HCV Advocate EASL 2009 Coverage

 

Updated April 29, 2009

·        Clinical Update - Debio 025 in Hepatitis C

·        Ocera Therapeutics Presents Data On AST-120 In Patients With Hepatic Encephalopathy At The European Association For The Study Of Liver Disease

·        EASL 2009: Combined Maternal Treatment and Infant Vaccination Effective in Reducing Mother-to-Child HBV Transmission

·        Schering Plough Highlights Hepatitis C Clinical Data Presentations At The European Association For The Study Of The Liver (EASL) Annual Meeting

·        Human Genome Sciences Reports Positive Late-Breaker Results at EASL from ACHIEVE Phase 3 Trials of Albuferon(R) in Patients with Chronic Hepatitis C

·        Hepatitis C Updates From EASL Liver Confab

·        Telaprevir Data Presented at EASL Show Unprecedented SVR Rates in HCV Treatment-Failure Patients in PROVE 3 Study

·        Adding Octreotide to Sorafenib May Benefit Patients With Advanced Hepatic Cell Carcinoma Who Have Failed Other Therapies: Presented at EASL

·        Future For Radioembolisation In Patients With Advanced Hepatocellular Carcinoma

·        Ground-Breaking Combination of All-Oral Agents Demonstrates Potential as Hepatitis C Treatment Regimen

·        InterMune Reports Presentation Of Triple Combination Study Of ITMN-191 At European Association For The Study Of The Liver (EASL)

·        HIV No Barrier to Liver Transplant

·        GlobeImmune, Inc.'s Hepatitis C Therapeutic Vaccine, GI-5005, Improves EVR Rates to 94 Percent in Phase 2 Clinical Trial

·        Medivir: New Phase IIa Data on TMC435 in Patients with Hepatitis C Presented at the Ongoing EASL - Meeting

·        SCYNEXIS’ SCY-635 Demonstrates Clinically Relevant Single-Agent Results in a Phase 1b Study in Adults with HCV

·        Merck Announces Interim Phase IIa Study Results of MK-7009, an Investigational Oral Hepatitis C Virus Protease Inhibitor, in Patients with Chronic Hepatitis C

·        ANA598 Demonstrates Potent Antiviral Activity At All Dose Levels In Completed Phase Ib Study In Hepatitis C Patients

·        Final Results Of Boceprevir Phase II HCV SPRINT-1 Study Showed Significantly Higher SVR Rates Compared To Standard Of Care

·        Idenix Pharmaceuticals Reports Data From Three Hepatitis C Development Programs

·        First Evidence For DNA-Based Vaccination Against Chronic Hepatitis C

·        New Oncogene Gives Valuable Insight Into Hepatocellular Tumors In Humans

·        Diabetes, Obesity And Hypertension Increase Mortality In Hepatitis C Patients

·        UPDATE 2-Schering hepatitis C drug shines, but anemia seen

·        TRANSGENE : Transgene presents additional Phase I data for TG4040 in hepatitis C chronically infected patients at EASL and is now preparing for Phase II trial

·        Valeant Pharmaceuticals Highlights Taribavirin Phase IIb 60-Week Data Presentation at European Association for the Study of Liver (EASL) Annual Meeting

·        Bristol-Myers Squibb and ZymoGenetics Present Positive 4-week Results of PEG-Interferon lambda with Ribavirin in Hepatitis C

 

Clinical Update - Debio 025 in Hepatitis C

http://news.prnewswire.com

 

Debiopharm Presents Promising Phase IIa Results Showing Potent Antiviral Activity

 

LAUSANNE, Switzerland, April 28 /PRNewswire/ -- Debiopharm Group (Debiopharm), a global biopharmaceutical development specialist that focuses on serious medical conditions, particularly in the field of oncology, presented results from a phase IIa study with Debio 025, a selective cyclophilin (Cyp) inhibitor with a potent anti-hepatitis C (HCV) effect. Revealed at the 44th Annual Meeting of the European Association for the Study of the Liver, in Copenhagen, these findings showed potent antiviral activity.

 

The phase IIa study investigated the efficacy and safety of Debio 025 in combination with Peg interferon alpha 2a (peg-IFN alpha-2a) and ribavirin in previously null-responder genotype 1 HCV patients. Results demonstrated that Debio 025 at doses of 400 mg (with initial loading) and 800 mg daily for 29 days shows a statistically significant reduction of HCV RNA of respectively -1.96 log (-98.9%) and -2.38 log (-99.5%) when co-administered with Peg-IFN alpha-2a and ribavirin in previous null responders.

 

"These results in patients who are highly unlikely to respond to re-treatment with an interferon-based regimen, are very important to us, as they confirm that Debio 025 is a potent anti-HCV agent," said Rolland-Yves Mauvernay, President and Founder of Debiopharm Group. "We are making it our mission to find a cure for this widely spread and life threatening disease and these findings bring us one step closer to our goal."

 

About the phase IIa triple therapy study

Debiopharm investigated different dosing regimens of Debio 025 in combination with peg-IFNÿ±2a at 180 micrograms/week and ribavirin at 1000/1200 mg/day in genotype 1 chronic HCV patients that were previously null responders (< 2 log10 HCV-RNA reduction after 12 weeks with peg-IFN(alpha) 2a and ribavirin). Fifty patients were randomised in an open phase IIa study to receive one of five treatment regimens for 29 days. Afterwards patients continued treatment on Peg-IFN alpha-2a and Ribavirin. A loading dose of Debio 025 at the start of treatment accelerates the onset of action and enhances efficacy in the early stage of treatment.

 

About Debio 025

Debio 025 is a synthetic first-in-class Cyp inhibitor, being tested in humans as a potential anti-HCV drug. Debio 025 binds strongly to Cyp, host cell proteins thought to confer a replication advantage to HCV. Its potent inhibitory activity on the HCV replication was shown in the following clinical studies. Results of a phase Ib study demonstrate that Debio 025 monotherapy for 15 days induced a strong anti-HCV effect (3.6 log10 reduction) in HIV-1/HCV co-infected patients. (Hepatology, 47:817-26). Results of a phase IIa study with Debio 025 indicate that Debio 025 shows an important additive anti-HCV effect (4.6 log10 reduction) when co-administered with peg-IFN(alpha)2a to treatment-naive HCV patients. (Hepatology, in press)

 

Ocera Therapeutics Presents Data On AST-120 In Patients With Hepatic Encephalopathy At The European Association For The Study Of Liver Disease

http://www.medicalnewstoday.com

 

Ocera Therapeutics, Inc., a privately held biopharmaceutical company, announced that data from its phase 2 study of AST-120 for the treatment of patients with low-grade hepatic encephalopathy was presented April 25th at the 44th Annual Meeting of the European Association for the Study of Liver Disease (EASL) in Copenhagen. The study showed that AST-120 was better tolerated than lactulose, the standard of care in this population, with similar overall efficacy. An improvement on neurocognitive measures was also seen with AST-120. Based on these positive data, Ocera has initiated and dosed their first patient in the ASTUTE study, a phase 2b study of AST-120 in patients with mild hepatic encephalopathy (MHE).

 

The phase 2a study randomly assigned 47 patients with West Haven Scale (WHS) Grade 1-2 hepatic encephalopathy to 4 weeks of treatment with either AST-120 2g sachets (A) QID or lactulose (L) titrated to bowel movements. Forty-one patients were evaluable (n=21 A, 20 L) and 6 were excluded (n=3 L: non-compliance, n=3 A: other causes). Treatment response by WHS at Week 4 was similar between treatment groups (38.1% vs. 35.0%, A vs. L). AST-120 also produced an improvement in neurocognitive measures. A statistically significant reduction in pruritus, a secondary endpoint of the trial, was seen with AST-120 compared to lactulose. Adverse events related to diarrhea (p = 0.04) and flatulence (p = 0.02) were significantly less in patients treated with AST-120.

 

The improvement seen in neurocognitive measures is consistent with reports that neuropsychometric testing is required to truly measure deficits and detect changes in neurocognitive functioning in the MHE patient population.

 

"Patients with mild hepatic encephalopathy often don't comply with lactulose therapy because of the side effects," said Paul Pockros, M.D., division head of gastroenterology and hepatology at Scripps Clinic and the principal investigator of the study. "A safe, easily tolerated alternative such as AST-120 would be of great benefit in the management of these patients."

 

The ASTUTE Trial ("AST-120 Use for the Treatment of Hepatic Encephalopathy") is a Phase 2 multi-site, randomized, double-blind, placebo-controlled 8-week study in up to 150 patients with MHE. Patients will be evaluated on neurocognitive improvement at the end of the study, defined as the change in the global summary score of the RBANS or Repeatable Battery for the Assessment of Neuropsychological Status.

 

"The ASTUTE trial will use a battery of neuropsychometric tests to assess the efficacy of AST-120 in an MHE population," said Scott Harris, M.D., Ocera's chief medical officer, "Up to 60 percent of patients with cirrhosis have MHE and impaired neurocognitive function, a condition for which no drugs are approved."

 

About AST-120

AST-120 is a novel microspherical carbon adsorbent with a selective adsorption profile for a variety of unwanted substances in the digestive tract. These substances may be responsible for a number of conditions, including Hepatic Encephalopathy (HE), Irritable Bowel Syndrome (IBS), and pouchitis. They include ammonia, indoles (serotonin, octopamine), histamine, secondary bile acids, advanced glycation endproducts (AGE), and certain bacterial toxins. Ocera licensed the compound from the Kureha Corporation (Japan) in 2005.

 

About Ocera Therapeutics, Inc.

Ocera Therapeutics, based in San Diego, California, USA, is a privately held biopharmaceutical company focused on the development and commercialization of proprietary compounds to treat acute and chronic liver diseases and a broad range of gastrointestinal disorders. In addition to AST-120, Ocera is developing OCR-002 in hepatic encephalopathy due to complications of cirrhosis and acute liver failure. Ocera has raised $62.5 million dollars in venture financing from Domain Associates, Sofinnova Ventures, Thomas, McNerney & Partners, Montagu Newhall and InterWest Partners.

 

Source: Ocera Therapeutics, Inc

 

EASL 2009: Combined Maternal Treatment and Infant Vaccination Effective in Reducing Mother-to-Child HBV Transmission

www.medscape.com

Becky McCall

 

April 28, 2009 (Copenhagen, Denmark) — Using a novel combination strategy — vaccination of infants born to women infected with hepatitis B virus (HBV) who had high levels of HBV DNA plus prenatal treatment of the women — might reduce the vaccine failure rate from 39% to 18%, according to new research presented here at the European Association for the Study of the Liver 44th Annual Meeting. These data confirm earlier data from the Netherlands that showed a risk reduction for vaccine failure from 28% to 13%.

 

The strategy was developed by Robert de Man, MD, PhD, associate professor from the Department of Gastroenterology and Hepatology, Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues.

 

HBV is most prevalent in Asia and sub-Saharan Africa, but is also found in migrant populations and second-generation immigrants in industrialized countries. One million people die each year from hepatocellular carcinoma caused by HBV, and it is the ninth leading cause of death worldwide. High-risk pregnant Chinese women with HBV have been shown in previous studies to experience an increase in gestational diabetes mellitus, an increase in antepartum hemorrhage, and a trend toward preterm labor. Infants born to mothers with acute HBV infection during pregnancy can experience low birth weight and premature delivery.

 

The child is also at risk. Pregnant women who are hepatitis B e antigen (HBeAg)–positive have a high chance of transmitting HBV to the baby during birth. Most cases of HBV mother-to-child transmission are controlled with a combination of active and passive immunization of the baby. But children born to mothers who are highly viremic for HBV (HBeAg-positive) have a 32% chance of becoming infected during birth, despite prophylactic vaccination and hepatitis B immunoglobulin. Data suggest that this occurs if maternal HBV DNA levels exceed 150 pg/mL (1.2 × 109 copies/mL).

 

"Most babies receive HBV perinatally, but without any treatment around 70% to 90% of babies will become infected if the mother has a heavy viral load," Dr. de Man told Medscape Gastroenterology. He continued: "90% of these HBV-infected children will develop chronic HBV disease without intervention. This high chance of infection contributes to the continuing reservoir of ongoing disease. It is therefore essential to interrupt transmission at birth to lower total disease burden."

 

The study data show that infants born to women with high levels of HBV DNA can be treated using a different strategy. The pregnant woman should be treated during the last 4 to 6 weeks of pregnancy to lower the viral load, and postpartum, the infant should be immunized with vaccine and immunoglobulin, as should all infants born to HBV-infected women.

 

"The study results show that [the] 39% vaccination failure rate [is reduced] to 18% using this strategy. There is a clear group that benefits from this treatment," added Dr. de Man.

 

He emphasized that it is not clear whether maternal use of antiviral therapy is safe during pregnancy. Dr. de Man explained that despite limited data, a hepatic flare during pregnancy is dangerous for mother and child and that antiviral therapy in this setting is the outcome of a physician–patient decision made using the best information available.

 

There is no effective treatment for hepatitis B in either adults or children, so prevention of infection is essential. Deirdre Kelly, MD, professor of pediatric hepatology from the University of Birmingham in the United Kingdom, emphasized the need for prevention over cure. "Most of my new pediatric patients with hepatitis B are either new migrants from endemic areas who have not been vaccinated or children who have failed vaccination."

 

Dr. Kelly believes that effective antenatal screening is essential to identify at-risk women who need active support and management during pregnancy.

 

"In mothers who have high levels of HBV DNA, antivirals for the last trimester are of considerable value in preventing transmission. More clinicians should be aware of this treatment strategy and implement it. It is also vital that children of carrier mothers receive adequate vaccination with immunoglobulin and vaccine and are checked at 12 months to ensure that the vaccination has been successful," she concluded.

 

Dr. de Man also drew attention to the need to assess the status of liver disease in pregnant women. The woman becomes tolerant or there is no worsening of liver disease in the majority of women during pregnancy. Liver enzymes frequently normalize, he said.

 

However, postpartum, liver disease in the mother often becomes more active, with alanine aminotransferase levels flaring after delivery in around 40% of patients. He stressed the importance of monitoring the mother as well as the child. "The message is that all countries have screening programs at 12 to 16 weeks to detect hepatitis B in the mother and to be able to vaccinate the baby, but it is essential not to forget to evaluate the extent of the liver disease in the mother at 3 months after delivery. Many of these mothers are lost to care," Dr. de Man explained.

 

Dr. de Man and Dr. Kelly have disclosed no relevant financial relationships.

 

European Association for the Study of the Liver 44th Annual Meeting: Symposium 7. Presented April 25, 2009.

 

Schering Plough Highlights Hepatitis C Clinical Data Presentations At The European Association For The Study Of The Liver (EASL) Annual Meeting

http://www.medicalnewstoday.com

 

Schering-Plough Corporation (NYSE: SGP) reported that final results of three large PEGINTRON(TM) (peginterferon alfa-2b) clinical studies address longstanding questions in the hepatitis C research community and provide important insights. The results of the studies, involving a total of more than 2,700 patients, were presented at the 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting.

 

"Physicians are constantly looking for ways to improve hepatitis C treatment outcomes by increasing response rates or reducing side effects and making treatment more tolerable for their patients," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "We undertook these large PEGINTRON studies to help investigators address these important clinical issues. Conducting these studies demonstrates Schering-Plough's longstanding commitment to investigating potential new treatment strategies for patients with hepatitis C."

 

Combination therapy with peginterferon and ribavirin is a recognized standard of care worldwide for treating chronic hepatitis C virus (HCV) infection. Patients with HCV genotype 1, the most common and hardest to treat form of hepatitis C, are typically treated for 48 weeks, while patients with HCV genotypes 2 or 3 are treated for 24 weeks.

 

The aim of the three PEGINTRON studies was to evaluate investigational regimens in these patient populations compared to current standard practice.

 

KEY FINDINGS

 

PEGINTRON Maintenance Therapy in Cirrhotic (Metavir F4) HCV Patients Who Failed to Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis Maintenance Trial(1)

The large EPIC3 clinical study program includes a prospective trial designed to assess the efficacy and tolerability of long-term, low-dose maintenance therapy with PEGINTRON 0.5 mcg/kg/week in patients who previously failed treatment with any alfa-interferon plus ribavirin combination therapy. A total of 631 patients were randomized to PEGINTRON or observational control. Of these, 454 patients were from the retreatment study portion of the EPIC3 program and 172 were direct enrollers into the maintenance study. The primary efficacy measure for the study was time to development of first clinical event, defined as liver decompensation (variceal bleeding, Child-Pugh class C, grade 2 or higher hepatic encephalopathy, ascites requiring therapeutic paracentesis and/or additional therapy), development of hepatocellular carcinoma (HCC), liver transplantation or death. All events other than transplantation and death were adjudicated by an independent committee of experts blinded to the study arm. The secondary efficacy analyses included time to disease progression, including additional events of Child-Pugh class B, emergence of varices and enlargement of pre-existing varices requiring additional therapy.

 

In the primary efficacy analysis, 36 patients in the control arm and 27 in the treatment arm had clinical events (P=0.14), a non-statistically significant difference. However, in the secondary efficacy analysis there were 87 clinical events in the control arm and 63 in the treatment arm (P=0.01), a statistically significant difference. The main events causing the difference on secondary analysis were emergence or enlargement of varices (43 control vs. 16 treatment). In patients with pre-existing esophageal varices (n=82) there were significantly more events (n=14) in the observation arm compared to the treatment arm (n=4) (P=0.01). Overall the safety profile for PEGINTRON was similar to that in previous studies; however, there were more serious infections in the treatment group (25 vs. 3), although these were not linked to neutropenia. None were unexpected events, nor was there a pattern to them.

 

In the primary analysis, PEGINTRON maintenance therapy was not superior to observational control in preventing the occurrence of clinical events. However, there was a statistically significant reduction in clinical events of hepatic decompensation on protocol-defined secondary analysis as well as in subjects with pre-existing esophageal varices.

 

Extended Treatment Duration in Chronic Hepatitis C Genotype 1-Infected Slow Responders: Final Results of the SUCCESS Study(2)

The primary objective of the SUCCESS study was to evaluate the effect of extending treatment duration to 72 weeks with PEGINTRON and REBETOL(R) (ribavirin, USP) combination therapy in genotype 1-infected patients who have slow response to therapy, defined as having detectable virus (HCV RNA) with at least a 2 log10 reduction in viral load at treatment week 12 and undetectable virus at treatment week 24. In this large, prospective, randomized, multinational clinical trial, slow responders were randomized at treatment week 36 to receive PEGINTRON combination therapy for a total of 48 weeks (n=86) (standard approved duration) or 72 weeks (n=73). Patients with undetectable virus at week 12 (complete early virologic response), received treatment for 48 weeks (n=816), whereas patients who did not respond to treatment (less than a 2 log10 reduction in viral load at week 12) were discontinued from the study. In total, 1,419 patients were treated.

 

In this study, sustained virologic response (SVR)(3) with 72-week treatment was not statistically superior to the 48-week treatment in slow responders (47.9 percent (35/73) vs. 43.0 percent (37/86), respectively), the primary endpoint of the study. Relapse rates between these two arms also were not significantly different (32.7 percent (16/49) vs. 47.1 percent (32/68), respectively) and adverse events were similar among treatment groups (secondary endpoints). Early discontinuation rates were higher in the 72-week arm compared to the 48-week arm (23.3 percent (17/73) vs. 9.3 percent (8/86), respectively).

 

Reduced Dose and Duration of Peginterferon Alfa-2b + Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial)(4)

Shorter duration treatment of patients chronically infected with HCV genotype 2 or 3 (G2/3) with peginterferon and ribavirin has been largely unsuccessful compared with standard-duration treatment (24 weeks). The implications of a reduced peginterferon dose in G2/3 patients were unknown. The primary objective of the REDD 2/3 study was to evaluate the effect of reduced treatment duration or a reduced PEGINTRON dose on SVR and relapse rates among treatment-naive G2/3 patients in an international, multicenter, non-inferiority study. The study began as a real-world, investigator-initiated study conducted in Germany and then the patient population was expanded to include centers in Europe and Asia-Pacific. In total, 682 patients were treated. Of these, 80.2 percent were G3 and 53.1 percent had high baseline viral load (greater than or equal to 600,000 IU/mL), both negative factors for achieving SVR.

 

Eligible patients were randomized to one of three arms: (A) PEGINTRON (1.5 mcg/kg/wk) for 24 weeks (approved dose), (B) PEGINTRON (1.0 mcg/kg/wk) for 24 weeks (low dose) or (C) PEGINTRON (1.5 mcg/kg/wk) for 16 weeks (short duration), each in combination with weight-based REBETOL (800-1200 mg/day). Co-primary end points were non-inferiority between arms A and B and A and C. SVR rates overall were (A) 66.5 percent (153/230), (B) 64.3 percent (144/224) and (C) 56.6 percent (129/228). Neither co-primary endpoint was met. Relapse rates were lower with 24 weeks compared to 16 weeks of therapy (17.8 percent (29/163) and 16.3 percent (27/166) vs. 29.3 percent (49/167), respectively). Adverse events were similar, regardless of treatment duration or PEGINTRON dose.

 

References

1. Bruix J, Poynard T, et al. PEGINTRON Maintenance Therapy in Cirrhotic (Metavir F4) HCV Patients Who Failed to Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis Maintenance Trial. Oral presentation at: 44th European Association for the Study of the Liver (EASL); April 22-26, Copenhagen, Denmark.

 

2. Buti M, Esteban R, et al. Extended Treatment Duration in Chronic Hepatitis C Genotype 1-Infected Slow-Responders: Final Results of the SUCCESS Study. Oral presentation at: 44th annual meeting of the European Association for the Study of the Liver (EASL); April 22-26, Copenhagen, Denmark.

 

3. SVR is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment.

 

4. Manns M, Zeuzem S, et al. Reduced Dose and Duration of Peginterferon Alfa-2b + Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial). Oral presentation at: 44th European Association for the Study of the Liver (EASL); April 22-26, Copenhagen, Denmark.

 

Source: Schering Plough Corporation

 

Human Genome Sciences Reports Positive Late-Breaker Results at EASL from ACHIEVE Phase 3 Trials of Albuferon(R) in Patients with Chronic Hepatitis C

http://www.bio-medicine.org

 

- With half as many injections, in two pivotal Phase 3 trials, Albuferon (albinterferon alfa-2b) met the primary efficacy endpoint of sustained virologic response comparable to Pegasys (peginterferon alfa-2a) -

 

- Patients receiving 900-mcg Albuferon had comparable rates of serious and/or severe adverse events across the two Phase 3 trials, versus peginterferon alfa-2a -

 

- Submission of global marketing applications planned in fall 2009 -

 

ROCKVILLE, Md., April 25 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. (Nasdaq: HGSI) today reported that the final results of two pivotal Phase 3 trials demonstrate that Albuferon(R) (albinterferon alfa-2b) met its primary endpoint of non-inferiority to peginterferon alfa-2a (Pegasys) in the treatment of patients with chronic hepatitis C. The Phase 3 results were the subject of two late-breaker oral presentations today in Copenhagen at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL). Albinterferon alfa-2b is being developed by HGS and Novartis under an exclusive worldwide co-development and commercialization agreement entered into in June 2006.

 

"The Phase 3 data presented at EASL show that Albuferon, with half the injections, achieved a rate of sustained virologic response comparable to Pegasys," said David C. Stump, M.D., Executive Vice President, Research and Development, HGS. "Importantly, the rates of serious and/or severe adverse events were also comparable in these studies.

 

SOURCE Human Genome Sciences, Inc.

 

Hepatitis C Updates From EASL Liver Confab

http://www.thestreet.com

Adam Feuerstein

 

The European Association of the Study of Liver Disease wrapped up on Sunday in Copenhagen. Here are some of the hightlights of all things hepatitis C:

 

INFORM-1 Data

Roche, InterMune(ITMN Quote) and Pharmasset(VRUS Quote) provided the most eagerly anticipated clinical data of the conference Saturday with results from a 14-day trial combining two experimental direct antivirals -- InterMune's ITMN-191 with Pharmasset's R7128 -- given to patients with treatment-naïve hepatitis C. Roche is a development partner on both drugs.

 

The companies called the INFORM-1 study "ground breaking" and rightly so in that this trial was the first time that two oral drugs -- both of which stop the hepatitis C virus from replicating itself, albeit in different ways -- were shown to be safe and effective in lowering viral loads in patients when taken in combination.

 

However, the viral load reductions and number of patients with undetectable levels of virus achieved by various dose combinations of ITMN-191 and R7128 over 14 days fell short of past studies combining a more potent oral drug like Vertex Pharmaceuticals'(VRTX Quote) telaprevir with standard of care for hepatitis C (long-acting injectable interferon and ribavirin).

 

The INFORM-1 study is a solid proof of concept that an all-oral combination therapy for hepatitis C is possible, but Roche, InterMune and Pharmasset are going to have to show that higher doses of the drugs, especially of InterMune's ITMN-191, produce stronger antiviral efficacy in order to make it possible to eliminate the use of interferon and ribavirin.

 

Vertex's Telaprevir

Vertex had a fairly quiet EASL conference, mainly because telaprevir is in the middle of phase III studies that won't have data available until next year. Still, the company did present previously disclosed data showing that telaprevir is capable of significantly improving cure rates in the most difficult-to-treat patients who had failed prior treatment with the current standard drug regimen for hepatitis C -- a 48-week course of long-acting interferon plus ribavirin.

 

This data keeps telaprevir ahead of its hepatitis C rivals because no other drug has yet shown the ability to improve the cure rates for both patients new to therapy as well as those who have failed prior therapy.

 

Telaprevir was the "butt" of some negative EASL chatter due to an anecdotal report that the drug was causing severe anal itching in patient(s). One EASL attendee described the side effect as "fire in the hole."

 

All jokes aside, itchy rash is a well-known and documented side effect of telaprevir, but there have been no confirmed reports of anal pruritis (the medical term for anal itching) in any of the telaprevir studies presented to date. In fact, patient discontinuation rates due to telaprevir-induced rash appear to be on the decline, as doctors and patients learn how to better manage the side effect.

 

This should lead to higher cure rates for telaprevir in the ongoing phase III studies compared to the already high rates seen in the phase II trials.

 

Anadys' ANA598 and Rash

Anadys Pharmaceuticals'(ANDS Quote) share price has not yet recovered from the emergence last week of a rash associated with its experimental drug ANA598. The company contends that investors are more worried about rash than doctors using the drug in clinical trials and the emergence of this potential side effect will not derail the drug's development.

 

However, Anadys only has another quarter or two of cash left and doesn't have enough money on hand to begin the next round of ANA598 clinical trials. Anadys is negotiating with potential partners for ANA598 but if talks are delayed, the company could be forced to raise money though another dilutive financing.

 

Schering-Plough's Boceprevir

Schering-Plough's(SGP Quote) boceprevir made some headlines last week with phase II cure rates numerically higher than what's been reported by Vertex's telaprevir in its phase II studies. But boceprevir still doesn't look competitive because the drug is causing significant rates of anemia in patients and requires dosing up to 48 weeks compared to 24-week dosing for telaprevir. Boceprevir is also ineffective for patients who have failed prior treatment.

 

J&J, Merck and ITMN-191

The other challengers to telaprevir also presented new data at the EASL conference, but none seemed ready yet for a full fight. Johnson & Johnson's(JNJ Quote) TMC-435 appears to have at least a signal for liver toxicity; Merck's(MRK Quote) MK-7009 reported high rates of vomiting; while InterMune's ITMN-191 isn't very potent on its own, especially when dosed twice daily.

 

Adding Octreotide to Sorafenib May Benefit Patients With Advanced Hepatic Cell Carcinoma Who Have Failed Other Therapies: Presented at EASL

http://www.docguide.com

By Cameron Johnston

 

COPENHAGEN, Denmark -- April 25, 2009 -- The addition of octreotide to sorafenib may offer a synergistic benefit for patients with advanced hepatic cell carcinoma (HCC) who have failed or been nonresponsive to other local therapies, researchers stated here at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL).

 

According to the investigators, who presented their findings on April 24, the combination therapy could represent a much-needed weapon for treating this select, and difficult to treat, population.

 

"Octreotide has been used previously as monotherapy in patients with HCC but with little success," Liliana Montella, MD, San Giovanni di Dio Hospital, Naples, Italy, told DocGuide. "When patients fail local therapy, they have few chances of a cure, and generally, a poor prognosis."

 

Originally, 87 patients with HCC who had previously failed radiofrequency ablation, chemoembolisation, surgery, or chemotherapy, or a combination of these treatments were recruited for the study.

 

The data presented at the poster presentation covered the first 43 patients, although more than 50 have now been evaluated. The patient cohort included 28 with hepatitis C, 10 with hepatitis B, and 1 with both B and C type disease. Four had disease of unknown etiology.

 

Patients were treated with sorafenib 800 mg/day for 28 days continuous dosing, followed by 1 week of rest. Octreotide 40 mg was introduced on day 10 of the cycle and given every month thereafter.

 

The analysis showed 1 partial response (2.3%), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, but Dr. Montella said this would be higher if the EASL criteria were used.

 

There were 32 cases of stable disease (74%) and 11 cases of progressive disease (23.7%). Median time to progression was 7.0 months (95% confidence interval [CI], 3.0-10.9 months).

 

Overall survival, at the time of the analysis was 9.9 months (95% CI, 8.2-11.6 months), but Dr. Montella said this has now increased to more than 10 months with 95% confidence intervals ranging from 8.2-17.0 months.

 

The most common adverse event was diarrhoea, which occurred in 27.9% of patients (4.6% grade 3). Hand-foot syndrome occurred in 9.3% of patients, and hypertension, abdominal pain, and rectal bleeding occurred in 6.9% of patients.

 

"I personally think that in this select group of liver cancer patients, octreotide can be a very useful drug," concluded Dr. Montella. "We can combine these 2 drugs together to produce some very interesting results in this population of patients."

 

[Presentation title: Sorafenib Plus Octreotide in Advanced Hepatocellular Carcinoma: Updated Results of a Multicenter Study. Poster 785]

 

Telaprevir Data Presented at EASL Show Unprecedented SVR Rates in HCV Treatment-Failure Patients in PROVE 3 Study

http://www.finanzen.net

 

Unprecedented sustained viral response (SVR) rates were achieved in hepatitis C-infected treatment-failure patients, including those with cirrhosis, with telaprevir-based treatment according to PROVE 3 trial results presented today in the late breaker session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark. Telaprevir is being developed by Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) in collaboration with Tibotec and Mitsubishi Tanabe Pharma.

 

In this intent-to-treat analysis, 51% and 52% of treatment-failure patients achieved SVR in the 24-week and 48-week telaprevir-based regimens, respectively. In comparison, SVR rates were achieved by 14% of patients randomized to receive 48 weeks of peg-IFN and RBV alone. Adverse events were generally consistent with those reported in prior telaprevir Phase 2 trials.

 

"Previously treated patients who didn’t achieve SVR represent the hardest to treat patient population in physicians’ practices,” said Michael P. Manns, M.D., Principal Investigator for the PROVE 3 Study and Director of the Department of Gastroenterology, Hepatology and Endocrinology at Medical School of Hannover, Germany. "Today’s compelling PROVE 3 results represent important progress as we seek to address a serious unmet need in patients who currently have very few options. We observed superior SVR rates across all telaprevir-based treatment arms compared to the control arm in patients who had previously failed treatment for hepatitis C, including patients with cirrhosis. This represents an exciting potential medical advance.”

 

"The SVR rates achieved in this difficult-to-treat population, with safety results consistent with prior telaprevir studies, add to the growing body of data supporting further development of telaprevir across the broad HCV patient population,” said Freda Lewis-Hall, M.D., Executive Vice President, Medicines Development and Chief Medical Officer at Vertex. "Telaprevir is the only STAT-C agent to show SVR rates at this level in the treatment-failure patient group.”

 

PROVE 3 SVR Results

PROVE 3 was a randomized, double-blind, placebo-controlled Phase 2b study that enrolled patients who failed prior treatment with peg-IFN and RBV. Patients enrolled in PROVE 3 included prior non-responders, prior relapsers and prior breakthroughs to peg-IFN and RBV treatment. The results included 453 patients who were enrolled and received at least one dose of study drug.

 

A summary of available on-treatment and post-treatment antiviral data from the 24-week telaprevir-based regimen compared to the 48-week standard of care regimen is presented below:

 

PROVE 3 Sustained Viral Response rates; intent-to-treat analysis

 

 

 

TVR12/PR24

 

TVR24/PR48

 

PR48

Non-responders [1]

 

39% (n=66)

 

38% (n=64)

 

9% (n=68)

Relapsers [2]

 

69% (n=42)

 

76% (n=41)

 

20% (n=41)

Breakthroughs [3]

 

57% (n=7)

 

50% (n=8)

 

40% (n=5)

Total

 

51% (n=115)

 

52% (n=113)

 

14% (n=114)

 

 

 

 

 

 

 

 

[1] Non-responders are defined as patients who never achieved undetectable HCV RNA during or at the end of prior therapy.

[2] Relapsers are defined as patients who achieved undetectable HCV RNA at the completion of prior treatment, but relapsed during follow-up.

[3] Breakthroughs are defined as patients who had undetectable HCV RNA during prior treatment, but had detectable HCV RNA before the end of prior treatment.

 

Sixty-nine and 76% of prior relapsers in the 24- and 48-week telaprevir-based treatment arms, respectively, achieved SVR as compared to 20% in the control arm, and 39% and 38% of prior non-responders in the 24- and 48-week telaprevir-based treatment arms, respectively, achieved SVR as compared to 9% in the control arm. A sub-analysis showed that 53% and 45%, respectively, of patients with cirrhosis in the 24- and 48-week telaprevir-based treatment arms achieved SVR compared to 8% in the control arm – these results were similar to those obtained for patients without cirrhosis.

 

In PROVE 3, an overall relapse rate of 13% (10 of 76 patients) was observed in patients in the 48-week telaprevir-based treatment regimen arm, while patients in the control arm relapsed at a rate of 53% (18 of 34 patients). A third arm of the study, evaluating a 24-week telaprevir-based regimen, showed a similar SVR rate compared to the 48-week telaprevir arm and an overall relapse rate of 30% (26 of 87 patients). In a completers’ analysis, a relapse rate of 4% (2 of 53 patients) was observed in patients who completed treatment with a 48-week telaprevir-based treatment regimen, while patients who completed treatment in the control arm relapsed at a rate of 52% (17 of 33 patients). A third arm of the study, evaluating a 24-week telaprevir-based regimen, had a relapse rate of 28% (22 of 80 patients) in patients who completed treatment with a 24-week telaprevir-based regimen. These results suggest that a telaprevir-based regimen that includes a total of 48 weeks of treatment with peg-IFN and RBV including 12 weeks of telaprevir may be warranted in treatment-failure patients. REALIZE, a Phase 3 study designed to evaluate this treatment regimen in non-responders (null and partial responders) and relapsers, is currently underway.

 

Safety and Tolerability in PROVE 3

In PROVE 3, adverse events were generally consistent with those reported in prior Phase 2 telaprevir trials including fatigue, nausea, headache, rash, pruritus, diarrhea, insomnia, pyrexia, alopecia, and chills. In the PROVE 3 telaprevir treatment arms, rash led to discontinuations in 5% of patients (17 of 339) and was manageable and reversible upon cessation of treatment. A 1% discontinuation rate due to anemia (3 of 339) was observed which was similar to that in the control arm. Erythropoiesis stimulating agents (ESA) were not recommended for the PROVE 3 study and were rarely used (in less than 1% (2 of 339) of patients) in the telaprevir-based treatment arms.

 

About Telaprevir

Telaprevir (VX-950) is an investigational oral inhibitor of HCV protease, an enzyme essential for viral replication, and is one of the most advanced investigational antiviral agents in development that specifically targets HCV. Telaprevir is in Phase 3 clinical trials in treatment-naive and treatment-failure patients.

 

Vertex retains commercial rights to telaprevir in North America. Vertex and Tibotec are collaborating to develop and commercialize telaprevir in Europe, South America, Australia, the Middle East and other countries. Vertex is collaborating with Mitsubishi Tanabe Pharma to develop and commercialize telaprevir in Japan and certain Far East countries.

 

Future For Radioembolisation In Patients With Advanced Hepatocellular Carcinoma

http://www.medicalnewstoday.com

 

Radioembolisation with Yttrium-90 (Y-90) glass microspheres is a safe and effective treatment for patients with advanced HCC ± portal vein thrombosis, according to new research presented at EASL 2009, the Annual Meeting of the European Association for the Study of the Liver in Copenhagen, Denmark.

 

According to the researchers, these findings create the foundation for a trial comparing and combining radioembolisation with multi-targeted kinase inhibitor, sorafenib. This would represent a new treatment option for sufferers of advanced HCC who currently have limited therapeutic choices.

 

HCC is a primary malignancy of the liver cells, generally leading to death within 6-20 months. It is currently one of the most common worldwide causes of cancer death. Locoregional treatment of HCC is considered the most effective palliative therapeutic approach. However, advanced tumour stages including portal vein thrombosis, diffuse multifocal liver infiltration and large tumour burden are obstacles for conventional local treatments. Due to the possibility of unselective application, radioembolisation with Yttrium-90 glass microspheres may allow effective local ablative therapy even in patients with intra-hepatic advanced HCC.

 

The aim of this open-label phase II study was to evaluate the safety and efficacy of radioembolisation in a European cohort of patients with locally advanced HCC and to assess the response rate according to different approved response criteria (WHO, RECIST and EASL).

 

Professor Guido Gerken, Head of Department of Hepatology and Gastroenterology, Essen University Hospital, Germany, who led the study, said: "In terms of a global strategy, we hope to achieve a major impact on the incidence of HCC through current vaccination strategies for HBV virus infection, screening and treatment for HCV infections, and from the reduction of alcoholic liver disease. However, because the latency period from hepatic damage to HCC development is very long, it may be many years until the incidence of HCC decreases as a result of these interventions. Previous therapeutic options have been limited to transplant or selective locoregional treatment but this exciting advance means new hope for HCC sufferers in the form of a novel treatment."

 

From November 2006 to August 2008, researchers in this study assessed 71 patients with advanced unresectable HCC ± portal vein thrombosis for inclusion in this prospective study. Y-90 microsphere radiotherapy was performed in a lobar fashion via the right or left hepatic artery. In bilobar disease, right and left liver lobes were treated with 4-6 weeks intervals in between. The mean radiation dose was 115 (±23) Gy per treatment. Response rate was assessed according to (WHO, RECIST and EASL) criteria with sequential computed tomography scans till the last clinical visit or death. The safety of this technique was evaluated according to CTC toxicity criteria.

 

51/71 patients had a follow-up of at least six months. 52/71 patients had liver cirrhosis. 7.30% of the patients had portal vein thrombosis before therapy. Partial response rate was detected in 52%. With consideration of necrosis (EASL criteria) partial response was 80%. During the limited follow up, 2/70 patients died within the first month after therapy. 11/70 patients died within at least 6 months after therapy. Time to progression (TTP) was 6 months. One year survival rate was 72%. TTP and overall survival seem comparable to systemic therapy. The main adverse events were a transient fatigue-syndrome and lymphopenia. Five patients developed bilirubin elevation after therapy.

 

Source: Camilla Dormer, European Association for the Study of the Liver

 

Ground-Breaking Combination of All-Oral Agents Demonstrates Potential as Hepatitis C Treatment Regimen

http://www.sunherald.com

 

- Combination of R7227, protease inhibitor, and R7128, nucleoside polymerase inhibitor, shows significant potency in reducing viral load in patients with hepatitis C

 

Roche, InterMune, Inc. (Nasdaq: ITMN) and Pharmasset (Nasdaq: VRUS) today announced the first results from their innovative, interferon-free regimen of direct acting antiviral (DAA) combination therapy for the treatment of patients chronically infected with the hepatitis C virus (HCV)(1). The study combined two oral DAAs, R7227 (also known as ITMN-191) and R7128, for the first time in patients. There were no serious adverse events reported during the 14 days of dosing, and the reductions in levels of HCV RNA were significant.

 

Results of the INFORM-1 study were presented today during the late-breaker session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen.

 

The trial, conducted in centers in New Zealand and Australia, is the first to investigate the combination of two oral antiviral medicines in the absence of interferon and ribavirin. The results demonstrated for the first time that the combination of an oral protease inhibitor and an oral nucleoside polymerase inhibitor resulted in significant HCV viral load reduction in patients with HCV. Roche is developing R7227, a protease inhibitor, with InterMune, and R7128, a nucleoside polymerase inhibitor, with Pharmasset.

 

Further studies will test the activity and safety of the combination of R7227 and R7128 with and without interferon and/or ribavirin. The current standard of care for HCV is a combination of pegylated interferon plus ribavirin, which delivers overall sustained virologic response rates (SVR) of 50-60 percent.

 

"These are exciting times in our fight against hepatitis C, and the investigation of the innovative oral treatment regimen in INFORM-1, if validated in further study, may radically change future treatment strategies in our patients with chronic HCV infection," said Edward Gane, M.D., Associate Professor, University of Auckland and Director, Auckland Clinical Studies Limited. "The initial results from this study of the R7227/R7128 combination raise hopes of the possibility for an interferon-free treatment regimen, as well as the potential for a shorter, more potent interferon-based regimen."

 

INFORM-1 Results in Brief

INFORM-1 is a randomized, double-blind, ascending dose Phase I trial which has enrolled a total of 57 patients.

 

Patients receiving the combination of R7227 and R7128 for 14 days -- without pegylated interferon or ribavirin -- experienced a median reduction in viral levels of -4.8 to -5.2 log(10) IU/mL in the highest doses tested. The addition of R7128 to R7227 resulted in sustained viral load reductions over the dosing period, with aproximately 63 percent of patients experiencing a decrease in viral levels below the quantification limit of the diagnostic assay (less than 40 IU/mL). Furthermore, 25 percent of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) after 14 days.

 

In the early low-dose groups, after only three days of dosing, the mean reduction in viral load levels was 0.6 log(10) IU/mL greater with combination treatment (-2.9), compared to the performance of the individual compounds when administered as a single agent (-0.46 and -1.84 for R7128 and R7227, respectively). This suggests an additive effect for the combination.

 

No treatment-related serious adverse events (SAEs), no dose reductions and no discontinuations were reported in the study. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.

 

Next Steps in the Development Program

The companies are now exploring twice-daily dosing of R7227 and higher total daily doses (600 mg twice-daily and 900 mg twice-daily) than those explored in the first patient cohorts of INFORM-1. The companies also plan to explore the innovative DAA combination therapy in "treatment-experienced" patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.

 

Other Clinical Studies with R7227 and R7128

In addition to clinical studies of combination DAA regimens such as those studied in INFORM-1, R7227 and R7128 each are proceeding rapidly in development in combination with Roche's PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin). A Phase IIb study with R7128 has now begun, while a Phase IIb study with R7227 is slated to begin in the summer.

 

Dial-In and Webcast Details

InterMune and Pharmasset will host a live webcast of a discussion of the INFORM-1 results from the EASL conference today, Saturday, April 25, 2009, at 7:00 p.m. CEST (1:00 p.m. EDT). Participating in the discussion will be Dr. Ed Gane, principal investigator in the INFORM-1 trial. Members of management from Roche, InterMune and Pharmasset will also be available to answer questions. A live webcast and slide presentation will be available through the Investor Relations pages of both InterMune and Pharmasset at www.intermune.com or www.pharmasset.com, respectively. Alternatively, interested parties may access the discussion and ask questions by dialing 888-799-0528 (U.S. and Canada) or 973-200-3372 (international), conference ID # 95452531. A webcast replay will be available approximately three hours after the call and will be archived at www.intermune.com  and at http://www.pharmasset.com .

 

InterMune Reports Presentation Of Triple Combination Study Of ITMN-191 At European Association For The Study Of The Liver (EASL)

http://www.medicalnewstoday.com

 

InterMune, Inc. (Nasdaq: ITMN) announced that results from a 14-day Phase 1b clinical study of ITMN-191 (R7227) in combination with the current standard of care were presented by Stefan Zeuzem, M.D., of the J.W. Goethe University, Frankfurt, Germany, in an oral presentation at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark. The study explored the use of ITMN-191 in combination with Pegasys(R) (peginterferon alfa-2a) and Copegus(R) (ribavirin) for 14 days of treatment in hepatitis C virus (HCV) treatment-naive patients infected with HCV genotype 1. ITMN-191 is an HCV protease inhibitor being developed in collaboration with Roche.

 

Among the highlights of his presentation, Dr. Zeuzem reported:

·        The combination of ITMN-191 plus the standard of care for 14 days resulted in rapid and sustained reductions in HCV RNA.

·        Substantial antiviral activity was observed in both the q8h and q12h dosing cohorts; the most rapid declines in HCV RNA occurred in the ITMN-191 900 mg q12h dosing cohort.

·        Viral rebound was not observed in any patient receiving treatment with ITMN-191 plus Pegasys and ribavirin.

·        ITMN-191 plus standard-of-care therapy was safe and generally well tolerated.

·        The findings support the continued evaluation of ITMN-191-based combination regimens of twice-daily and three-times-daily dosing in patients with chronic HCV infection.

 

Dr. Zeuzem, protocol chair of the study, said, "Based on the totality of the viral kinetic data, the q12h and q8h regimens delivered very convincing results and appeared to perform very comparably in this 14-day study. The safety and tolerability profile of ITMN-191 in both the earlier monotherapy study and in the present triple combination study was also encouraging, as no issues of concern were observed. We look forward to the Phase 2b study to determine if the very promising profile of ITMN-191 observed will be confirmed."

 

InterMune noted that a Phase 2b triple combination trial of ITMN-191 is planned for initiation in the summer of 2009. A Phase 1 trial of ITMN-191 and polymerase inhibitor R7128 (INFORM-1 Study) is currently underway.

 

Steven Porter, M.D., Ph.D., Chief Medical Officer of InterMune, said, "The Phase 1b triple combination study was designed to inform the dose selection and study design of the ITMN-191 Phase 2 program. The Phase 2b program will study both q12h regimens (600mg and 900mg q12h) and a q8h regimen (300mg q8h) and both 12-week and 24-week treatment durations. We believe that the viral kinetic and safety results reported today provide evidence that ITMN-191 has the potential to deliver superior sustained virologic response (SVR) rates in patients chronically infected with the hepatitis C virus."

 

Viral Kinetic Performance

After 14 days of triple combination therapy, the median change in HCV RNA from baseline exceeded 5 logs in five of the six cohorts and was -5.4 log and -5.7 log in the best performing q12h and q8h cohorts, respectively. Considering all cohorts, HCV RNA was below the limit of quantification in nearly three-quarters (71%, or 32 of 45) of patients who received treatment with ITMN-191 after only 14 days of treatment. In all q12h and q8h cohorts, reductions in HCV RNA occurred rapidly and there was no evidence of viral rebound during ITMN-191 treatment.

 

Safety and Tolerability Profile

ITMN-191 was generally safe and well tolerated. There were no serious adverse events (SAE) or Grade 4 adverse events (AEs) during treatment with ITMN-191. AEs reported during study treatment (ITMN-191 or placebo) were predominantly mild to moderate in severity, typically consistent with the well-described AE profile of standard of care (SOC) and none led to treatment discontinuation.

 

Only four Grade 3 AEs were reported during study treatment, two of which (sciatica and back pain) were deemed by the investigator to be unrelated to ITMN-191. The other two were neutropenia and indirect bilirubin elevation. Neutropenia occurred with a similar pattern, frequency and severity in the placebo and ITMN-191 groups. Minor and transient elevations in indirect bilirubin levels were observed in a small number of placebo and ITMN-191 patients and were deemed not clinically significant by the investigator. There were no other laboratory or ECG findings during study treatment that were attributable to ITMN-191.

 

Phase 1b Triple Combination Trial Design

The Phase 1b randomized, double-blind, placebo-controlled, 14-day triple combination study was conducted in treatment-naive patients chronically infected with HCV genotype 1. The study objectives were to assess the safety, pharmacokinetic and viral kinetic effects of various doses and regimens of ITMN-191 for 14 days in combination with Pegasys and Copegus compared to treatment with Pegasys and Copegus alone. Patient follow-up continued for 30 days following the completion of study treatment.

 

INFORM-1 Program

In November 2008, Roche, InterMune and Pharmasset initiated the first all-oral combination study of direct-acting antivirals (DAAs) in the absence of interferon or ribavirin, known as the INFORM-1 study. Interim results from the INFORM-1 study will be presented in an oral late-breaker session of the EASL meeting on Saturday, April 25, 2009.

 

About InterMune

InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has an R&D portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes pirfenidone for which a Phase 3 program in patients with IPF (CAPACITY) has been completed and the compound is currently in the pre-registration stage. The company also has a research program focused on a pirfenidone analog named ITMN-520. The hepatology portfolio includes the HCV protease inhibitor compound ITMN-191 (referred to as R7227 at Roche) expected to enter Phase 2b in the summer of 2009 and a second-generation HCV protease inhibitor research program.

 

Source: InterMune, Inc

 

HIV No Barrier to Liver Transplant

http://www.medpagetoday.com

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco 

 

TORONTO, April 24 -- People with HIV do just as well as others after a liver transplant -- as long as they don't have hepatitis C as well, researchers said in Copenhagen.

 

In one of the few studies with data on long-term outcomes, those with HIV had one- and five-year survival rates of 86.5% and 74% respectively, according to John O'Grady, M.D., of Kings College Hospital in London.

 

By comparison, HIV-negative liver transplant patients in the prospective UK Transplant Database had rates of 87.1% and 78%, which were not significantly different, Dr. O'Grady reported at the annual meeting of the European Association for the Study of the Liver.

 

"In terms of HIV, the clinical guidance is that theses patients do very well, (and) they should be considered for transplant in the normal way," he said. "They don't present any particular different clinical problem than the general liver transplant population."

 

On the other hand, he said, patients with both HIV and hepatitis C are a significantly greater challenge.

 

"They need to be counseled that severe recurrence of hepatitis may be a problem after the transplant," he said, adding that he and other specialists are anxiously awaiting new medications.

 

"We are desperate to get the newer agents, evolving agents, tested in this population at an early stage, because they have clearly an urgent need for drugs to control hepatitis C replication," Dr. O'Grady said.

 

Dr. O'Grady and his colleagues analyzed outcomes of all patients having a liver transplant in the U.K. from March 1994 through April 2008.

 

The database includes 33 people with HIV, 847 with hepatitis C, and 5,435 HIV-negative patients. Of the HIV-positive patients, 22 also had hepatitis C.

 

The researchers compared patients with both HIV and hepatitis C, those with HIV, and those with hepatitis C only.

 

The analysis found that:

·        Model for End Stage Liver Disease (MELD) scores were comparable between the three groups.

·        Patients with both viruses lived, on average, for 29 months post-transplant, compared with 47.7 months for those with hepatitis C only, a difference that was significant at P=0.04.

·        One- and five-year survival rates were 73% and 53% for those with both diseases, compared with 100% and 100% for those with just HIV, and 87% and 69% for those with just hepatitis C. The differences were significant at P=0.04.

 

Interestingly, despite the promising one- and five-year survival rates, patients with HIV had a mean post-transplant survival rate of 44 months compared with 57.1 months for HIV-negative patients, a difference that was significant at P=0.0001.

 

Dr. O'Grady said that difference is probably an artifact of the changing face of HIV -- the analysis included only a few patients transplanted early in the HIV pandemic, who tended to do very poorly.

 

In a univariate analysis, hepatitis C infection was a significant predictor of death after transplant in HIV-positive patients, with an odds ratio of 10 and a 95% confidence interval from 1.03 to 97.04.

 

But in a multivariate logistic regression model, the effect of hepatitis C was not independent of other covariates, such as MELD score and recipient and donor ages.

 

The researchers did not report study support or conflicts.

 

Source reference:

Joshi D, et al "UK liver transplant experience of HIV: Long term outcomes" EASL 2009; 

 

GlobeImmune, Inc.'s Hepatitis C Therapeutic Vaccine, GI-5005, Improves EVR Rates to 94 Percent in Phase 2 Clinical Trial

http://www.biospace.com

 

LOUISVILLE, CO--(MARKET WIRE)--Apr 24, 2009 -- Twelve-week Phase 2 clinical trial data show that patients treated with GI-5005, GlobeImmune's targeted molecular immunogen (Tarmogen®) for the treatment of hepatitis C virus infection, had 94 percent early virologic response (EVR) rate in treatment naïve patients. The study compared GI-5005 plus standard of care (SOC) -- pegylated interferon and ribavirin -- versus SOC alone in patients with chronic genotype 1 hepatitis C infection.

 

The study data will be presented in a poster presentation tomorrow by Eric Lawitz, M.D., of Alamo Medical Research Center, San Antonio, Tex. at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark. The 94 percent EVR rate in naïve subgroups including those with high baseline viral loads, is defined as a greater than 100-fold reduction of HCV RNA from baseline at 12 weeks and is an eight to twelve percent improvement over the SOC alone arm.

 

"We were pleased to see a 94 percent EVR rate in the treatment naïve patient population," said Dr. Lawitz, the study's lead author. "We believe that this increase in EVR over standard of care alone may indicate that the GI-5005 mechanism of action is complementary to the current standard care."

 

Additional exploratory analyses of serum fibrosis (Fibrotest) and necrosis (Actitest) markers showed a two-fold improvement in the proportion of patients with improved serum Fibrotest, and a fifty percent reduction in the number of patients with worsening Fibrotest scores after 24 weeks in the group receiving the triple therapy. At the 24 week time point, the triple therapy improved serum Actitest scores by up to 14 percent in treatment naïve patients when compared to SOC alone. The treatment naïve group with high viral load receiving the triple therapy also saw a 14 percent advantage over the SOC group in normalization of alanine transaminase (ALT), a marker of liver damage.

 

"We believe that the improvement in ALT, Actitest and Fibrotest scores seen in patients in the triple therapy arm of the study suggests that triple therapy with GI-5005 may lead to improvements in liver inflammation, necrosis and fibrosis compared to standard of care alone," said David Apelian, M.D., Ph.D., GlobeImmune's Chief Medical Officer. "At this interim stage of our Phase 2 program, we are encouraged by the data as we believe they suggest that triple therapy including GI-5005 may improve sustained virologic response as well as liver histology, both of which will be measured in the current study and could serve as primary or co-primary efficacy endpoints in a future Phase 3 HCV program."

 

The GI-5005-02 clinical trial is a randomized, multi-center, Phase 2 study evaluating 140 patients, all with genotype 1 HCV infection. In the trial, 74 percent of patients had never received prior treatment, and the remaining 26 percent had failed prior treatment.

 

About GlobeImmune

GlobeImmune Inc. is a private company developing targeted molecular immunogens, Tarmogens, for the treatment of cancer and infectious diseases. The company's lead product candidate, GI-5005, is a Tarmogen for the treatment of chronic hepatitis C infection (HCV). GI-5005 is designed to complement both the current standard of care and emerging novel therapies for HCV. The company's lead oncology program, GI-4000, targets cancers caused by mutated versions of the Ras oncoprotein. GI-4000 is being investigated in clinical trials for the treatment of pancreas cancer as well as other cancers that contain mutated Ras, including non-small cell lung cancer and colorectal cancer.

 

Medivir: New Phase IIa Data on TMC435 in Patients with Hepatitis C Presented at the Ongoing EASL - Meeting 

http://www.earthtimes.org 

 

STOCKHOLM, Sweden - (Business Wire) Regulatory News:

 

Data were presented from the phase IIa trial (OPERA-1) for TMC435 at the ongoing 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22-26.

 

TMC435 is an investigational protease inhibitor, being developed by Tibotec in collaboration with Medivir (STO:MVIRB), for the treatment of hepatitis C virus (HCV).

 

Data for TMC435 in treatment naïve genotype-1 HCV patients have been presented in an oral lecture. Furthermore, data in patients with genotype-1 HCV infection who failed previous IFN-based therapy were presented during a late breaker poster session.

 

TMC435 in treatment-naïve genotype-1 HCV patients

The results from 25, 75 and 200 mg in treatment-naive patients are summarized below:

 

1. Viral load reduction, (RNA log10 IU/mL), at week 4 on triple therapy groups (SoC and TMC435) was 5.5 and 5.4 log10 IU/mL for the 75 mg and 200 mg TMC435, QD respectively.

 

2. Undetectable levels (< 10 IU/mL) in 8/9 patients in the 75 mg group and 7/10 in the 200 mg group was observed after 4 weeks of treatment with triple therapy.

 

3. After 12 weeks (4 weeks triple + 8 weeks SoC), 6/9, 9/9 and 10/10 had undetectable virus (< 10 IU/mL) in the 25mg, 75 and 200 mg groups, respectively.

 

4. No breakthroughs observed after 4 weeks of triple therapy in any of the groups (25, 75 or 200 mg).

 

5. No treatment related discontinuations, most AEs were mild to moderate.

 

6. No evidence of TMC related hepatic, renal, CV or blood (haematopoietic) adverse events.

 

7. Mild and reversible increases in bilirubin observed in highest dose groups (200 mg).

 

8. Substantial decreases of liver transaminases were observed.

 

TMC435 in patients that failed previous IFN-based treatment

The results from 75, 150 and 200mg are summarized below:

 

1. Potent, dose-dependent, antiviral activity after 4 weeks treatment with triple therapy with 4.3, 5.5 and 5.3 log 10 IU/mL reduction for 75, 150 and 200 mg QD groups, respectively, compared to 1.5 in the placebo group

 

2. Three viral breakthroughs were observed in prior non-responders with G1b, 2 in 75 mg and 1 in the 150 mg QD group.

 

3. At Day 28, 4/9 (44%), 7/9 (78%) and 7/10 (70%) patients achieved plasma HCV RNA levels <25 IU/mL in the 75, 150 and 200 mg QD treatment groups, respectively, compared with no patients (0/9) in the placebo group

 

4. 2/9 (22%), 5/9 (56%) and 3/10 (30%) patients in 75, 150 and the 200 mg groups reached undetectable levels (< 10 IU/mL) after 4 weeks of treatment, compared to 0/9 patients on placebo.

 

5. There were no serious adverse events and no treatment discontinuations due to adverse events, which generally were of mild to moderate grade.

 

6. Liver enzymes were reduced by TMC treatment.

 

7. Bilirubin increases were observed in some patients on TMC, mostly with the 200 mg group. These elevations were reversible and generally mild.

 

Conclusions:

In treatment-naïve patients infected with HCV genotype-1, TMC435 in combination with SoC over 4 weeks of treatment:

• demonstrated potent antiviral activity

• was generally safe and well tolerated

• was not associated with AE-related treatment discontinuations

These results support the development of TMC435 for treatment-naïve patients infected with HCV genotype-1.

 

In treatment experienced patients infected with HCV genotype 1, 28 days of once-daily treatment with TMC435 (75, 150 and 200 mg) as part of a triple therapy regimen with PEGIFN-2a and RBV:

• demonstrated potent, dose-dependent antiviral activity.

• was generally safe and well tolerated.

• was not associated with AE-related treatment discontinuations.

 

SCYNEXIS’ SCY-635 Demonstrates Clinically Relevant Single-Agent Results in a Phase 1b Study in Adults with HCV

http://au.sys-con.com

By: Business Wire

 

Drug discovery company SCYNEXIS, Inc. today presented positive results from a Phase 1b single-agent, randomized, double-blind, placebo-controlled study of its lead, oral, antiviral drug candidate, SCY-635, in adult patients with genotype 1 chronic hepatitis C infection. SCY-635, a novel cyclophilin inhibitor, represents a new pharmacological class of inhibitors of hepatitis C virus (HCV) replication. Results were presented during an oral presentation at the European Association for the Study of the Liver (EASL) Annual Meeting in Copenhagen on April 24, 2009.

 

In this 15-day study, SCY-635 was well-tolerated with no serious adverse events, no discontinuations and no dose-limiting toxicities. At the highest dose tested in the study (900 milligrams/day) SCY-635 exhibited clinically relevant antiviral activity and substantial suppression of plasma viremia throughout the treatment period. In the 900 mg cohort all treated patients showed a viral load reduction with a group mean maximum decrease of 2.2 log10 on the last day of the study (p < 0.05 for the day 15 comparison).

 

“In this single-agent study SCY-635 demonstrated highly potent antiviral activity that was sustained throughout treatment with the nadir occurring on the last day of the study, suggesting that with a longer treatment period we may see even greater reductions in viral load,” said Dr. Sam Hopkins, SCYNEXIS’ Chief Scientific Officer. “These clinical results combined with earlier preclinical work demonstrating additive or synergistic activity with both approved and investigational agents suggest that in a combination regimen, SCY-635 may improve rates of sustained virological response.”

 

“These results establish proof-of-concept for SCY-635 in HCV patients and more broadly support our proprietary discovery platform, which is focused on the development of cyclophilin inhibitors for multiple diseases,” said Dr. Yves Ribeill, President and Chief Executive Officer of SCYNEXIS. “Given that we have seen no dose related adverse events at our highest tested dose, we are in the process of optimizing the dose and regimen of SCY-635 in ongoing Phase 1 studies and plan to initiate a Phase 2 study in patients infected with HCV in the second half of the year.”

 

About the Clinical Trial

The clinical study was conducted as a Phase 1b, randomized, double-blind, placebo-controlled, multi-dose study in adult volunteers with genotype 1 chronic hepatitis C infection. SCY-635 was given as an oral capsule for 15 consecutive days. Patients were eligible for entry if they had plasma viremia in excess of 100,000 IU/ml, no evidence of decompensated liver function, no co-infections and if liver function tests were ≤ 2.5x Upper Limit of Normal. The study was conducted in two parts. Thirty-six subjects received SCY-635 once daily and twenty subjects received SCY-635 three times daily. All studies were conducted in the U.S.

 

About SCY-635 and SCYNEXIS’ Cyclophilin Inhibitor Platform

SCY-635 represents a new class of therapeutic agents for the treatment of HCV infection. SCY-635 is the first candidate in a novel class of non-immunosuppressive cyclophilin inhibitors owned by SCYNEXIS. Cyclophilins are a family of enzymatic proteins that assist in the folding and transport of other proteins synthesized within a cell. Cyclophilin inhibitors, such as Cyclosporine A, have been used for decades for the prophylaxis of organ rejection in transplant patients. Scientists at SCYNEXIS have synthesized derivatives of Cyclosporine A in which cyclophilin binding activity (which mediates anti-HCV activity) is separated from calcineurin binding activity (which mediates immunosuppression). A growing body of scientific evidence indicates that non-immunosuppressive analogs of Cyclosporine A may have applications in multiple therapeutic areas. Cyclophilins play a central role in the pathophysiology of chronic viral infection, neurodegenerative diseases and malignant transformation. Cyclophilin inhibition therefore represents an attractive target for drug discovery and development.

 

About SCYNEXIS

SCYNEXIS is a premier drug discovery and development company delivering effective and innovative drug pipeline solutions to pharmaceutical and global health partners. The Company, which is located in Research Triangle Park, North Carolina, is also developing a proprietary internal pipeline based on cyclophilin inhibitors, a class of drugs that hold significant potential for the treatment of a broad range of diseases. Please visit our website at www.scynexis.com 

 

Merck Announces Interim Phase IIa Study Results of MK-7009, an Investigational Oral Hepatitis C Virus Protease Inhibitor, in Patients with Chronic Hepatitis C

http://www.fiercebiotech.com

 

Phase IIb Trial will Further Assess Efficacy, Safety and Tolerability of MK-7009

 

COPENHAGEN, DENMARK, April 23, 2009 - Results from an ongoing Phase IIa study showed that MK-7009, an investigational oral hepatitis C virus (HCV) protease inhibitor under development by Merck & Co., Inc., Whitehouse Station, N.J., U.S.A.,, in combination therapy significantly improved rapid viral response, defined as viral suppression to undetectable levels within 28 days, compared to placebo in combination therapy in previously untreated (treatment-naïve) patients infected with chronic HCV genotype 1, one of the most difficult to treat genotypes of HCV [1] (p<0.0001).  All patients received MK-7009 or placebo in combination with pegylated interferon and ribavirin (peg-IFN/RBV), the current standard of care for treatment of HCV infection.  (Poster 2701) These findings were presented today at the 44th Annual European Association for the Study of the Liver (EASL) meeting in Copenhagen, Denmark.

 

According to the World Health Organization, an estimated 180 million people are infected with HCV worldwide, 130 million of whom are chronic HCV carriers at risk of developing liver cirrhosis and/or liver cancer. It is estimated that three to four million persons are infected each year.[2]

 

"In this ongoing study, MK-7009 in combination therapy rapidly lowered and generally maintained the amount of virus in the blood to below detectable levels in previously untreated HCV patients," said Robin Isaacs, vice president and therapeutic head for Infectious Diseases, Merck Research Laboratories.   "These preliminary results help us understand the efficacy and tolerability profile of MK-7009 and support the further development of MK-7009 for the treatment of HCV."

 

These findings are the primary analysis from an ongoing, randomized, placebo-controlled, double-blind study of MK-7009 in treatment-naïve, chronic HCV patients.  In this study, 95 patients were randomized across five treatment arms with regimens of MK-7009 300 mg or 600 mg twice daily, MK-7009 600 mg or 800 mg once daily, or placebo, for 28 days. Patients in all treatment arms received standard doses of peg-IFN/RBV in combination with the MK-7009 or placebo regimens, and are continuing to receive peg-IFN/RBV for an additional 44 weeks.  HCV RNA was measured by the HCV RNA PCR TaqMan 2.0 assay, which has a lower limit of detection (LLOD) of 10 IU/mL and a lower limit of quantification (LLOQ) of 25 IU/mL. The primary endpoint of the study was reduction in HCV RNA to undetectable levels (<10 IU/mL) at day 28.

 

Suppression of viral load to undetectable levels by day 28

After 28 days of therapy, 69 to 82 percent of patients in the regimens containing MK-7009 (n= 68 included in the per-protocol analysis) versus 6 percent of patients in the placebo regimen (n=18 included in the per-protocol analysis) achieved undetectable HCV RNA levels (p<0.0001). More than 80 percent of patients in the regimens containing MK-7009 versus 11 percent of patients in the placebo regimen experienced viral suppression to below LLOQ (<25 IU/mL) on day 28.

 

Viral suppression continued in the majority of patients following termination of MK-7009 treatment at day 28. At day 42, HCV RNA was undetectable in 77 to 94 percent of the patients in the regimens that had contained MK-7009 versus 12 percent of patients in the regimen that had contained placebo (p<0.0001).  Additionally, all subjects in the 600 mg twice daily regimen group achieved HCV RNA to below LLOQ (<25 IU/ml) from Day 21 through Day 42.

 

Tolerability and safety profile of MK-7009

There were no serious adverse events and no discontinuations due to an adverse event during the first 42 days of the study. The most commonly reported adverse experiences (> 20 percent in one or more treatment arms) in patients receiving MK-7009 versus patients receiving placebo, respectively, were nausea (28 to 40 percent versus 26 percent), headache (16 to 45 percent versus 37 percent), fatigue (5 to 35 percent versus 32 percent), flu-like symptoms (20 to 26 percent versus 16 percent), anorexia (5 to 25  percent versus 11 percent), diarrhea (6 to 25 percent versus 21 percent), indigestion (0 to 22 percent versus 21 percent), rash (10 to 17 percent versus 21 percent) and vomiting (0 to 40 percent versus 5 percent).  The incidence of vomiting was higher in the treatment arm containing MK-7009 600 mg twice daily (40 percent) versus the treatment arm containing placebo (5 percent); vomiting did not require anti-emetic treatment and did not lead to discontinuation or dose reduction of MK-7009.

 

Phase IIb study to further assess efficacy, safety and tolerability of MK-7009

A Phase IIb study has been initiated to evaluate the safety, tolerability and efficacy of MK-7009 when administered concomitantly with peg-IFN/RBV to previously treated (treatment-experienced) patients with chronic hepatitis C genotype 1 infection. Patients will receive either placebo or MK-7009 at 300 mg or 600 mg twice daily in combination with standard doses of peg-IFN/RBV. The trial is a multicenter, partially double-blind, randomized, placebo-controlled trial that aims to enroll approximately 200 patients in multiple countries.

 

The study will measure the safety and tolerability of MK-7009 at all dose regimens as compared to placebo through 48 weeks.  Additionally, the study will evaluate the proportion of patients in the MK-7009 600 mg treatment regimens achieving sustained viral response, i.e., undetectable viral load 24 weeks after the end of all study therapy, as compared to patients in the placebo regimen.

 

Bristol-Myers Squibb and ZymoGenetics Present Positive 4-week Results of PEG-Interferon lambda with Ribavirin in Hepatitis C

http://finance.yahoo.com

 

- PEG-Interferon lambda well tolerated in combination with Ribavirin -

 

- Mean maximum HCV RNA viral load decrease 3.0 logs or greater at all weekly dose levels -

 

PRINCETON, N.J. & SEATTLE--(BUSINESS WIRE)--Bristol-Myers Squibb (NYSE:BMY - News) and ZymoGenetics, Inc. (NASDAQ:ZGEN - News), today reported that the administration of the investigational compound PEG-Interferon lambda in combination with ribavirin in 10 patients resulted in a significant reduction in hepatitis C virus (HCV) RNA and was well tolerated in patients with relapsed HCV in an ongoing Phase 1b clinical trial. Antiviral activity was observed at all dose levels tested either as single agent or in combination with ribavirin. Treatment was well-tolerated with reversible, dose-dependent increases in liver enzyme levels and bilirubin. There was no evidence for potentiation of ribavirin-induced toxicities in the combination groups. The interim results were presented at the European Association for the Study of the Liver (EASL) annual meeting in Copenhagen, Denmark.

 

 PEG-Interferon lambda showed antiviral effects as a single agent and also in combination with ribavirin. The lack of hematologic adverse effects in the trial is very encouraging,” said Mitchell Shiffman, M.D., Virginia Commonwealth Medical Center.

 

The Phase 1b clinical trial was designed to evaluate the safety and antiviral activity of PEG-Interferon lambda as a single agent or in combination with ribavirin in genotype 1 HCV patients with relapsed disease. The single agent part of the study, designed to assess PEG-Interferon lambda administered subcutaneously either with a weekly or every other week dose-escalation schedule at 1.5 mcg/kg and 3.0 mcg/kg for four weeks, is complete. In the combination part of the study, data are available for the first 10 subjects who have received weekly subcutaneous administration of PEG-Interferon lambda at doses of 0.75 mcg/kg (3 patients) or 1.5 mcg/kg (7 patients) with daily oral ribavirin administered per the package insert over a four-week period.

 

Antiviral activity was seen in all cohorts, with a mean maximum decrease in HCV RNA viral load of at least 3.0 log10 in all single agent and combination cohorts receiving weekly dosing. Of the 22 patients dosed weekly, 86% showed a 2 log10 or greater decrease in HCV RNA at Day 29 and 50% had less than 1,000 HCV RNA copies. Of the six patients treated weekly with 3.0 mcg/kg single agent, 50% achieved a rapid virologic response (RVR; undetectable HCV RNA copies at 4 weeks).

 

PEG-Interferon lambda was well tolerated over four weeks of treatment with minimal hematologic effects or constitutional symptoms. No fever was reported. The majority of adverse events were Grade 1 or 2, the most common of which were fatigue (18%) and nausea (18%). Reversible, dose-dependent increases in liver enzymes (ALT, AST) meeting the protocol criteria for dose-limiting toxicity were observed in four patients, of which three also experienced reversible increases in bilirubin. There were no clinically significant changes in serum chemistry or renal function. Decreases in mean hemoglobin values occurred only in ribavirin cohorts, and there was no neutropenia.

 

The EASL poster presentations will be made available on the ZymoGenetics website at www.zymogenetics.com.

 

PEG-Interferon lambda

PEG-Interferon lambda (IL-29) is a novel type 3 interferon currently in Phase 1b development for hepatitis C. The native human protein Interferon lambda is generated by the immune system in response to viral infection.

 

Valeant Pharmaceuticals Highlights Taribavirin Phase IIb 60-Week Data Presentation at European Association for the Study of Liver (EASL) Annual Meeting

http://news.prnewswire.com

  

ALISO VIEJO, Calif., April 23 /PRNewswire-FirstCall/ -- Valeant Pharmaceuticals (NYSE: VRX) today announced that results from the week-60 analysis for its Phase IIb dose-finding clinical trial for taribavirin, a prodrug of ribavirin which is in development for the treatment of chronic hepatitis C in conjunction with a pegylated interferon, was presented today at the European Association for the Study of Liver (EASL) 44th Annual Meeting in Copenhagen, Denmark.

 

The results were presented in an abstract entitled "Efficacy And Safety of Weight-Based Regimens of Taribavirin or Ribavirin, Given With Peginterferon Alfa-2b, At 12 Weeks After Treatment (SVR12) In Naive Patients With Genotype 1 Chronic-Hepatitis C", with an oral presentation given by Fred Poordad, M.D., Chief of Hepatology at the Center for Liver Disease and Transplant, Cedars-Sinai Medical Center, Los Angeles, CA and principal investigator in this study.

 

The company previously reported week 12 and 48 results from this Phase IIb trial. The study consists of 48 weeks of treatment with a 24-week post-treatment follow-up period during which period the week 60 results were collected from the arms receiving 20mg/kg and 25mg/kg taribavirin and the ribavirin control arm. Similar to the week 12 and 48 results, the 60-week viral response data continue to show comparable reductions in viral load for weight-based doses of taribavirin and ribavirin in a difficult-to-treat population of subjects infected Hepatitis C genotype 1. At the end of week 60, the statistically significantly lower anemia rate for patients receiving taribavirin in the 20mg/kg and 25mg/kg arms versus the ribavirin control arm has been maintained at a rate similar to the end of treatment (week 48).

 

Table:  Efficacy/Safety (intent-to-treat)

 

The most common adverse events during treatment were fatigue, nausea, flu-like symptoms, headache and diarrhea. The incidence rates for these adverse events among treatment arms were generally comparable except with respect to diarrhea, where incidence of diarrhea was approximately twice as common in patients receiving taribavirin compared to patients receiving ribavirin. However, the diarrhea was generally mild and not treatment limiting for taribavirin or ribavirin patients.

 

The Phase IIb trial is a U.S. multi-center, randomized, parallel, open-label study in 278 treatment-naive, genotype 1 patients evaluating taribavirin at weight-based doses of 20 mg/kg, 25 mg/kg, and 30 mg/kg per day in combination with pegylated interferon alfa-2b. The control group was administered weight-based dose ribavirin (800/1000/1200/1400mg daily) and pegylated interferon alfa-2b. Overall treatment duration is 48 weeks with a post-treatment follow-up period of 24 weeks.

 

About Taribavirin

Taribavirin is an investigational compound that has not been found by the Food and Drug Administration (FDA) or any other regulatory agency to be safe or effective in the diagnosis, mitigation, treatment or cure of any disease or illness. It may not be sold or promoted in the United States unless and until approved for marketing by the FDA. Similar restrictions apply in other countries.

 

About Study 204

In the Phase IIb study (previously disclosed as Study 204), 278 treatment naive, genotype 1 patients were randomized with the following patient demographics: mean age 48.8 yrs, 61.1% male, 30% African-American or Latino, 80.7% viral load ¿400,000 IU/mL and 82.1 kg mean weight. Week (TW) 60 efficacy and safety results for the intention-to-treat (ITT) population are shown in the table above.

 

About Valeant

Valeant Pharmaceuticals International (NYSE: VRX) is a multinational specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of neurology and dermatology. More information about Valeant can be found at www.valeant.com.

 

TRANSGENE : Transgene presents additional Phase I data for TG4040 in hepatitis C chronically infected patients at EASL and is now preparing for Phase II trial    

http://www.euronext.com

 

Parc d'Innovation, Illkirch, France, April 23rd, 2009 - Transgene S.A. (Euronext Paris: FR0005175080) today announced additional interim results from its ongoing Phase I clinical study of its therapeutic vaccine TG4040 (MVA-HCV) conducted in treatment-naive patients chronically infected with the Hepatitis C Virus (HCV), and its decision to initiate a Phase II trial, planned for the beginning of 2010, in combination with standard of care (pegylated interferon alpha plus ribavirin).

 

A detailed analysis of these results was presented today at an oral session of the EASL (European Association for the Study of Liver disease) annual meeting held in Copenhagen. The TG4040 Phase I data are as follows:

 

·        All studied doses were safe and well-tolerated. The most frequent adverse events were minor to moderate injection site reactions and influenza-like symptoms. No adverse event leading to discontinuation or treatment modification and no serious adverse event related to TG4040 were reported.

·        Overall, 6 out of 15 patients experienced a decrease in viral load ranging from 0.5 to 1.4 log10 IU / mL from baseline.

·        For the 2 patients showing the most significant viral load reduction (0.8 and 1.4 log10), this decrease coincided with an increase of vaccine-specific T-cell response (up to three times baseline levels). Furthermore, for one of those two patients, IFN-gamma-producing cells peaked one to two weeks after the third injection and remained detectable until the last follow-up analysis (six months), while during the same period the viral load remained significantly low. For those patients with no or minimal change in viral load, no immune responses to NS3 and NS4B viral antigens related to the vaccine, or to NS5A non-related to the vaccine were detectable by IFN-gamma ELISpot at any time during follow up.

 

Philippe Archinard, Chief Executive Officer of Transgene, stated: "These additional Phase I results are encouraging as they support the expected mechanism of action of TG4040 that aims at inducing an effective HCV-specific T cell-based immune response associated with the control of viral replication. The data also confirm the very good safety profile of TG4040. This promising exploratory study allows us to actively prepare the next clinical steps, which will involve the initiation of a large proof of concept controlled Phase II clinical trial that will seek to demonstrate synergy of TG4040 in combination with standard of care. We anticipate the product's entry into this controlled Phase II trial early next year."

 

About the TG4040 Phase I Trial programme

The current trial is an open-label, multi-centre, dose-escalation study testing the safety and biological activity of TG4040 in treatment-naive patients chronically infected by HCV (genotype 1). The trial is being conducted in three clinical sites in France and enrolled 15 treatment-naive patients chronically infected with the genotype 1 HCV. The patients received three weekly subcutaneous injections of TG4040. Dosing was escalated from 106 pfu (cohort 1 = three patients), to 107 pfu (cohort 2 = three patients), and to 108 pfu (cohort 3 = nine patients). Patients treated with the highest dose also received a boost injection of TG4040 at month 6.

 

In March 2008, the study was extended to include 27 patients in 3 additional cohorts. This extension aimed at fine-tuning the timing of the boost with cohorts 5 and 6 receiving boost injection respectively at 2 and 4 months, and at evaluating safety in more advanced liver diseases in cohort 4. Fourteen additional patients have been included in the study so far. We anticipate results of the study extension in the third quarter 2009.

 

In January 2006, Transgene was awarded a E1.3 million grant by the Lyonbiopôle Competitiveness Cluster for the development of its therapeutic vaccine TG4040 against hepatitis C chronic infection. The funding, which originates from the French Ministry of Industry, is expected to cover approximately 30% of the research and development costs for the programme.

 

Another Phase I trial is being conducted in Canada and involves the treatment of 24 patients that are chronically infected with the Hepatitis C Virus (HCV) and who have relapsed after standard treatment with ribavirin and pegylated interferon alpha. The trial is sponsored by the University of Montreal and supported by the Canadian Network for Vaccines and Immunotherapies. Availability of safety data as well as preliminary viral and immunological data is planned by the end of 2009.

 

About TG4040

Transgene's TG4040 product is based on the MVA virus carrying and expressing non-structural proteins (NS3, NS4 and NS5B) of the hepatitis C virus. The MVA vector is a highly attenuated strain of vaccinia virus that combines an extensive history of safety with the ability to stimulate a strong immune response to antigens.

 

UPDATE 2-Schering hepatitis C drug shines, but anemia seen

www.reuters.com

By Ransdell Pierson

 

* Best response seen for any drug in mid-stage trials

* But anemia seen in half of treated patients

* 39 to 51 pct of treated patients needed EPO for anemia

 

 

NEW YORK, April 23 (Reuters) - A Schering-Plough Corp (SGP.N) drug knocked the hepatitis C virus down to undetectable levels in three-fourths of patients in a mid-stage study, twice the effectiveness seen with standard treatments, researchers said on Thursday.

 

But half the patients taking the boceprevir experimental medicine developed anemia -- a potential commercial disadvantage to a similar pill called telaprevir that Vertex Pharmaceutical Inc (VRTX.O) is developing.

 

Both drugs work through a new mechanism -- by blocking a protein called protease that the virus needs to replicate -- and are considered potential big-selling products. As many as 4 million Americans are believed to be infected with the virus, the leading reason for liver transplants.

 

Results of the Phase II boceprevir trial, involving 595 patients who were infected with the virus but had not previously been treated, were presented in Copenhagen at the annual meeting of the European Association for the Study of the Liver. Patients had genotype 1, the most common form of the virus.

 

During the first month of the study, all patients received the two standard hepatitis C treatments sold by Schering-Plough -- a long-acting form of interferon called Pegintron and the anti-viral pill ribavirin.

 

One group of patients then added boceprevir to Pegintron and ribavirin for 44 weeks, while another group took only Pegintron and ribavirin over the same period.

 

After the 48-week trial concluded, 75 percent of those in the boceprevir group had a sustained virologic response (SVR) -- meaning undetectable levels of virus.

 

"This is the highest sustained virologic response reported for any Phase II study of patients with genotype 1," said Dr. Paul Kwo, an associate professor at Indiana University School of Medicine, the study's chief investigator.

 

By contrast, only 38 percent of patients who did not get boceprevir drove the virus down to undetectable levels in the same 48-week period.

 

Researchers also determined that after only 28 weeks of treatment with boceprevir, Pegintron and ribavirin, 56 percent of patients achieved SVR.

 

Anemia was seen in about half of patients taking boceprevir, and in a third of patients taking only Pegintron and ribavirin.

 

Erythropoietin (EPO), a widely used anemia treatment, was used by 39 percent to 51 percent of patients taking boceprevir, and by 26 percent of those taking only Pegintron and ribavirin.

 

"Management of anemia with EPO is a common practice in hepatitis C treatment today," said Kwo, who noted that ribavirin and protease inhibitors both increase the risk of anemia.

 

A lesser incidence of anemia was reported last year for Vertex' rival telaprevir in mid-stage trials -- ranging from 29 to 37 percent of patients. Telaprevir knocked the virus to undetectable levels in about two thirds of patients.

 

Kwo, who has also tested the Vertex product, said data from late-stage trials of boceprevir and telaprevir will provide a clearer indication of relative anemia risk for the two new protease inhibitors.

 

Geoffrey Porges, a biotech analyst for Sanford Bernstein who is attending the Copenhagen meeting, said the need to take EPO to control anemia will hurt boceprevir.

 

"It would be very unusual for a drug to go forward and more or less require the use of another drug that's not even approved for that indication," Porges said.

 

Boceprevir is considered one of the most important of Schering-Plough's experimental drugs. Merck & Co (MRK.N) will inherit the pill when it completes its planned purchase of Schering later this year.

 

Shares of Merck were down 0.57 percent to $22.85, while Schering-Plough fell 0.14 percent to $21.64, both in late morning trading on the New York Stock Exchange.

 

(Additional reporting by Bill Berkrot) (Reporting by Ransdell Pierson; Editing by Lisa Von Ahn and Gunna Dickson)

 

ANA598 Demonstrates Potent Antiviral Activity At All Dose Levels In Completed Phase Ib Study In Hepatitis C Patients

http://www.medicalnewstoday.com/

 

Anadys Pharmaceuticals, Inc. (Nasdaq: ANDS) announced that ANA598, the Company's investigational non-nucleoside polymerase inhibitor, demonstrated potent antiviral activity at all dose levels and was well tolerated in a Phase Ib study in which patients chronically infected with the Hepatitis C virus (HCV) were treated for three days. The results from the recently completed study are being presented today during the late-breaker poster session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark.

 

In the study, ANA598 treatment resulted in rapid and sustained reductions in HCV RNA with median reductions at end of treatment (Day 4) exceeding 2 log10 (>99%) at all dose levels. At 200 mg bid (twice-daily), the median viral load reduction was 2.4 log10 (range of 0.4 to 3.4); at 400 mg bid, 2.3 log10 (range of 1.6 to 3.5); and at 800 mg bid, 2.9 log10 (range of 2.2 to 3.4). Genotype 1a patients demonstrated median reductions of 1.4 log10, 1.8 log10, and 2.5 log10 at 200, 400 and 800 mg bid, respectively. In 10 of the 12 genotype 1a patients who received ANA598, viral load was still declining at the end of the three days of treatment. Genotype 1b patients demonstrated median reductions of 2.6 log10, 2.5 log10, and 3.2 log10, at 200, 400 and 800 mg bid, respectively. No patient showed evidence of viral rebound while on ANA598. ANA598 was well-tolerated in this short term study and there were no serious adverse events.

 

Steve Worland, Ph.D., Anadys' President and CEO, commented that "The potent antiviral activity demonstrated at all three doses in this study is very encouraging for the prospects of ANA598 when used in combination with other HCV agents. With the successful conclusion of this study in patients and the 14-day study in healthy volunteers, the positive 13-week animal toxicology results and ongoing manufacturing activities, the ANA598 program continues on track to be ready for Phase II in mid-2009."

 

The Phase Ib study was a randomized, double-blind, placebo-controlled, multiple ascending dose trial conducted to evaluate the safety, tolerability and antiviral activity of orally administered ANA598 in treatment-naive patients with chronic HCV genotype 1 infection. Patients were treated with ANA598 capsules (or matching placebo) at doses of 200 mg, 400 mg or 800 mg bid for three days. 35 patients participated in the study, with 11 receiving 200 mg bid, eight receiving 400 mg bid, eight receiving 800 mg bid and eight receiving placebo (with none of the patients receiving placebo showing an end of treatment response greater than 0.2 log10 reduction in viral load). Viral load at Day 4 (12 hours after the last dose) was compared to baseline HCV RNA levels.

 

"We're very pleased with the antiviral activity and safety of ANA598 in this study," commented James Freddo, M.D., Senior Vice President, Drug Development and Chief Medical Officer. "We believe the data continue to position ANA598 as a leading non-nucleoside polymerase inhibitor in development for the treatment of HCV, and we look forward to investigating ANA598 in longer-term studies in combination with current standard of care."

 

ANA598 Program Update

Anadys continues to make progress on all aspects of the ANA598 program, including toxicology, manufacturing and a recently completed 14-day clinical study in healthy volunteers. The Company reiterates its expectation for the program to be ready mid-year for the first Phase II study of ANA598 in combination with pegylated interferon and ribavirin. The actual timing for the initiation of Phase II studies may depend on a number of factors, including FDA review timelines, the timing of any potential transaction around ANA598 or ANA773, available cash resources and funding activities, and the engagement of clinical sites.

 

14 Day Healthy Volunteer Study

Anadys recently completed dosing healthy volunteers in a 14-day study conducted to extend the safety and pharmacokinetic profile of ANA598. Thirty subjects participated in the study, with eight subjects receiving ANA598 and two subjects receiving placebo at each dose level (400 mg once-daily, 800 mg once-daily and 600 mg bid). Subjects received ANA598 or placebo on day one followed by pharmacokinetic assessment over days two and three and received subsequent doses consecutively on days four through fourteen. Preliminary results from the study indicate that ANA598 was generally well-tolerated in all cohorts with no serious adverse events, although three subjects receiving ANA598 (two in the 800 mg once-daily cohort and one in the 600 mg bid cohort) developed grade 2 rash and discontinued treatment after either six or seven days of consecutive dosing. There were no other instances of rash in this or any other study of ANA598. Data receipt and analysis from this study is continuing, and the Company expects to present the results at a clinical conference later this year. The Company believes the results of this study, combined with the results of the Phase Ib study in HCV patients, contribute to the attractive profile of ANA598 as an antiviral likely to be active in long-term studies in combination with pegylated interferon and ribavirin, and help position the program to be ready for Phase II in mid-2009.

 

Long-term Toxicology Studies

In September 2008, Anadys initiated long-term, chronic toxicology studies of ANA598, of 26 weeks duration in rats and 39 weeks duration in monkeys. Based on a now completed analysis of data at the 13-week interim in both species, the No Observed Adverse Effect Level (NOAEL) in monkeys and male rats remains 1000 mg/kg at 13 weeks, the highest dose being tested in the chronic studies. In female rats the NOAEL at the 13-week interim was 300 mg/kg, with the only adverse finding in female rats, observed only in the 1000 mg/kg dose group, being a marginal decrease in the rate of weight gain. Anadys previously reported NOAELs in both species after 28 days of 1000 mg/kg, the highest dose tested in that study. The dosing portion of the 26-week study in rats is now complete, while the dosing portion of the 39-week study in monkeys is scheduled to conclude in June. Anadys expects that the results from these chronic toxicology studies, if continuing to be favorable, will enable dosing of ANA598 for up to 48 weeks in the Phase II study of ANA598 in combination with pegylated interferon and ribavirin.

 

ANA598 Preclinical Data at EASL Meeting

In addition to the results of the Phase Ib HCV patient study, Anadys is presenting additional data on the preclinical profile of ANA598 at the EASL Meeting at 4 p.m. CEST (7 a.m. PDT) on Friday, April 24. In an oral presentation, Anadys will present in vitro data showing that combinations of ANA598 with interferon-alpha, the protease inhibitor telaprevir and the nucleoside polymerase inhibitor PSI-6130 are synergistic. These studies also show that ANA598 retains activity against mutants known to confer resistance to other classes of direct antivirals, including protease inhibitors, nucleoside inhibitors, and non-nucleosides that, through virtue of binding at a different site than ANA598, display a resistance profile distinct from that of ANA598. Genotypic mutations resistant to ANA598 will be shown to be fully susceptible to interferon-alpha, telaprevir and PSI-6130.

 

About ANA598

Anadys retains worldwide rights to ANA598, which was fully discovered at the Company. Preclinical evaluation of ANA598 was completed in the first quarter of 2008, leading to submission of an Investigational New Drug Application (IND) to the U.S. Food and Drug Administration (FDA), subsequent allowance of the IND by the FDA and initiation of clinical investigation in the second quarter of 2008. In December 2008, Anadys announced that the FDA granted fast track designation to ANA598 for the treatment of chronic HCV.

 

In October 2008, Anadys initiated patient dosing in the Phase Ib study of ANA598 in HCV patients and in February 2009 Anadys initiated dosing in a 14 day study in healthy volunteers.

 

In an earlier Phase I study in healthy volunteers, ANA598 was administered as capsules at single oral doses of 400 mg, 800 mg, 1400 mg, 2000 mg (fed and fasted) and 3000 mg. In addition, a separate cohort received two 800 mg doses 12 hours apart. ANA598 was well tolerated at all doses and there were no serious adverse events or withdrawals from the study. All reported adverse events were classified as mild or moderate, with no apparent dose relationship. The pharmacokinetic profile demonstrated sustained plasma levels of ANA598 consistent with the potential for once-daily or twice-daily oral dosing.

 

In the preclinical program, ANA598 was well tolerated at all doses tested in 28-day GLP toxicology studies. In September 2008, Anadys initiated long-term, chronic toxicology studies of ANA598.

 

If ANA598 is successful in early stage development, the Company anticipates completion of the clinical, toxicology and manufacturing activities required to initiate Phase II studies of ANA598 in combination with current standard of care in mid-2009.

 

Source: Anadys Pharmaceuticals, Inc

 

Final Results Of Boceprevir Phase II HCV SPRINT-1 Study Showed Significantly Higher SVR Rates Compared To Standard Of Care

http://www.medicalnewstoday.com

 

Schering-Plough Corporation (NYSE: SGP) reported that final results of the HCV SPRINT-1 study showed boceprevir, its investigational oral hepatitis C protease inhibitor, in combination with peginterferon alfa-2b and ribavirin, significantly increased sustained virologic response (SVR)(1) rates with 28 and 48 weeks of therapy compared to current standard of care, peginterferon and ribavirin for 48 weeks (control group). The results from this Phase II study in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 were presented at the 44th European Association for the Study of the Liver (EASL) 2009 Annual Meeting.(2) Genotype 1 is the most common and hardest to treat form of hepatitis C.

 

In Part I of the study, a 48-week boceprevir regimen achieved a 75 percent SVR rate (n=77/103) in patients who received 4 weeks of PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) (P/R) followed by the addition of boceprevir (800 mg TID) for 44 weeks (boceprevir P/R lead-in regimen). This represents a near doubling of the 38 percent SVR rate (n=39/104) for patients in the control group (p<0.0001). In a 28-week boceprevir P/R lead-in regimen 56 percent of patients (n=58/103) achieved SVR (p=0.005).(3)

 

Importantly, the likelihood (predictability) of attaining SVR was greater for patients who received the boceprevir P/R lead-in regimens compared to the no lead-in arms. Of patients in the boceprevir P/R lead-in arms who achieved a rapid virologic response (RVR), 94 percent in the 48-week regimen and 82 percent in the 28-week regimen achieved SVR. RVR is defined as undetectable virus (HCV RNA) in plasma at 4 weeks after the addition of boceprevir. In the lead-in arms, 64 percent of patients achieved RVR. Fewer patients in the lead-in arms discontinued treatment due to viral breakthrough.

 

"These results are very exciting and provide important insights to help further define response guided therapy using a P/R lead-in boceprevir regimen with peginterferon and ribavirin backbone treatment," said Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, and lead investigator of the study. "Building on these results, the boceprevir Phase III clinical program individualizes treatment based on response, utilizing RVR criteria at week 4 of boceprevir treatment to determine overall duration of therapy. Based on the RVR rate seen in this Phase II study, we are hopeful that the majority of patients can be treated with 28 weeks of therapy."

 

Part II of the HCV SPRINT-1 study explored a low-dose ribavirin strategy in which boceprevir was given in combination with PEGINTRON and low-dose REBETOL for 48 weeks. SVR for the low-dose REBETOL arm was 36 percent (n=21/59) compared to 50 percent for a 48-week control arm with PEGINTRON and standard-dose REBETOL plus boceprevir (n=8/16). In contrast to the results seen in Part I, the low-dose REBETOL regimen was associated with increased viral breakthrough during treatment, higher relapse rates after the end of treatment and lower SVR, strongly indicating that standard-dose ribavirin is required to optimize response.

 

Another key finding of the HCV SPRINT-1 study is that treatment-emergent anemia appeared to be associated with higher SVR, with anemic patients (hemoglobin decreasing to less than 10 g/dL) having higher SVR rates than those without anemia (hemoglobin did not decrease to less than 10 g/dL). Anemia is a known adverse event with combination therapy for hepatitis C and this association with higher SVR has been seen in other clinical studies with peginterferon and ribavirin, including the IDEAL study.(4) Boceprevir is associated with about a 1 g/dL incremental decrease in hemoglobin. In the HCV SPRINT-1 study, anemia occurred in approximately half of the patients in the boceprevir arms and over a third of patients in the control arm. Erythropoietin (EPO) supplementation was allowed in the study at the discretion of the investigator and was used by 26 percent of patients in the control arm and 39-51 percent of patients in the boceprevir arms with standard-dose REBETOL.

 

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. The incidence of skin adverse events (rash or pruritus) observed in the boceprevir arms was similar to that seen in the PEGINTRON and REBETOL control arm.

 

Treatment discontinuations due to adverse events in Part I of the study were between 9 and 19 percent for patients in the boceprevir arms, compared to 8 percent for the control arm. Treatment discontinuations for boceprevir patients due to viral breakthrough were fewer in the 28- and 48-week lead-in arms (4 and 5 percent, respectively) compared to the no lead-in arms (7 and 12 percent, respectively).

 

SCH 900518 (Next-Generation HCV Protease Inhibitor) Data at EASL

Researchers at EASL also presented early phase clinical data for SCH 900518, Schering-Plough's investigational next-generation HCV protease inhibitor.(5) This proof-of-concept study explored the safety and antiviral activity of two different dosing regimens for SCH 900518 administered as monotherapy and in combination therapy with PEGINTRON with or without ritonavir in treatment-naive and treatment-experienced patients with HCV genotype 1. In this study, low doses of ritonavir were used for metabolic inhibition to enhance the levels of SCH 900518 within the body and reduce the frequency of SCH 900518 dosing (BID vs. TID).

 

In the study, SCH 900518 administered as monotherapy exhibited potent antiviral activity, achieving 4.0-4.5 log10 decreases in viral load (HCV RNA) from baseline at day 8. SCH 900518 was well tolerated, with no drug related serious adverse events. Pharmacokinetic and pharmacodynamic modeling from this study was used to design the ongoing Phase IIa dose-finding study of SCH 900518 with ritonavir in combination with PEGINTRON and REBETOL. This study, known as NEXT-1, explores SCH 900518 in 200 mg, 400 mg or 600 mg once daily (QD) doses with low-dose ritonavir (100 mg) in combination with PEGINTRON and REBETOL (with and without a 4-week P/R lead-in period) in treatment-naive patients with HCV genotype 1.

 

About the HCV SPRINT-1 Study

In this Phase II study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) was evaluated in three treatment regimens: 4 weeks of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment), boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28 or 48 weeks, and, in Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL (400-1000 mg daily based on patient weight) for 48 weeks. In Part I of the study, the boceprevir regimens were compared to a control of PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). In Part II of the study, boceprevir in combination with PEGINTRON and low-dose REBETOL for 48 weeks was compared to a contemporaneous control of PEGINTRON, full-dose REBETOL and boceprevir for 48 weeks. The primary endpoint of the study was SVR after 24 weeks of follow up. In the study, the 28-week and 48-week boceprevir no lead-in arms had SVR rates of 54 percent (n=58/107) and 67 percent (n=69/103), respectively.

 

The HCV SPRINT-1 study was conducted at sites across the United States, Canada and Europe. Overall, 77 percent of the 595 patients in the study were enrolled in the United States. African-Americans represented 16 percent of the patients enrolled and 7 percent of the patients in the study were cirrhotic.

 

Rationale for Lead-In Regimen

The use of the P/R lead-in prior to the addition of boceprevir was shown in the HCV SPRINT-1 study to reduce the incidence of viral breakthrough regardless of treatment duration. The rationale for the lead-in treatment regimen is based on the fact that both PEGINTRON and REBETOL reach steady-state concentrations by week 4, therefore patients have the protease inhibitor added at a time when the backbone drug levels have been optimized and viral load (HCV RNA) has been reduced. In addition, the patient's immune system will have been activated and primed by PEGINTRON at the time that boceprevir is added to the regimen. This approach may minimize the period of time when there is a "functional monotherapy" with a direct antiviral agent, potentially reducing the likelihood for the development of resistance.

 

About Ongoing Boceprevir Phase III Registration Studies

Patient enrollment has been completed in two ongoing randomized, double-blind, placebo-controlled registration studies evaluating boceprevir in combination with PEGINTRON and REBETOL compared to standard of care with PEGINTRON and REBETOL alone. More than 1,500 patients were enrolled in these studies at U.S. and international sites.

 

The HCV SPRINT-2 study evaluates the efficacy of 28- and 48-week lead-in regimens of boceprevir (800 mg TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks in treatment-naive adult patients with chronic HCV genotype 1. The study enrolled a total of 1,099 patients, including 158 African-American/Black patients.

 

The HCV RESPOND-2 study evaluates 36- and 48-week lead-in regimens of boceprevir in combination with PEGINTRON and REBETOL at the same doses as described above compared to a control of PEGINTRON and REBETOL alone for 48 weeks in adult patients with chronic HCV genotype 1 who failed prior treatment (relapsers and nonresponders) with peginterferon and ribavirin combination therapy. The study enrolled a total of 404 patients.

 

In both registration studies, RVR criteria at 4 weeks of boceprevir treatment (treatment week 8) is used to determine which boceprevir patients can stop all treatment at 28 weeks (HCV SPRINT-2) or 36 weeks (HCV RESPOND-2).

 

Source: Schering-Plough Corporation

 

Idenix Pharmaceuticals Reports Data From Three Hepatitis C Development Programs

http://www.medicalnewstoday.com

 

Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, reported data from its three hepatitis C development programs being presented this week at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark. These presentations include data on IDX184, a once-daily, oral nucleotide polymerase inhibitor prodrug currently being evaluated in a phase Ib/IIa clinical trial, and data on two clinical candidates: IDX375, a non-nucleoside polymerase inhibitor and IDX316, a protease inhibitor, both currently undergoing IND-enabling preclinical studies.

 

"Idenix's primary goal is to discover and develop the leading HCV antiviral platform," said Jean-Pierre Sommadossi, Ph.D., chief executive officer of Idenix. "With drug candidates in each of the three major classes of direct-acting HCV antivirals in our pipeline, we believe that we are well positioned to design an optimal combination therapy."

 

IDX184 Nucleotide Prodrug Polymerase Inhibitor

IDX184 is a liver-targeted, oral nucleotide prodrug designed to enhance the formation of its active triphosphate in the liver, while minimizing systemic exposure to IDX184 and the resulting nucleoside metabolite (NM). IDX184 is fully active against HCV genotypes 1, 2, 3 and 4 and, preclinically, has demonstrated increased antiviral activity when tested in combination with HCV protease inhibitors, non-nucleoside polymerase inhibitors, interferon or ribavirin.

 

IDX184 has been evaluated in a seven-day study in HCV-infected chimpanzees, in which six genotype-1 infected chimpanzees received 10 mg/kg of IDX184 daily for four days. Data presented at EASL confirm a pharmacokinetic/pharmacodynamic (PK/PD) relationship between nucleoside metabolite concentrations in serum and viral load reductions in this study. Trough serum nucleoside metabolite levels were low, ranging from 2-8 ng/mL, and there was a direct correlation between levels of NM and HCV RNA, with greater viral load reductions observed as the NM levels increased. Specifically, serum trough NM levels of greater than 2 ng/mL were associated with HCV RNA reductions of 1 log10 or greater.

 

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

 

A phase I/II proof-of-concept clinical trial of IDX184 in treatment-naive HCV genotype-1 patients is ongoing.

 

IDX316 Protease Inhibitor

IDX316 exhibited potent activity against HCV NS3/4A proteases from multiple genotypes (1a, 1b, 2a and 4a) and in HCV replicons. Long-term in vitro treatment (14 days) with IDX316 produced high levels of suppression that was maintained over the treatment period without evidence of rebound or cytotoxicity. IDX316 also demonstrated high selectivity, with tight binding to the HCV protease and no activity observed against eight human cellular proteases. IDX316 retained activity against common mutations in NS3 and exhibited enhanced activity when combined with standard-of-care agents or other Idenix compounds in development (IDX184 and IDX375). Favorable PK profiles in rodent and non-human primate species suggest the potential for once- or twice-daily dosing in humans (half-life of 4.0-5.2 h; bioavailability of ~20%).

 

IDX375 Non-Nucleoside Polymerase Inhibitor

The preclinical pharmacokinetic and toxicology profile of IDX375 was also presented at EASL. Data support once- or twice-daily dosing in HCV-infected patients based on favorable bioavailability and plasma drug exposure levels in animal studies. IDX375 showed limited metabolism and no cytotoxicity when incubated with mouse, rat, monkey or human hepatocytes. IDX375 demonstrated no adverse effects in monkeys given daily oral doses of 10 or 100 mg/kg for 7 days.

 

About Idenix

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of infections caused by hepatitis C virus.

 

Source: Idenix Pharmaceuticals, Inc

 

First Evidence For DNA-Based Vaccination Against Chronic Hepatitis C

http://www.medicalnewstoday.com

 

The first-proof-of-concept for a DNA-based therapeutic vaccination against chronic hepatitis C was announced at EASL 2009, the Annual Meeting of the European Association for the Study of the Liver in Copenhagen, Denmark.

 

In the first clinical trial of a therapeutic vaccination using naked DNA delivered by in vivo electroporation (EP), antiviral effects were shown in patients with hepatitis C (HCV). Researchers hope that this will encourage further clinical development. The data also provide further evidence for the antiviral role of the HCV-specific T cell response.

 

It is estimated that some 3% of the world's population is infected with HCV. In industrialised countries, hepatitis C accounts for 70% of chronic hepatitis cases. One of the main concerns is that HCV infection remains asymptomatic until advanced stages of the disease.

 

Clearance of HCV infection correlates with activation of the host T cell response. Therefore, in this study, researchers developed a T cell vaccine based on a codon-optimised HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C®) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.

 

Professor Matti Sallberg of Laboratory Medicine, the Karolinska Institutet, Stockholm, Sweden, who led the study, said: "In 50-80% of adult cases, the immune system fails to eliminate the HCV virus and the disease becomes chronic. Given that only about 50% of HCV infected persons are diagnosed in most developed countries and that two-thirds need to undergo antiviral treatment, this new vaccination has huge implications in terms of the future management of this widespread disease."

 

In this study, a volume of 0.5 ml saline containing ChronVac-C® DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses administered using a 1.5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). The study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load <800,000 IU/ml were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.

 

In the 167µg group, no severe side effects were observed, two patients mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose, no severe side effects were observed, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses, both patients had reductions in the viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient, no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose, no severe side effects were observed, and one patient developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1.2 log10 and 2.4 log10, respectively. Thus, 67% (four out of six) of patients in the two highest dose groups had reductions in the viral load exceeding 0.5 log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.

 

Source:  Camilla Dormer, European Association for the Study of the Liver

 

New Oncogene Gives Valuable Insight Into Hepatocellular Tumors In Humans

http://www.medicalnewstoday.com

 

The first identification of GP130 somatic activating mutations* in human tumours was announced at EASL 2009, the Annual Meeting of the European Association for the Study of Liver Disease in Copenhagen, Denmark.

 

Identification of recurrent somatic mutation activating GP130 in inflammatory hepatocellular tumours reveals a new pathway of tumourigenesis in humans, according to researchers. This finding reinforces the role of inflammation in hepatocarcinogenesis and particularly in the malignant transformation of hepatocellular adenomas (HCA). Moreover, GP130 mutations will enable the refinement of the molecular classification of hepatocellular tumors in humans.

 

Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by an over-expression of inflammatory proteins. IHCA are usually developed in women and their occurrence is frequently associated with obesity and alcohol intake. Recently, somatic mutations were identified that activated GP130 in 60% of IHCA (Rebouissou et al, Nature, 2009), thus defining GP130 as a new oncogene in human tumours. This study aimed to evaluate frequency of GP130 mutations in a wide series of tumours.

 

Dr Jessica Zucman-Rossi of Inserm U674, Paris, France, who led the study, said: "This exciting advance means we now have a novel means of further investigating the development pathway of hepatocellular tumours as well as a new tool in the classification of hepatocellular tumours. It is an important step forward in our understanding of hepatocarcinogenesis and the future management of this disease."

 

Researchers in this study screened a series of 400 well-characterised hepatocellular tumours including hepatocellular adenomas, carcinomas, hepatocholangio-carcinoma, fibrolamellar carcinomas and intra-hepatic cholangiocarcinomas. 100 tumours from different organs were also collected. To search for mutations, GP130 exons were screened in all samples and the function of 7 different mutants was analysed in HEP3B.

 

A somatic mutation was identified in 65% of the IHCA including 24 different small in-frame deletions or duplications. A spectrum of mutations shows that mutations clearly target the IL-6 binding site in GP130. Also demonstrated was the fact that the expression of the most frequent GP130 mutants in HEP3B cells activates STAT3 in absence of IL-6. The researchers searched for possible interaction and cooperation of GP130 activation with other pathways altered in hepatocellular adenoma. HNF1α inactivation and gp130 activation were mutually exclusive in HCA (P< 10-4). By contrast, in half of the ß-catenin activating HCA, a GP130-activating mutation was identified. For two IHCA associated with a malignant transformation, both an activating gp130 and ß-catenin mutations were found. Further, analysis of 220 hepatocellular carcinomas revealed rare GP130 alterations in all cases accompanied by ß-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant transformation of hepatocytes.

 

*Somatic activating mutation of GP130 = the modification of only a few "coding letters" of the gp130 gene that leads to activation of the inflammatory response and escape of tumour hepatocytes from external control.

 

Source: Camilla Dormer, European Association for the Study of the Liver

 

Diabetes, Obesity And Hypertension Increase Mortality In Hepatitis C Patients

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The specific impact of metabolic syndrome on mortality in hepatitis C patients has been revealed by new research to be presented on Sunday April 26 at EASL 2009, the Annual Meeting of the European Association for the Study of the Liver in Copenhagen, Denmark.

 

According to the results of the research, type 2 diabetes (DM), obesity and hypertension (HTN) are associated with overall and liver related mortality in hepatitis C (HCV) infected patients. In HCV-infected patients, the top three predictors of liver related mortality were having higher body mass index (BMI), presence of insulin resistance (IR) and elevated serum cholesterol. Overall mortality in HCV patients was most linked to metabolic syndrome, higher BMI and hypertension.

 

Metabolic syndrome is a combination of medical problems that increase risks of cardiovascular disease and diabetes. It affects one in five people, and prevalence increases with age. Recent data have suggested that metabolic syndrome is associated with adverse outcomes in HCV patients. This study set out to assess which aspects of metabolic syndrome are of most risk to such HCV patients and to quantify their specific impact on mortality.

 

Professor Zobair Younossi MD, MPH from the Center for Liver Diseases at Inova Fairfax Hospital and the Executive Director of Betty and Guy Beatty's Center for Integrated Research, Virginia, USA, who led the study, said: "Exploring the risk factors associated with adverse outcomes in HCV patients helps us to better understand the complex nature of this highly prevalent disease. This study shows a clear association between key components of metabolic syndrome and mortality in HCV patients and demonstrates the importance of lifestyle improvements and coaching in the management of HCV patients, to potentially minimise the onset and impact of metabolic syndrome and its associated mortality risks."

 

Researchers in this study utilised the Third National Health and Nutrition Examination Survey (NHANES III) and Linked Mortality Files. HCV was defined as positive HCV RNA by PCR assay. Subjects without other causes of chronic liver disease such as presumed NAFLD with elevated serum aminotransferases (ALT> 40 U/L, AST> 37 U/L in men, and ALT> 31 U/L, AST>31 U/L in women), excessive alcohol use (>10 grams/day in women and > 20 grams/day in men), elevated transferrin saturation (>50%) and positive hepatitis Bs antigen were designated controls without liver disease. HCV patients were compared to HCV-negative individuals and controls without liver disease using Rao-Scott chi-square statistics. Adjusted hazard ratios (AHR, 95% CI) for overall mortality and cause-specific mortality were calculated for HCV patients using persons without HCV. The Cox proportional hazard model was used for calculation of AHR for independent risk factors, and for the presence of HCV as a potential risk factor for overall mortality and cause-specific mortalities. MS was defined according to ATP-III and insulin resistance (IR) was defined as HOMA>3.0.

 

The cohort included 15,866 individuals with complete data. Among those, 264 patients were HCV-positive, and 13,004 were considered controls. HCV patients had more IR (37.4±3.2% vs. 22.8±0.9%, p< 0.0001) and higher rate of DM (9.2±2.3% vs. 5.5±0.3%, p=0.0885) than controls. In comparison to the HCV-negative patients, HCV patients had higher overall mortality (AHR=2.80, 2.79-2.81), higher liver-related mortality (AHR=17.96, 17.80-18.12), higher DM-related mortality (AHR=18.55, 18.36-18.74) and higher mortality from solid organ malignancy (AHR=1.601, 1.587-1.616). In HCV patients, increased overall mortality was associated with components of MS [DM (AHR=2.139, 2.11-2.16), higher BMI (AHR=1.054, 1.53-1.055) and HTN (AHR=1.408, 1.394-1.422)]. In HCV patients, increased liver-related mortality was associated with higher BMI (AHR=1.275, 1.274-1.277) and HTN (AHR=3.751, 3.653-3.851).

 

Dr Younossi added "This is the largest population-based study to provide the strongest evidence confirming an association between components of MS, especially type 2 diabetes and obesity, with adverse mortality outcomes for HCV infected patients. These data should help us not only develop better targeted treatment strategies for HCV patients but also encourage public health policies to address the increasing epidemic of obesity and type 2 diabetes that may affect a large number of population, including those infected with HCV".

 

Source: The European Association for the Study of the Liver