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Largest U.S. Hepatitis C Trial Provides Insight Into Optimizing Treatment for Patients



Community-Based WIN-R Study Shows Significantly Better Outcomes with Weight-Based Dosing



LOS ANGELES (May 24, 2006) — Researchers who participated in the WIN-R trial, the largest hepatitis C study ever conducted in U.S. patients, reported key factors affecting treatment outcomes in five data presentations here at the Digestive Disease Week (DDW) annual meeting, and provided important insights for optimizing treatment with PEG-INTRON® (peginterferon alfa-2b) and REBETOL® (ribavirin, USP) combination therapy for patients with chronic hepatitis C virus (HCV) infection, a potentially deadly liver disease. WIN-R (Weight-Based Dosing of PEG-INTRON and (REBETOL), a community-based trial, involved more than 4,900 patients at 225 centers across the United States.

In the WIN-R study, patients achieved significantly better outcomes overall with weight-based dosing of ribavirin in combination with PEG-INTRON as compared to the combination using a flat dose of ribavirin. These results included significantly higher rates of sustained virologic response (SVR), i the standard measure of treatment success, for patients overall (44 percent vs. 41 percent; p=0.01), and for patients with HCV genotype 1, the most difficult type to treat (34 percent vs. 29 percent; p=0.004). The study also showed that, for patients infected with HCV genotype 2 or 3, a shorter, 24-week course of therapy was as effective as the standard 48-week course, with better tolerability. ii

Researchers presenting WIN-R data at DDW examined the effect specific predictive factors had on the likelihood of patients achieving an SVR, including factors such as HCV genotype and pretreatment viral load, degree of fibrosis or cirrhosis, cigarette smoking and prior HCV treatment experience at the study sites.

"These WIN-R findings help us better understand how to optimize hepatitis C treatment for our patients and how certain patient characteristics affect response to therapy in real-world community settings," said principal investigator Ira M. Jacobson, M.D., Vincent Astor Professor of Clinical Medicine at Weill Medical College of Cornell University, and Chief of the Division of Gastroenterology and Hepatology at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York City. "These results, in the large number of patients who participated in this study, provide a wealth of information that not only help confirm what many treating physicians have come to know in their everyday practice, but also add exciting new information that gives physicians added confidence that they can optimize the chance for cure in their hepatitis C patients."

Treating U.S. HCV patients can be especially challenging as they tend to have disease characteristics associated with poor treatment response, including a high prevalence of HCV genotype 1, high viral load and advanced liver fibrosis (scar tissue). Other factors such as age, high body weight and African-American ethnicity also have been shown to be associated with poor response to treatment.


WIN-R Presentations at Digestive Disease Week



Differences in Treatment Outcome based on genotype and viral load in patients with HCV genotype 2 or 3.
For patients in the WIN-R trial with HCV genotype 2 or 3 (n=1829), 24 weeks of PEG-INTRON and REBETOL combination therapy was as effective as 48 weeks, with better tolerability. In the weight-based REBETOL dosing arms, the SVR rate was 68 percent for the 24-week course compared to 60 percent for the 48-week course, with the lower percentage attributable to more missing follow-up data. In the 24-week arm, patients with genotype 2 had a higher SVR and lower relapse rate overall than those with genotype 3 (71 percent vs. 60 percent and 6 percent vs. 10 percent, respectively). Safety and rates of drug discontinuation were similar between the weight-based and fixed-dose treatment groups. Overall, the analyses showed that genotype 2 (vs. 3), less advanced fibrosis and 24 weeks of therapy were associated with a greater likelihood of achieving an SVR. Investigators concluded that PEG-INTRON plus fixed-dose ribavirin for 24 weeks is sufficient for patients with genotype 2. However, there is a suggestion that weight-based doses of ribavirin may benefit patients with genotype 3 and high viral load. iii

The effect of liver fibrosis and cirrhosis on SVR.
Fibrosis is a known predictor of SVR in hepatitis C, however, the majority of prior studies do not involve enough patients with cirrhosis to truly define the effect of advanced fibrosis on SVR. In the WIN-R trial, the effect of each individual fibrosis stage on SVR was determined for all patients (n=4913). For those with stage 0 to 2 fibrosis, there was no difference in SVR for patients receiving PEG-INTRON and weight-based ribavirin (45 percent) compared to those receiving the combination with flat-dosed ribavirin (42 percent). However SVR in patients with stage 3 to 4 fibrosis was significantly higher in the weight-based group compared to the flat-dosed group (43 percent vs. 37 percent; p=0.02). All stages were significantly superior to the Stage 4 cirrhosis group, which had an SVR of 34 percent (p less than 0.0001). Researchers concluded that weight-based dosing of ribavirin is important to increase SVR in patients with advanced stages of fibrosis and cirrhotic patients require optimal therapy, including weight-based ribavirin. iv

Impact of viral load on SVR in patients with HCV genotype 1.
To assess the relationship of pretreatment HCV viral load with treatment outcomes, SVR rates in patients with low viral load (less than 2 million copies/ml) were compared to those in patients with high viral load (2 million copies/ml or greater) for the 3018 patients in WIN-R with HCV genotype 1. SVR was significantly higher in patients with a low viral load than in those with a high viral load (35 percent vs. 31 percent; p=0.006). Interestingly, reductions in SVR were seen in more patients with baseline viral loads of 2-15 million copies/ml than in patients with greater than 15 million copies/ml. Researchers concluded that within the genotype 1 patient population with high viral load, those with very high viral loads do not have impaired rates of SVR. v

The influence of cigarette smoking on SVR.
Cigarette smoking has been associated with increased inflammation and fibrosis in patients with HCV, but there is little data on the effect of smoking on SVR rates in patients with HCV. During enrollment of the WIN-R trial, investigators noted whether patients were cigarette smokers or nonsmokers. Among the subset of patients with available data, there were 893 smokers (31.3 percent) and 1966 nonsmokers (68.7 percent). Cigarette smokers with HCV genotype 2 and 3 had lower SVR than nonsmokers. However, SVR rates among smokers and nonsmokers with HCV genotype 1 were not significantly different. The lower SVR rates observed in smokers with HCV genotype 2 or 3 were not accounted for by stage of fibrosis, gender or pretreatment viral load. Researchers concluded that additional studies are need to evaluate the dose-related effects of cigarette smoking and the potential effect on SVR of smoking cessation prior to treatment. vi

Prior HCV treatment experience at study sites and its relationship to SVR.
Registration trials using peginterferon and ribavirin have demonstrated overall SVR rates of 54 percent to 56 percent. vii, viii Whether these SVR rates can be replicated in clinical practice in the community is unclear. WIN-R results were analyzed to determine investigator factors that affected SVR rates in HCV patients treated in academic or community settings. In all, 225 sites enrolled 4913 patients. Twenty-five academic and community investigators, all having extensive experience in HCV therapy, served as regional principal investigators (PIs). High enrollment sites (25 or more patients) had selected data verified by a study monitor. Researchers found that patients treated within regional PI sites (sites with more HCV treatment experience) were more likely to achieve SVR and less likely to drop out than patients treated within non-regional PI sites. There were no differences seen in SVR or drop out rates for monitored vs. non-monitored sites. Researchers concluded that the higher drop out rates in non-regional PI sites were primarily explained by a higher rate of treatment discontinuation due to noncompliance. ix


About the WIN-R Study


In the WIN-R study, 4913 patients were randomized to receive weight-based PEG-INTRON (1.5 mcg/kg weekly) in combination with REBETOL given either as a flat dose (800 mg daily) or a weight-based dose (800 mg, 1,000 mg, 1,200 mg or 1,400 mg daily for body weights of less than 65 kg, 65 to 85 kg, 86 to 105 kg, or 106 to 125 kg, respectively). Patients with HCV genotype 1 were treated for 48 weeks; those with genotype 2 or 3 were treated for 48 weeks or 24 weeks. Patients in the treatment arms were evenly matched for gender, age, body weight, genotype, viral load and stage of liver fibrosis.

Serving with Dr. Jacobson as co-principal investigator of the WIN-R study is Robert S. Brown Jr., M.D., M.P.H., Associate Professor of Medicine and Surgery at Columbia University College of Physicians and Surgeons, and Chief of Clinical Hepatology and Medical Director of the Center of Liver Disease and Transplantation at New York-Presbyterian Hospital/Columbia University Medical Center. Drs. Jacobson and Brown are also co-directors of New York-Presbyterian Healthcare System’s Liver Clinical Trials Network (LCTN).

Dr. Jacobson also is Medical Director of the Center for the Study of Hepatitis C, a unique interdisciplinary center established jointly by The Rockefeller University, New York-Presbyterian Hospital and Weill Cornell Medical College in New York City.

WIN-R is an investigator-initiated clinical study supported by Schering-Plough Corporation and monitored by Schering-Plough Research Institute as part of a post-marketing commitment to the U.S. Food and Drug Administration (FDA). PEG-INTRON and REBETOL are registered trademarks of Schering-Plough.


About Hepatitis C


Hepatitis C is the most common blood-borne infection in America, affecting approximately 4 million people or about one in every 50 adults. Chronic hepatitis C can cause cirrhosis, liver failure and liver cancer. It has been estimated that at least 20 percent of patients with chronic hepatitis C develop cirrhosis, and a smaller percentage of patients with chronic disease develop liver cancer. Patients with chronic hepatitis C and related cirrhosis are 100 times more likely to develop liver cancer than uninfected persons. x About half of all cases of primary liver cancer in the developed world are caused by hepatitis C, and hepatitis C related liver disease is now the leading cause for liver transplants. xi


About New York-Presbyterian Hospital/Weill Cornell Medical Center


The New York-Presbyterian Hospital/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital New York-Presbyterian Hospital and its academic partner Weill Cornell Medical College. NewYork-Presbyterian/Weill Cornell provides state-of-the-art in-patient, ambulatory, and preventive care in all areas of medicine, and is committed to excellence in patient care, research, education, and community service.


About Digestive Disease Week


Digestive Disease Week (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy and the Society for Surgery of the Alimentary Tract, DDW takes place May 20-25, 2006, at the Los Angeles Convention Center. The meeting showcases approximately 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.


References


i Sustained virologic response (SVR) is defined as undetectable virus (HCV-RNA) levels in the blood at 6 months after the end of therapy.

ii Jacobson I, Brown Jr. R, Freilich B, Afdahl N, Kwo P, Santoro J, Becker S, Wakil A, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Bala N, Araya V, Davis M, Monsour H, Vierling J, Regenstein F, Balan V, Dragutsky M, Epstein M,. Herring RW, Rubin R, Galler G, Pauly MP, Griffel LH, Brass CA, the WIN-R Study Group. Weight based ribavirin dosing (WBD) increases sustained viral response (SVR) in patients with chronic hepatitis C (CHC): final results of the WIN-R study, a U.S. community-based trial. Oral presentation at: 56th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, CA, Nov 11-15, 2005.

iii Brown Jr. R, Jacobson I, Afdahl N, Freilich B, Regenstein F, Flamm S, Kwo P, Pauly MP, Griffel LH, Brass CA. Difference in treatment outcome to antiviral therapy based on genotype and viral load in hepatitis C genotypes 2 and 3 in the WIN-R trial. Oral presentation 523 at: 2006 Annual Meeting of Digestive Disease Week, Los Angeles, CA, May 20-25, 2006.

iv Afdahl N, Jacobson I, Brown Jr. R, Freilich B, Santoro J, Griffel LH, Brass CA, The WIN-R study group. The effect of liver fibrosis and cirrhosis on SVR in 4913 patients with hepatitis C; results from the WIN-R trial. Oral presentation 655 at: 2006 Annual Meeting of Digestive Disease Week, Los Angeles, CA, May 20-25, 2006.

v Jacobson I, Brown Jr. R, Freilich B, Afdahl N, Kwo P, Santoro J, Becker S, Wakil A, Pound D, Ahmed F, Griffel LH, Brass CA, WIN-R Study. Stratification of high viral load: impact on sustained virologic response in the WIN-R trial. Poster presentation 1806 at: 2006 Annual Meeting of Digestive Disease Week, Los Angeles, CA, May 20-25, 2006.

vi Pauly MP, Sheinbaum AJ, Szpakowski J, Ready JB, Brown Jr. R, Freilich B, Afdahl N, Kwo P, Santoro J, Becker S, Jacobson I, Griffel LH, Brass CA. The influence of cigarette smoking on response to treatment with pegylated interferon alfa-2b and ribavirin in patients with chronic hepatitis C. Poster presentation 1923 at: 2006 Annual Meeting of Digestive Disease Week, Los Angeles, CA, May 20-25, 2006.

vii Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001 Sep 22;358(9286):958-65.

viii Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347(13):975-82.

ix Kwo P, Jacobson I, Brown Jr. R, Freilich B, Afdahl N, Santoro J, Becker S, Wakil A, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Bala N, Arraya V, Davis M, Monsour H, Vierling J, Regenstein F, Balan V, Dragutsky M, Epsetin M, Herring R, Griffel LH, Brass CA. Prior HCV treatment experience and its relationship to sustained virologic response (SVR): an analysis of the WIN-R study database, A US academic community based trial. Poster presentation 1802 at: 2006 Annual Meeting of Digestive Disease Week, Los Angeles, CA, May 20-25, 2006.

x Ince N, Wands JR. The increasing incidence of hepatocellular carcinoma. N Engl J Med 1999 March 11;340:10.

xi Centers for Disease Control and Prevention. Recommendations for prevention and treatment of hepatitis C virus (HCV) and HCV-related chronic disease. MMWR Weekly Report 1998 Oct. 16;1.

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