Schering Rebetron Hepatitis C Therapy Five Year Phase IV Data Requested

Schering-Plough will submit five-year follow-up data from its four pivotal trials of Rebetron as part of its Phase IV commitments to FDA. The combination therapy of Schering's Intron A (interferon alfa-2b) injection and Rebetol (Schering/ICN's ribavirin) for hepatitis C was approved June 3.

The agency requested follow-up data from the two Rebetron trials in relapsed patients upon which approval hinged, as well as from two recently completed trials in interferon treatment-naive patients. Schering has committed to working with investigators to enroll patients, regardless of response to therapy, into the long-term follow-up protocols.

The long-term protocols will follow patients for development of liver failure and hepatic carcinomas. FDA noted in a June 3 "Talk Paper" that Rebetron "is not a cure for chronic hepatitis C, and it is unknown if this treatment will delay liver disease progression." An estimated 4 mil. people in the U.S. are infected with hepatitis C and about 12,000 die from the disease annually.

Rebetron was approved for "the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed following alpha interferon therapy."

Phase III results from the trials in treatment-naive patients are expected to expand the indication of Rebetron. The results will be submitted to FDA soon in an NDA supplement, Schering has said ("The Pink Sheet" May 11, p. 3).

Distribution of Rebetron began immediately following approval, with nationwide availability expected by mid-June.

The average wholesale price for the 24-week treatment regimen is $8,600 per 1,200 mg Rebetol/Intron A dose; $7,800 per 1,000 mg Rebetol/Intron A dose; and $6,400 per 600 mg Rebetol/Intron A dose, Schering said.

Rebetron will be available in combination packages consisting of six Intron A 3 million international unit vials or one 18 MIU multidose vial, plus two boxes of 35 Rebetol 200 mg capsules (70) for dosing of patients less than 75 kg. An 18 MIU Intron A cartridge for multi-dose injection pen with Rebetol is expected to be available by July.

For patients over 75 kg, Rebetron combination packages consisting of six Intron A 3 MIU vials, one 18 MIU multidose vial or one 18 MIU multidose pen, plus two boxes of 42 Rebetol capsules (84) will be available. There is also a Rebetol dose reduction package that contains only one box of 42 capsules.

The approval of Rebetron was based on virologic and histologic response data from a 153-patient U.S. and a 192-patient international trial. Patients in the trials were treated with 1,200 mg/day ribavirin (1,000 mg/day for patients weighing less than 75 mg) plus 3 MIU three times a week of Intron A or Intron A plus placebo for 24 weeks. The studies included 24 weeks of off-therapy follow-up.

Rebetron demonstrated a virological response (hepatitis C viral RNA below the limit of detection by RT-PCR assay) in 43% of patients in the U.S. trial and 48% in the international trial, compared to 4% and 5% for patients receiving Intron A with placebo, labeling states.

Histological response rates were closer, with liver biopsy improvements noted in 49% of Rebetron-treated patients in the U.S. trial and 51% in the international study, versus 36% and 31% of patients receiving Intron A and placebo. A chart in labeling notes that histological response data were missing on 18% of patients in the U.S. study and 21% of patients in the international trial.

Schering has agreed to analyze the hepatitis clinical database to assess the relationship between virologic and histologic response with Intron A monotherapy and in combination with ribavirin.

FDA is also interested in the company's assessment of the relationship between virologic and histologic responses for pegylated alfa interferon (PEG-Intron A) with or without ribavirin. PEG-Intron A, a once-weekly long-acting formulation developed under an agreement with Enzon, is in Phase III for hepatitis C.

Schering has agreed to establish a voluntary pregnancy registry that will be operational at the launch of the product.

Rebetron carries a boxed warning against use in women who are or may become pregnant because of the teratogenic and/or embryocidal effects of ribavirin in animals. Rebetron therapy "should not be initiated until a report of a negative pregnancy test has been obtained," labeling states. "Women of childbearing potential and men must use effective contraception during treatment and during the six months post-treatment follow-up period," labeling adds.

Schering will also initiate three carcinogenicity, dose-finding studies as part of its Phase IV commitments.

Rebetron labeling states that carcinogenicity studies with interferon-alfa "have not been performed because neutralizing activity appears in the serum after multiple dosing" and that "adequate studies to assess the carcinogenic potential of ribavirin in animals have not been conducted." Ribavirin should be considered a potential carcinogen because of positive findings in in vitro and in vivo genotoxicity assays, labeling adds.

Rebetron is also contraindicated in patients with autoimmune hepatitis. Schering is currently supporting an AmFAR-sponsored trial of the combination therapy in HIV/hepatitis C co-infected patients.

The company has also agreed to conduct studies in additional populations including pediatric patients, liver transplant patients, and patients with cirrhosis. Two trials have begun in liver transplant patients.

Results from an ongoing study of the safety and efficacy of lower doses of ribavirin in combination with interferon will be submitted to FDA upon completion. FDA also asked the company to assess the feasibility of studies to investigate potential food effects on Rebetol's safety and efficacy profile.

Rebetron carries a bolded warning that anemia occurred in 10% of patients within one to two weeks of beginning Rebetron therapy.

"Because of this initial acute drop in hemoglobin, it is advised that complete blood counts should be obtained pretreatment and at week two and week four of therapy, or more frequently if clinically indicated," labeling warns. "Patients should then be followed as clinically appropriate."

"Cardiac disease may be worsened by drug-induced anemia [so] patients with a history of significant or unstable cardiac disease should not use" Rebetron therapy, labeling adds.

Labeling also warns of severe psychiatric adverse events, such as depression, suicidal ideation and suicide associated with interferon-alfa, and states that the treatment should "be used with extreme caution in patients with a history of pre-existing psychiatric disorders who report a history of severe depression."

Common adverse events associated with Rebetron combination therapy include headache (66% U.S. trial, 47% international), fatigue (66% and 35%), myalgia (61% and 30%), nausea (47% and 35%) and fever (32% and 31%). Depression was reported in 23% of U.S. patients and in 10% of patients in the international trial receiving Rebetron treatment.

Patients taking Rebetron will have the opportunity to enroll in the existing "Be In Charge Program" patient support program for Intron A, which disseminates educational materials, newsletters and provides a toll-free information number, Schering reported.

The Rebetron NDA (20-903) was submitted Dec. 3 and received a priority review. Approval came one month after a unanimous recommendation by FDA's Antiviral Drugs Advisory Committee. Schering is currently preparing to file an application in Europe.

Schering licenses oral ribavirin from ICN Pharmaceut-icals, which markets an aerosol formulation for pediatric respiratory syncytial virus infection under the tradename Virazole. Schering's Intron A was granted a hepatitis C indication in February 1991.

The only other therapy currently approved for initial hepatitis C therapy that can also be used in patients who have failed prior alfa interferon therapy is Amgen's Infergen (interferon alfacon-1). Infergen has a wholesale acquisition cost of $2,116 for 24 weeks.

Infergen labeling states that a 15 mcg dose three times weekly demonstrated an overall 9% virological response rate (HCV RNA less than 100 copies/mL) at the end of 24 weeks in patients who had never fully responded to interferon initial therapy or relapsed after a response. In patients who had relapsed following a response, Infergen had a 25% virologic response rate.

A more recent study in 337 patients conducted by the University of Miami found 58% of relapsed patients had virological response to 15 mcg t.i.w. Infergen therapy at the end of 48 weeks. Nonresponders to previous interferon therapy had a 13% response rate to Infergen second-line treatment.