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  • byteme
    Schering-Plough Reports Results of PEG-INTRON(TM) Phase III Studies at European Association for The Study of The Liver (EASL) Meeting Phase II PEG-INTRON Plus
    Message 1 of 106 , May 2, 2000
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      Schering-Plough Reports Results of PEG-INTRON(TM) Phase III Studies at
      European Association for The Study of The Liver (EASL) Meeting

      Phase II PEG-INTRON Plus RIBAVIRIN Results Also Reported

      ROTTERDAM, Netherlands, May 1 /PRNewswire/ -- Schering-Plough
      Corporation
      (NYSE: SGP) today reported that results of a pivotal Phase III clinical
      study presented for the first time here at the 35th Annual Meeting of
      the
      European Association for the Study of the Liver (EASL) demonstrated that

      once weekly administration of PEG-INTRON(TM) (peginterferon alfa-2b)
      Injection is twice as active as INTRON(R) A (interferon alfa-2b,
      recombinant) Injection administered three times weekly as monotherapy in

      achieving sustained loss of detectable(1) hepatitis C virus (HCV) in
      adult
      patients with chronic hepatitis C.

      PEG-INTRON is a longer-acting form of INTRON A that uses proprietary PEG

      technology developed by Enzon, Inc. (Nasdaq: ENZN) of Piscataway, N.J.
      Schering-Plough holds an exclusive worldwide license to PEG-INTRON.

      "PEG-INTRON at all three doses studied showed higher rates of sustained
      response than INTRON A and was just as well tolerated," said Christian
      Trepo, M.D., Ph.D., director, hepatitis research unit, Hopital Hotel
      Dieu,
      Service d'Hepatologie, Lyon, France, who presented the data.
      "Consistent
      with previous studies, the rates of sustained virologic response
      achieved
      in this study were greatly influenced by genotype, and ranged from 11%
      for
      patients with genotype 1, the predominant genotype worldwide and the
      most
      difficult to treat, to 49% for patients with genotype 2 or 3, compared
      to
      6% to 28% for INTRON A," Trepo said.

      In this study, patients treated with PEG-INTRON achieved significantly
      greater loss of detectable hepatitis C virus during treatment, at the
      end
      of treatment and at the end of follow up, compared to patients treated
      with INTRON A.

      The randomized, controlled Phase III study was designed to establish the

      safety and efficacy of PEG-INTRON versus INTRON A monotherapy in adult
      patients with previously untreated chronic hepatitis C and compensated
      liver disease. A total of 1,219 patients, who were positive for serum
      HCV-RNA(2) and who had elevated liver enzymes (serum alanine
      aminotransferase), were treated with one of three doses of PEG-INTRON
      (0.5, 1.0, 1.5 &g/kg) administered once weekly or INTRON A (3 MIU)
      administered three times weekly for 48 weeks. The primary efficacy
      endpoint of the study was sustained loss of detectable HCV-RNA at 24
      weeks
      from the end of 48 weeks of treatment.

      The demographic/disease characteristics of patients in this study were
      similar to those in previous Schering-Plough hepatitis C registration
      studies, with a majority of patients having genotype 1, the most
      difficult
      genotype to treat (70% genotype 1), and high viral load (74% HCV-RNA > 2

      million copies/ml).

      Adverse events (AEs) for all doses of PEG-INTRON were similar to those
      for
      INTRON A. Most AEs were mild to moderate and were manageable with dose
      adjustment. Discontinuation of therapy due to AEs was similar for all
      treatment groups (6-11%). Dose reductions were similar for INTRON A and

      PEG- INTRON 0.5 &g/kg and higher for PEG-INTRON 1.0 and 1.5 &g/kg (6%,
      9%,
      14% and 19%, respectively). The most common side effects occurring with

      PEG-INTRON were "flu-like" symptoms, such as headache, fatigue, myalgia
      and fever, which appeared to decrease in severity as treatment
      continued.

      PEG-INTRON PLUS REBETOL(R) COMBINATION THERAPY

      Results of a Phase II dose-ranging study of PEG-INTRON in combination
      with
      REBETOL (Ribavirin, USP) Capsules were presented by Rafael Esteban Mur,
      M.D., professor of medicine, Servei de Medicina Interna-Hepatologia,
      Hospital Vall d'Hebron, Barcelona, Spain, at a satellite symposium
      sponsored by Schering-Plough. "The results of this study indicate that
      REBETOL enhances the antiviral activity of PEG-INTRON and that sustained

      virologic response with the combination therapy is dose dependent,"
      Esteban Mur said. "While preliminary, these results are encouraging."
      The combination of PEG-INTRON and REBETOL is currently being studied in
      Phase III trials to further define its clinical profile.

      A total of 72 patients with chronic hepatitis C and compensated liver
      disease were enrolled into the Phase II, open-label, randomized, active
      controlled study. Fewer patients in this study than in the PEG-INTRON
      Phase III monotherapy study were genotype 1 (44% vs. 70% respectively)
      and
      fewer had high viral load (58% vs. 74% HCV-RNA > 2 million copies/ml).
      Patients in this study received either PEG-INTRON (0.35, 0.7 or 1.4
      &g/kg)
      once weekly alone or in combination with daily REBETOL (600, 800 or
      1,000-1,200 mg) for 24 weeks, with 24 weeks of follow up. Patients
      treated with PEG-INTRON 0.35, 0.7 or 1.4 &g/kg in combination with
      REBETOL
      achieved higher rates of sustained virologic response at 48 weeks
      compared
      to patients receiving the same doses of PEG-INTRON alone. In this
      study,
      the tolerance profile of PEG-INTRON/REBETOL was comparable to the known
      tolerance profile of INTRON A/REBETOL.

      PEG-INTRON FOR HCV

      Schering-Plough on Dec. 23, 1999 submitted a Biologics License
      Application
      (BLA) to the U.S. Food and Drug Administration (FDA) seeking marketing
      approval for PEG-INTRON for the treatment of chronic hepatitis C. On
      Feb.
      17, 2000, the European Union's (EU) Committee for Proprietary Medicinal
      Products (CPMP) of the European Agency for the Evaluation of Medicinal
      Products (EMEA) issued a positive opinion recommending approval of
      PEG-INTRON for the treatment of hepatitis C. The CPMP opinion serves as

      the basis for European Commission approval, which would result in one
      single Marketing Authorization with unified labeling that would be valid

      in all 15 EU-Member States.

      Some 4 million Americans are infected with the hepatitis C virus,
      according to the Centers for Disease Control and Prevention (CDC). As
      many as 5 million Europeans (1% to 2% of the general population) are
      chronically infected with the hepatitis C virus, according to a study
      conducted by the World Health Organization (WHO). Chronic hepatitis C
      is
      the leading cause of chronic liver disease and the most common reason
      for
      liver transplant, according to WHO.

      INTRON A is a recombinant version of naturally occurring alpha
      interferon,
      which has been shown to exert both antiviral and immunomodulatory
      effects.
      Schering-Plough markets INTRON A, the world's largest-selling alpha
      interferon, worldwide for 16 major antiviral and anticancer indications.

      REBETOL is an oral formulation of ribavirin, a synthetic nucleoside
      analog
      with broad-spectrum antiviral activity. Schering-Plough has exclusive
      rights to market oral ribavirin for hepatitis C in all major world
      markets
      through a licensing agreement with ICN Pharmaceuticals, Inc. (NYSE: ICN)

      of Costa Mesa, Calif.

      Schering-Plough is a research-based company engaged in the discovery,
      development, manufacturing and marketing of pharmaceutical products
      worldwide.

      (1) Detection limit 100 copies/ml (NGI Assay)

      (2) HCV-RNA: hepatitis C viral RNA (ribonucleic acid)

      SOURCE Schering-Plough Corporation

      CO: Schering-Plough Corporation

      ST: New Jersey, Netherlands
    • 2byteme@bellsouth.net
      Hepatology Focus Update on Hepatitis C Treatment Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles,
      Message 106 of 106 , Feb 25, 2001
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        Hepatology Focus
        Update on Hepatitis C Treatment

        Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
        School of
        Medicine, Los Angeles, California

        Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
        Angeles, California, and
        Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
        Medical Center,
        Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
        California

        [Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]

        Background

        Although screening of blood products and other interventions such as
        clean-needle exchange
        programs have significantly reduced the incidence of acute hepatitis C
        in the United States and
        elsewhere, there remains a large reservoir of chronically infected
        individuals, many of whom are
        unaware of their infection. Current estimates suggest a seroprevalence
        of 1.8% among Americans,
        most of whom are viremic.[1] The clinical burden of chronic hepatitis C
        virus (HCV) infection is
        expected to increase over the next 2-3 decades as a large cohort of
        patients infected between the
        1960s and 1980s, primarily as a result of recreational drug use,
        develops progressive liver disease.
        Between 8000 and 10,000 deaths each year in the United States are
        believed to be caused by
        infection with HCV -- which is now the most frequent indication for
        liver transplantation.[2]

        Even before identification of HCV, interferon-alfa (IFN-alfa) had been
        evaluated as a potential
        therapy for what had been called chronic non-A, non-B hepatitis.[3]

        Further studies using normalization of serum alanine aminotransferase
        (ALT) levels and
        improvement in liver histology as endpoints demonstrated the efficacy of
        IFN-alfa as therapy for
        the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
        Subsequent advances in
        molecular diagnosis have now increasingly allowed establishment of
        virologic criteria to evaluate
        efficacy of treatment in patients with chronic hepatitis C (see Table).

        Definition of Virologic Response in Patients Receiving Therapy for
        Chronic Hepatitis C

        End-of-treatment response (ETR) refers to absence of viremia (ie, serum
        HCV RNA below level
        of detection) at completion of therapy. Sustained response (SR)
        indicates persistent absence of
        serum HCV RNA 6 months or more after cessation of therapy. A study by
        Marcellin and
        coworkers[6] on the long-term clinical outcome in 80 patients with
        chronic HCV followed for a
        mean of 4 years following therapy highlighted the clinical implications
        of a virologic SR. Persistent
        absence of HCV RNA from serum was observed in 96% of patients with a
        lack of histologic
        progression on serial liver biopsy. In addition, ALT levels were
        persistently normal in over 90%.
        The most recent follow-up biopsy showed normal or near normal histologic
        findings in 62% of
        these patients. Thus, virologic SR was shown to be associated with both
        an absence of detectable
        serum HCV RNA and marked histologic improvement.

        Relapsers are defined as patients who have undetectable serum HCV RNA at
        completion of
        therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
        patients who fail to
        clear HCV RNA from serum during therapy.

        A recent paper by Everson and associates[7] underscores the importance
        of HCV RNA testing in
        defining treatment response. In patients with marked fibrosis and
        cirrhosis, they found a major
        discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
        to therapy. Two of
        7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
        cirrhosis cleared HCV RNA
        without normalizing ALT. In contrast, only 3 patients (10%) without
        significant fibrosis had an
        HCV RNA response without normalization of ALT. Thus, clinical trials for
        chronic HCV are now
        typically reported using virologic response rates.

        What then are the current goals of antiviral therapy in patients with
        chronic hepatitis C? Immediate
        goals are eradication of viral replication and improvement in hepatic
        inflammation and fibrosis.
        Long-term potential goals include prevention of cirrhosis,
        hepatocellular carcinoma, and liver
        failure.

        Interferon Monotherapy

        IFN-alfa 2 was the first agent approved for the treatment of chronic
        HCV. Since the initial trials
        establishing its efficacy, data regarding treatment duration and dose
        have evolved. Currently, 2
        forms of IFN-alfa that differ by a single amino acid residue are
        approved for treatment of chronic
        HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
        IFN-alfa 2a
        (Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
        million units 3 times each
        week for up to 12 months.

        When used alone in monotherapy, the alfa interferons have similar
        efficacies, with SRs of only 10%
        to 20%, with the modestly higher response rates associated with more
        prolonged therapy.
        Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
        between 8% and 20% in
        treatment-naive patients. High-dose IFN-alfa has also been studied in
        NRs and relapsers, but with
        mixed results. With prior NR, SRs achieved with higher doses are only
        between 0% and 4%. In
        relapsers, SRs range from 20% to 40%. However, side effects are more
        troublesome with higher
        doses.[8]

        Because of the low overall response rate to standard IFN-alfa, more
        recent studies have focused
        on newer regimens, including synthetic IFN (IFN alfacon-1),
        "combination" therapy (IFN-alfa 2b
        + ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
        pretherapy predictors
        of NR have been identified, notably HCV genotype 1, the presence of
        cirrhosis, and higher viral
        load.[9] In addition, patient's race appears to affect response to IFN,
        with African Americans
        having an overall low SR to therapy.[10]

        Combination Therapy

        A significant improvement in SR resulted from the addition of ribavirin
        to standard IFN-alfa.
        Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
        for chronic HCV because
        of its antiviral activity against other RNA viruses.[11-13] Although as
        monotherapy it reduces ALT
        levels, it does not appear to have a direct antiviral effect and fails
        to lower serum HCV RNA
        levels. Moreover, results of most studies with ribavirin have found no
        improvement in hepatic
        histology, although a longer 2-year treatment regimen was shown to
        reduce necroinflammatory
        activity.[13]

        However, in combination with IFN-alfa 2b, ribavirin leads to a
        significant increase in SR in
        treatment-naive patients.[14] SRs of 31% with 24 weeks and 38% with 48
        weeks of combination
        therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
        monotherapy.[14] In
        relapsers, enhanced SR rates also occur on retreatment using combination
        therapy, from 30% to
        49%; in prior NRs, SR of 14% has been reported with 6 months of
        combination therapy.[15,16]

        Histologic improvement was more common among treatment-naive patients
        treated with
        combination therapy.[14] Similar improvement was found in a randomized
        controlled trial of
        treatment-relapse patients.[15]

        However, the improved SR rates observed with combination therapy are
        also associated with
        more expense and an increased frequency of adverse effects compared with
        IFN-alfa
        monotherapy.[14] Dose-related hemolytic anemia is a particular concern
        with ribavirin[11,13] as is
        teratogenicity, based on animal studies.[16] The mean drop in hemoglobin
        in patients treated with
        combination therapy is between 2 and 3 g/dL, although a fall of more
        than 4 g/dL has been
        observed in about 10% of patients. The anemia may be poorly tolerated in
        patients with ischemic
        heart disease in particular as treatment is extended to older
        patients.[17] Accumulation of ribavirin
        metabolites that are not cleared by dialysis occurs in end-stage renal
        disease.(18)

        Consensus Interferon

        Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
        a genetically
        engineered compound synthesized by combining the most common amino acid
        sequences from
        naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
        and 30% with
        IFN-beta. Although it has greater cytokine induction, antiviral,
        antiproliferative, natural killer cell,
        and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
        an equal mass basis, initial
        studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
        with chronic hepatitis C
        resulted in viral response rates similar to those achieved with standard
        IFN-alfa monotherapy.[19,20]

        More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
        reported to result in
        virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48
        weeks.[21]

        Pegylated Interferon

        Pharmacokinetic studies have provided a rationale for enhanced IFN
        dosing. The initial decline in
        serum HCV RNA levels seen after a single dose of IFN therapy is believed
        to reflect a direct
        antiviral effect, whereas the subsequent and more delayed decline in HCV
        RNA levels is due to
        destruction of infected hepatocytes.[22] An important limitation of the
        antiviral effect of standard
        IFN dosing is the rapid decline in circulating drug level with
        thrice-weekly administration. The short
        half-life of the drug and the rapid production of HCV virions diminish
        the efficacy of standard IFN
        therapy. In an effort to achieve more stable and efficacious IFN
        activity, pegylated formulations
        have been developed.

        The production of a pegylated IFN involves the addition of a nontoxic
        long-acting formulation of
        interferon using the drug delivery system of pegylation. Polyethylene
        glycol molecules are added to
        IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
        Schering-Plough).
        Pegylation is already used in the delivery of other drugs. Its
        attachment to IFN-alfa permits
        once-weekly dosing.

        In a recent report, Zeuzem and colleagues[23] indicate that at week 72,
        the SR was 39% after 48
        weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
        compared with a 19% SR in
        control patients. Drug discontinuation in these treatment-naive patients
        and frequency of dose
        reduction were similar in the 2 treatment arms. Heathcote and
        colleagues[24] have also reported on
        the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
        patients. SR was 30% following 48
        weeks of therapy with 180 mcg, compared with 8% for patients treated
        with standard alfa IFN,
        again without a significant increase in side effects with the pegylated
        product.

        Trepo and colleagues[25] have also reported, in abstract form, initial
        studies with pegylated IFN-alfa
        2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
        weekly for 48 weeks) was
        12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
        with 0.5 mcg/kg,
        1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
        treatment-naive patients.

        As with standard IFN-alfa monotherapy, ribavirin may augment response
        rates when combined
        with the pegylated IFNs.[26,27] Recent trials will help evaluate further
        the role of ribavirin in
        augmenting the efficacy of pegylated IFN (see Figure).



        Figure. Initial antiviral therapy against hepatitis C virus.*
        * Abbreviations: IFN = interferon; CSN = consensus interferon;
        IFN/RIB =
        interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
        pegylated interferon +
        ribavirin.

        Future Trends

        There has been continued interest in developing non-IFN-based therapies
        for HCV despite the
        promise of the pegylated IFNs. A recent study examined the role of human
        interleukin-10 in
        treating prior NRs with chronic HCV.[28] Although, HCV RNA remained
        detectable in all patients
        at the end of treatment,[25] 5 (23%) of the 22 treated patients had
        persistent ALT normalization at
        the end of follow-up. Future studies should determine whether combining
        interleukin-10 with other
        antiviral agents will increase efficacy in this setting. Interleukin-12
        has also been evaluated as
        monotherapy, again without clear antiviral benefit.[29]

        There is also increasing enthusiasm for targeting HCV molecular
        products. For example, ribozyme
        gene therapy has the potential to accurately degrade HCV RNA.[30] Human
        studies are anticipated.

        Conclusion

        Treatment options for HCV infection continue to expand. Whereas SRs of
        10% were achieved
        with IFN monotherapy only several years ago, it may soon be possible to
        achieve SR rates greater
        than 50% with combination pegylated IFN and ribavirin. Molecular-based,
        specific therapeutic
        strategies are also likely to become a reality in the future, although
        therapy will remain
        interferon-based the next several years.

        Table. Response (HCV RNA/ALT*) to Antiviral Therapy

        Type of Response†
        During
        Treatment
        End of
        Treatment
        6 Months After
        Treatment
        Completed
        End-of-Treatment
        Negative
        Negative

        Sustained
        Negative
        Negative
        Negative
        Relapse
        Negative
        Negative
        Positive
        Nonresponder
        Positive
        Positive
        Positive


        * HCV RNA measured by polymerase chain reaction; ALT = alanine
        aminotransferase; HCV = hepatitis C virus.
        † Positive denotes HCV RNA present in the serum by polymerase chain
        reaction and
        abnormal alanine aminotransferase values. Negative denotes no serum
        HCV RNA by
        polymerase chain reaction and normal alanine aminotransferase
        values.

        References

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        2000;118:655-660.
        29.Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of
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        1999;29:1280-1287.
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