Eltrombopag Improves SVR in Thrombocytopenic Patients With HCV

SAN FRANCISCO – Use of the oral thrombopoietin receptor agonist eltrombopag allows most thrombocytopenic patients with chronic hepatitis C to receive antiviral therapy and improves their odds of achieving a sustained virologic response, according to final results of the ENABLE 1 trial.

In the phase III randomized trial, 95% of 716 patients given eltrombopag were able to start antiviral therapy with pegylated interferon alfa-2a and ribavirin, lead investigator Dr. Nezam H. Afdhal reported at the annual meeting of the American Association for the Study of Liver Diseases.

After starting antiviral therapy, patients who continued on eltrombopag were less likely than their counterparts switched to placebo to have to stop the hepatitis C therapy and more likely to achieve a sustained virologic response (SVR), although the rate was still fairly low (23% vs. 14%).

Eltrombopag also had a good safety profile, with no increase in the rate of thromboembolic events, compared with placebo (2% in each group).

"The results from ENABLE 1 show that eltrombopag treatment in thrombocytopenic patients with HCV [hepatitis C virus] and advanced fibrosis enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for treatment," commented Dr. Afdhal, an associate professor of medicine at Harvard Medical School and director of hepatology at the Beth Israel Deaconess Medical Center, both in Boston.

"We saw a statistically significant and meaningful improvement in SVR vs. placebo in this population that is difficult to treat," Dr. Afdhal noted.

"The SVR rates are obviously low in comparison to some of the dynamic numbers we have seen at this meeting," he added. "And this is because these patients are constrained by lack of interferon efficacy in patients with advanced disease."

Dr. Afdhal also presented some late-breaking data from the ENABLE 2 trial, which has an identical design except that it uses pegylated interferon alfa-2b instead of alfa-2a. Findings among the 758 patients here were essentially the same for SVR, favoring eltrombopag over placebo (19% vs. 13%), but there was a hint of an increased rate of thromboembolic events with the drug in this case (4% vs. less than 1%). "ENABLE 2 results are truly preliminary and under full evaluation, and we will hopefully be presenting them at a subsequent meeting," he commented.

Thrombocytopenia is a problematic complication of chronic liver disease in patients with viral hepatitis, Dr. Afdhal noted. "Up until now, these patients have typically been ineligible for antiviral treatment and have been excluded from nearly all of the clinical trials that we see," he pointed out. Additionally, dose reduction and treatment discontinuation are recommended for patients on antiviral therapy who develop thrombocytopenia, which may reduce their chances of achieving SVR.

Patients were eligible for the ENABLE 1 trial if they had chronic hepatitis C and a platelet count less than 75,000 per mcL.

In the first part of the trial, all were treated on an open-label basis with increasing doses of eltrombopag (Promacta), up to 100 mg/day, until they achieved a platelet count of at least 90,000 per mcL and could start antiviral therapy. (Eltrombopag is currently approved only for treating thrombocytopenia in patients with chronic immune [idiopathic] thrombocytopenic purpura.)

In the second part of the trial, patients were randomized 2:1 to double-blind treatment with eltrombopag or placebo, along with antiviral therapy (pegylated interferon alfa-2a and ribavirin). Therapy was planned to continue for up to 24-48 weeks, depending on viral genotype.

The interferon was reduced or discontinued if a patient’s platelet count fell below 50,000 per mcL. Growth factors were allowed to manage anemia and neutropenia.

Results showed that fully 95% of enrolled patients were able to achieve the platelet count required to start antiviral therapy and proceed to randomization. The randomized patients had a median age of 52 years. The majority had viral genotype 1. More than two-thirds were interferon naive.

Compared with the placebo group, the eltrombopag group had a higher rate of SVR at 24 weeks after the end of antiviral therapy (23% vs. 14%, P = .006), Dr. Afdhal reported. Results were much the same in subgroups stratified by viral genotype, baseline platelet count, and baseline viral load.

Median platelet counts in the eltrombopag group never fell below the threshold for reducing the dose of antiviral therapy, but they were below this threshold the majority of time in the placebo group. The proportion of patients not needing any interferon dose reduction was about twice as high in the former group (57% vs. 30%).

The rate, type, and severity of adverse events were generally similar between treatment groups. "What we see are the standard side effects that we see in the majority of patients on interferon-ribavirin therapy," Dr. Afdhal commented.

Patients in the eltrombopag group had a higher rate of events suggestive of progressive liver disease, 13% vs. 8%. However, "the majority of these events are those that are typical of patients with chronic liver disease," he noted. "In addition, what we did see is that there was no change throughout the study in either arm in MELD [Model for End-stage Liver Disease] score, Child-Pugh score, albumin, bilirubin, INR [international normalized ratio], or any of the standard parameters."

Patients in the trial were rigorously monitored for portal vein thrombosis with serial ultrasound and Doppler imaging, according to Dr. Afdhal. The rare thromboses detected were evident only on ultrasound, except for a single clinical thrombosis in a patient in the placebo group who had a tumor invading the portal vein.

"Unlike what we have previously presented, where there was a significant correlation between the elevation of thrombocytes and portal vein thrombosis, there is no easily apparent association here," he noted. "Many of these events took place in patients with platelet counts of less than 50,000, and many of these took place after the study was over."

Dr. Afdhal reported that he receives research support from Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasset, and Abbott, and is an adviser to Gilead, Echosens, Biogen, Vertex, Novartis, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biolex, FibroGen, Ligand, Spring Bank, Synexis, and GlaxoSmithKline, which manufactures Promacta.

SAN FRANCISCO – Use of the oral thrombopoietin receptor agonist eltrombopag allows most thrombocytopenic patients with chronic hepatitis C to receive antiviral therapy and improves their odds of achieving a sustained virologic response, according to final results of the ENABLE 1 trial.

In the phase III randomized trial, 95% of 716 patients given eltrombopag were able to start antiviral therapy with pegylated interferon alfa-2a and ribavirin, lead investigator Dr. Nezam H. Afdhal reported at the annual meeting of the American Association for the Study of Liver Diseases.

After starting antiviral therapy, patients who continued on eltrombopag were less likely than their counterparts switched to placebo to have to stop the hepatitis C therapy and more likely to achieve a sustained virologic response (SVR), although the rate was still fairly low (23% vs. 14%).

Eltrombopag also had a good safety profile, with no increase in the rate of thromboembolic events, compared with placebo (2% in each group).

"The results from ENABLE 1 show that eltrombopag treatment in thrombocytopenic patients with HCV [hepatitis C virus] and advanced fibrosis enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for treatment," commented Dr. Afdhal, an associate professor of medicine at Harvard Medical School and director of hepatology at the Beth Israel Deaconess Medical Center, both in Boston.

"We saw a statistically significant and meaningful improvement in SVR vs. placebo in this population that is difficult to treat," Dr. Afdhal noted.

"The SVR rates are obviously low in comparison to some of the dynamic numbers we have seen at this meeting," he added. "And this is because these patients are constrained by lack of interferon efficacy in patients with advanced disease."

Dr. Afdhal also presented some late-breaking data from the ENABLE 2 trial, which has an identical design except that it uses pegylated interferon alfa-2b instead of alfa-2a. Findings among the 758 patients here were essentially the same for SVR, favoring eltrombopag over placebo (19% vs. 13%), but there was a hint of an increased rate of thromboembolic events with the drug in this case (4% vs. less than 1%). "ENABLE 2 results are truly preliminary and under full evaluation, and we will hopefully be presenting them at a subsequent meeting," he commented.

Thrombocytopenia is a problematic complication of chronic liver disease in patients with viral hepatitis, Dr. Afdhal noted. "Up until now, these patients have typically been ineligible for antiviral treatment and have been excluded from nearly all of the clinical trials that we see," he pointed out. Additionally, dose reduction and treatment discontinuation are recommended for patients on antiviral therapy who develop thrombocytopenia, which may reduce their chances of achieving SVR.

Patients were eligible for the ENABLE 1 trial if they had chronic hepatitis C and a platelet count less than 75,000 per mcL.

In the first part of the trial, all were treated on an open-label basis with increasing doses of eltrombopag (Promacta), up to 100 mg/day, until they achieved a platelet count of at least 90,000 per mcL and could start antiviral therapy. (Eltrombopag is currently approved only for treating thrombocytopenia in patients with chronic immune [idiopathic] thrombocytopenic purpura.)

In the second part of the trial, patients were randomized 2:1 to double-blind treatment with eltrombopag or placebo, along with antiviral therapy (pegylated interferon alfa-2a and ribavirin). Therapy was planned to continue for up to 24-48 weeks, depending on viral genotype.

The interferon was reduced or discontinued if a patient’s platelet count fell below 50,000 per mcL. Growth factors were allowed to manage anemia and neutropenia.

Results showed that fully 95% of enrolled patients were able to achieve the platelet count required to start antiviral therapy and proceed to randomization. The randomized patients had a median age of 52 years. The majority had viral genotype 1. More than two-thirds were interferon naive.

Compared with the placebo group, the eltrombopag group had a higher rate of SVR at 24 weeks after the end of antiviral therapy (23% vs. 14%, P = .006), Dr. Afdhal reported. Results were much the same in subgroups stratified by viral genotype, baseline platelet count, and baseline viral load.

Median platelet counts in the eltrombopag group never fell below the threshold for reducing the dose of antiviral therapy, but they were below this threshold the majority of time in the placebo group. The proportion of patients not needing any interferon dose reduction was about twice as high in the former group (57% vs. 30%).

The rate, type, and severity of adverse events were generally similar between treatment groups. "What we see are the standard side effects that we see in the majority of patients on interferon-ribavirin therapy," Dr. Afdhal commented.

Patients in the eltrombopag group had a higher rate of events suggestive of progressive liver disease, 13% vs. 8%. However, "the majority of these events are those that are typical of patients with chronic liver disease," he noted. "In addition, what we did see is that there was no change throughout the study in either arm in MELD [Model for End-stage Liver Disease] score, Child-Pugh score, albumin, bilirubin, INR [international normalized ratio], or any of the standard parameters."

Patients in the trial were rigorously monitored for portal vein thrombosis with serial ultrasound and Doppler imaging, according to Dr. Afdhal. The rare thromboses detected were evident only on ultrasound, except for a single clinical thrombosis in a patient in the placebo group who had a tumor invading the portal vein.

"Unlike what we have previously presented, where there was a significant correlation between the elevation of thrombocytes and portal vein thrombosis, there is no easily apparent association here," he noted. "Many of these events took place in patients with platelet counts of less than 50,000, and many of these took place after the study was over."

Dr. Afdhal reported that he receives research support from Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasset, and Abbott, and is an adviser to Gilead, Echosens, Biogen, Vertex, Novartis, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biolex, FibroGen, Ligand, Spring Bank, Synexis, and GlaxoSmithKline, which manufactures Promacta.

SAN FRANCISCO – Use of the oral thrombopoietin receptor agonist eltrombopag allows most thrombocytopenic patients with chronic hepatitis C to receive antiviral therapy and improves their odds of achieving a sustained virologic response, according to final results of the ENABLE 1 trial.

In the phase III randomized trial, 95% of 716 patients given eltrombopag were able to start antiviral therapy with pegylated interferon alfa-2a and ribavirin, lead investigator Dr. Nezam H. Afdhal reported at the annual meeting of the American Association for the Study of Liver Diseases.

After starting antiviral therapy, patients who continued on eltrombopag were less likely than their counterparts switched to placebo to have to stop the hepatitis C therapy and more likely to achieve a sustained virologic response (SVR), although the rate was still fairly low (23% vs. 14%).

Eltrombopag also had a good safety profile, with no increase in the rate of thromboembolic events, compared with placebo (2% in each group).

"The results from ENABLE 1 show that eltrombopag treatment in thrombocytopenic patients with HCV [hepatitis C virus] and advanced fibrosis enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for treatment," commented Dr. Afdhal, an associate professor of medicine at Harvard Medical School and director of hepatology at the Beth Israel Deaconess Medical Center, both in Boston.

"We saw a statistically significant and meaningful improvement in SVR vs. placebo in this population that is difficult to treat," Dr. Afdhal noted.

"The SVR rates are obviously low in comparison to some of the dynamic numbers we have seen at this meeting," he added. "And this is because these patients are constrained by lack of interferon efficacy in patients with advanced disease."

Dr. Afdhal also presented some late-breaking data from the ENABLE 2 trial, which has an identical design except that it uses pegylated interferon alfa-2b instead of alfa-2a. Findings among the 758 patients here were essentially the same for SVR, favoring eltrombopag over placebo (19% vs. 13%), but there was a hint of an increased rate of thromboembolic events with the drug in this case (4% vs. less than 1%). "ENABLE 2 results are truly preliminary and under full evaluation, and we will hopefully be presenting them at a subsequent meeting," he commented.

Thrombocytopenia is a problematic complication of chronic liver disease in patients with viral hepatitis, Dr. Afdhal noted. "Up until now, these patients have typically been ineligible for antiviral treatment and have been excluded from nearly all of the clinical trials that we see," he pointed out. Additionally, dose reduction and treatment discontinuation are recommended for patients on antiviral therapy who develop thrombocytopenia, which may reduce their chances of achieving SVR.

Patients were eligible for the ENABLE 1 trial if they had chronic hepatitis C and a platelet count less than 75,000 per mcL.

In the first part of the trial, all were treated on an open-label basis with increasing doses of eltrombopag (Promacta), up to 100 mg/day, until they achieved a platelet count of at least 90,000 per mcL and could start antiviral therapy. (Eltrombopag is currently approved only for treating thrombocytopenia in patients with chronic immune [idiopathic] thrombocytopenic purpura.)

In the second part of the trial, patients were randomized 2:1 to double-blind treatment with eltrombopag or placebo, along with antiviral therapy (pegylated interferon alfa-2a and ribavirin). Therapy was planned to continue for up to 24-48 weeks, depending on viral genotype.

The interferon was reduced or discontinued if a patient’s platelet count fell below 50,000 per mcL. Growth factors were allowed to manage anemia and neutropenia.

Results showed that fully 95% of enrolled patients were able to achieve the platelet count required to start antiviral therapy and proceed to randomization. The randomized patients had a median age of 52 years. The majority had viral genotype 1. More than two-thirds were interferon naive.

Compared with the placebo group, the eltrombopag group had a higher rate of SVR at 24 weeks after the end of antiviral therapy (23% vs. 14%, P = .006), Dr. Afdhal reported. Results were much the same in subgroups stratified by viral genotype, baseline platelet count, and baseline viral load.

Median platelet counts in the eltrombopag group never fell below the threshold for reducing the dose of antiviral therapy, but they were below this threshold the majority of time in the placebo group. The proportion of patients not needing any interferon dose reduction was about twice as high in the former group (57% vs. 30%).

The rate, type, and severity of adverse events were generally similar between treatment groups. "What we see are the standard side effects that we see in the majority of patients on interferon-ribavirin therapy," Dr. Afdhal commented.

Patients in the eltrombopag group had a higher rate of events suggestive of progressive liver disease, 13% vs. 8%. However, "the majority of these events are those that are typical of patients with chronic liver disease," he noted. "In addition, what we did see is that there was no change throughout the study in either arm in MELD [Model for End-stage Liver Disease] score, Child-Pugh score, albumin, bilirubin, INR [international normalized ratio], or any of the standard parameters."

Patients in the trial were rigorously monitored for portal vein thrombosis with serial ultrasound and Doppler imaging, according to Dr. Afdhal. The rare thromboses detected were evident only on ultrasound, except for a single clinical thrombosis in a patient in the placebo group who had a tumor invading the portal vein.

"Unlike what we have previously presented, where there was a significant correlation between the elevation of thrombocytes and portal vein thrombosis, there is no easily apparent association here," he noted. "Many of these events took place in patients with platelet counts of less than 50,000, and many of these took place after the study was over."

Dr. Afdhal reported that he receives research support from Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasset, and Abbott, and is an adviser to Gilead, Echosens, Biogen, Vertex, Novartis, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biolex, FibroGen, Ligand, Spring Bank, Synexis, and GlaxoSmithKline, which manufactures Promacta.