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Fw: NATAP: New HCV Drug Albuferon in Nonresponders

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  • Alley Pat
    NATAP http://natap.org/ ... A Phase 2 Dose-Escalation Study of (Albuferon) albumin interferon alfa-2b Combined with Ribavirin in Non-responders to Prior
    Message 1 of 1 , May 4, 2006
      NATAP http://natap.org/
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      A Phase 2 Dose-Escalation Study of (Albuferon) albumin interferon alfa-2b Combined with Ribavirin in Non-responders to Prior Interferon Based Therapy for Chronic Hepatitis C Infection Phase

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

      Author: Vinod Rustgi et. al.
      Disclosure: Relationship with Human Genome Sciences, Inc., Rockville, MD - Investigator and Consultant
      Study sponsored by Human Genome Sciences, Inc., Rockville, MD, USA

      Phase 2 Non Responder Study
      Definition of Non-responder to IFN therapy
      o Lack of ETR (failed to clear HCV RNA on therapy)
      o At least 12 weeks of therapy with lack of EVR
      o At least 50% should be PEG-IFN+RBV NR

      Author Summary of Safety
      1. 48 week safety profile is acceptable for the 900/1200 _g cohorts
      o No increase in AE between weeks 12-24-48
      o Hematologic reductions stabilize by week 8
      o Immunogenicity rates are low and and there are no apparent clinical correlations
      o Q4w appears to be better tolerated (less hematologic
      reductions)

      2. 24+ week safety profile is acceptable for the 1500 _g cohort

      3. 12-24 week safety profile for the 1800 _g cohort is comparable to the lower dose cohorts

      Conclusions
      o Antiviral activity is promising in a non-responder population
      - ETR rate is 31% (22/71) in the 900-1200 ug cohorts
      - Viral response at w12 follow-up after ETR is 14/71 (20%)
      - The 1800 ug arm shows maximal activity at week 24 in GT1 PEG+RBV non-responders
      o Long term safety profile is favorable
      - No significant increase in severity of adverse events between week 12 and 24
      - Hematologic reductions stabilized by week 8 and are well managed with dose reductions
      - Little drug accumulation between week 12 and 24
      - No significant increase in severity or number of adverse events with increased dose of alb-IFN


      Pharmacokinetics



      Rationale for Dose Selection
      (GT1 Naïve Phase 2a Dose Finding Study)

      Bain et al, J. Hepatol., April, 2006

      Study Design
      1st 3 arms randomized; then sequential dose escalation



      o Endpoints
      - Primary: Safety and tolerability
      - Secondary: Antiviral response (SVR)
      o HCV RNA: Real time PCR (Quantasure: range 10 IU-100 million IU/mL)

      *All RBV 1000-1200 mg/d (weight-based)


      Baseline Characteristics



      Efficacy in the Five alb-IFN Cohorts


      o Treatment was extended to 72 weeks for subjects who became RNA negative after week 24: 2 subjects in the 900 ug Q2w and 1 subject in the 1200 ug Q4w cohort

      HCV RNA Reduction
      (GT1, PEG+RBV Non-responders, N=75)



      Week 12 Antiviral Response
      (GT1, PEG+RBV Non-responders, N=75)


      Week 24 Antiviral Response
      (GT1, PEG+RBV Non-responders, N=75)



      Summary of Efficacy
      1. Week 48 RNA negativity rate (ETR) was 31% in the 900-1200 ug cohorts
      2. The preliminary SVR rate is 20% based on w12 FU. The relapse rate to date is low
      3. The 1800 ug cohort shows the greatest w24 HCV RNA negativity rates in GT1, PEG+RBV non responders
      4. Few viral breakthroughs were observed. The 1200 ug Q4w cohort is able to maintain RNA negativity

      Safety and Tolerability
      o Well tolerated with the most common moderate-severe adverse events of fatigue (50%), headache (34%), arthralgia (24%) and myalgia (21%)
      - No significant increase in severity over the first 24 weeks
      - The incidence was similar across the 5 cohorts
      - 10.4% (12/115) required dose reductions for AEs and 5.2% (6/115) required discontinuations for AEs
      o 4 serious adverse events: brain aneurysm, abdominal pain (LUQ), ethylene glycol toxicity, appendicitis

      Discontinuations

      o Data through 24 weeks; ** Data through 12 weeks

      Hematologic Reductions (ANC)
      Stabilize by Week 8


      Alb-IFN Dose Reduction

      *Week 24 exposure; ** Week 12 exposure

      Immunogenicity
      19 (16.5%) had pre-dose anti-IFN Ab
      2 (1.7%) had pre-dose anti-HSA Ab
      No correlation with antiviral response or adverse events

      *Pre-dose negative to post-dose positive




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