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EASL 2004: New HCV Drug, NM283, polymerase inhibitor: first data in patient:

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    NATAP - www.natap.org New HCV Drug, NM283, polymerase inhibitor: first data in patient: 1 log viral load decline in highest dose Reported by Jules Levin 39th
    Message 1 of 1 , Apr 18, 2004
      NATAP - www.natap.org

      New HCV Drug, NM283, polymerase inhibitor: first data in patient: 1
      log viral load decline in highest dose

      Reported by Jules Levin
      39th Annual European Association for the Study of the Liver (EASL)
      April 14-18, 2004
      Berlin, Germany


      FIRST CLINICAL RESULTS FOR A NOVEL ANTIVIRAL TREATMENT FOR HEPATITIS
      C: A PHASE I/II DOSE ESCALATION TRIAL ASSESSING TOLERANCE,
      PHARMACOKINETICS, AND ANTIVIRAL ACTIVITY OF NM283

      Nat Brown from Idenix Pharmaceuticals reported the exciting study
      results that captured the imagination of the audience. The conference
      saved this presentation until the last, unfortunately the room was
      half empty as many conference attendees had already left the
      conference.

      NM283 is a novel candidate HCV RNA polymerase inhibitor, has
      anti-flavivirus activity that is highly synergistic with
      interferon-alpha in vitro, and suppresses viremia in chimpanzees
      chronically infected with human-derived HCV-1 (Standring, EASL2003).

      NM283 is a prodrug for NM107. NM107 was not very bioavailable but
      NM283 is much more bioavailable. NM107 has submicromolar activity (at
      low doses) in the BVDV assay. It has no activity against HIV or DNA
      viruses. In a surrogate virus model (BVDV) NM107 reduced BVDV virus
      titer by almost 4 logs within 4 days when used as monotherapy, and
      interferon reduced virus titer by less than 1 log, but the
      combination of interferon 200 units/mL plus NM107 was synergistic in
      reducing virus titer by 8 logs at day 6 in this cell-based persistent
      BVDV infection model.

      NM283 inhibited HCV-1 replication in chronically infected
      chimpanzees. 5 chimps chronically infected with HCV received 2
      different oral once daily doses (NM283 8.3 mg/kg/day or NM283 16.6
      mg/kg/day) of NM283 and 1 chimp received placebo. Serum HCV RNA was
      quantified by Roche Amplicor PCR. HCV RNA was reduced by 0.83 log
      (low dose) and 1.05 log (high dose) at day 7 on treatment and there
      was no change in the placebo chimp.

      Brown reported the first data in HCV+ patients, a dose escalation
      study. The study evaluates safety, antiviral activity, and PK during
      15 days treatment and 2 weeks followup. Adult patients were all
      genotype 1, and treatment-naive or interferon failures. Serum HCV RNA
      was >5 log copies/ml and ALT was <5 x ULN. All had compensated liver
      disease, no cirrhosis. Dosing levels were 50, 100, 200, 400, and 800
      mg once daily. Each dosing patient group had 12 eligible patients
      randomized 10:2 to NM283 or placebo. Patients were mostly male
      Caucasians; 86% had prior IFN experience; they had high HCV viral
      load- 6.7 log copies/ml. Average ALT was 64.

      Brown showed PK data demonstrating the drug is well absorbed. There
      was no accumulation of the drug, day 15 steady state levels were the
      same as on day 1. There was a dose proportionality to observed drug
      levels.

      RESULTS

      MEAN LOG REDUCTIONS. At day 15, the lowest dose reduced viral load by
      .15 log, the middle doses reduced viral load by 0.4 log. The 400mg
      dose reduced viral load by 0.7 at day 15. They saw GI side effects in
      some patients on the 400mg dose. The dose titration group dosed up
      from 100 to 800mg and had a 0.7 log viral load reduction at day 15. A
      patient group dose escalate from 400 to 800 and reached 800 mg by the
      second week. They took antiemetic for the first two days. The average
      viral load reduction for this group was 1 log by day 15. After
      stopping the drug viral loads rebounded. The rate of decline in viral
      load appears to exceed that seen with interferon.

      SAFETY & TOLERANCE

      Brown said the overall clinical safety was satisfactory. There were
      no serious adverse events or dose limiting toxicities. All 49
      compliant patients completed treatment. 1 patient discontinued for
      non-compliance. No patients discontinued treatment for adverse event.


      There was no grade 3 or 4 lab abnormalities during treatment; no
      pattern of lab abnormalities. GI side effects seen in some patients
      was transient; 3 patients had vomiting. 15 of 18 patients who had
      nausea said it was mild, 3 moderate. The GI effects tend to onset in
      the first 2 days and tend to be transient as they last <1 day in 64%
      of affected patients. None changed or discontinued treatment. Brown
      commented that side effects compare favorably to
      interferon/ribavirin.

      Brown summarized: we see consistent antiviral activity in HCV+
      patients including previous IFN experience. The viral load reductions
      seen corresponds to 80-90% reductions in 2 weeks. Overall safety is
      satisfactory with no dose-limiting toxicities, transient nausea, and
      vomiting in some patients. All patients were compliant with
      treatment. The next study is a 4 week combination trial of NM283 and
      pegIFN.

      If all goes well it could take about 4 years to develop NM283 before
      it becomes available.






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