks (SVR24)[1].

Transient and reversible increase in bilirubin was observed in association with the initial DEB025 loading dose[1]. A small proportion of patients (4.2%) had a transient increase in bilirubin more than five times the upper limit of normal (ULN), but this was not associated with liver damage[1].

A pivotal Phase III study with DEB025 commenced recently to evaluate the efficacy and safety of DEB025 combined with standard of care and enrolling previously untreated HCV G1 patients. Other Phase II studies are ongoing in other patient populations i.e., G1 treatment-experienced patients and G2 and G3 treatment-naive patients.

Novartis in-licensed DEB025 from Debiopharm Group(TM), an independent biopharmaceuticals company based in Switzerland, under an agreement which gives Novartis exclusive worldwide development, manufacturing and marketing rights (excluding Japan).

Read Complete Press Release…..

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Inhibitex Reports Positive Safety and Antiviral Data from Its Phase 1b Study of HCV Nucleotide Inhibitor INX-189

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

Inhibitex, Inc. (Nasdaq: INHX) today reported positive top-line safety and antiviral data from its multiple ascending dose Phase 1b clinical trial of INX-189, an oral nucleotide polymerase inhibitor being developed to treat chronic infections caused by hepatitis C virus (HCV).

The trial was a double-blind, placebo-controlled, dose escalation study designed to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of INX-189, administered orally once-daily for seven days, in HCV genotype 1 treatment naïve patients. A total of 70 subjects were randomized into the trial among seven different dosing cohorts, including five monotherapy treatment arms and two arms of adjunctive treatment with ribavirin (RBV). Each treatment cohort in the study was comprised of 10 patients, eight of whom received INX-189 and two that received placebo.

INX-189, dosed once-daily at 9, 25, 50 and 100 mg for seven days, demonstrated potent and dose-dependent antiviral activity with median HCV RNA reductions from baseline of -0.64, -1.00, -1.47, and -2.53 log10 IU/mL, respectively. INX-189, dosed once-daily at 50 mg for one day, followed by 9 mg for six days, achieved a median HCV RNA reduction from baseline of -0.50 log10 IU/mL. The median HCV RNA decline from baseline observed in patients that received placebo was -0.20 log10 IU/mL. INX-189, dosed once-daily in combination with RBV for seven days at 9 mg and 25 mg, resulted in median HCV RNA reductions from baseline of -0.75 and -1.56 log10 IU/mL, respectively. The median HCV RNA decline from baseline observed in patients that received placebo and RBV was 0.04 log10 IU/mL.


Cohort (INX-189 QD)	Median HCV log10 IU/mL RNA Viral Load Decline after 3 doses	Median HCV log10 IU/mL RNA Viral Load Decline after 7 doses	Range Day 7 HCV log10 IU/mL RNA
Placebo (n=10)	0.25	-0.20	0.60 to -0.30
9 mg (n=7)	-0.29	-0.64	-0.19 to -1.06
25 mg (n=8)	-0.85	-1.00	-0.56 to -1.58
50 mg (n=8)	-1.34	-1.47	-1.17 to -2.30
100 mg (n=8)	-1.46	-2.53	-1.35 to -2.78
50 mg x 1 day 9 mg x 6 days (n=7)	-0.46	-0.50	0.11 to -0.88
RBV with Placebo (n=4)	-0.13	0.04	1.47 to -0.61
9 mg with RBV (n=7)	-0.45	-0.75	-0.35 to -0.93
25 mg with RBV (n=8)	-1.35	-1.56	-0.77 to -2.68

In addition to these median reductions in viral load, clinically meaningful decreases in alanine transaminase (ALT) levels were observed for patients receiving INX-189 at all dose levels, and no patients experienced viral breakthrough.

Additional data available from the Phase 1b study indicate that INX-189 was generally well tolerated. There was one serious adverse event reported in a subject treated with RBV and placebo (atrial fibrillation in a subject with a previous history). All other reported adverse events were mild or moderate, with the most common adverse event in INX-189 treated subjects being headache. There were no discontinuations of treatment due to adverse events and there were no adverse events related to changes in clinical laboratory evaluations or ECGs.

“Nucleotide polymerase inhibitors are likely to be a key component of combination direct antiviral therapy,” stated Dr. Eric Lawitz, President and Medical Director at Alamo Medical Research, San Antonio, Texas and a principal investigator of the Phase 1b study. “Further, the antiviral activity observed at the low INX-189 doses evaluated is promising, provides proof of concept, and provides the foundation for future studies.”

“The potent antiviral activity in monotherapy and the synergistic activity observed in combination with RBV support our belief that INX-189 has the potential to play a pivotal role in future HCV combination therapy,” commented Joseph M. Patti, Ph.D., Inhibitex’s CSO and Senior Vice-President of Research. “We believe these data, taken together with the successful completion of our 13-week GLP toxicology studies, support advancing INX-189 into Phase 2 clinical trials later this year.”

About HCV and INX-189
Hepatitis C is a disease of the liver caused by HCV. It is estimated that over 4 million Americans and 170 million individuals worldwide are infected with HCV, the majority of which represent chronic infections that can cause liver disease, cirrhosis and cancer, and is the leading cause of liver transplants in the United States.

Inhibitex is developing a series of proprietary nucleotide inhibitors that target the RNA-dependent RNA polymerase (NS5b) of HCV. INX-189 is a protide of a 2’-C-methyl guanosine analogue. The Company believes that preclinical and clinical studies of INX-189 completed to-date support its potential as a potent, once-daily, low dose oral therapy amenable to combination with other antivirals for the treatment of patients with all known genotypes of HCV.

About Inhibitex
Inhibitex, Inc. is a clinical stage biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. In addition to INX-189, the Company’s clinical stage pipeline includes FV-100, a bicyclic nucleoside inhibitor in Phase 2 development for the treatment of shingles. The Company also has additional HCV nucleotide polymerase inhibitors in various stages of preclinical development, and has licensed the use of its proprietary MSCRAMM® protein platform to Pfizer for the development of active staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.

Press Release Source: Inhibitex

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Drug Cocktail Offers New Hope for Hepatitis C Patients

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

A three-drug cocktail can eliminate the hepatitis C virus in patients far more effectively than the current two-drug regimen, according to researchers at Henry Ford Hospital.

“This study represents a remarkable advance and a potential cure for people with hepatitis C who have not responded to previous therapy,” says co-author Stuart C. Gordon, M.D., section chief for the Division of Hepatology at Henry Ford Hospital.

“We will soon have a new standard of treatment for hepatitis C patients,” says Dr. Gordon. “This study ushers in a new era of drug development that will provide a host of antiviral agents to treat hepatitis C, and we are now witnessing dramatic and rapid advances in how we will be able to treat these patients.”

The results of the global study are in the March 31 issue of The New England Journal of Medicine.
At least 3.2 million Americans are infected with hepatitis C, a chronic viral disease affecting the liver. The Centers for Disease Control and Prevention estimates that more than 12,000 people die each year of liver disease and liver cancer associated with the hepatitis C virus.

Most people who are infected with hepatitis C remain without symptoms for years. When symptoms of advanced liver disease do occur, it is often too late to offer the current treatment regimens. The infection may lead to scarring of the liver (cirrhosis), liver cancer or the need for liver transplant.

The virus was previously spread through contact with infected blood products before 1990, and often via injection drug use or the sharing of straws during the use of cocaine. Among immigrants to the U.S. from Asian, African, Middle Eastern and Eastern European countries, the virus may have been transmitted via the use of non-sterile glass syringes used for vaccination purposes.

There is currently no vaccine for hepatitis C.

In the study, researchers randomly assigned patients to one of three groups. In all three groups, patients received peginterferon and ribavirin (the current standard of care) for four weeks. A control group (group 1) continued to receive only peginterferon–ribavirin for 44 additional weeks; group 2 received boceprevir plus peginterferon–ribavirin for 32 weeks, and patients with a detectable hepatitis C virus level at treatment week 8 received placebo plus peginterferon–ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks.

Boceprevir is a protease inhibitor, a new class of direct-acting antiviral agent that specifically targets and inhibits the replication of the hepatitis C virus.

Results showed the rate of sustained virologic response (loss of the virus) was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%).

Among patients with an undetectable hepatitis C virus level at treatment week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. A sustained virologic response generally translates into a long-term eradication of virus, or cure.

“We can conclude that boceprevir, when added to peginterferon and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients,” explains Dr. Gordon.

In an accompanying article in the same issue of The New England Journal of Medicine, treatment of previously untreated hepatitis C patients with the same three-drug cocktail likewise showed significantly higher response rates than the current two drug regimen.

The study was funded by Schering-Plough (now Merck).

Press Release Source: Eurekalert

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Presidio Pharmaceuticals, Inc. Announces Positive Results in a Phase 1b Clinical Trial of PPI-461, a Novel, Potent Broadly-Active Hepatitis C Virus (HCV) Inhibitor

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

San Francisco, CA – March 30, 2011 – Presidio Pharmaceuticals, Inc. announced today positive preliminary results from a Phase 1b clinical trial of PPI-461, a novel HCV NS5A inhibitor for the treatment of patients with chronic hepatitis C.

The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.

The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.

Pharmacokinetic (PK) analyses of patients’ PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.

Virologic data from the first two dosing groups indicate rapid and marked reductions in patients’ serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).

Efficacy data for individual patients receiving active PPI-461 treatment in the first two dosing cohorts in the Phase 1b trial are presented in Table 1:

Table 1

HCV RNA Reduction log10 IU/mL
DosePatient	1	2	3	4	5	6

50 mg	0.4*	2.6	2.7	3.3	3.4	3.5

100 mg	2.6	3.7	3.7	3.8	4.0	4.1

Four NS5A-specific linked mutations in 100% of virus population at study entry “These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality,” said Nathaniel A. Brown, M.D., Presidio’s Chief Medical Officer. The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year. About Presidio’s HCV NS5A Inhibitors* Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase). PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio’s NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series. About Presidio Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: www.presidiopharma.com.

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Pharmasset Initiates Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes

Posted on March 31, 2011 by HCV AdvocateMarch 31, 2011

PRINCETON, N.J., March 30, 2011 /PRNewswire/ — Pharmasset, Inc. (Nasdaq: VRUS) announced today that screening has begun in a Phase 2b study of PSI-7977, a nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 400mg QD with pegylated interferon and ribavirin in patients with HCV genotype 1, 4, 5 or 6 who have not been treated previously.

“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 ATOMIC trial is designed to explore 12 and 24 week durations of PSI-7977. The potency, high barrier to resistance, and consistent antiviral activity across genotypes provided the data to support an interferon free dosing period in this trial, as well as enabling us to enroll multiple genotypes in this trial.”

About the Phase 2b ATOMIC Trial
This Phase 2b trial is planned to enroll approximately 300 patients with chronic HCV genotype 1 who have not been treated previously. The primary endpoint of the trial will be the safety and tolerability of PSI-7977 in combination with peginterferon and ribavirin over 12 or 24 weeks. The trial will be conducted in the U.S. Patients will be randomized (1:2:3) into the following arms:

PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks;
PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks;
PSI-7977 400mg QD with peginterferon and ribavirin for 12 weeks, followed by either PSI-7977 400mg QD monotherapy for 12 weeks or PSI-7977 400mg QD plus ribavirin for 12 weeks.

HCV GT1 patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. An additional 25 treatment-naïve patients with HCV genotype 4, 5, 6 or indeterminate genotype, will receive PSI-7977 400mg QD with peginterferon and ribavirin for 24 weeks.
Additional details on this and all Pharmasset 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 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 three clinical-stage product candidates. Mericitabine (RG7128, MCB), a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys® plus Copegus® and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys® and Copegus®, all conducted through a strategic collaboration with Roche. PSI-7977 is our unpartnered uracil nucleotide analog currently dosing in three Phase 2 studies in patients with HCV genotypes 1 through 6, including studies with abbreviated duration or no interferon. PSI-938 is our unpartnered guanosine nucleotide analog which recently completed a 14-day monotherapy and combination study with PSI-7977. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.
Pegasys® and Copegus® are registered trademarks of Roche.

SOURCE Pharmasset, Inc.

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Achillion Announces Positive RVR Results With ACH-1625 to Treat Chronic Hepatitis C

Posted on March 30, 2011 by HCV AdvocateMarch 30, 2011

Once-Daily Dose Achieves 75 – 81% RVR in a Well Tolerated Combination Regimen

NEW HAVEN, Conn., March 30, 2011 (GLOBE NEWSWIRE) — Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) today announced top-line results from its on-going Phase 2a clinical trial of ACH-1625 dosed once daily (QD) in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin), a current standard of care (SOC) in patients with chronic hepatitis C (HCV) infection. The analysis demonstrated that 75-81% of patients receiving ACH-1625 achieved rapid virologic response (RVR) with a promising safety and tolerability profile. ACH-1625 is an inhibitor of HCV NS3 protease that was discovered by and is being developed by Achillion.

Study Design
In this first of a two segment Phase 2a trial, a total of 64 patients were enrolled and randomized across three doses of ACH-1625 given once daily (200mg, 400mg or 800mg) or placebo with peginterferon alfa-2a and ribavirin, and were dosed for 4 weeks of therapy. Patients then continue on SOC for up to an additional 44 weeks. Subjects were randomized and stratified by HCV genotype and IL28B genotype.

Top-line Results
The majority of the 64 patients enrolled were HCV genotype 1a (73%), with a smaller percentage of HCV genotype 1b patients (25%). A total of 75% of the patients enrolled were genotype CT/TT, a marker of the patient’s diminished response to interferon, and 25% were genotype CC. All patients receiving 4 weeks of treatment with ACH-1625 demonstrated continuous and substantial declines in HCV RNA with no viral breakthrough during therapy at any of the doses. Preliminary results for the 64 patients enrolled demonstrate RVR percent and viral load reduction as follows:


	ACH-1625			Placebo
	200 mg QD N=16	400mg QD N=16	800 mg QD N=17	N=15
Week 4 RVR Subjects with HCV RNA < 25 IU/mL	13/16 (81%)	12/16 (75%)	13/17 (76%)	3/15 (20%)
Mean maximum HCV RNA decline through Week 4 (log10)	4.90	4.63	4.96	2.25

Safety results from a planned safety analysis included 56 patients from this segment of the trial and indicated that adverse events (AEs) were similar to those observed in the previously reported Phase 1a and 1b trials of ACH-1625. Over 4 weeks of co-administration of ACH-1625 with SOC, there were no discontinuations due to adverse events and there were no serious adverse events (SAEs) reported. Most reported AEs in patients receiving ACH-1625 were classified as mild to moderate and were transient. The most common AEs were consistent with peginterferon alfa-2a and ribavirin.

“These data reflect a positive outcome with high RVR, irrespective of IL28B status, which places ACH-1625 among the most potent protease inhibitors in development,” commented Elizabeth A. Olek, M.D., Vice President and Chief Medical Officer of Achillion. “We look forward to selecting two of these doses and beginning the second segment of the trial, dosing ACH-1625 with SOC over 12 weeks, and anticipate reporting cEVR data by the end of this year.”

“We are quite pleased with the continued robust efficacy results and good safety profile with once-daily doses of ACH-1625,” said Michael D. Kishbauch, Achillion’s President and Chief Executive Officer. “ACH-1625 continues to demonstrate best-in-class features, including once-daily dosing, robust antiviral activity, coupled with safety and tolerability for patients. These attributes distinguish our drug and suggest it could offer improvements over other next-generation protease inhibitors that will reach the market mid-decade.”

The preliminary safety profile of ACH-1625 continues to support future plans to combine this protease inhibitor with other directly acting antiviral agents. Achillion expects to initiate during 2012 a clinical trial evaluating ACH-1625 in combination with ACH-2928, an internally discovered and developed NS5A inhibitor.

About ACH-1625
ACH-1625 is a HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. ACH-1625 has rapid and extensive partitioning to the liver, as well as high liver/plasma ratios. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50 of approximately 1nM.

In Phase 1a clinical studies, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg per day for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no SAEs, and no clinically significant changes in vital signs, electrocardiograms or laboratory evaluations. In Phase 1b clinical studies, HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.63 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of at least 1log10 from baseline through day 12, the last day of viral load measurement in the study.

About Achillion Pharmaceuticals
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion’s proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease including hepatitis C and resistant bacterial infections. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.

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