By Charles Bankhead, Staff Writer, MedPage Today
Published: November 14, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SAN FRANCISCO -- Patients with chronic hepatitis C virus (HCV) infection and thrombocytopenia had significant improvement in virologic response when pegylated interferon alpha 2a (Pegasys) was given with eltrombopag (Promacta), results of a randomized trial showed.
Overall, 66% of patients treated with eltrombopag plus peginterferon alpha 2a and ribavirin had an early virologic response compared with 50% of patients who received peginterferon 2a, ribavirin, and a placebo (P<0.0001). Additionally, 23% of the eltrombopag group achieved a sustained virologic response versus 14% of the placebo group (P=0.0064).
Treatment with eltrombopag was associated with an increased time-to-first-dose reduction of peginterferon and with fewer dose reductions, as reported here at the American Association for the Study of Liver Diseases meeting.
"Eltrombopag treatment enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for pegylated interferon 2-alpha therapy," said Nezam H. Afdhal, MD, of Harvard and Beth Israel Deaconess Medical Center in Boston.
"Treatment with eltrombopag provided a statistically significant and clinically meaningful improvement in sustained virologic response versus placebo."
"Eltrombopag showed an acceptable safety profile in high-risk patients with cirrhosis," he added.
Preliminary data from a companion study demonstrated similar improvement in early and sustained virologic response when eltrombopag was administered with peginterferon alpha 2b (PEG-Intron).
Patients with advanced liver fibrosis and portal hypertension frequently develop thrombocytopenia, which usually precludes antiviral therapy. Recommended platelet counts for initiation of peginterferon alpha 2a or 2b are ≥90,000/µL and ≥100,000/µL, respectively. Platelet counts commonly decline during peginterferon therapy as a result of myelosuppression.
Eltrombopag is an oral thrombopoietin receptor agonist that increases platelet count by increasing megakaryocyte differentiation and proliferation, Afdhal noted. The drug is approved in the U.S. for second-line treatment of chronic idiopathic thrombocytopenic purpura.
Investigators in two international randomized, placebo-controlled clinical trials sought to determine whether use of eltrombopag would enable patients with HCV infection, advanced liver fibrosis, and thrombocytopenia to receive peginterferon alpha 2a (ENABLE 1) or 2b (ENABLE 2).
Afdhal reported final results from ENABLE 1 and provided a glimpse of the initial results from ENABLE 2.
ENABLE 1 investigators enrolled patients who had HCV cirrhosis and platelet counts <75,000/µL. The trial had two phases. During the first phase, all patients received open-label eltrombopag at a starting dose of 25 mg, which was titrated to a maximum dose of 100 mg or until a platelet count of ≥90,000/µL was reached.
Patients who achieved the platelet threshold entered the randomized phase of the study, wherein they were allocated 2:1 to receive eltrombopag or placebo, in addition to peginterferon alpha 2a and ribavirin. Patients with HCV genotype 2 or 3 continued treatment for 24 weeks; all others were treated for 48 weeks. The primary endpoint was sustained virologic response.
Afdhal reported that 715 patients entered the open-label phase of the study and had a median baseline platelet count of 59,000/µL, increasing to 89,000/µL by the end of open-label eltrombopag therapy.
Subsequently, 682 patients initiated randomized therapy. They had a median baseline platelet count of about 130,000/µL. After four weeks of treatment, the median platelet count had decreased to 90,000/µL in the eltrombopag arm and to 43,500/µL in the placebo group.
The median platelet count remained >80,000/µL throughout the study in the eltrombopag arm and <50,000/µL in the placebo arm.
In addition to the intention-to-treat analysis, subgroup analyses by HCV genotype showed a consistent difference between groups in favor of eltrombopag. Among genotype 1 patients (N=462), 58% of the eltrombopag group versus 41% of the placebo group had an early virologic response, and 18% versus 10%, respectively, had a sustained virologic response.
Among genotype 2/3 patients, early virologic response occurred in 84% of the eltrombopag group versus 67% of the placebo group and sustained virologic response in 35% versus 24%, respectively.
Afdhal said that 57% of eltrombopag patients required no peginterferon alpha 2a dose reductions, as compared with 30% of the placebo group. Treatment with the thrombopoietin agonist was associated with significant prolongation of the time to first peginterferon dose reduction (P<0.0001).
Adverse events, serious adverse events, and drug-related adverse events occurred in a similar proportion of patients in the two treatment groups. The most common adverse events in both groups were anemia, neutropenia, fatigue, pyrexia, and headache. Thrombotic adverse events occurred in 2% of patients in each group.
A preliminary intention-to-treat analysis of data from ENABLE 2 showed that 62% of eltrombopag-treated patients had an early virologic response compared with 41% of the placebo group (P<0.0001) and sustained virologic response in 19% and 13% of patients, respectively (P=0.020).
"Sustained virologic response rates remain constrained by a lack of interferon efficacy in patients with advanced disease," Afdhal said.
The study was supported by GlaxoSmithKline.
Afdhal disclosed relationships with Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasett, Abbott, Biogen, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biodex, Fibrogen, Ligand, and Springbank.
Primary source: American Association for the Study of Liver Diseases
Afdhal NH, et al "Final results of ENABLE 1, a phase III, multicenter study of eltrombopag as an adjunct for antiviral treatment of hepatitis C virus-related chronic liver disease associated with thrombocytopenia" AASLD 2011; Abstract LB-3.