By Lisa Seachrist
Gaithersburg, Md. — An FDA advisory panel unanimously recommended Monday a combination of Schering-Plough Corp.'s Intron A (recombinant alpha interferon) and ICN Pharmaceuticals Inc.'s antiviral Rebetol (ribavirin) for the treatment of relapsed hepatitis C virus (HCV).
The Antiviral Drugs Advisory Committee concluded that Intron A injections in combination with Rebetol capsules is a safe and effective treatment for chronic hepatitis in adult patients with compensated liver disease who have relapsed following traditional alpha-interferon therapy. The committee suggested the conducting of pediatric studies to assess whether the combination is effective in children as well.
"We are very, very pleased with the unanimous recommendation," said Robert Consalvo, director of media relations for Madison, N.J.-based Schering-Plough. "We are continuing to work with the agency for our ultimate goal — marketing approval. Barring something unforeseen, we expect to be able to market as soon as we receive approval."
HCV, which affects about 4 million Americans, is the most pervasive of the seemingly innumerable hepatitis viruses. It is spread by contact with the blood of an infected person, and approximately 30 percent of those infected with the virus will suffer a chronic form of the disease, in which the virus never clears the bloodstream. Chronic HCV can lead to cirrhosis of the liver and liver cancer, and is the leading reason for liver transplants in the U.S.
Schering-Plough's Intron A has already been approved by the FDA as a treatment for HCV. However, that treatment is effective in only about 20 percent of patients.
After the FDA refused to approve ribavirin as a monotherapy for HCV, Schering-Plough licensed it from ICN in August 1995 to examine whether Intron A in combination with ribavirin could prove more effective than alpha interferon alone.
Ribavirin, a synthetic nucleoside with antiviral activity, is currently approved as an inhaled treatment for respiratory syncytial virus under the brand name Virazole.
Schering-Plough presented two Phase III studies testing the efficacy of a 24-week course of treatment with Intron A and Rebetol, which is Schering-Plough's capsule version of ribavirin, versus Intron A and placebo. The two studies collectively randomized 345 patients to receive Intron A injections three times a week in combination with oral Rebetol or placebo.
The patients were tested six months after stopping treatment for the presence of HCV in their bloodstreams. In the combination therapy group, 48.6 percent of patients had no detectable virus, compared to 4.7 percent of patients in the Intron-A-only group.
"This translates to a ten-fold increase in response in patients known to be resistant to interferon therapy," Consalvo said.
Common side effects for the combination therapy were anemia, reduced levels of certain white blood cells, nausea, heart irregularities and depression. Loss of red blood cells was the primary side effect associated with the combination therapy, and researchers compensated for the effect by lowering the Rebetol dosage. Overall, however, the side-effect profile for the two-drug combination offered no surprises.
"There were no synergistic effects associated with the combination therapy," Consalvo noted. "The side effects were the same that are found with alpha interferon and ribavirin individually."
Schering-Plough has completed a Phase III trial of the combination therapy in patients who have never been treated with interferon and expects to submit those results to the agency for review sometime this year. The company has exclusive worldwide rights to market oral ribavirin for HCV, except in the European Union, where ICN and Schering-Plough share marketing rights.
ICN will receive royalty payments on all sales of ribavirin. Ribavirin is also approved for the treatment of a number of viral infections in more than 40 countries worldwide.
The FDA is under no obligation to follow the recommendations of its advisory panels but usually does. *