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Fw: NATAP/DDW: Eltrombopag Maintains Platelet Count on Peg/RBV

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  • alleypat
    NATAP http://natap.org/ ... Eltrombopag Maintains Platelet Counts During Myelosuppressive Pegylated Interferon Alpha Treatment of Chronic Hepatitis C Virus
    Message 1 of 1 , Jun 6 9:39 AM
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      Eltrombopag Maintains Platelet Counts During Myelosuppressive Pegylated Interferon Alpha Treatment of Chronic Hepatitis C Virus Infection

      Reported by Jules Levin
      DDW May 2007, Wash DC

      G.M. Dusheiko1, J.G. McHutchison2, N.H Afdhal3, M.L Shiffman4, M. Rodriguez-Torres5, S. Sigal6, M. Bourliere7, T. Berg8, N. Blackman9, F.M. Campbell10, S. White9, D. Theodore11
      1Royal Free Hospital, London, United Kingdom; 2Duke Clinical Research Institute, Durham, NC; 3Beth Israel Deaconess Medical Center, Boston, MA; 4Virginia Commonwealth University Health System, Richmond, VA; 5Fundacion de Investigacion de Diego, San Juan,
      Puerto Rico; 6Weill Medical College of Cornell University, New York, NY; 7Hopital Saint Joseph, Marseille, France; 8Charite, Berlin, Germany; 9GlaxoSmithKline, Philadelphia, PA; 10GlaxoSmithKline, Greenford, United Kingdom; 11GlaxoSmithKline, Research Triangle Park, NC

      Background
      Eltrombopag is an oral, non-peptide, small-molecule thrombopoietin receptor agonist.

      The safety, efficacy, and pharmacokinetics of eltrombopag in hepatitis C virus (HCV)-infected patients with thrombocytopenia precluding initiation of pegylated interferon (PEG-IFN) and ribavirin have been reported (McHutchison et al. 57th AASLD. 2006; Abstract LB3).

      In study TPL102357, eltrombopag monotherapy was shown to increase platelet counts to > 100,000/_L at Week 4 in a dose-dependent manner (overall P value < 0.0001 for treatment effect). This effect was statistically significant versus placebo, with no patients in the placebo group achieving platelet counts > 100,000/uL.

      As a result, two-thirds of patients were able to initiate their antiviral treatment [N = 49: 4/18 (22%) in the placebo group; 10/14 (71%), 14/19 (74%), and 21/23 (91%) in the 30-mg, 50-mg, and 75-mg eltrombopag groups, respectively].

      Objectives
      We examined the ability of eltrombopag to counteract the myelosuppressive effects of PEG-IFN on platelet counts in HCV-infected patients during antiviral treatment phase.

      We analyzed a subset of the data from study TPL102357 to determine if eltrombopag is able to sustain platelet counts in thrombocytopenic patients during PEG-IFN treatment, to avoid the deleterious consequences of reductions in PEG-IFN dosing.

      Rationale
      There is an unmet need for a safe and effective treatment of disease and IFN-associated thrombocytopenia in HCV-infected patients to help facilitate optimal antiviral treatment.

      Limited yet promising data with alternate thrombopoietic agents suggest that there is a potential role for eltrombopag in HCV-infected patients (Rustgi et al. 53rd AASLD. 2002; Abstract 791. Ghalib et al. Hepatology. 2003;37:1165-1171).

      Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed in a phase I trial of eltrombopag 75 mg, administered once daily for 10 days in healthy volunteers (Jenkins et al. Blood. 2007;109(11): in press).
      -- Eltrombopag was well tolerated and exhibited a linear pharmacokinetic profile.
      -- A dose-dependent increase in platelet count was observed beginning on Day 7.

      Methods
      Double-blind, placebo-controlled study to evaluate the effects of eltrombopag on the initiation and subsequent maintenance of IFN-based antiviral therapy.

      74 HCV-infected patients with platelet counts between 20,000 and 70,000/_L were randomized to receive eltrombopag (30, 50, or 75 mg daily) or placebo for 4 weeks. The primary endpoint was a platelet count increase to 3> 100,000/_L at Week 4. Patients could then initiate PEG-IFN and ribavirin and continue eltrombopag or placebo for 12 additional weeks.

      49 patients entered this antiviral treatment phase and these data are now presented.

      Eligibility Criteria
      --Male or female patients 3 18 years of age.
      -- Chronic HCV infection (detectable HCV RNA).
      --Compensated liver disease (Child-Pugh A classification).
      --Pre-existing thrombocytopenia: 20,000-70,000 platelets/_L.
      --Patients stratified by baseline platelet count: 20,000-50,000/_L and >50,000-70,000/_L.
      --No history of thrombosis, HIV, or active infection with hepatitis B.

      STUDY DESIGN


      RESULTS

      Demographics (N = 49)
      Median baseline platelet count was 59,000 in placebo, 61,000/ul in 30mg QD group, 53,000/ul in 50mg QD group, and 54,000/ul in 75mg QD group. 25-38% of study participants had 20 to 50,000/ul platelet count.


      Mean Platelet Count by Study Day*
      *Intention to treat, last observation carried forward in Part 1; observed in Part 2



      Summary of Minimum Platelet Counts After 12 Weeks
      (End of Part 2)


      Time to Interferon Dose Modification
      During the First 12 Weeks of Antiviral Therapy


      Conclusions
      Eltrombopag effectively maintained platelet counts above 50,000/_L in up to 81% of patients during the first 12 weeks of antiviral treatment, counteracting the myelosuppressive effects of PEG-IFN.

      Eltrombopag use avoided the need for PEG-IFN dose modification in approximately 90% of patients during the first 12 weeks of antiviral treatment.

      Further research into the long-term use (48 weeks) of eltrombopag in patients with HCV-associated thrombocytopenia is warranted.







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