3 New Combination Therapies
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LOS ANGELES (May 21, 2006) According to recent estimates, hepatitis has become a worldwide health problem, affecting millions of people in the U.S. and abroad. Researchers are experimenting with combinations of anti-inflammatory medicines like interferons to improve hepatitis symptoms. In research presented today at Digestive Disease Week® 2006 (DDW), new combinations of therapies are making significant progress to improve symptoms of the disease. DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
Hepatitis is caused by a virus that attacks the liver, triggering painful inflammation and often leading to more serious conditions like liver failure and even death. Several different forms of hepatitis exist, including hepatitis A, B and C. Hepatitis A is generally food-borne, while hepatitis B and C are spread primarily through parenteral or sexual routes. The disease is often caused by a virus, but can also result from alcohol, toxins or drugs.
“Despite the significant number of people suffering from hepatitis, treatment options have been lagging in comparison to other major diseases,” said John Vierling, M.D., FACP, president, the American Association for the Study of Liver Diseases (AASLD); professor of Medicine and Surgery at the Baylor College of Medicine in Houston, Texas; and director of Baylor Liver Health and Chief of Hepatology. “We hope that continued research like these studies will lead to more significant breakthroughs and relief for these patients.”
Valopicitabine (NM283), Alone or with Peg-Interferon, Compared to Peg Interferon/Ribavirin (pegIFN/RBV) Retreatment in Hepatitis C Patients with Prior Non-Response to PegIFN/RBV: Week 24 Results [Abstract 4]
More than half of currently treated hepatitis patients are infected with strains of hepatitis C that do not respond to current interferon therapies and have no other effective treatment options. Combination treatment using a new antiviral therapy is showing promise in suppressing the virus, according to a phase II US multi-center study. The therapy, valopicitabine, has shown anti-HCV activity alone and in combination with pegIFN (pegylated interferon) in early trials, without viral breakthrough for study periods up to six months.
The current study compared the outcomes of five different treatments in patients who have not experienced remission with standard therapies: valopicitabine alone (800 mg/d), one of three combination arms with the drug at 400 mg/d, 800 mg/d or dose-ramping 400 to 800 mg/d plus pegIFN, or pegIFN with ribavirin as a control group.
For the 162 patients who have completed the trial period at 24 weeks, results show that the two higher-dose combination arms had much better response rates than the control group, experiencing on average a 2.5 to 3.0 log decrease in hepatitis RNA reductions by week 24, a significantly better response than the comparator. No viral breakthrough has been seen to date. However, vomiting and dehydration requiring hospitalization occurred in three patients taking the highest dose (800 mg), forcing the research team to halt the use of that dose and continue using only the lower doses of 200 to 400 mg of the drug.
“For patients whose disease has not responded to current therapies, this new combination treatment may produce excellent results, at the maximally acceptable dosage,” according to Paul Pockros, M.D., of Scripps Clinic in California, and lead study author. “Continued treatment will determine if these encouraging early responses will result in a sustained response, hopefully improving patient quality of life and long-term survival.”
Comparison of Daily Consensus Interferon versus Peginterferon alfa 2a Extended Therapy of 72 Weeks for Peginterferon / Ribavirin Relapse Patients with Chronic Hepatitis C [Abstract S1060]
In chronic diseases like hepatitis, symptoms have a tendency to fluctuate in severity. As a result, researchers are finding that the diseases may react more successfully to a longer duration of therapy. In this study, researchers at the University of Tuebingen in Germany compared two combination therapies for an extended treatment period of 72 weeks, compared to the current standard of 48 weeks, in patients with chronic hepatitis C.
Previous studies have shown that with 48 weeks of therapy, relapse rates are near 20 to 30 percent, but with an extended duration of 72 weeks, rates may be reduced. The research team compared the efficacy of daily doses of CIFN (consensus interferon) plus ribavirin (RBV) versus pegIFN (pegylated interferon alfa 2a) plus RBV for 72 weeks in patients with a prior relapse to 48 weeks of treatment. A total of 81 patients were treated with either CIFN or with pegIFN a2a for 72 weeks, both in combination with RBV.
After the initial 12 weeks, a primary response to therapy, noted as a reduction in hepatitis RNA, was observed in 83 percent of patients in the CIFN group and 78 percent of the pegIFN group. At the end of treatment at week 72, the vast majority (89 percent) of both the CIFN group and pegIFN group (76 percent) were in remission. After finishing treatment, two-thirds of the CIFN group (69 percent) experienced sustained response, but less than half of the pegIFN group (44 percent) experienced these results, indicating a significantly higher relapse rate in this group.
“While many patients did relapse after discontinuing treatment, the overall sustained response rates are nevertheless promising, showing a sustained response in up to 70 percent of patients,” said Stephan Kaiser, M.D., of the University of Tuebingen, and lead study author. “We believe that extended treatment with CIFN combined with RBV may be a better option than current standards for this difficult-to-treat patient group.”
The overall tolerability of the CIFN regimen was comparable to PEG IFN. Three patients experienced thrombocytopenias (reduced blood platelets), but there were no severe neutropenias (low white blood cell count) or thrombocytopenias. CIFN patients experienced a higher rate of injection site reactions and a slightly higher drop-out rate of 18 percent, compared to only 12 percent of the pegIFN group.
28 Days of the Hepatitis C Protease Inhibitor VX-950, In Combination with Peg-Interferon-Alfa-2a and Ribavirin, is Well-Tolerated and Demonstrates Robust Antiviral Effects [Abstract 686f]
Scientists are reviewing new compounds in combination with current standard hepatitis therapies to produce better patient outcomes. A new oral peptidomimetic protease inhibitor, VX-950, has previously shown substantial anti-viral effects in combination with the frequently used hepatitis therapy pegylated interferon (pegIFN). In this study, researchers evaluated the safety and antiviral response of VX-950 in combination with pegIFN and ribavirin (RBV).
The study included 12 hepatitis C patients who received 750 mg of VX-950 every eight hours, 180 ìg of pegIFN weekly, and either 1000 or 1200 mg of RBV daily. After 28 days, patients began standard therapy with pegIFN/RBV.
All patients responded to the study drug regimen and showed continual declines in hepatitis RNA throughout the treatment period. Two patients had levels of HCV RNA in their blood below the limits of detection of a highly sensitive assay after just eight days. All patients had undetectable HCV RNA by the end of 28 days. No patients experienced viral breakthrough at any time.
“These data confirm the rapid and dramatic antiviral effects of VX-950. All subjects achieving undetectable HCV RNA within 28 days of treatment is an unprecedented result with an investigational agent,” said Eric Lawitz, M.D., of Alamo Medical Research, Texas, and lead author of the study. “We look forward to future studies which will evaluate the ability of VX-950 to produce sustained viral responses with as little as 12 weeks of therapy.”
VX-950 + pegIFN + RBV was well tolerated, with no serious adverse events and no treatment discontinuations. A detailed analysis of adverse events will be presented.
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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 (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 20-25, 2006 in Los Angeles, California. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.
Reprinted with permission of Digestive Disease Week® 2006.
