AASLD Publishes New Guideline on HCC

Gastroenterology & Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by Christina Frangou

The American Association for the Study of Liver Diseases (AASLD) has issued a new practice guideline on the management of hepatocellular carcinoma (HCC), after recent data made a 2005 version obsolete. The authors called for greater surveillance of high-risk groups as well as changes to diagnostic, surveillance and staging techniques, including dropping alpha-fetoprotein (AFP) from the list of recommended tests and adding sorafenib to the list of acceptable treatments.

“In the past decade, [HCC] has gone from being an almost universal death sentence to a cancer that can be prevented if detected at an early stage and effectively treated,” wrote the authors of the guideline, which was published in the March 2011 issue of the journal Hepatology (Bruix J et al. Hepatology 53:1020-1022).

Gastroenterologist Lewis R. Roberts, MB, ChB, PhD, called the document a “very important” aid for clinicians. “There were no major surprises in the guideline,” said Dr. Roberts, professor of medicine at Mayo Clinic in Rochester, Minn. “It reflects the preponderance of evidence for screening diagnosis and therapy for HCC. And it recognizes our change in viewpoint that HCC has become a cancer that can be detected at an early stage and effectively treated or transformed into a chronic disease.”

AFP Testing

In a letter to Hepatology, Jorge A. Marrero, MD, associate professor of internal medicine at the University of Michigan, Ann Arbor, and Hashem B. El-Serag, MD, professor of medicine at Baylor College of Medicine, Houston, criticized the omission of AFP, saying the guidelines “ignore a significant amount of data” about its efficacy in surveillance of patients at risk of HCC (2011;53:1060-1061). “In the absence of randomized studies in patients with cirrhosis, the current evidence points to US [ultrasonography] combined with serum AFP as the most effective surveillance strategy for patients at risk for HCC. The guidelines should be revised to recommend US with AFP as the best-available surveillance strategy,” they wrote.

The guideline authors responded, saying they stand by their recommendation of surveillance by US every six months.

“Although the randomized controlled study of HCC screening used both AFP and US, we believe that contribution of AFP to the outcome was minimal and maintain our position that it should not be used. US is a better test, and we should not be recommending inferior tests in guidelines such as this,” they said.

Screening and Surveillance

Much of the guidelines focus on improving surveillance for HCC. Surveillance is considered cost effective if the expected risks exceed 1.5% per year in patients with hepatitis C and 0.2% in patients with hepatitis B. Screening is recommended every six months for Asian male hepatitis B carriers over age 40; Asian female hepatitis B carriers over age 50; hepatitis B carriers with a family history of HCC; African/North American blacks with hepatitis B; cirrhotic hepatitis B carriers; and patients with hepatitis C cirrhosis, stage 4 primary biliary cirrhosis, genetic hemochromatosis and cirrhosis, alpha-1 antitrypsin deficiency and cirrhosis.

Diagnosis should be based on imaging techniques and/or biopsy. Staining for glypican 3, heat shock protein 70 and glutamine synthetase can help reinforce expert pathology diagnoses. Positive results on two of the three stains confirm HCC. The authors do not recommend contract-enhanced US, saying it may offer false-positive HCC diagnosis in patients with cholangiocarcinoma. Moreover, they recommend diagnostic imaging criteria be applied only to patients with cirrhosis of any etiology and patients with chronic hepatitis B who may not have fully developed cirrhosis or regressed cirrhosis.

The standard for staging has changed as well. The authors said that the Barcelona-Clinic Liver Cancer staging system has become the “de facto system that is used.”

Treatment Options

Sorafenib, the first approved targeted agent for the treatment of HCC, is now considered the “first-line treatment” in patients with HCC who can no longer be treated with potentially more effective therapies.

“These patients did not have any effective option until now and the availability of a treatment option represents a major advancement,” said Dr. Bruix.

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Novel Pegylated Interferon Safer, More Effective Than Current Treatment, Study Shows

Gastroenterology and Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by David Wild

Berlin—A novel variant of pegylated interferon (PegIFN) called PegIFN-lambda is significantly more effective than PegIFN-alfa-2a (Pegasys, Genentech) at suppressing viral loads in patients with certain genotypes of hepatitis C virus (HCV), according to preliminary findings from an ongoing randomized trial. Patients also experienced fewer adverse events on the novel PegIFN.

“If the superior virological response rates and minimal adverse events are sustained through the completion of this study and replicated in other research, this form of interferon will represent a major advance in the treatment of chronic hepatitis C,” said Emmet Keeffe, MD, professor emeritus of medicine, Stanford University Medical Center, Palo Alto, Calif., who was not involved in the study.

An estimated 20% of patients stop treatment for HCV because of side effects associated with PegIFN-alfa-2a. PegIFN-lambda attaches to fewer cellular receptors than PegIFN-alpha-2a and thus may be a safer and equally effective alternative.

In this study, lead researcher Stefan Zeuzem, MD, and colleagues at 39 international centers randomly assigned individuals with chronic HCV to receive ribavirin in combination with PegIFN-alfa-2a 180 mcg (n=132), PegIFN-lambda 120 mcg (n=130), PegIFN-lambda 180 mcg (n=131) or PegIFN-lambda 240 mcg (n=133). The study is ongoing, but the current efficacy and safety findings are based on 12 weeks of double-blinded treatment.

The data showed that 14.7% and 16.5% of those with HCV genotypes 1 and 4 who received 180 and 240 mcg of PegIFN-lambda, respectively, experienced a rapid virologic response (RVR) to the novel drug compared with 5.8% of patients with the same HCV genotypes who took PegIFN-alfa-2a (P<0.05). The RVR rate among individuals with genotypes 1 and 4 who received 120 mcg of PegIFN-lambda was 6%.

Complete early virologic response rates were 55%, 55.9% and 56.3% among those with HCV genotypes 1 and 4 who received 120, 180 and 240 mcg of PegIFN-lambda compared with 37.9% among PegIFN-alfa-2a recipients (P<0.05). Response rates among those with HCV genotypes 2 and 3 did not differ significantly between the treatment groups, the researchers reported.

Patients administered PegIFN-lambda also experienced fewer flu-like and musculoskeletal symptoms as well as fewer cytopenias (Table). However, aspartate and alanine transaminase levels rose to more than five times the upper limit of normal in 17.4% of those receiving the highest dose of PegIFN-lambda, and direct bilirubin concentration exceeded 1.2 mg/dL in 7.6% of patients in the same group. These adverse events resolved with dose reduction or drug discontinuation.

Table. Adverse Events in Patients Receiving PegIFN-lambdaa For Hepatitis C Virus Infection PegIFN-alfa-2a 180 mcg (n=132) PegIFN-lambda 240 mcg (n=133) PegIFN-lambda 180 mcg (n=131) PegIFN-lambda 120 mcg (n=130) Flu-like symptoms 42.9% 9.7% 9.9% 12.5% Musculoskeletal symptoms 46.6% 14.2% 14.5% 18% Hemoglobin <10 g/dL 44% 12.9% 15.4% 20.5% Neutrophils <750/mm3 15.2% – 0.8% – Platelets <50,000/mm3 14.4% – – – PegIFN, pegylated interferon a All patients also received ribavirin.

“This is indeed a promising new drug,” said Dr. Zeuzem, professor and chair, Department of Medicine, Johann-Wolfgang Goethe University Hospital, Frankfurt/Main, Germany, who presented his group’s findings at the 46th annual meeting of the European Association for the Study of the Liver (Abstract 1360).

“Now we need to assess longer-term sustained virological responses and to accumulate more safety data,” he said.

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Statin Appears To Boost Efficacy of Pegylated Interferon-Ribavirin for Treatment of Hepatitis C

Gastroenterology and Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by David Wild

Berlin—A new study found that adding 20 mg daily of fluvastatin to pegylated interferon-ribavirin (PegIFN-ribavirin) significantly increased the likelihood that patients with chronic hepatitis C virus (HCV) infection will have early and sustained virologic responses. The findings add to a growing body of evidence that shows statins have an important place in the treatment of chronic HCV infection.

“These data, as well as preliminary findings from an ongoing trial I am helping conduct, support the addition of fluvastatin to peginterferon and ribavirin for treating some hepatitis C patients,” commented Ted Bader, MD, director of liver diseases at the University of Oklahoma Health Sciences Center, in Norman, who was not involved in the current study.

Since a study that was published in 2008 showed fluvastatin monotherapy reduced HCV loads in 31 infected patients, interest in the potential use of the drug for this indication has increased (Bader T et al. Am J Gastroenterol 2008;103:1383-1389).

To further explore the drug’s use in treating HCV, Eugen Georgescu, MD, PhD, and colleagues compared viral loads and liver function between 104 patients with HCV who were randomly assigned to receive PegIFN-ribavirin plus fluvastatin 20 mg once daily and 105 patients with HCV given PegIFN-ribavirin plus a placebo, both for 48 weeks. None of the subjects had used statin medications within the year before study onset and all were followed for 24 weeks. Fifty subjects had metabolic syndrome.

Dr. Georgescu, who presented the findings at the 46th annual meeting of the European Association for the Study of the Liver (abstract 2922), said that viral loads at study onset were similar in both groups: 3.79±0.29 10⁶ IU/mL for placebo versus 3.47±0.26 10⁶ IU/mL for the fluvastatin group. After 12 weeks of treatment, mean HCV loads decreased to 0.33±0.04 10⁶ IU/mL in the placebo group and 0.21±0.03 10⁶ IU/mL in the fluvastatin group. The reduction in viral loads was significantly greater in the treatment group (94.53%) than in the placebo group (91.74%) compared with baseline (P=0.031).

Moreover, 76% of statin recipients experienced an early virologic response after 12 weeks of treatment, in contrast to 62% of patients in the placebo group (P=0.049). Viral suppression persisted at 72 weeks in significantly more patients who received fluvastatin compared with placebo recipients (63% vs. 50%, respectively; P=0.05).

The added efficacy of fluvastatin held regardless of metabolic syndrome status; 85% of fluvastatin and 71% of placebo recipients without metabolic syndrome had an early virologic response, and 74% and 58% of the same groups showed a sustained response at 72 weeks (P<0.05 for both).

The researchers said that although fluvastatin use resulted in statistically significant improvements, the changes were relatively modest.

“Nevertheless, our results justify further research to confirm statins as an adjuvant therapy in chronic hepatitis C and to understand the mechanisms underlying its synergistic effects with PegIFN-ribavirin therapy,” concluded Dr. Georgescu, professor in the Department of Internal Medicine/Gastroenterology, Filantropia Municipal Hospital, in Craiova, Romania.

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Hepatitis C Treatment Changing Rapidly With Approvals Of Two New Drugs

Gastroenterology & Endoscopy News
ISSUE: JUNE 2011 | VOLUME: 62:06

by Rosemary Frei

On the heels of data presented at the 46th annual meeting of the European Association for the Study of the Liver (EASL) meeting and this year’s Digestive Disease Week meeting came the FDA approval of two new drugs designed to boost the effectiveness of peginterferon-ribavirin therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection. On May 13, the FDA approved boceprevir (Victrelis, Merck) followed days later by the approval of telaprevir (Incivek, Vertex/Tibotec), marking an eagerly anticipated revolution in the management of patients with HCV.

Cascade of Data

Data on the new drugs have not been in short supply. An article published last year in The New England Journal of Medicine on the use of telaprevir for previously treated patients with chronic HCV genotype 1 infection brought this new class of agents—inhibitors of HCV protease—into the spotlight (McHutchison JG et al. 2010;362:1292-1303). The results of the randomized, double-blind phase II study—known as PROVE3 (Protease Inhibition for Viral Evaluation 3)—indicated that the addition of telaprevir for as few as 12 weeks significantly increased sustained virologic response (SVR).

Two Phase III studies published in March indicated that boceprevir also boosted efficacy in as few as 24 weeks. Results of the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2) trial indicated that the three-drug cocktail nearly tripled SVR rates in previously treated patients (Bacon BR et al. N Engl J Med 2011;364:1207-1217). Furthermore, data from the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial also showed that SVR rates in treatment-naïve patients are boosted significantly with the addition of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).

Final results from the Phase III REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial also were presented at the EASL meeting. These data included all three major subgroups of patients who were not cured with a prior course of interferon-based therapy, including null responders.

All of the boceprevir studies were paid for by Merck, and the telaprevir studies were sponsored by Vertex and its collaborator, Tibotec.

Stephen H. Caldwell, MD, professor of medicine and director of hepatology, University of Virginia Health System, Charlottesville, pointed out that the emerging therapies for hepatitis C offer a significant increase in sustained viral eradication but also bring treatment complexity, side effects and expense.

“Emerging from the myriad of study names are new monitoring recommendations and prognostic indicators that will take time to really understand,” Dr. Caldwell said. “We should recall that the best-performed studies are closely monitored, often at a level unachievable in clinical practice. Clearly, the field has changed rapidly in a very short period of time. Careful assessment and thoughtful consideration will be key to optimizing success and minimizing failure,” he said.

Boceprevir Trials

In a poster presented at the EASL meeting, John M. Vierling, MD, and colleagues from Baylor College of Medicine in Houston analyzed the relationship between patients’ response during the lead-in period in the boceprevir trials and overall SVR rates. The investigators defined response during the lead-in period as at least a 1.0-log₁₀ reduction in HCV RNA. Data from the SPRINT-2 and RESPOND-2 trials were combined for this study.

The researchers found a steady, stepwise increase in the percentage of patients achieving SVR after at least 24 weeks of triple-agent therapy based on the level of decrease in viral load after the four-week lead-in period with peginterferon-ribavirin alone. The pattern was particularly noticeable among non-black patients. Overall, the advantage of adding boceprevir was greatest for patients with less responsiveness to interferon.

“Patients in the boceprevir arms with a poor response to interferon had sufficiently high rates of SVR as compared with the control group. … [This] dispels concern that the addition of boceprevir to the treatment regimen would be the equivalent of functional monotherapy,” the investigators noted. “However, patients who have a poor response to the interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available.”

They add that conversely, addition of boceprevir may not boost SVR rates among patients with undetectable HCV RNA levels after the lead-in period, but that “in the majority of these patients, total treatment duration is shortened to 28 weeks.”

The four most common treatment-related adverse events (AEs) in the RESPOND-2 and SPRINT-2 studies were fatigue, headache, nausea and anemia. In RESPOND-2, treatment discontinuation due to anemia occurred in 3% of boceprevir patients in 48-week treatment only. None of the controls discontinued due to anemia. The respective numbers for SPRINT-2 were 2%, 2% and 1%.

Erythropoietin was allowed for the treatment of anemia at the discretion of the investigators, and in RESPOND-2 was used by 41% and 46% of boceprevir patients in the response-guided and 48-week treatment arms, respectively, compared with 21% of patients in the control arm. In SPRINT-2, the respective numbers were 43%, 43% and 24%. (P values were not supplied.)

Fred Poordad, MD, chief of hepatology and liver transplantation at the Comprehensive Transplant Center at Cedars-Sinai Medical Center in Los Angeles, and lead investigator of the SPRINT-2 trial, gave a talk at the EASL meeting outlining the utility of using an interleukin (IL)-28B polymorphism as a baseline predictor of four- and eight-week response to triple-agent therapy. Dr. Poordad and colleagues from the SPRINT-2 and RESPOND-2 trials examined on SVR rates in patients with three different IL-28B polymorphisms: cysteine–cysteine, thymine–thymine and cysteine–thymine. They determined that the cysteine–cysteine polymorphism is associated most strongly with SVR response; patients with this polymorphism may be eligible for short-duration therapy.

Dr. Poordad’s team also found that lead-in response is a stronger predictor of SVR than any other single baseline characteristic, including IL-28B polymorphism. They concluded that because IL-28B polymorphism status and lead-in response “are powerful predictors of SVR,” the optimal approach may be to use both.

“Taken together, these data showed that the addition of boceprevir to peginterferon and ribavirin achieved significantly higher SVR rates in patients with chronic HCV genotype 1 compared with peginterferon and ribavirin alone, and that nearly half of all patients were eligible to receive a shorter duration of therapy,” Dr. Poordad said.

Telaprevir Trials

The REALIZE trial was a randomized, double-blind, placebo-controlled study of people who were previously treated unsuccessfully for HCV infection.

Subjects were randomized 2:2:1 into two telaprevir-based treatment arms—a “lead-in” arm and a “simultaneous-start” arm—and a control arm, which comprised 48 weeks of treatment with peginterferon-ribavirin alone. The lead-in arm included a four-week lead-in period of treatment with peginterferon-ribavirin followed by the addition of telaprevir for 12 weeks, then followed by 32 weeks of treatment with peginterferon-ribavirin alone. The simultaneous-start arm involved 12 weeks of triple-combination therapy, followed by 36 weeks of peginterferon-ribavirin alone.

Forty-eight percent (316 of 662) of the patients had advanced liver fibrosis or cirrhosis, and 89% (586 of 662) had a high HCV RNA load (≥800,000 IU/mL) at study entry.

The primary end point in all three groups was SVR. The results were analyzed based on three subgroups of patients: patients with undetectable levels of HCV RNA during at least 42 weeks of prior treatment that later became detectable (prior relapsers); patients who achieved at least a 2-log₁₀ decrease in HCV RNA by week 12 of treatment but who did not achieve undetectable levels by week 24 (prior partial responders); and, those who did not achieve a 2-log₁₀ decrease in HCV RNA by week 12 of treatment (prior null responders).

SVR rates for all patients in the telaprevir treatment arms were significantly greater compared with patients in the control group (Table; P<0.001). This held true for patients in the two telaprevir-containing arms combined, among which 86% (245 of 286) of the prior relapsers achieved SVR, 57% (55 of 97) of prior partial responders had an SVR and 31% (46 of 147) of the prior null responders had an SVR.

Table. SVR Rates in the REALIZE Trial Treatment Arm Prior Relapsers (n=354) Prior Partial Responders (n=124) Prior Null Responders (n=184) Lead-in with telaprevira 88%d (124/141) 54%d (26/48) 33%d (25/75) Simultaneous start with telaprevirb 83%d (121/145) 59%d (29/49) 29%d (21/72) Controlc (no telaprevir) 24% (16/68) 15% (4/27) 5% (2/37) a Four-week lead-in period of treatment with peginterferon-ribavirin, followed by the addition of telaprevir for 12 weeks, followed by 32 weeks of treatment with peginterferon-ribavirin alone b Combination therapy with telaprevir and peginterferon-ribavirin for 12 weeks started simultaneously, followed by 36 weeks of peginterferon-ribavirin alone c Forty-eight weeks of treatment with peginterferon-ribavirin alone d P<0.001, compared with control REALIZE, Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes; SVR, sustained virologic response

“We believe the data showed that an immediate start of a 12-week telaprevir-based regimen substantially improved viral cure rates in all three major subgroups of people who were not cured with currently available medicines,” said Robert Kauffman, MD, PhD, senior vice president and chief medical officer, Vertex Pharmaceuticals.

The most common AEs in the telaprevir studies were fatigue, pruritus, nausea, headache, rash and anemia. Anemia occurred in 36% of patients in the treatment lead-in arm, 30% of subjects in the simultaneous-start arm and 15% in the control arm; erythropoietin treatment was not allowed in the study. Rash was present in 36% of patients in the lead-in arm, 37% in the simultaneous-start arm and 19% of the control arm. Three percent of patients in the telaprevir-treatment arms discontinued all treatment because of anemia and 3% did so because of rash. (No P values were provided.)

Series Editor Tarun Mullick, MD Clinical Faculty Rush-Copley Medical Center Aurora, Illinois Clinical Staff Delnor Hospital Geneva, Illinois Provena Mercy Medical Center Aurora, Illinois Commentary by Dr. Mullick For the past decade, treatment with pegylated interferon and ribavirin for hepatitis C virus (HCV) genotypes 2 and 3 was able to provide a sustained virologic response (SVR) of approximately 80% after 24 weeks of treatment. However, the more difficult to treat HCV genotype 1 not only requires 48 weeks of treatment with pegylated interferon and ribavirin, but also is associated with an SVR ranging from 40% to 50%. The problem with pegylated interferon and ribavirin and prior therapies was that they do not target the virus directly in a way that effectively puts the virus in a dormant state. Until now, therapies for patients with HCV genotype 1 infection were limited in their efficacy. With the arrival of two new HCV protease inhibitors, telaprevir and boceprevir, we now have drugs available that target the virus in a more direct and effective manner. In combination with pegylated interferon and ribavirin, the new protease inhibitors cut the duration of treatment to 24 weeks and achieve an SVR approaching 80%! The potential for side effects exists for each of the new drugs, with rash and bone marrow–related issues among them. Overall, however, this is the largest breakthrough in hepatitis C treatment in a decade. By the time other future therapies become available, these medications will likely have treated 80% of patients with HCV infection. These drugs have the potential to dramatically reduce the number of HCV patients who develop cirrhosis, liver cancer and who require liver transplant for this disease. Fantastic!

Retrospective analyses of IL-28B polymorphisms in patients treated with telaprevir also were presented at the EASL meeting. Data from the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) trial, a Phase III study of treatment-naïve patients with HCV, indicated that the cysteine–cysteine variation of the IL-28B polymorphism is associated with the highest SVR rates, at 90% compared with 73% among patients with the thymine–thymine polymorphism and 71% among individuals with the cysteine–thymine polymorphism.

Retrospective analysis of data from REALIZE indicated that the cysteine–cysteine variant also is associated with the highest SVR rates, at 79% compared with 61% for the thymine–thymine polymorphism and 60% for the cysteine–thymine polymorphism.

Additionally, interim results from a Phase II study of treatment-naïve HCV patients with the combination of telaprevir, peginterferon-ribavirin and the polymerase inhibitor VX-222 (Vertex) also were presented at the meeting. Of patients who received a combination of the four agents, 90% had undetectable HCV RNA after 12 weeks. In another group of patients who received a combination of the four agents with a lower dose of VX-222, 83% showed undetectable levels of HCV RNA.

“Boceprevir and telaprevir will greatly improve our ability to eradicate hepatitis C from both treatment-naïve as well as treatment-experienced patients,” commented Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Disease, University of Chicago Medical Center, who wrote an editorial accompanying the published results of RESPOND-2 and SPRINT-2 (N Engl J Med 2011;364:1272-1274). “However, this success will come at a cost—an increase in side effects and some increase in treatment complexity.”

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Noninvasive liver tests may predict hepatitis C patient survival

Public release date: 14-Jun-2011

Contact: Alissa J. Cruz
media@gastro.org
301-272-1602
American Gastroenterological Association

Non-invasive tests for liver fibrosis, such as liver stiffness measurement or the FibroTest, can predict survival of patients with chronic hepatitis C, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute.

"Liver stiffness measurement and/or the FibroTest could replace liver biopsy for the evaluation of hepatitis C, regardless of the stage of the disease," said Victor de Lédinghen, MD, PhD, of the Centre d' Investigation de la Fibrose Hépatique and lead author of this study. "Thus, these tools may help physicians assess prognosis early and discuss specific treatments."

Findings of this study are of major importance since liver stiffness, as a good predictive factor of survival, may help physicians evaluate the severity of liver disease earlier, decide with stronger arguments on a liver transplant or a portosystemic shunt (to bypass the liver), and evaluate more precisely the surgical risk of cirrhotic patients.

In chronic liver diseases, fibrosis assessment predicts liver-related complications and survival. In this study, doctors evaluated the five-year prognostic value of liver stiffness, non-invasive tests of liver fibrosis and liver biopsy to predict overall survival and survival without liver-related death in chronic hepatitis C.

A total of 1,457 patients with chronic hepatitis C were included. At five years, 77 patients died (39 liver-related deaths) and 16 patients had liver transplantation. Overall survival was 91.7 percent and survival without liver-related death was 94.4 percent. Survival was significantly decreased in patients diagnosed with severe fibrosis, no matter which non-invasive method was used.

All methods were able to predict shorter survival times; liver stiffness measurement and results of the FibroTest had higher predictive values. Doctors assessed fibrosis and — on the same day — liver stiffness, performed noninvasive tests of fibrosis (FibroTest, the aspartate aminotransferase to platelet ratio index, FIB-4), and analyzed liver biopsy samples.

"To our knowledge, this study is the first showing that liver stiffness has a prognostic value for overall survival and survival without liver-related death in patients with chronic hepatitis C virus infection," added Dr. Lédinghen. "The present study independently validated the prognostic value of the FibroTest and showed that liver stiffness and FibroTest can predict survival."

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For more information on hepatitis, please read the AGA brochure "Understanding Hepatitis" at www.gastro.org/patient-center/digestive-conditions/hepatitis.

About the AGA Institute
The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization. www.gastro.org.

About Gastroenterology
Gastroenterology, the official journal of the AGA Institute, is the most prominent scientific journal in the specialty and is in the top 1 percent of indexed medical journals internationally. The journal publishes clinical and basic science studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The journal is abstracted and indexed in Biological Abstracts, Current Awareness in Biological Sciences, Chemical Abstracts, Current Contents, Excerpta Medica, Index Medicus, Nutrition Abstracts and Science Citation Index. For more information, visit www.gastrojournal.org.

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Vertex and Alios BioPharma Announce Exclusive Worldwide Licensing Agreement for Two Nucleotide Drug Candidates, Broadening Vertex's Efforts to Develop New Combinations of Medicines for Hepatitis C

June 13, 2011

-Vertex gains worldwide rights to two distinct nucleotide analogues, ALS-2200 and ALS-2158, that act on hepatitis C polymerase-

-Collaboration provides multiple opportunities to develop new "all-oral" combination regimens-

CAMBRIDGE, Mass., & SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Alios BioPharma, Inc. today announced an exclusive worldwide licensing agreement that will add two distinct nucleotide analogues to Vertex's hepatitis C portfolio. The compounds, which were discovered by Alios and are known as ALS-2200 and ALS-2158, have shown in in vitro studies to be potent inhibitors of the hepatitis C virus (HCV) polymerase, an enzyme essential for replication of the virus. The addition of these compounds provides Vertex with multiple opportunities to develop potential, new, all-oral combination regimens for chronic hepatitis C. Vertex expects ALS-2200 and ALS-2158 to enter clinical development later this year.

"We are excited to begin working with Vertex, as we believe that the Alios nucleotide analogues provide an important opportunity to improve patient care in hepatitis C," said Lawrence M. Blatt, Ph.D., Founder and Chief Executive Officer of Alios BioPharma. "For more than a decade, Vertex has been a leader in the development of new approaches for treating hepatitis C, and together we have the potential to create an all-oral, interferon-free, combination therapy that could improve the safety, efficacy and ease of administration for patients. We look forward to initiating clinical development later this year."

"The recent approval of INCIVEK was a milestone in hepatitis C care, and today's announcement underscores our long-term commitment to further improving the treatment of this disease with new combinations of medicines," said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. "Alios has discovered anti-HCV nucleotides that have the potential to be leading agents in hepatitis C. Based on impressive in vitro data, we look forward to evaluating ALS-2200 and ALS-2158 together and in combination with our approved and investigational hepatitis C medicines with the goal of creating a highly potent all-oral regimen in the years ahead."

About ALS-2200 and ALS-2158

ALS-2200 and ALS-2158, currently in preclinical development, are highly potent nucleotide analogues that appear in in vitro and non-clinical studies to have a high barrier to drug resistance and the potential to be dosed once-daily. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound has its own unique mechanism of action, which supports the potential for developing these compounds together as a dual nucleotide regimen and as part of combination therapy regimens with Vertex's other approved and investigational medicines for chronic hepatitis C, including INCIVEK^TM (telaprevir), an FDA-approved hepatitis C protease inhibitor, and VX-222, an investigational hepatitis C non-nucleoside polymerase inhibitor. Data from in vitro studies showed that both ALS-2200 and ALS-2158 had a synergistic effect when combined together and with INCIVEK and VX-222. Additionally, in those in vitro studies, both compounds showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the U.S. Pan-genotypic compounds for hepatitis C have the potential to be used across a broad range of people with hepatitis C worldwide.

As part of this agreement, Vertex gains worldwide rights to both compounds, further enabling the company to potentially expand development and commercialization efforts in hepatitis C to areas outside North America over the coming years. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on the hepatitis C polymerase. Vertex will have the option to select compounds for development emerging from the research program.

Future Development Plans: Alios and Vertex plan to initiate clinical development of each compound in the fourth quarter of 2011, which is expected to include studies of the compounds in healthy volunteers followed by short-duration safety and viral kinetic studies in people with hepatitis C. The goal of the first clinical studies of these compounds is to generate data to enable the initiation of Phase 2 studies as early as the end of 2012. These Phase 2 studies are expected to evaluate multiple combination regimens of ALS-2200, ALS-2158, INCIVEK and VX-222. The combination studies would be designed to generate sustained viral response (SVR or viral cure) data. Additional details on the clinical development program for ALS-2200 and ALS-2158 will be provided later in 2011 upon initiation of the first clinical study.

Terms of the Transaction

As part of the agreement, Alios will receive a $60 million up-front payment from Vertex for the worldwide rights to ALS-2200 and ALS-2158. Vertex is responsible for development costs related to ALS-2200 and ALS-2158 and will also provide research funding to Alios. In addition, Alios would be eligible to receive research and development milestone payments up to $715 million if both compounds are approved. Vertex expects to pay approximately $35 million in development milestones in 2011. Alios is also eligible to receive up to $750 million in sales milestones on sales of all approved medicines under the collaboration. The agreement also includes tiered royalties on product sales.

Important Information About INCIVEK^TM (telaprevir) tablets
Indication

INCIVEK^TM (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment.

It is not known if INCIVEK is safe and effective in children under 18 years of age.

IMPORTANT SAFETY INFORMATION

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, you should not take INCIVEK combination treatment if you are pregnant or may become pregnant, or if you are a man with a sexual partner who is pregnant.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines you cannot take with INCIVEK combination treatment. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including rash and anemia. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Tell your healthcare provider about any side effect that bothers you or doesn't go away.

You are encouraged to report negative side effects of prescription drugs to the FDA at 1-800-FDA-1088 OR 1-800-332-1088 or www.fda.gov/medwatch. You may also report side effects to Vertex at 1-877-824-4281.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹

Unlike HIV and hepatitis B virus, chronic hepatitis C is curable.² However, approximately 60 percent of people with genotype 1 chronic hepatitis C do not achieve SVR,^3,4,5 or viral cure,⁶ after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.⁹ Hepatitis C is four times more prevalent in the United States compared to HIV.⁹ Genotype 1 is the most common form of HCV in the United States, accounting for around 70 percent of cases.¹³ However, different forms are more common in other parts of the world. The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.¹⁰ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.^11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.⁹

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives. Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

For more information and to view Vertex's press releases, please visit www.vrtx.com.

About Alios BioPharma

Alios BioPharma is a biotechnology company located in South San Francisco, California, that is developing novel medicines aimed at the treatment of viral diseases. Alios has an innovative team of highly experienced scientists and clinical researchers who are developing direct acting antiviral agents against several human viral pathogens of public health importance including, Hepatotropic viruses, Respiratory viruses and other chronic, acute and emerging viral diseases. Additionally, Alios is developing molecular activators of an interferon induced, broad spectrum antiviral innate immune pathway called RNase-L. The overall goal for the Alios therapeutic platform is to maximize patient benefits in areas of high unmet medical need through optimization of potency, safety and tolerability.
INCIVEK™ is a trademark of Vertex Pharmaceuticals Incorporated.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) Vertex broadening its efforts to develop new combinations of medicines for hepatitis C; (ii) multiple opportunities to develop new "all-oral" combination regimens; (iii) the expectation that clinical development of ALS-2200 and ALS-2158 will begin in 2011; (iv) the potential to create an all-oral, interferon-free, combination therapy that could improve the safety, efficacy and ease of administration for patients; (v) Vertex's long-term commitment to further improving the treatment of Hep C with new combinations of medicines; (vi) the anti-HCV nucleotides having the potential to be leading agents in hepatitis C; (vii) the goal of creating a highly potent all-oral regimen in the years ahead; (viii) the potential for development of these compounds together as a dual nucleotide regimen and as part of combination therapy regimens with INCIVEK (telaprevir) and VX-222; (ix) the potential to expand development and commercialization efforts in hepatitis C to areas outside North America over the coming years; (x) Alios' future research program and Vertex's option to select compounds that may emerge from the research program; (xi) all of the statements under the caption "Future Development Plans;" (xii) Vertex's responsibility for development and research funding; and (xiii) potential development and commercialization milestones and royalty payments. While the Company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the outcomes for our planned clinical trials and studies may not be favorable, that there may be varying interpretations of data produced by one or more of our clinical trials, that the Company may not obtain the benefits it expects to obtain from this transaction for a variety of reasons including the possibilities that the Company may not be able to successfully develop combination therapies involving INCIVEK and/or VX-222 and the drug candidates that the Company is acquiring in this transaction; and that in vitro data regarding ALS-2200 and ALS-2158 may not be predictive of results that may be obtained from clinical trials, and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the Company's website at www.vrtx.com. The Company disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX - GEN)

¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.
² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.
³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
⁷ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
⁹ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.
¹⁰ Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
¹¹ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
¹² Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
¹³ Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis in the United States. J Viral Hepat. 2000; 7:196-202.

Vertex Pharmaceuticals Incorporated

Investors:
Michael Partridge, 617-444-6108
Lora Pike, 617-444-6755
Matthew Osborne, 617-444-6057
or
Media:
Zachry Barber, 617-444-6992
mediainfo@vrtx.com
or
Alios:
John Donovan, 650-635-5504
Chief Business Officer
jdonovan@aliosbiopharma.com

Source: Vertex Pharmaceuticals Incorporated

Source

Massive Opportunity Exists in Hepatitis C Market for Recently Approved Protease Inhibitors Victrelis and Incivek According to a New Report by BioTrends Research Group

June 13, 2011 10:55 AM Eastern Daylight Time

 

EXTON, Pa.--(BUSINESS WIRE)--Results from an on-line survey fielded just prior to the FDA approval of Victrelis (boceprevir by Merck & Co.) and Incivek (telaprevir by Vertex/Johnson & Johnson/Mitsubishi Tanabe Pharma) suggest that uptake of the new protease inhibitors will be rapid and that a significant proportion of Hepatitis C (HCV) patients have been delaying treatment in anticipation of these new agents.

In TreatmentTrends®: Hepatitis C, BioTrends surveyed 150 gastroenterologists, hepatologists and infectious disease specialists about their current treatment of HCV, perceptions of Roche’s Pegasys and Merck & Co’s PegIntron, and anticipated future changes in disease management with emphasis on the expected use of Victrelis and Incivek.

The vast majority of respondents reported a high unmet need for HCV treatment options and noted that a high proportion of both prior treatment failures and treatment-naïve patients were waiting for approval of the new protease inhibitors before initiating (or re-initiating) therapy. In fact, the survey respondents reported that the leading change in treatment patterns over the past year was the “warehousing” of patients (delaying treatment) in anticipation of the approval of new treatment options. Within six months, respondents estimate that approximately three-quarters of genotype 1 HCV patients will be treated with the triple regimen of a protease inhibitor, peg-interferon and ribavirin.

Pegasys and PegIntron will likely see a boost related to the warehoused patients being initiated on triple therapy regimens. However, physicians are divided about which peg-interferon they will likely choose for these combination regimens. About one-third of the respondents report that they will follow the clinical trial regimen (PegIntron/Victrelis or Pegasys/Incivek), another third will use the peg-interferons interchangeably with either protease inhibitor and the remaining third will stick with their preferred peg-interferon regardless of which protease inhibitor brand they select.

The most desired attributes in new agents for the treatment of HCV were all efficacy oriented, despite the fact that many patients discontinue HCV therapy due to poor tolerability. There were no significant differences in familiarity or interest ratings between Victrelis and Incivek, although the survey respondents predicted higher market share for Incivek in the first six months of launch. BioTrends will follow the market uptake of Victrelis and Incivek in its LaunchTrends series, which will pulse the market at one, three and six months post launch to assess trial and adoption, promotional efforts and obstacles to growth for both brands.

About BioTrends Research Group, LLC

BioTrends Research Group, LLC provides syndicated and custom market research to pharmaceutical manufacturers competing in clinically evolving, specialty pharmaceutical markets. For information on BioTrends publications and research capabilities, please contact us at (610) 363-3872 or www.bio-trends.com.

About Decision Resources, Inc.

Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at www.DecisionResourcesInc.com.

All company, brand, or product names contained in this document may be trademarks of their respective holders.

Contacts
    

BioTrends Research Group, LLC
Sharon Funk, 404-223-2963
sfunk@bio-trends.com
or
Decision Resources, Inc.
Christopher Comfort, 781-993-2597
ccomfort@dresources.com

Source

Peginterferon Alfa-2a Is Superior to Peginterferon Alfa-2b in the Treatment of Naïve Patients with Hepatitis C Virus Infection: Meta-Analysis of Randomized Controlled Trials

Dig Dis Sci. 2011 Jun 4. [Epub ahead of print]

 

Singal AK, Jampana SC, Anand BS.

 

Department of Internal Medicine, University of Texas Medical Branch, Galveston, 77555-0764, TX, USA, aksingal@utmb.edu.

Abstract

BACKGROUND:

Pegylated interferon (PEGIFN) and ribavirin combination is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV-infected patients have shown conflicting results.

AIM:
We performed a systematic review and meta-analysis of studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in HCV-infected patients naïve to treatment.

METHODS:
Nine studies (five abstracts) with 3,546 patients (1,771 treated with PEGIFN alfa-2a) comparing PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV patients were analyzed. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects (SAE).

RESULTS:
Pooled data on outcomes (reported as odds ratios [ORs] with 95% confidence intervals [CIs]: [OR (95% CI)]) showed higher SVR in patients treated with PEGIFN alfa-2a as compared to treatment with PEGIFN alfa-2b [1.36 (1.07-1.73); P = 0.01]. Subgroup analysis of good quality studies on SVR in genotypes 2 and 3 also favored PEGIFN alfa-2a over PEGIFN alfa-2b (1.91 [1.09-3.37]; P = 0.02). SVR results obtained with the two types of IFN showed no impact of viral load and the presence or absence of cirrhosis. Treatment discontinuation rates due to SAE, reported in six studies (two abstracts) on 3,211 patients (1,604 treated with PEGIFN alfa-2a), were similar in the two types of PEGIFN [0.66 (0.37-1.16); P = 0.15].

CONCLUSIONS:
PEGIFN alfa-2a has superior efficacy with higher SVR as compared to PEGIFN alfa-2b in treatment-naïve HCV-infected patients. The safety profile of the two types of PEGIFN was similar.

Source

Cyclosporine A-Based Immunosuppression Reduces Relapse Rate After Antiviral Therapy in Transplanted Patients With Hepatitis C Virus Infection: A Large Multicenter Cohort Study

Transplantation. 2011 Jun 8. [Epub ahead of print]

 

ReViS-TC Study Group.

 

Abstract

BACKGROUND.: The influence of immunosuppression on the response to antiviral treatment in recurrent hepatitis C is still under debate. The purpose of this study was to identify those factors that might predict sustained viral response and relapse. METHODS.: The ReViS-TC, a multicenter cohort study conducted in 14 Spanish liver centers, included data from liver transplant recipients from January 2000 to December 2006 who had recurrent hepatitis C virus and who had undergone antiviral treatment with pegylated interferon plus ribavirin. Sustained virological response (SVR) and viral relapse were evaluated. A multivariate logistic regression model was used to investigate host, donor, and therapeutic factors associated with SVR and relapse. RESULTS.: The analysis included 410 patients, 30% treated with cyclosporine A (CsA) and 70% with tacrolimus. SVR was achieved in 48% of patients with CsA and in 37% with tacrolimus (P=0.037), with a relapse rate of 18% and 36%, respectively (P=0.006). In the multivariate model, the administration of CsA (odds ratio [OR] 0.37, P=0.021) in conjunction with a longer antiviral treatment duration (OR 0.86, P=0.024) correlated with lower relapse rate, whereas the older age of the donor (OR 1.03, P=0.006) and the presence of genotype 1 (OR 3.45, P=0.032) were associated with a higher probability of relapse. CONCLUSIONS.: Our results suggest that the use of CsA-based immunosuppression regimens and longer treatment duration may protect patients against viral relapse after a positive response to pegylated interferon plus ribavirin therapy. These data need to be further confirmed in clinical trials.

Source

Retreatment of patients with chronic hepatitis C relapsers to a previous antiviral treatment

Eur J Gastroenterol Hepatol. 2011 Jun 4. [Epub ahead of print]

 

Floreani A, Cazzagon N, Furlan P, Baldovin T, Egoue J, Antoniazzi S, Baldo V, Minola E.

 

aDepartment of Surgical and Gastroenterological Sciences, University of Padova bDepartment of Hygiene and Public Health, University of Padova, Padova cDepartment of Infectious Disease, Bergamo Hospital, Bergamo, Italy.

Abstract

BACKGROUND:

The efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin for patients relapsing after a previous treatment remains to be fully elucidated, although extended treatment seems to be the best option in such cases.

AIM:
To evaluate the efficacy of two extended protocols in patients with genotypes 1 or 4, or those with genotypes 2 or 3.

METHODS:
A total of 181 patients who had relapsed after a previous antiviral treatment with PEG-IFNα2a plus weight-based ribavirin were offered retreatment with the same dose of both PEG-IFN plus ribavirin, to be continued for 48 weeks in those with genotypes 2 or 3 (group 1), and for 72 weeks in those with genotypes 1 or 4 (group 2).

RESULTS:
A total of 59 patients (32.5%) refused the retreatment, while 122 (78 men, 44 women) patients were enrolled in the study: 41 were allocated in group 1 and 81 in group 2. Cirrhosis at baseline (staging 5/6 according to Ishak's score was recorded in 11 patients, six in group 1 and five in group 2). Nine patients (7.3%) in group 2 discontinued the treatment (due to lack of response). The remaining patients completed the treatment and were followed-up for at least 12 months after the treatment. Sustained virological response (SVR) rate was 82.9% in group 1 and 50.6% in group 2.

CONCLUSION:
Patients with chronic hepatitis C with 'easy genotypes' relapsers to a previous antiviral treatment have more than 80% probability of achieving a SVR with a 48-week retreatment. Patients with 'difficult genotypes' have more than 50% chance of a SVR after a 72-week extended treatment.

Source

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

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

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

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

About the Trial

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

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

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

• PSI-7977 400mg monotherapy for 12 weeks.

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

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

About Pharmasset

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

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

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

SOURCE Pharmasset, Inc.

RELATED LINKS
http://www.pharmasset.com

Source

Retreatment of Hepatitis C with Consensus Interferon and Ribavirin After Nonresponse or Relapse to Pegylated Interferon and Ribavirin: A National VA Clinical Practice Study

Dig Dis Sci. 2011 Jun 2. [Epub ahead of print]

 

Yee HS, Currie SL, Tortorice K, Cozen M, Shen H, Chapman S, Cunningham F, Monto A.

 

Gastroenterology Section, Department of Veterans Affairs Medical Center (VAMC), 4150 Clement Street (111B), San Francisco, CA, 94121, USA.

Abstract

BACKGROUND:

Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV) of hepatitis C virus (HCV)-infected patients who failed prior pegylated interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical practice were evaluated within the Department of Veterans Affairs (VA), the largest national, integrated system for HCV care.

AIMS:
The purpose of this study was to determine rates of sustained virologic response (SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective review of national VA data in HCV-infected patients who had previously failed ≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003 and September 30, 2006.

RESULTS:
A total of 597 patients met the study criteria. CIFN was primarily dosed as 15 mcg subcutaneously daily combined with standard doses of RBV. Mean treatment duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%. Hematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders (31% vs. 6%, respectively; P < 0.0001). A 2-log(10) or greater drop in HCV RNA after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV.

CONCLUSIONS:
CIFN/RBV was used frequently in clinical practice for retreatment of PEG-IFN/RBV. In this setting, early treatment discontinuation was common. Overall SVR was low, although response was significantly better in prior PEG-IFN/RBV relapsers and those who had a 2-log(10) or greater decline than in nonresponders.

Source

Outcomes of treatment for hepatitis C virus infection by primary care providers

N Engl J Med. 2011 Jun 9;364(23):2199-207. Epub 2011 Jun 1.

 

Arora S, Thornton K, Murata G, Deming P, Kalishman S, Dion D, Parish B, Burke T, Pak W, Dunkelberg J, Kistin M, Brown J, Jenkusky S, Komaromy M, Qualls C.

 

Department of Internal Medicine, University of New Mexico, Albuquerque, USA. sarora@salud.unm.edu

Abstract

BACKGROUND:

The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for underserved populations with complex health problems such as hepatitis C virus (HCV) infection. With the use of video-conferencing technology, the ECHO program trains primary care providers to treat complex diseases.

METHODS:
We conducted a prospective cohort study comparing treatment for HCV infection at the University of New Mexico (UNM) HCV clinic with treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 patients with chronic HCV infection who had received no previous treatment for the infection were enrolled. The primary end point was a sustained virologic response.

RESULTS:
A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, -9.2 to 10.7; P=0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites.

CONCLUSIONS:
The results of this study show that the ECHO model is an effective way to treat HCV infection in underserved communities. Implementation of this model would allow other states and nations to treat a greater number of patients infected with HCV than they are currently able to treat. (Funded by the Agency for Healthcare Research and Quality and others.).

Comment in

N Engl J Med. 2011 Jun 9;364(23):2258-9.

Source

IL28B But Not ITPA Polymorphism Is Predictive of Response to Pegylated Interferon, Ribavirin, and Telaprevir Triple Therapy in Patients With Genotype 1 Hepatitis C

J Infect Dis. 2011 Jul;204(1):84-93.

 

Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, Toyota J, Nakamura Y, Kamatani N, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H.

Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN.

Abstract

Background. Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent. Methods. We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins. Results. Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes. Conclusions. Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.

Source

A first step towards a mouse model for hepatitis C virus infection containing a human immune system

J Hepatol. 2011 May 14. [Epub ahead of print]

 

Robinet E, Baumert TF.

 

Inserm, U748, Strasbourg, France; Université de Strasbourg, Strasbourg, France.

Abstract

COMMENTARY ON:: A humanized mouse model to study hepatitis C virus infection, immune response and liver disease. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, Barry W, Ploss A, Rice CM, Su L. Gastroenterology. 2011 Apr;140(4):1334-44. Copyright (2011). Abstract reprinted with permission from the American Gastroenterological Association. http://www.ncbi.nlm.nih.gov/pubmed/21237170. ABSTRACT: Background & Aims: Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C pathogenesis and treatment. Methods: To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under the control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2(-/-) γC-null mice. Co-transplantation of human CD34(+) human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leucocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. Results: AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. Conclusions: AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease, because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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