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Pegasys + ribavirin (Edie)

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  • Claudine Crews
    Edie, Here is one study, and although it is comprised of a very small group of people, you have to admitt it is still pretty interesting! And no, this isn t
    Message 1 of 1 , Jun 3, 2000
      Edie,
      Here is one study, and although it is comprised of a very small group
      of people, you have to admitt it is still pretty interesting! And no, this
      isn't the study I was thinking was on relapsers, I believe these people had
      never been treated.
      Claudine


      Treatment of HCV with Long-Acting "Pegylated" Alfa * Interferon Shows
      Impressive Results

      For 16 patients with genotype 1, end-of-treatment response rate is 63%;
      for
      4 patients with genotype 2, sustained response rate is 100%

      by Harvey Bartnof, MD

      There were several abstracts today that addressed the experimental
      pegylated
      forms of alfa * interferon. Pegylated means that the active drug is
      encased
      in a fat molecule called polyethylene glycol, or "peg" in an
      abbreviated
      acronym. This slows the metabolism significantly, allowing for a once
      weekly
      injection instead of the 3-times weekly approved dosing for the
      non-pegylated form. The version from Hoffman-La Roche will be called
      Pegasys
      (pegylated interferon alfa-2a, while the version from Schering-Plough
      will
      be called Peg-Intron (pegylated interferon alfa-2b).


      Hoffman-La Roche's Pegasys
      A phase II, single arm, open-label study was presented that combined
      Roche's
      Pegasys with Rebetol (ribavirin) for the treatment of chronic infection
      with
      hepatitis C virus (HCV). The lead author was M. Sulkowski, MD, from The
      Johns Hopkins University School of Medicine. Even though there were
      only 20
      patients, the results were impressive. Sixteen of the patients had
      genotype
      1, which is the most difficult to treat. The other four patients had
      genotype 2, which is more responsive to treatment. All 20 patients had
      chronic hepatitis C. This was defined as (1) a persistently elevated
      blood
      ALT (alanine aminotransferase, liver enzyme); (2) an HCV RNA viral load
      greater than 2,000 copies per milliliter using the Amplicor Monitor
      test;
      and (3) an abnormal liver biopsy sample consistent with "compensated
      non-cirrhotic liver disease." All patients were therapy-naove (never
      treated
      for hepatitis C). Exclusion criteria included heart disease, kidney
      disease,
      pre-existing severe depression or other psychiatric disorders, seizure
      disorder, retinopathy (eye disease), other liver diseases, and HIV
      infection.

      The dosage was once-weekly Pegasys (180 micrograms) injection under the
      skin
      plus oral Rebetol 1,000-1,200 mg daily. Since genotype 1 is more
      refractory
      to therapy, the duration of treatment for those patients was 48 weeks,
      if
      there was a normal ALT or undetectable HCV viral load at 24 weeks. For
      those
      with genotype 2, the treatment duration was 24 weeks. Those durations
      reflect the standard guidelines based on genotype testing. The median
      baseline HCV viral load was not stated.

      The results showed that for those patients with genotype 1, the
      end-of-treatment response was 63%. That means that 63% had an
      undetectable
      HCV viral load (limit 100 copies per milliliter) at the end of 48 weeks
      of
      therapy. (All results are reported using a stricter "intent-to-treat"
      analysis, meaning that all enrolled patients are included.) Whereas,
      for
      those patients with genotype 2, the sustained response rate was 100%.
      (Those
      with genotype 2 received 24 weeks of therapy, followed by a 24-week
      treatment-free follow-up period.) While the numbers of patients are
      small,
      these viral load undetectability rates are among the highest ever
      reported
      for patients treated for hepatitis C.

      When the results of the entire 20 patients were analyzed together, at
      the
      48-week time point, the following were found: the percentage with a
      normal
      ALT was 60%, while those with an undetectable HCV viral load was 70%.
      Interestingly, the percentage with an undetectable viral load at 12
      weeks
      was also approximately 70%.

      Adverse events included lowered blood cell counts, which are known side
      effects. The neutrophil (white blood cell) count and hemoglobin
      (oxygen-carrying molecule in red blood cells, lowered in anemia)
      stabilized
      at week four. The decrease in blood platelets (for normal clotting)
      stabilized by week 12. No patient withdrew from the study due to
      abnormal
      laboratory test results.

      Two patients (10%) withdrew prematurely from the study. One had a
      seizure
      ("convulsion" or "fit"), while another had bleeding in the back of the
      eye
      (retinal hemorrhage). Interferon has been associated with a lowered
      seizure
      threshold in past studies. The hemorrhage was not depicted further in
      the
      poster presentation. However, eight patients did have dosing changes,
      due to
      adverse events. Four changes were due to anemia and two were due to
      neutropenia. Six other patients had a dose modification due to "other
      adverse events."

      The patients will be followed for a longer period. The poster did not
      state
      whether liver biopsies would be performed at the end of the observation
      period. The evaluation of a liver biopsy correlates much better with
      long-term disease progression. HCV viral loads do not necessarily
      correlate
      with long-term outcome.

      Even though these results are only interim, the authors conclude that
      the
      combination of Pegasys and Rebetol "appears to have acceptable
      tolerability
      and promising antiviral activity in the treatment of chronic hepatitis
      C."
      It is quite possible that the sustained response rate for those with
      genotype 1 will be lower than the end-of-treatment response (ETR) rate.
      Often, this is the observed pattern. However, an ETR of 63% for
      genotype 1
      is higher than has been reported for any other therapy(ies) to date. It
      appears that significant advances are being made in the treatment of
      this
      disease.

      In a separate poster presentation, the half-life (amount of time for
      half of
      an original amount to be remaining) of Pegasys was found to be 77
      hours,
      while a standard interferon injection had a half-life of nine hours.
      The
      phase II dose-ranging study had 20 HCV negative volunteers. The
      remainder of
      the study evaluated pharmacokinetic and pharmacodynamic (metabolism
      measurements) of Pegasys. The authors determined that the weekly
      self-injected dose under the skin would be 180 micrograms. The lead
      author
      was N.E. Algranati, MD, from Hoffman-La Roche.


      Schering Plough's PEG-Intron
      Another poster addressed a different formulation of the same drug.
      PEG-Intron (pegylated Intron, interferon alfa-2b, Schering-Plough)
      injected
      under the skin once weekly showed the same or better anti-HCV effects
      as
      standard Intron-A dosed at 3 million units injected 3-times weekly. The
      pharmacokinetics and pharmacodynamics (metabolism measurements) of this
      long
      acting form of the drug were measured in a 24-week study of HCV
      positive
      patients. The half-life (time for an original amount to be reduced by
      half)
      of PEG-Intron was calculated to be 54 hours, compared to 8 hours for
      standard Intron-A. No unexpected adverse effects occurred. Common
      symptoms
      include "flu"-like symptoms. Abnormal laboratory values included a low
      white
      cell count (neutropenia) and a low blood platelet count (for normal
      blood
      clotting, thrombocytopenia). The weekly dose will be 0.5 micrograms per
      kilogram once weekly (weight in pounds X 0.454 = weight in kilograms).
      The
      lead author was Paul Glue, MD, from Schering-Plough.

      * Note that all generic versions use the spelling 'alfa' and not
      'alpha.'

      11/7/99

      References:
      Algranati NE and others. A branched methoxy 40 KD/ polyethylene glycol
      (PEG)
      moiety optimizes the pharmacokinetics (PK) of peg-interferon alpha-2a
      (PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C
      (CHC). Abstract and poster presentation 120 at the 50th Annual Meeting
      of
      the American Association for the Study of Liver Diseases. Dallas,
      Texas;
      November 5-9, 1999. Hepatology 30(4) Supp2, 190A. Glue P and others.
      Peg-interferon-alpha-2b: pharmacokinetics, pharmacodynamics, safety and
      preliminary efficacy data. Abstract and poster presentation 115 at the
      50th
      Annual Meeting of the American Association for the Study of Liver
      Diseases.
      Dallas, Texas; November 5-9, 1999. Hepatology 30(4) Supp2, 189A.
      Sulkowski M
      and others. Combination therapy with peginterferon alfa-2a (PEG-IFN)
      and
      ribavirin in the treatment of patients with chronic hepatitis C: a
      phase II
      open-label study. Abstract and poster presentation 145 at the 50th
      Annual
      Meeting of the American Association for the Study of Liver Diseases.
      Dallas,
      Texas; November 5-9, 1999. Hepatology 30(4) Supp2, 197A.






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