By
Liz Highleyman
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 and platelet
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 75 mg daily) or placebo
daily for 4 weeks.
The
primary end-point was 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
•
At week
4, among patients with available data, platelet counts increased to 100,000
cells/mm3 or more in a dose-dependent manner, as follows:
o
0 of 17
patients 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).
•
Anti-HCV therapy was initiated in 49 patients (4 of 18 receiving placebo,
10 of 14 receiving 30 mg eltrombopag, 14 of 19 receiving
50 mg, and 21 of 23 receiving 75 mg).
•
12 weeks of antiviral therapy with concurrent eltrombopag
or placebo were completed by 6% in
the placebo group, 36% in the 30 mg eltrombopag arm,
53% in the 50 mg arm, and 65% in the 75 mg arm.
•
The most common adverse
event during the initial 4 weeks was headache; thereafter, the adverse events
were those expected with interferon-based therapy.
Conclusion
Based
on these findings, the authors concluded, “Eltrombopag
therapy increases platelet counts in patients 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
Sources
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.
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.
