Eltrombopag Raises Platelet Counts, Enabling Initiation of Interferon-based Therapy for Hepatitis C

Thrombocytopenia, or low platelet count, can lead to easy bruising and prolonged bleeding. People with advanced liver fibrosis or cirrhosis often develop thrombocytopenia, and it can also be a side effect of interferon alfa therapy. For this reason, patients with pre-existing thrombocytopenia are typically advised not to use interferon-based therapy for hepatitis C, even though they may be the ones who need treatment most urgently.

Numerous studies have shown that blood cell growth factors can help manage the hematological side effects of HCV treatment, including erythropoietin (EPO) for ribavirin-induced anemia and granulocyte colony-stimulating factor (G-CSF) for interferon-induced neutropenia. These adjunct therapies can help patients stay on interferon and ribavirin.

In the November 29, 2007 New England Journal of Medicine, an international researcher team reported results from a study of eltrombopag (Revolade or Promacta), an oral blood platelet growth factor used to manage thrombocytopenia.

The trial included 74 patients with HCV-related cirrhosis andplatelet counts ranging from 20,000 to less than 70,000 cells/mm3 (150,000-400,000 cells/mm3 is normal for healthy adults) were randomly assigned to receive eltrombopag (30, 50, or 75mg daily) or placebo daily for 4 weeks.

The primary end-pointwas achievement of a platelet count of at least 100,000 cells/mm3 at week 4. Pegylated interferon plus ribavirin could then be initiated,with continuation of eltrombopag or placebo for 12 additional weeks.

Results

o   0 of 17patients receiving placebo;

o   9 of 12 (75%) receiving 30 mg eltrombopag;

o   15 of 19 (79%) receiving 50 mg;

o   20 of 21 (95%) receiving 75 mg (P<0.001).

Conclusion

Based on these findings, the authors concluded, “Eltrombopag therapy increases platelet counts inpatients with thrombocytopenia due to HCV-related cirrhosis,thereby permitting the initiation of antiviral therapy.”

In November, GlaxoSmithKline announced the initiation of 2 parallel Phase III studies -- ENABLE 1 and ENABLE 2 -- to assess the clinical benefits of eltrombopag in patients with hepatitis C-associated thrombocytopenia.

Each study will consist of an open-label pre-antiviral treatment phase (Part 1) and a randomized, double-blind, placebo controlled antiviral treatment phase (Part 2). Both studies will enroll approximately 750 chronic hepatitis C patients with detectable HCV RNA with baseline platelet counts below 75,000 cells/mm3.

In Part 1, all participants will receive open-label eltrombopag in increasing doses for up to 9 weeks before being randomly assigned to double-blind eltrombopag or placebo plus antiviral therapy for up to 48 weeks. ENABLE 1 will assess pegylated interferon alfa-2a (Pegasys) plus ribavirin, while ENABLE 2 will assess pegylated interferon alfa-2b (PegIntron) plus ribavirin.

For further details on these studies, see www.clinicaltrials.gov (search for “eltrombopag”).

Duke University and Duke Clinical Research Institute, Durham, NC; Royal Free Hospital, London, UK; Virginia Commonwealth University Medical Center, Richmond, VA; Fundacion de Investigacion de Diego, San Juan, Puerto Rico; Weill Medical College of Cornell University, New York, NY; Hôpital Saint Joseph, Marseille, France; Charité, Berlin, Germany; Henry Ford Hospital and Health System, Detroit, MI; GlaxoSmithKline, Greenford, UK; Beth Israel Deaconess Medical Center, Boston, MA; GlaxoSmithKline, Research Triangle Park, NC; GlaxoSmithKline, Philadelphia, PA.

12/14/07

Reference

JG McHutchison, G Dusheiko, ML Shiffman, and others.Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. New England Journal of Medicine 357(22): 2227-2236. November 29, 2007.

Other Source

GlaxoSmithKline. GlaxoSmithKline initiates trials of Promacta/Revolade (eltrombopag) to investigate the potential to aid hepatitis C patients in achieving sustained virological response. Press release. November 5, 2007.