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Review of Satellite Symposium on Pegylated Interferons Held During Conference on Liver Diseases Roche-sponsored program features state of the art information on new formulations of interferon alfa.

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    Review of Satellite Symposium on Pegylated Interferons Held During Conference on Liver Diseases Roche-sponsored program features state-of-the-art information
    Message 1 of 1 , Dec 8, 2000
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      Review of Satellite Symposium on Pegylated
      Interferons Held During
      Conference on Liver Diseases Roche-sponsored program
      features
      state-of-the-art information on new formulations of
      interferon alfa
      by Paul Martin, MD

      Dr. Martin is Medical Director of Liver
      Transplantation at Cedars Sinai
      Medical Center, Los Angeles, and Associate Professor
      of Medicine at the
      UCLA
      School of Medicine

      Editor's Note: The satellite symposium on pegylated
      interferons,
      sponsored
      by Professional Postgraduate Services, was held
      October 30, 2000 in
      Dallas,
      Texas in conjunction with the 51st Annual Meeting of
      the American
      Association for the Study of Liver Diseases (AASLD).
      The symposium was
      supported by an unrestricted educational grant from
      Hoffman-La Roche
      Inc.

      The agenda for the symposium consisted of an
      introduction by the
      co-chairs
      of the program, followed by four oral presentations
      and a question
      andanswer
      session. The symposium co-chairs were Alfredo Alberti,
      MD, Professor of
      Medicine at the University of Padova, Padova, Italy,
      and Michael Hill,
      MD,
      Associate Professor of Medicine at the University of
      North Carolina at
      Chapel Hill, Chapel Hill, North Carolina.

      Four distinguished liver specialists gave
      presentations on various
      aspects
      of the two pegylated interferons now in Phase III
      testing and under
      review
      by the US Food and Drug Administration (FDA).

      Rationale for the Development of the Pegylated
      Interferons to Treat
      Chronic
      Hepatitis C
      Paul Martin, MD

      Currently, approved therapy for chronic hepatitis C
      (HCV) is interferon
      alfa
      monotherapy or combination therapy with ribavirin
      [Rebetol]. Despite
      enhanced response rates with the addition of
      ribavirin, most treated
      patients fail to have a sustained virological
      response. Efficacy is
      limited
      in part due to fluctuations in plasma concentrations
      with interferon
      therapy
      administered thrice weekly. The attachment of a
      nontoxic polyethylene
      glycol
      (PEG) moiety to the interferon molecule results in
      sustained
      absorption,
      restricted biodistribution, reduced clearance and
      avoidance of the wide
      fluctuations in serum concentrations typical with
      current interferon
      therapy
      dosing. Improved understanding of interferon
      pharmacokinetics as well
      as HCV
      viral kinetics has lead to development of alternate
      interferon
      formulations.

      Two Pegylated alpha interferons are currently in
      clinical trials: PEG
      (12
      kDa) IFN a-2b (Peg-Intron) is formed by attachment of
      a linear
      12-kilodalton
      PEG to IFN a-2b and PEG (40 kDa) IFN a-2a formed by
      covalent attachment
      of a
      branched 40-kilodalton PEG moiety to IFN a-2a.
      (Pegasys)

      The different molecular size and shape affects the
      pharmacokinetic
      properties of these two products. Standard interferon
      alpha has a
      terminal
      half-life of 3-5 hours, for Peg-interferon it is 30 -
      55 hours and for
      Pegasys it is 55 - 65 hours. Clearance is
      substantially diminished by
      pegylation by a factor of 10 for Peg interferon and a
      factor of 100 for
      Pegasys. Interferon absorption remains rapid following
      pegylation but
      Pegasys also has sustained absorption over several
      days following
      injection.
      The volume of distribution is also restricted by the
      pegylation process
      with
      Pegasys limited to the blood and interstitial fluid
      surrounding the
      major
      organs in contrast to the wider distribution with
      standard interferon
      alpha
      and Peg Intron. Reflecting the diminished clearance
      circulatory drug
      levels
      are increased with the pegylated interferons.

      With repeated weekly dosing, steady-state
      concentrations of Pegasys are
      attained within 5 to 8 weeks. Pegasys is cleared
      primarily hepatically
      with
      its pharmacokinetics generally unaffected in patients
      with chronic
      renal
      insufficiency although 2'5' oligo adenylate synthesis
      (OAS) induction
      is
      lessened in the presence of severe renal impairment.
      No change in
      Pegasys
      dose will be necessary in the patient with renal
      insufficiency. In
      older
      patients OAS induction is also reduced suggesting that
      dose reduction
      in
      this population will also not be required. Pegasys
      pharmacokinetics in
      patient with cirrhosis are also similar to those in
      healthy volunteers.

      Based on data presented at AASLD, Pegasys also appears
      to have improved
      efficacy in difficult-to-treat groups such as African
      Americans and
      patients
      with genotype 4 (Shiffman ML et al, 2000 and Sherman M
      et al, 2000).

      ------------------------

      Update on Clinical Trials with the Pegylated
      Interferons to Treat
      Chronic
      HCV
      Paul J. Pockros, MD, Head, Division of
      Gastroenterology/Hepatology,
      Scripps
      Clinic and Research Foundation, La Jolla, CA

      A sustained virologic response (SVR) rate with Pegasys
      of 39% has
      previously
      been reported in treatment na�ve patients by Zeuzem S
      et al compared to
      19%
      with interferon alpha monotherapy. The adverse event
      and laboratory
      test
      side effects due to Pegasys are similar to standard
      IFN monotherapy. In
      a
      report by Trepo comparing Peg-Intron 1.0 mg/kg
      compared to IFN a-2b 3
      MIU, a
      sustained viral response was observed in 25% and 12%
      of treated
      patients
      presented at the European Association for the Study of
      Liver Diseases
      Meeting earlier this year.

      The combination of ribavirin with pegylated interferon
      has also been
      reported this year. In an open-label pilot study of 20
      patients
      receiving 48
      weeks of treatment with Pegasys 180-mg qw plus
      ribavirin 1,000 mg to
      1,200
      mg qd, sustained virological roles rates were 50%
      overall, 38% for
      genotype
      1 and 100% for non-1 genotype is in a report by
      Sulkowski M at
      Digestive
      Diseases Week this summer.

      Manns and colleagues at AASLD in a large multicenter
      study reported a
      sustained response rate of 54% in patients receiving
      combination Peg
      Intron
      and ribavirin with a sustained response rate of 42%
      for genotype 1
      patients.
      The control group treated with standard interferon
      alpha and ribavirin
      had a
      sustained response rate of 47% with 33% for genotype
      1.

      Analysis of the Pegasys database by Lee as reported at
      AASLD has
      identified
      additional predictors of sustained response in
      addition to the standard
      predictors of non-1 genotype, lower viral load,
      absence of cirrhosis
      and
      lower body weight. These new pretreatment predictors
      are ALT elevated
      more
      than 3 times the upper limit of normal, hepatic
      activity index more
      than 10
      and or a 2 log10 drop from baseline at week 12 of
      therapy.
      --------------------

      Effect of Therapy on Quality of Life
      David E. Bernstein, MD, Director of Hepatology and
      Associate Professor
      of
      Medicine at New York University School of Medicine

      The impact of therapy on quality of life was reviewed
      by Dr. David
      Bernstein
      (NYU). Perrillo and colleagues reported at AASLD that
      work productivity
      was
      less impaired by Pegasys treatment with only 3.3% of
      time missed from
      work
      compared to 19.1% on Rebetron. Rasenack reported, also
      at AASLD, that
      in a
      72-week multinational trial with patients (n=264)
      randomized to either
      Pegasys 180 mg weekly or IFN a-2a 6 MIU tiw for 12
      weeks followed by 3
      MIU
      tiw for 36 weeks quality of life and fatigue were
      studied by the
      standardized 36-question short form health survey
      (SF-36) as well as a
      fatigue severity scale (FSS). At weeks 2 and 12 of
      therapy patients in
      the
      Pegasys group had statistically better QOL scores.
      Pegasys was
      associated
      with less profound fatigue as measured by FSS scores
      relative to their
      standard IFN counterparts (P<0.05). This indicates
      that Pegasys therapy
      is
      better tolerated than currently available interferon
      therapy.

      ---------------------
      The Kinetics of HCV Production and Clearance
      Jean-Michel Pawlotsky, MD, PhD, Professor of medicine
      and Chief,
      Virology
      Unit at Hopital Henri Mondor Universite, Paris, France

      In chronic HCV infection, there is a high rate of
      production of HCV
      virions
      by infected hepatocytes in the order of 1012/day and
      when released into
      the
      circulation having a half-life of 3 hours.
      Administration of interferon
      results in a two-phase response with the initial
      decline in HCV RNA due
      to
      inhibition of viral replication and a slower decline
      due to death of
      infected hepatocytes. With improved insight into HCV
      kinetics it has
      become
      possible to further define categories of virologic
      response to
      antiviral
      therapy as described by Neumann and colleagues,
      non-responders and
      relapsers, flat partial responders, slow partial
      responders, and rapid
      virologic responders. The rapidity of decline of HCV
      RNA during the
      first 4
      weeks of therapy may be a better predictor of response
      than baseline
      viral
      load. Therapy in the future may be tailored to the
      virological response
      to
      initial therapy.

      12/1/00

      Reference:
      Chronic Hepatitis C: Newly Emerging Data on Pegylated
      Interferons.
      Satellite Symposium. October 30, 2000. Wyndam Anatole
      Hotel, Dallas,
      Texas.
      Sponsored by Professional Postgraduate Services, a
      division of
      Physicians
      World Communications Group.

      http://www.hivandhepatitis.com/hepc/c12010002.html



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