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Fw: NATAP/EASL: HCV Protease SCH503034 Resistance Profile

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  • Alley Pat
    NATAP http://natap.org/ ... The HCV Protease Inhibitor SCH 503034 in Combination with PEG-IFN a-2b in the treatment of HCV-1 PEG-IFN +/- Ribavirin
    Message 1 of 1 , May 2, 2006
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      The HCV Protease Inhibitor SCH 503034 in Combination with PEG-IFN a-2b in the treatment of HCV-1 PEG-IFN +/- Ribavirin Non-Responders: Antiviral Activity & HCV Variant Analysis

      Reported by Jules Levin
      EASL, April 26-30, 2006
      Vienna, Austria

      S Zeuzem (Saarland University Hospital, Homburg, Germany) reported these study results for his coinvestigators and Schering-Plough at EASL in an oral presentation. Study sponsored by Schering-Plough Research Institute.

      Background provided by Zeuzem: Evasion of Intracellular Host Defense by HCV
      Hepatitis C virus / host interaction with-
      - RIG-1/cardif
      - TLR-3/trif
      serves to control host immune responses and may attenuate the action of IFN.

      This interaction therefore provides a foundation for persistent HCV replication and spread.

      NS3 protease may represent a dual therapeutic target.

      HCV protease inhibitors will
      -Suppress viral replication
      -improve host interferon responsiveness

      SCH 503034 + Peg-IFNa-2b in HCV-1 Non-Responders: study design
      Population:
      --HCV-1 Peg-IFN a-2b nonresponders: previous treatment was for 12 weeks with or without ribavirin ; HCV RNA reduction was <2 logs. Patients have compensated liver disease for this study.

      Study Design:
      Open-label, 3-period crossover
      All patients received all 3 regimens with at least a 2 week wash-out period:
      --Peg-IFN a-2b: 1.5 ug/kg once weekly (QW)
      --SCH 503034: 200 mg or 400 mg TID (3 times a day)
      --Combination of the Peg-IFN a-2b (1.5 ug/kg QW) and SCH 503034 (200 mg or 400 mg TID)



      Mean HCV RNA was 6.3 log at baseline for 200 mg arm & 5.6 log for 400 mg arm. ALTs were mean 80-83.




      METHODS
      Pharmacodynamics
      -SCH 503034 Monotherapy:
      days -1, 1-4, 6, 7, and D28 (F/U)

      -Peg-IFN alfa-2b +/- SCH 503034
      days -1, 1.4, 6, 8-11, 13-14 and Day 28 (F/U

      Resistance evaluation
      --Day 1, 6 PI-monotherapy
      --Day 1, 6, 13 Peg-IFN alfa 2b +/- SCH 503034
      --Day 28 F/U final period
      --cDNA sequencing
      --sensitivity about 10-20%

      Safety
      --vital signs
      --clinical lab tests
      --time-matched ECG

      Individual Viral Responses of SCH 503034 (200 mg TID) + Peg-IFN Therapy



      Individual Viral Response of SCH 503034 (400 mg TID) + Peg-IFN Therapy


      SCH 503034 Pharmacodynamics: Distribution of Virology Response


      Correlation Between Maximal Viral Log Decrease during Combination Treatment and Peg-IFN Treatment

      The slope is in line with in vitro data that shows synergistic activity between PegIFN and SCH503034.

      Sequence Analysis of HCV Protease
      -- 18/19 patients had no detectable variants
      -- patient #105: a single mutation at position T54 was identified during SCH 503034 mono- and combination tx
      -- Variant became non-detectable after washout period
      -- Quasi-species analysis are under way
      NOTE from Jules Levin: at the meeting after Zeuzem gave his talk I asked him from the microphone why they had so little resistance, 1 mutation in 1 patient, compared to VX-950, for which Vertex presented much resistance data, the response Zeuzem said was-the resistance test used in this study was not as sensitive and SCH503034 was not potent enough to cause resistance.


      Safety
      --Sch503034 + PegIFNa-2b combination therapy was well tolerated.
      --Mosr AEs were mild and moderate
      --No dose-related increase in AE frequency
      --Most frequently reported AEs in combination therapy were: headache, myalgia, fever
      --Single SAE leading to discontinuation (seizure)
      --Clinical lab values and ECGs were similar to Peg-IFNa-2b alone.

      Most Frequent Adverse Events


      AUTHOR SUMMARY
      SCH 503034 + PegIFNa-2b was well tolerated in genotype 1 patients who had previously not responded to standard therapy.
      Combination did not affect the oscillatory pharmacodynamic pattern of PegIFNa-2b.

      Antiviral activity of SCH 503034+ PegIFNa-2b was potent and at least additive (combination superior to either monotherapy).

      4/10 HCV-1 non-responders became HCV RNA negative within two weeks of SCH 503034 (400 mg TID) + PegIFNa-2b.







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