Elizabeth Mechcatie

WASHINGTON – The addition of ribavirin to a fixed-dose combination of sofosbuvir and ledipasvir, two potent direct-acting hepatitis C antiviral drugs, increased the response rate from 70% to 100% in previously-treated patients with chronic hepatitis C infection and fibrosis or cirrhosis.

That finding emerged from a phase II study presented by Dr. Edward Gane at the annual meeting of the American Association for the Study of Liver Diseases.

Sofosbuvir, a nucleotide polymerase inhibitor, has potent antiviral activity against HCV genotypes 1-6, and ledipasvir, an NS5A inhibitor, has potency against genotypes 1a and 1b1. Both are taken once a day orally. To date, more than 2,000 people have been treated with the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg), which is now in phase III trials, said Dr. Gane, chief hepatologist and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital.

The study evaluated the efficacy and safety of the sofosbuvir-ledipasvir fixed-dose combination for 12 weeks in treatment-experienced patients with HCV genotype 1 and advanced fibrosis or cirrhosis. The investigators also looked at the shortest duration of the combination required in treatment-naive patients with genotype 1 who did not have cirrhosis. The primary endpoint was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12).

Most of the patients were white, and most were male. Their mean age was 51-61 years, and most had genotype 1a (60%-85%).

Patients were divided into three different groups:

• Treatment-experienced patients with HCV genotype 1 and cirrhosis, treated with the fixed dose combination without ribavirin (10 patients) or with ribavirin (9 patients) for 12 weeks.

Among those on the fixed-dose combination only, 70% reached SVR12. When ribavirin was added, SVR12 was reached by all patients.

• Treatment-naive patients with HCV genotypes 2 and 3, treated with the fixed-dose combination and ribavirin (10 patients) for 12 weeks. Again, 100% of these patients reached SVR12.

• An exploratory cohort of 25 treatment-naive noncirrhotic patients with HCV genotype 1 treated with the fixed-dose combination plus ribavirin for 6 weeks. Fewer of these patients (68%) reached SVR 12.

Sofosbuvir-ledipasvir, with or without ribavirin, "was generally safe and well-tolerated," with no serious adverse events reported or treatment discontinuations, Dr. Gane said. In general, adverse events were mild, and grade 3/4 laboratory abnormalities were infrequent and consistent with the safety profile of ribavirin, he added.

"In the historically difficult to treat treatment-experienced patients with cirrhosis, the addition of ribavirin ... enhances the efficacy of sofosbuvir plus ledipasvir when given for 12 weeks," Dr. Gane said.

The optimal duration of this combination in genotype 1 patients appears to be more than 6 weeks, he added, "with unacceptable relapse rates" when treatment is reduced to 6 weeks.

Importantly, the study also found that the efficacy of the combination was not reduced in patients with resistance-associated variants at baseline, Dr. Gane said.

Patients in the studies were enrolled in the ELECTRON or ELECTRON 2 studies.

Neither sofosbuvir or ledipasvir is approved by the Food and Drug Administration, but at an Oct. 25 meeting, an FDA advisory panel unanimously recommended the approval of sofosbuvir for two groups of patients with chronic hepatitis C infection: treatment-naive adults with genotype 1 and 4 infections, in combination with pegylated interferon and ribavirin; and for adults with genotype 2 and 3 infections, in combination with ribavirin. An approval decision is expected by Dec. 8.

Dr. Gane disclosed that he served on the advisory board committees for Gilead, Roche, AbbVie, Achillion, Janssen, Novartis, and Vertex within the previous 12 months. The study was funded by Gilead Sciences, maker of the fixed-dose combination. Several of the authors of the study are Gilead employees.

[email protected]

WASHINGTON – The addition of ribavirin to a fixed-dose combination of sofosbuvir and ledipasvir, two potent direct-acting hepatitis C antiviral drugs, increased the response rate from 70% to 100% in previously-treated patients with chronic hepatitis C infection and fibrosis or cirrhosis.

That finding emerged from a phase II study presented by Dr. Edward Gane at the annual meeting of the American Association for the Study of Liver Diseases.

Sofosbuvir, a nucleotide polymerase inhibitor, has potent antiviral activity against HCV genotypes 1-6, and ledipasvir, an NS5A inhibitor, has potency against genotypes 1a and 1b1. Both are taken once a day orally. To date, more than 2,000 people have been treated with the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg), which is now in phase III trials, said Dr. Gane, chief hepatologist and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital.

The study evaluated the efficacy and safety of the sofosbuvir-ledipasvir fixed-dose combination for 12 weeks in treatment-experienced patients with HCV genotype 1 and advanced fibrosis or cirrhosis. The investigators also looked at the shortest duration of the combination required in treatment-naive patients with genotype 1 who did not have cirrhosis. The primary endpoint was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12).

Most of the patients were white, and most were male. Their mean age was 51-61 years, and most had genotype 1a (60%-85%).

Patients were divided into three different groups:

• Treatment-experienced patients with HCV genotype 1 and cirrhosis, treated with the fixed dose combination without ribavirin (10 patients) or with ribavirin (9 patients) for 12 weeks.

Among those on the fixed-dose combination only, 70% reached SVR12. When ribavirin was added, SVR12 was reached by all patients.

• Treatment-naive patients with HCV genotypes 2 and 3, treated with the fixed-dose combination and ribavirin (10 patients) for 12 weeks. Again, 100% of these patients reached SVR12.

• An exploratory cohort of 25 treatment-naive noncirrhotic patients with HCV genotype 1 treated with the fixed-dose combination plus ribavirin for 6 weeks. Fewer of these patients (68%) reached SVR 12.

Sofosbuvir-ledipasvir, with or without ribavirin, "was generally safe and well-tolerated," with no serious adverse events reported or treatment discontinuations, Dr. Gane said. In general, adverse events were mild, and grade 3/4 laboratory abnormalities were infrequent and consistent with the safety profile of ribavirin, he added.

"In the historically difficult to treat treatment-experienced patients with cirrhosis, the addition of ribavirin ... enhances the efficacy of sofosbuvir plus ledipasvir when given for 12 weeks," Dr. Gane said.

The optimal duration of this combination in genotype 1 patients appears to be more than 6 weeks, he added, "with unacceptable relapse rates" when treatment is reduced to 6 weeks.

Importantly, the study also found that the efficacy of the combination was not reduced in patients with resistance-associated variants at baseline, Dr. Gane said.

Patients in the studies were enrolled in the ELECTRON or ELECTRON 2 studies.

Neither sofosbuvir or ledipasvir is approved by the Food and Drug Administration, but at an Oct. 25 meeting, an FDA advisory panel unanimously recommended the approval of sofosbuvir for two groups of patients with chronic hepatitis C infection: treatment-naive adults with genotype 1 and 4 infections, in combination with pegylated interferon and ribavirin; and for adults with genotype 2 and 3 infections, in combination with ribavirin. An approval decision is expected by Dec. 8.

Dr. Gane disclosed that he served on the advisory board committees for Gilead, Roche, AbbVie, Achillion, Janssen, Novartis, and Vertex within the previous 12 months. The study was funded by Gilead Sciences, maker of the fixed-dose combination. Several of the authors of the study are Gilead employees.

[email protected]

WASHINGTON – The addition of ribavirin to a fixed-dose combination of sofosbuvir and ledipasvir, two potent direct-acting hepatitis C antiviral drugs, increased the response rate from 70% to 100% in previously-treated patients with chronic hepatitis C infection and fibrosis or cirrhosis.

That finding emerged from a phase II study presented by Dr. Edward Gane at the annual meeting of the American Association for the Study of Liver Diseases.

Sofosbuvir, a nucleotide polymerase inhibitor, has potent antiviral activity against HCV genotypes 1-6, and ledipasvir, an NS5A inhibitor, has potency against genotypes 1a and 1b1. Both are taken once a day orally. To date, more than 2,000 people have been treated with the fixed-dose combination of sofosbuvir (400 mg) and ledipasvir (90 mg), which is now in phase III trials, said Dr. Gane, chief hepatologist and deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital.

The study evaluated the efficacy and safety of the sofosbuvir-ledipasvir fixed-dose combination for 12 weeks in treatment-experienced patients with HCV genotype 1 and advanced fibrosis or cirrhosis. The investigators also looked at the shortest duration of the combination required in treatment-naive patients with genotype 1 who did not have cirrhosis. The primary endpoint was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12).

Most of the patients were white, and most were male. Their mean age was 51-61 years, and most had genotype 1a (60%-85%).

Patients were divided into three different groups:

• Treatment-experienced patients with HCV genotype 1 and cirrhosis, treated with the fixed dose combination without ribavirin (10 patients) or with ribavirin (9 patients) for 12 weeks.

Among those on the fixed-dose combination only, 70% reached SVR12. When ribavirin was added, SVR12 was reached by all patients.

• Treatment-naive patients with HCV genotypes 2 and 3, treated with the fixed-dose combination and ribavirin (10 patients) for 12 weeks. Again, 100% of these patients reached SVR12.

• An exploratory cohort of 25 treatment-naive noncirrhotic patients with HCV genotype 1 treated with the fixed-dose combination plus ribavirin for 6 weeks. Fewer of these patients (68%) reached SVR 12.

Sofosbuvir-ledipasvir, with or without ribavirin, "was generally safe and well-tolerated," with no serious adverse events reported or treatment discontinuations, Dr. Gane said. In general, adverse events were mild, and grade 3/4 laboratory abnormalities were infrequent and consistent with the safety profile of ribavirin, he added.

"In the historically difficult to treat treatment-experienced patients with cirrhosis, the addition of ribavirin ... enhances the efficacy of sofosbuvir plus ledipasvir when given for 12 weeks," Dr. Gane said.

The optimal duration of this combination in genotype 1 patients appears to be more than 6 weeks, he added, "with unacceptable relapse rates" when treatment is reduced to 6 weeks.

Importantly, the study also found that the efficacy of the combination was not reduced in patients with resistance-associated variants at baseline, Dr. Gane said.

Patients in the studies were enrolled in the ELECTRON or ELECTRON 2 studies.

Neither sofosbuvir or ledipasvir is approved by the Food and Drug Administration, but at an Oct. 25 meeting, an FDA advisory panel unanimously recommended the approval of sofosbuvir for two groups of patients with chronic hepatitis C infection: treatment-naive adults with genotype 1 and 4 infections, in combination with pegylated interferon and ribavirin; and for adults with genotype 2 and 3 infections, in combination with ribavirin. An approval decision is expected by Dec. 8.

Dr. Gane disclosed that he served on the advisory board committees for Gilead, Roche, AbbVie, Achillion, Janssen, Novartis, and Vertex within the previous 12 months. The study was funded by Gilead Sciences, maker of the fixed-dose combination. Several of the authors of the study are Gilead employees.

[email protected]

Obinutuzumab, a monoclonal antibody, has been approved for treating patients with previously untreated chronic lymphocytic leukemia, the Food and Drug Administration announced Nov. 1.

The approval, which is for use in combination with chlorambucil, makes this the first drug to be approved with a "breakthrough therapy designation," according to an FDA statement.

Obinutuzumab is a CD20-directed antibody that is administered in an intravenous infusion, for 6 cycles. It is designed to attach to CD20, a protein found only on B cells, and "attacks targeted cells both directly and together with the body’s immune system," according to a statement issued by Genentech, the drug’s manufacturer. Genentech will market obinutuzumab as Gazyva.

The company requested breakthrough designation for obinutuzumab. The FDA can designate a drug as a breakthrough therapy at the manufacturer’s request "if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases," the FDA statement said.

Approval was based on a randomized, open-label study of 356 patients with previously untreated chronic lymphocytic leukemia (CLL), comparing obinutuzumab plus chlorambucil to chlorambucil alone. The median progression-free survival was 23 months in the obinutuzumab-treated group, compared with 11.1 months among those treated with chlorambucil alone, an 84% reduction in risk (hazard ratio, 0.16). The overall response rate also was higher among those on obinutuzumab (almost 76% vs. 32.1%), as were the complete response rate (27.8% vs. 0.9%) and the median duration of response (15.2 months vs. 3.5 months).

Infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and pyrexia were the most common adverse events reported among the patients treated with obinutuzumab. The prescribing information includes a boxed warning about the risk of hepatitis B reactivation, which in some cases, resulted in fulminant hepatitis, hepatic failure, and death; and progressive multifocal leukoencephalopathy (PML; reported in patients in other studies of obinutuzumab). A diagnosis of PML should be considered "in any patient presenting with new onset or changes to preexisting neurologic manifestations," the prescribing information states.

The Genentech statement notes that obinutuzumab will be available in the United States in about two weeks from approval. The drug is under review in other countries and in the European Union.

Citing National Cancer Institute estimates, the FDA statement said that 15,680 people in the United States will be diagnosed with CLL this year and 1,580 people will die from the disease.

The obinutuzumab label is available at the FDA website.

[email protected]

Obinutuzumab, a monoclonal antibody, has been approved for treating patients with previously untreated chronic lymphocytic leukemia, the Food and Drug Administration announced Nov. 1.

The approval, which is for use in combination with chlorambucil, makes this the first drug to be approved with a "breakthrough therapy designation," according to an FDA statement.

Obinutuzumab is a CD20-directed antibody that is administered in an intravenous infusion, for 6 cycles. It is designed to attach to CD20, a protein found only on B cells, and "attacks targeted cells both directly and together with the body’s immune system," according to a statement issued by Genentech, the drug’s manufacturer. Genentech will market obinutuzumab as Gazyva.

The company requested breakthrough designation for obinutuzumab. The FDA can designate a drug as a breakthrough therapy at the manufacturer’s request "if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases," the FDA statement said.

Approval was based on a randomized, open-label study of 356 patients with previously untreated chronic lymphocytic leukemia (CLL), comparing obinutuzumab plus chlorambucil to chlorambucil alone. The median progression-free survival was 23 months in the obinutuzumab-treated group, compared with 11.1 months among those treated with chlorambucil alone, an 84% reduction in risk (hazard ratio, 0.16). The overall response rate also was higher among those on obinutuzumab (almost 76% vs. 32.1%), as were the complete response rate (27.8% vs. 0.9%) and the median duration of response (15.2 months vs. 3.5 months).

Infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and pyrexia were the most common adverse events reported among the patients treated with obinutuzumab. The prescribing information includes a boxed warning about the risk of hepatitis B reactivation, which in some cases, resulted in fulminant hepatitis, hepatic failure, and death; and progressive multifocal leukoencephalopathy (PML; reported in patients in other studies of obinutuzumab). A diagnosis of PML should be considered "in any patient presenting with new onset or changes to preexisting neurologic manifestations," the prescribing information states.

The Genentech statement notes that obinutuzumab will be available in the United States in about two weeks from approval. The drug is under review in other countries and in the European Union.

Citing National Cancer Institute estimates, the FDA statement said that 15,680 people in the United States will be diagnosed with CLL this year and 1,580 people will die from the disease.

The obinutuzumab label is available at the FDA website.

[email protected]

Obinutuzumab, a monoclonal antibody, has been approved for treating patients with previously untreated chronic lymphocytic leukemia, the Food and Drug Administration announced Nov. 1.

The approval, which is for use in combination with chlorambucil, makes this the first drug to be approved with a "breakthrough therapy designation," according to an FDA statement.

Obinutuzumab is a CD20-directed antibody that is administered in an intravenous infusion, for 6 cycles. It is designed to attach to CD20, a protein found only on B cells, and "attacks targeted cells both directly and together with the body’s immune system," according to a statement issued by Genentech, the drug’s manufacturer. Genentech will market obinutuzumab as Gazyva.

The company requested breakthrough designation for obinutuzumab. The FDA can designate a drug as a breakthrough therapy at the manufacturer’s request "if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases," the FDA statement said.

Approval was based on a randomized, open-label study of 356 patients with previously untreated chronic lymphocytic leukemia (CLL), comparing obinutuzumab plus chlorambucil to chlorambucil alone. The median progression-free survival was 23 months in the obinutuzumab-treated group, compared with 11.1 months among those treated with chlorambucil alone, an 84% reduction in risk (hazard ratio, 0.16). The overall response rate also was higher among those on obinutuzumab (almost 76% vs. 32.1%), as were the complete response rate (27.8% vs. 0.9%) and the median duration of response (15.2 months vs. 3.5 months).

Infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and pyrexia were the most common adverse events reported among the patients treated with obinutuzumab. The prescribing information includes a boxed warning about the risk of hepatitis B reactivation, which in some cases, resulted in fulminant hepatitis, hepatic failure, and death; and progressive multifocal leukoencephalopathy (PML; reported in patients in other studies of obinutuzumab). A diagnosis of PML should be considered "in any patient presenting with new onset or changes to preexisting neurologic manifestations," the prescribing information states.

The Genentech statement notes that obinutuzumab will be available in the United States in about two weeks from approval. The drug is under review in other countries and in the European Union.

Citing National Cancer Institute estimates, the FDA statement said that 15,680 people in the United States will be diagnosed with CLL this year and 1,580 people will die from the disease.

The obinutuzumab label is available at the FDA website.

[email protected]

The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.

In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.

"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).

The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.
See the full algorithm here. 

The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.

The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.

The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.

Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.

The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "it is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration" defined by the response-guided therapy algorithm, they added.

The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.

The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.

[email protected]

The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.

In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.

"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).

The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.
See the full algorithm here. 

The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.

The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.

The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.

Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.

The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "it is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration" defined by the response-guided therapy algorithm, they added.

The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.

The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.

[email protected]

The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.

In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.

"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).

The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.
See the full algorithm here. 

The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.

The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.

The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.

Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.

The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "it is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration" defined by the response-guided therapy algorithm, they added.

The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.

The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.

[email protected]

A reduction of at least 50% in either of two different Crohn’s disease endoscopic activity scores after 26 weeks of treatment predicted those patients likely to be off of corticosteroid therapy after about 1 year of treatment, with a sensitivity approaching 75%, reported Dr. Marc Ferrante and his coinvestigators.

The study provides evidence that this cutoff could be used as a reliable predictor of clinical response, but it needs to be studied further, according to the authors, who are members of the International Organization for the Study of Inflammatory Bowel Diseases. The study was published in the Novemberissue of Gastroenterology.

Another study, published in the same issue of Gastroenterology, evaluated the reliability of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), an instrument recently created to assess the endoscopic severity of UC. This study randomized 25 investigators to assess and score 28 endoscopic videos of patients with UC – without knowledge of clinical features in most cases. The results indicated that the UCEIS provides a "satisfactory" level of intrainvestigator and interinvestigator agreement and that it is "a reliable instrument for measuring the endoscopic disease activity of UC," according to Dr. Simon Travis, of the translational gastroenterology unit at John Radcliffe Hospital, Oxford, England, and his coinvestigators.

The version of the UCEIS that provides a score from 0 to 8, based on findings of vascular pattern, bleeding, and erosions/ulcers, is the "favored version" but needs to be validated further, they concluded (Gastroenterol. 2013 July 29 [doi: 10.1053/j.gastro.2013.07.024]).

In the Crohn’s disease (CD) study, which used data on 172 patients enrolled in SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease), Dr. Ferrante, of the department of gastroenterology at University Hospitals Leuven, Belgium, and his colleagues identified a cutoff point in two endoscopic response scores after 26 weeks of treatment that was predictive of clinical response at 50 weeks.

At baseline, the patients had endoscopic lesions and CD Activity Index (CDAI) scores of 220-450 points (median, 277). Their median age was 34 years, and they had been diagnosed with CD for a median of 2.5 years. The patients were dependent on corticosteroids and were randomized to treatment with infliximab (Remicade) infusions and/or oral azathioprine, and were followed to 50 weeks. The primary endpoint of this study was corticosteroid-free clinical remission (CFREM) at week 26, and one of the secondary endpoints was complete healing of mucosal ulcerations.

The investigators evaluated different cutoff points of endoscopic responses for two methods used to score the severity of endoscopic lesions: SES-CD (Simple Endoscopic Score for CD) and CDEIS (CD Endoscopic Index of Severity).

Almost half of the patients achieved mucosal healing at the 26th week.

A decrease from baseline in the SES-CD of at least 50% at week 26 "appeared to be the best discriminative cutoff value" for predicting patients most likely to be in clinical remission (off steroids at week 50). This degree of SES-CD response was met by 112 (65%) patients, with 74% sensitivity and 48% specificity for predicting CFREM at week 50.

For the CDEIS values, the best cutoff was at least a 45% drop from baseline at week 26 for predicting patients most likely to achieve CFREM at week 50, with 75% sensitivity and 45% specificity.

Because of the "subtle" difference between the two measures (50% and 45% cutoffs), "we propose a definition of endoscopic response with a decrease in baseline in CDEIS of at least 50% at week 26 for both tests," the authors wrote. (For CDEIS, the 50% cutoff had a sensitivity of 73% and a specificity of 46%.)

"As such, this endoscopic endpoint could serve as a reliable predictor of the midterm clinical outcome of therapies," Dr. Ferrante and his coauthors concluded. A 50% reduction in endoscopic activity from baseline also has potential for use as an endpoint in studies evaluating pharmacotherapy or treatment strategies "to show healing capacity," they wrote.

These cutoff values should be validated in a prospective study, which should also look at correlations between the endoscopic response and "disease-modifying long-term outcomes," such as a sustained clinical response or surgery, they added.

In the study that evaluated the reliability of the UCEIS, 25 investigators from North America and Europe were randomized to assess 28 of 57 sigmoidoscopy videos of patients with UC, which included some duplicates to evaluate intraobserver reliability. Clinical details such as the number of stools per day were provided for only two of the videos. They were also trained.

The UCEIS provides a score of 0 to 8 based on the sum of three descriptors: vascular pattern (normal, patchy obliteration, or obliterated), bleeding (none, mucosal, luminal mild, luminal moderate, or severe), and erosions and ulcers (none, erosions, superficial ulcer, or deep ulcer). Almost 700 video evaluations were performed.

The results included a satisfactory level of intrainvestigator and interinvestigator reliability, indicating that the UCEIS is simple to use and also "reliably evaluates the overall endoscopic severity of UC and accounts for 88% of the variance between endoscopists," the authors concluded.

The study was the first step in the validation of the UCEIS and has "confirmed the reliability of the UCEIS, even if further validation is needed to establish thresholds for remission, the clinical relevance of different UCEIS scores, and responsiveness of the UCEIS to change in disease status," they noted.

The CD study was partly funded by Janssen Biotech; Dr. Ferrante was supported by the Belgian Society of Gastrointestinal Endoscopy and by Funds for Scientific Research, Belgium. The authors disclosed serving on advisory committees and review panels of, or serving as consultants and speakers for, multiple pharmaceutical manufacturers, as well as receiving grants or research support from the companies, including Janssen and Abbott. Several authors were employees of Janssen Biotech and Janssen Biologics, the manufacturer of infliximab. One author had no disclosures.

The UCEIS study was funded by Warner Chilcott, and one author was an employee of the company. The authors disclosed serving as consultants, advisers, and/or speakers for, and receiving research grants from, multiple pharmaceutical companies. Several authors had no disclosures.

[email protected]

A reduction of at least 50% in either of two different Crohn’s disease endoscopic activity scores after 26 weeks of treatment predicted those patients likely to be off of corticosteroid therapy after about 1 year of treatment, with a sensitivity approaching 75%, reported Dr. Marc Ferrante and his coinvestigators.

The study provides evidence that this cutoff could be used as a reliable predictor of clinical response, but it needs to be studied further, according to the authors, who are members of the International Organization for the Study of Inflammatory Bowel Diseases. The study was published in the Novemberissue of Gastroenterology.

Another study, published in the same issue of Gastroenterology, evaluated the reliability of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), an instrument recently created to assess the endoscopic severity of UC. This study randomized 25 investigators to assess and score 28 endoscopic videos of patients with UC – without knowledge of clinical features in most cases. The results indicated that the UCEIS provides a "satisfactory" level of intrainvestigator and interinvestigator agreement and that it is "a reliable instrument for measuring the endoscopic disease activity of UC," according to Dr. Simon Travis, of the translational gastroenterology unit at John Radcliffe Hospital, Oxford, England, and his coinvestigators.

The version of the UCEIS that provides a score from 0 to 8, based on findings of vascular pattern, bleeding, and erosions/ulcers, is the "favored version" but needs to be validated further, they concluded (Gastroenterol. 2013 July 29 [doi: 10.1053/j.gastro.2013.07.024]).

In the Crohn’s disease (CD) study, which used data on 172 patients enrolled in SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease), Dr. Ferrante, of the department of gastroenterology at University Hospitals Leuven, Belgium, and his colleagues identified a cutoff point in two endoscopic response scores after 26 weeks of treatment that was predictive of clinical response at 50 weeks.

At baseline, the patients had endoscopic lesions and CD Activity Index (CDAI) scores of 220-450 points (median, 277). Their median age was 34 years, and they had been diagnosed with CD for a median of 2.5 years. The patients were dependent on corticosteroids and were randomized to treatment with infliximab (Remicade) infusions and/or oral azathioprine, and were followed to 50 weeks. The primary endpoint of this study was corticosteroid-free clinical remission (CFREM) at week 26, and one of the secondary endpoints was complete healing of mucosal ulcerations.

The investigators evaluated different cutoff points of endoscopic responses for two methods used to score the severity of endoscopic lesions: SES-CD (Simple Endoscopic Score for CD) and CDEIS (CD Endoscopic Index of Severity).

Almost half of the patients achieved mucosal healing at the 26th week.

A decrease from baseline in the SES-CD of at least 50% at week 26 "appeared to be the best discriminative cutoff value" for predicting patients most likely to be in clinical remission (off steroids at week 50). This degree of SES-CD response was met by 112 (65%) patients, with 74% sensitivity and 48% specificity for predicting CFREM at week 50.

For the CDEIS values, the best cutoff was at least a 45% drop from baseline at week 26 for predicting patients most likely to achieve CFREM at week 50, with 75% sensitivity and 45% specificity.

Because of the "subtle" difference between the two measures (50% and 45% cutoffs), "we propose a definition of endoscopic response with a decrease in baseline in CDEIS of at least 50% at week 26 for both tests," the authors wrote. (For CDEIS, the 50% cutoff had a sensitivity of 73% and a specificity of 46%.)

"As such, this endoscopic endpoint could serve as a reliable predictor of the midterm clinical outcome of therapies," Dr. Ferrante and his coauthors concluded. A 50% reduction in endoscopic activity from baseline also has potential for use as an endpoint in studies evaluating pharmacotherapy or treatment strategies "to show healing capacity," they wrote.

These cutoff values should be validated in a prospective study, which should also look at correlations between the endoscopic response and "disease-modifying long-term outcomes," such as a sustained clinical response or surgery, they added.

In the study that evaluated the reliability of the UCEIS, 25 investigators from North America and Europe were randomized to assess 28 of 57 sigmoidoscopy videos of patients with UC, which included some duplicates to evaluate intraobserver reliability. Clinical details such as the number of stools per day were provided for only two of the videos. They were also trained.

The UCEIS provides a score of 0 to 8 based on the sum of three descriptors: vascular pattern (normal, patchy obliteration, or obliterated), bleeding (none, mucosal, luminal mild, luminal moderate, or severe), and erosions and ulcers (none, erosions, superficial ulcer, or deep ulcer). Almost 700 video evaluations were performed.

The results included a satisfactory level of intrainvestigator and interinvestigator reliability, indicating that the UCEIS is simple to use and also "reliably evaluates the overall endoscopic severity of UC and accounts for 88% of the variance between endoscopists," the authors concluded.

The study was the first step in the validation of the UCEIS and has "confirmed the reliability of the UCEIS, even if further validation is needed to establish thresholds for remission, the clinical relevance of different UCEIS scores, and responsiveness of the UCEIS to change in disease status," they noted.

The CD study was partly funded by Janssen Biotech; Dr. Ferrante was supported by the Belgian Society of Gastrointestinal Endoscopy and by Funds for Scientific Research, Belgium. The authors disclosed serving on advisory committees and review panels of, or serving as consultants and speakers for, multiple pharmaceutical manufacturers, as well as receiving grants or research support from the companies, including Janssen and Abbott. Several authors were employees of Janssen Biotech and Janssen Biologics, the manufacturer of infliximab. One author had no disclosures.

The UCEIS study was funded by Warner Chilcott, and one author was an employee of the company. The authors disclosed serving as consultants, advisers, and/or speakers for, and receiving research grants from, multiple pharmaceutical companies. Several authors had no disclosures.

[email protected]

A reduction of at least 50% in either of two different Crohn’s disease endoscopic activity scores after 26 weeks of treatment predicted those patients likely to be off of corticosteroid therapy after about 1 year of treatment, with a sensitivity approaching 75%, reported Dr. Marc Ferrante and his coinvestigators.

The study provides evidence that this cutoff could be used as a reliable predictor of clinical response, but it needs to be studied further, according to the authors, who are members of the International Organization for the Study of Inflammatory Bowel Diseases. The study was published in the Novemberissue of Gastroenterology.

Another study, published in the same issue of Gastroenterology, evaluated the reliability of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), an instrument recently created to assess the endoscopic severity of UC. This study randomized 25 investigators to assess and score 28 endoscopic videos of patients with UC – without knowledge of clinical features in most cases. The results indicated that the UCEIS provides a "satisfactory" level of intrainvestigator and interinvestigator agreement and that it is "a reliable instrument for measuring the endoscopic disease activity of UC," according to Dr. Simon Travis, of the translational gastroenterology unit at John Radcliffe Hospital, Oxford, England, and his coinvestigators.

The version of the UCEIS that provides a score from 0 to 8, based on findings of vascular pattern, bleeding, and erosions/ulcers, is the "favored version" but needs to be validated further, they concluded (Gastroenterol. 2013 July 29 [doi: 10.1053/j.gastro.2013.07.024]).

In the Crohn’s disease (CD) study, which used data on 172 patients enrolled in SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease), Dr. Ferrante, of the department of gastroenterology at University Hospitals Leuven, Belgium, and his colleagues identified a cutoff point in two endoscopic response scores after 26 weeks of treatment that was predictive of clinical response at 50 weeks.

At baseline, the patients had endoscopic lesions and CD Activity Index (CDAI) scores of 220-450 points (median, 277). Their median age was 34 years, and they had been diagnosed with CD for a median of 2.5 years. The patients were dependent on corticosteroids and were randomized to treatment with infliximab (Remicade) infusions and/or oral azathioprine, and were followed to 50 weeks. The primary endpoint of this study was corticosteroid-free clinical remission (CFREM) at week 26, and one of the secondary endpoints was complete healing of mucosal ulcerations.

The investigators evaluated different cutoff points of endoscopic responses for two methods used to score the severity of endoscopic lesions: SES-CD (Simple Endoscopic Score for CD) and CDEIS (CD Endoscopic Index of Severity).

Almost half of the patients achieved mucosal healing at the 26th week.

A decrease from baseline in the SES-CD of at least 50% at week 26 "appeared to be the best discriminative cutoff value" for predicting patients most likely to be in clinical remission (off steroids at week 50). This degree of SES-CD response was met by 112 (65%) patients, with 74% sensitivity and 48% specificity for predicting CFREM at week 50.

For the CDEIS values, the best cutoff was at least a 45% drop from baseline at week 26 for predicting patients most likely to achieve CFREM at week 50, with 75% sensitivity and 45% specificity.

Because of the "subtle" difference between the two measures (50% and 45% cutoffs), "we propose a definition of endoscopic response with a decrease in baseline in CDEIS of at least 50% at week 26 for both tests," the authors wrote. (For CDEIS, the 50% cutoff had a sensitivity of 73% and a specificity of 46%.)

"As such, this endoscopic endpoint could serve as a reliable predictor of the midterm clinical outcome of therapies," Dr. Ferrante and his coauthors concluded. A 50% reduction in endoscopic activity from baseline also has potential for use as an endpoint in studies evaluating pharmacotherapy or treatment strategies "to show healing capacity," they wrote.

These cutoff values should be validated in a prospective study, which should also look at correlations between the endoscopic response and "disease-modifying long-term outcomes," such as a sustained clinical response or surgery, they added.

In the study that evaluated the reliability of the UCEIS, 25 investigators from North America and Europe were randomized to assess 28 of 57 sigmoidoscopy videos of patients with UC, which included some duplicates to evaluate intraobserver reliability. Clinical details such as the number of stools per day were provided for only two of the videos. They were also trained.

The UCEIS provides a score of 0 to 8 based on the sum of three descriptors: vascular pattern (normal, patchy obliteration, or obliterated), bleeding (none, mucosal, luminal mild, luminal moderate, or severe), and erosions and ulcers (none, erosions, superficial ulcer, or deep ulcer). Almost 700 video evaluations were performed.

The results included a satisfactory level of intrainvestigator and interinvestigator reliability, indicating that the UCEIS is simple to use and also "reliably evaluates the overall endoscopic severity of UC and accounts for 88% of the variance between endoscopists," the authors concluded.

The study was the first step in the validation of the UCEIS and has "confirmed the reliability of the UCEIS, even if further validation is needed to establish thresholds for remission, the clinical relevance of different UCEIS scores, and responsiveness of the UCEIS to change in disease status," they noted.

The CD study was partly funded by Janssen Biotech; Dr. Ferrante was supported by the Belgian Society of Gastrointestinal Endoscopy and by Funds for Scientific Research, Belgium. The authors disclosed serving on advisory committees and review panels of, or serving as consultants and speakers for, multiple pharmaceutical manufacturers, as well as receiving grants or research support from the companies, including Janssen and Abbott. Several authors were employees of Janssen Biotech and Janssen Biologics, the manufacturer of infliximab. One author had no disclosures.

The UCEIS study was funded by Warner Chilcott, and one author was an employee of the company. The authors disclosed serving as consultants, advisers, and/or speakers for, and receiving research grants from, multiple pharmaceutical companies. Several authors had no disclosures.

[email protected]

The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.

In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.

"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).

The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.

The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.

The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.

The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.

Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.

The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "it is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration" defined by the response-guided therapy algorithm, they added.

The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.

The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.

[email protected]

The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.

In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.

"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).

The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.

The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.

The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.

The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.

Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.

The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "it is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration" defined by the response-guided therapy algorithm, they added.

The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.

The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.

[email protected]

The results of a randomized, open-label study suggest that reducing the ribavirin dose should be the "primary approach" for managing anemia associated with peginterferon, ribavirin, and boceprevir therapy in patients with chronic hepatitis C, the authors of the study concluded.

In the study, the effects of two anemia-management strategies, ribavirin (RBV) dose reduction and erythropoietin (EPO) treatment, on the sustained virologic response (SVR) were similar – there was less than 1% difference between the two groups, according to the investigators, Dr. Fred F. Poordad of the Texas Liver Institute, at the University of Texas Health Science Center, San Antonio, and his associates. They also found that SVR rates were significantly lower among those who received less than half of the total ribavirin dose during the entire treatment period, compared with those who received a greater proportion of the total dosage.

"There appears to be no apparent benefit of using EPO as a first-line anemia-management strategy to enhance SVR rate or minimize relapse," the authors concluded. "EPO can be used as a secondary management strategy to prevent treatment interruption if RBV dosage reduction alone is inadequate, but the safety of EPO use in this setting has not been clearly established," they added. The study was published in the November issue of Gastroenterology (2013 [doi:10.1053/j.gastro.2013.07.051]).

The study includes an algorithm for managing boceprevir-related anemia, based on the results of this and other clinical studies, and the authors’ expertise.

The study, conducted between December 2009 and October 2011, compared the two regimens in 500 of 687 previously untreated patients with chronic HCV genotype-1 infections, who became anemic (hemoglobin levels dropping to 10 g/dL or lower) during treatment with the three drugs: peginterferon alfa-2b (PegIntron) at a dose of 1.5 mcg/kg per week; ribavirin at a dose of 600-1400 mg per day depending on weight; and boceprevir (Victrelis) at a dose of 800 mg three times a day. (After 4 weeks of treatment with peginterferon and RBV, boceprevir was added for 24 or 44 weeks). Their mean age was about 50 years, 33% were men, 77% were white, and 18% were black; 91% had a baseline viral load of more than 400,000 IU/mL. Almost 90% were in the United States, the rest were in Canada and Europe.

The 500 patients were randomized to treatment with EPO (a subcutaneous infusion of 40,000 IU a week) or a reduction in the ribavirin dose (200 mg/day or, for those on the 1,400 mg daily dose, a 400-mg reduction). If hemoglobin levels dropped to 7.5 g/dL or lower, the patients were dropped from the study.

The SVR rate (undetectable HCV RNA 24 weeks after the end of treatment) was 71.5% among those whose ribavirin dosage was reduced and 70.9% among those treated with EPO. Among the 187 patients who did not develop anemia, the SVR rate was 40.1%; this group included a large number of patients who discontinued treatment because of adverse events. But of the 64 who completed treatment, the SVR rate was 89%. The overall SVR rate – among all 687 patients, those randomized and not randomized – was 63%.

Common adverse events were similar in the two randomized treatment groups, with anemia, fatigue, nausea, and headache being the most commonly reported. The rates of serious adverse events were 16% among those in the RBV dose-reduction arm and 13% of those on EPO. There were more thromboembolic events among the patients treated with EPO. There was one death in a patient in the RBV arm, a sudden cardiac death 3 weeks after stopping treatment.

The algorithm proposed by the authors, which has different hemoglobin monitoring recommendations for those with and without advanced fibrosis and cirrhosis, recommends that the primary intervention for managing anemia should be to reduce the RBV dosage. But if hemoglobin levels remain below 10 g/dL, "secondary interventions, such as administration of EPO, red cell transfusions, and reducing the dosage of peginterferon can be considered," the authors wrote. In addition, "it is important that the patient receives at least 50% of the total milligrams of RBV calculated from the initial RBV dosage (mg/d) and the assigned duration" defined by the response-guided therapy algorithm, they added.

The open-label design was one of the study’s limitations, and whether these results apply to other HCV treatment regimens is unclear, the authors noted. However, the results "would most likely be applicable to all RBV- and peginterferon/RBV-based regimens" for hepatitis C, they added.

The study was funded by Schering-Plough, the manufacturer of PegIntron and combination packs of PegIntron with ribavirin, which is now part of Merck. The investigator disclosures included having served as consultants and speakers, and/or having received grants from multiple pharmaceutical companies; the investigators include several current and former employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), the manufacturer of Victrelis.

[email protected]

The Food and Drug Administration has asked the manufacturer of ponatinib to suspend sales and marketing of the leukemia drug because of the risk of "life-threatening blood clots and severe narrowing of blood vessels" associated with the drug, the agency announced Oct. 31.

The request comes less than a year since the expedited approval of ponatinib for the treatment of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Ponatinib is a kinase inhibitor, marketed as Iclusig by ARIAD Pharmaceuticals. A recent FDA investigation determined that, since the drug was approved in December 2012, blood clots and narrowing of blood vessels have increased, according to the FDA statement. At the time of approval, 14% of patients on the drug experienced these events, according to an agency spokesperson. Two of the company’s clinical trials are now showing rates of 24% and 48%.

Patients who are not responding to treatment should be taken off the drug immediately and discuss alternative treatment with their clinicians, the agency has advised. In addition, patients who are responding to treatment, "whose health care professionals determine that the potential benefits outweigh the risks," should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program, the statement said.

About 24% of patients treated with ponatinib over a median of 1.3 years in a phase II study and about 48% of the patients in a phase I study treated for a median of 2.7 years have had serious adverse vascular events, which include fatal and life-threatening MIs, stroke, loss of blood flow to the extremities resulting in tissue death, "and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow," the statement said. These events have been reported in patients with and without cardiovascular risk factors. In studies, 67% of treated patients have developed hypertension; and 8% have developed heart failure, including fatal cases.

The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

"We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks," the FDA noted.

In a separate Oct. 31 statement, ARIAD confirmed that it was temporarily suspending sales and marketing of ponatinib. The company "believes that Iclusig is an important medicine for patients with resistant or intolerant Philadelphia-positive leukemias and is actively working with the FDA on actions to achieve the resumption of marketing of Iclusig," the company stated.

The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

Serious adverse events associated with ponatinib should be reported online to the FDA or by phone, 800-332-0178. Information about the IND program is available online.

[email protected]

The Food and Drug Administration has asked the manufacturer of ponatinib to suspend sales and marketing of the leukemia drug because of the risk of "life-threatening blood clots and severe narrowing of blood vessels" associated with the drug, the agency announced Oct. 31.

The request comes less than a year since the expedited approval of ponatinib for the treatment of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Ponatinib is a kinase inhibitor, marketed as Iclusig by ARIAD Pharmaceuticals. A recent FDA investigation determined that, since the drug was approved in December 2012, blood clots and narrowing of blood vessels have increased, according to the FDA statement. At the time of approval, 14% of patients on the drug experienced these events, according to an agency spokesperson. Two of the company’s clinical trials are now showing rates of 24% and 48%.

Patients who are not responding to treatment should be taken off the drug immediately and discuss alternative treatment with their clinicians, the agency has advised. In addition, patients who are responding to treatment, "whose health care professionals determine that the potential benefits outweigh the risks," should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program, the statement said.

About 24% of patients treated with ponatinib over a median of 1.3 years in a phase II study and about 48% of the patients in a phase I study treated for a median of 2.7 years have had serious adverse vascular events, which include fatal and life-threatening MIs, stroke, loss of blood flow to the extremities resulting in tissue death, "and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow," the statement said. These events have been reported in patients with and without cardiovascular risk factors. In studies, 67% of treated patients have developed hypertension; and 8% have developed heart failure, including fatal cases.

The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

"We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks," the FDA noted.

In a separate Oct. 31 statement, ARIAD confirmed that it was temporarily suspending sales and marketing of ponatinib. The company "believes that Iclusig is an important medicine for patients with resistant or intolerant Philadelphia-positive leukemias and is actively working with the FDA on actions to achieve the resumption of marketing of Iclusig," the company stated.

The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

Serious adverse events associated with ponatinib should be reported online to the FDA or by phone, 800-332-0178. Information about the IND program is available online.

[email protected]

The Food and Drug Administration has asked the manufacturer of ponatinib to suspend sales and marketing of the leukemia drug because of the risk of "life-threatening blood clots and severe narrowing of blood vessels" associated with the drug, the agency announced Oct. 31.

The request comes less than a year since the expedited approval of ponatinib for the treatment of chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Ponatinib is a kinase inhibitor, marketed as Iclusig by ARIAD Pharmaceuticals. A recent FDA investigation determined that, since the drug was approved in December 2012, blood clots and narrowing of blood vessels have increased, according to the FDA statement. At the time of approval, 14% of patients on the drug experienced these events, according to an agency spokesperson. Two of the company’s clinical trials are now showing rates of 24% and 48%.

Patients who are not responding to treatment should be taken off the drug immediately and discuss alternative treatment with their clinicians, the agency has advised. In addition, patients who are responding to treatment, "whose health care professionals determine that the potential benefits outweigh the risks," should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program, the statement said.

About 24% of patients treated with ponatinib over a median of 1.3 years in a phase II study and about 48% of the patients in a phase I study treated for a median of 2.7 years have had serious adverse vascular events, which include fatal and life-threatening MIs, stroke, loss of blood flow to the extremities resulting in tissue death, "and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow," the statement said. These events have been reported in patients with and without cardiovascular risk factors. In studies, 67% of treated patients have developed hypertension; and 8% have developed heart failure, including fatal cases.

The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

"We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks," the FDA noted.

In a separate Oct. 31 statement, ARIAD confirmed that it was temporarily suspending sales and marketing of ponatinib. The company "believes that Iclusig is an important medicine for patients with resistant or intolerant Philadelphia-positive leukemias and is actively working with the FDA on actions to achieve the resumption of marketing of Iclusig," the company stated.

The prescribing information for the drug includes a boxed warning about the risk of arterial thrombosis and hepatotoxicity associated with treatment.

Serious adverse events associated with ponatinib should be reported online to the FDA or by phone, 800-332-0178. Information about the IND program is available online.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the antiviral drug simeprevir as a treatment for chronic hepatitis C.

The approval was based on the highly favorable benefit-risk profile of the drug in studies that included sustained viral response rates of 79%-80% in phase III studies of patients with chronic HCV.

At a meeting on October 24, the FDA’s Antiviral Drugs Advisory Committee voted 19-0 that simeprevir, a hepatitis C virus (HCV) protease inhibitor, in combination with pegylated interferon and ribavirin (PR), be approved for the treatment of chronic hepatitis C genotype 1 (GT1) infection in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have failed previous interferon-based therapy. The dosing proposed by the manufacturer, Janssen Pharmaceutical Co., is a 150-mg capsule once a day for 12 weeks, combined with PR for 24 weeks, in patients who have never been treated for HCV and for those who have relapsed on treatment. For patients who have not responded to previous treatments, PR is continued for 48 weeks.

The panel agreed that the risk-benefit profile was favorable, and with the once-daily dose, simeprevir was much easier to take than the first-generation protease inhibitors currently approved for treating chronic HCV, telaprevir and boceprevir, which are the current standard of care and require a total of 6-12 pills a day, taken at three times a day. Simeprevir inhibits HCV NS3/4A serine protease, which is "essential for viral replication," according to Janssen.

"We clearly need better drugs, and evidence is strong that this is a better drug," said panelist Dr. Curt Hagedorn, chief of the medicine service, Central Arkansas Veterans Healthcare Services, Little Rock.

"As someone who treats patients with chronic hepatitis C every day, this regimen represents a much simpler one and much safer" than currently available treatments, added panelist Dr. Marc Ghany, staff physician in the liver disease branch of the National Institute of Diabetes, Digestive and Kidney Diseases.

Panelists, however, urged Janssen to study more black patients in postmarketing trials, since black patients were greatly underrepresented in the studies but make up a large proportion of those infected with HCV in the United States. Postmarketing studies should also evaluate the drug in Hispanics, those coinfected with HIV, pediatric patients, patients with renal failure, and more patients with cirrhosis, they added.

The main safety issue discussed was the higher rates of rashes and photosensitivity reactions associated with treatment, which the FDA has proposed be included in the warnings and precautions section of the drug’s prescribing information, including a recommendation for patients to use sun protection measures while taking the drug. The panel agreed with the FDA and the manufacturer that before starting treatment, patients with HCV genotype 1a infections should be screened for the "Q80K" viral polymorphism – which is common in the United States and was associated with lower efficacy rates in the studies.

If approved, simeprevir will be the third HCV protease inhibitor approved in the United States for treating hepatitis C. In May 2011, boceprevir (Victrelis) and telaprevir (Incivek), which are also HCV NS3/4A protease inhibitors, were approved. In addition to the number of daily pills required, adverse events associated with these drugs include anemia and rash.

In three phase III studies of almost 1,200 patients most of whom were white, with chronic HCV genotype 1 infections, who had not been treated previously or had relapsed on previous treatment, simeprevir, 150 mg once a day for 12 weeks, combined with PR, followed by PR alone for 12 or 36 weeks (depending on the patient’s response), was compared with PR alone for 48 weeks (which included a placebo for the first 12 weeks). The primary efficacy endpoint was the sustained virologic response at 12 weeks (SVR 12), defined as HCV RNA that was undetectable or was detected at a level below 25 IU/mL 12 weeks after treatment was planned to end. (In the different arms of the studies, 40%-57% of the patients had HCV genotype/subtype 1a, and 43%-59% had 1b.)

In the two studies of 785 treatment-naive patients, 80% of those treated with simeprevir achieved an SVR12, compared with 50% of controls. The "on-treatment failure" rates (those who had detectable HCV RNA at the end of treatment) were 8% of those treated with simeprevir, compared with 33% of controls. The rates of viral relapse were 12% among those on simeprevir, compared with 22% of those on placebo.

In the third study of 393 relapsers, the SVR12 rate was 79% among those on simeprevir, compared with 36% among those on PR alone. Among those on simeprevir, 3% were on-treatment failures and 19% had a viral relapse, compared with 29% and 48%, respectively, of those on placebo.

In phase III studies, fatigue, headache, and influenzalike illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Janssen is investigating the appropriate dose in people of Eastern Asian descent. Exposure in these patients is higher, and rashes, photosensitivity, and other adverse events are increased with greater drug exposures, according to the FDA. A 100-mg daily dose of simeprevir has been approved in Japan (the only country where the drug has been approved to date). The drug is also being reviewed for approval in the European Union.

Among people with chronic HCV infections in the United States, genotype 1 is the most common, accounting for 75% of cases, according to the FDA.

The FDA usually follows the recommendations of its advisory panels and is expected to make a decision on this application by Nov. 27. Members of FDA panels have been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

[email protected]

Another endothelin receptor blocker, macitentan, has been approved for treating pulmonary arterial hypertension, the Food and Drug Administration announced on Oct. 18.

In a study of 742 patients with pulmonary arterial hypertension (PAH), macitentan over an average of 2 years was "effective in delaying disease progression, a finding that included a decline in exercise ability, worsening symptoms of PAH or need for additional PAH medication," according to the FDA statement issued on Oct. 18. Anemia, nasopharyngitis, sore throat, bronchitis, headache, and urinary tract infection were among the common side effects associated with treatment, the statement said.

It will be marketed as Opsumit by Actelion Pharmaceuticals US. The approved indication is for the treatment of PAH, WHO Group I, to delay disease progression, which includes death, initiation of intravenous or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment, according to Actelion). The approved dose is 10 mg daily; it is an oral medication.

Like the other endothelin receptor blockers, macitentan’s label includes a boxed warning that it is a teratogen and should not be used in pregnant women, and that women can receive the drug only through a REMS (Risk Evaluation and Mitigation Strategy) program that will restrict the drug’s distribution. Under the Opsumit REMS, distribution of the drug will be restricted and prescribers will have to enroll in the REMS and become certified to prescribe the drug. Female patients will also need to be enrolled and must comply with pregnancy testing and contraception requirements before starting treatment. Pharmacies that dispense the drug will need to be certified and will dispense the drug only to authorized patients, the FDA said.

The study of 742 patients was SERAPHIN (Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), which compared treatment with 3 mg or 10 mg of macitentan once a day, or placebo, and were allowed to be treated with phosphodiesterase-5 inhibitors or oral or inhaled prostanoids, according to Actelion.

The primary end point, a composite of a PAH event or death from any cause, was reached by 38% of patients receiving 3-mg macitentan and 31% of those receiving 10-mg macitentan, compared with 46% of patients receiving placebo. The hazard ratios of 0.7 for the 3-mg dose and 0.55 for the 10-mg dose were statistically significant.

Macitentan is under review in Europe, Canada, Switzerland, Australia, Taiwan, Korea and Mexico, according to Actelion.

Actelion also markets bosentan (Tracleer), another endothelin receptor antagonist, which was approved for treating PAH in 2001. Ambrisentan (Letairis; Gilead), also an endothelin receptor antagonist, was approved in 2007.

[email protected]

Another endothelin receptor blocker, macitentan, has been approved for treating pulmonary arterial hypertension, the Food and Drug Administration announced on Oct. 18.

In a study of 742 patients with pulmonary arterial hypertension (PAH), macitentan over an average of 2 years was "effective in delaying disease progression, a finding that included a decline in exercise ability, worsening symptoms of PAH or need for additional PAH medication," according to the FDA statement issued on Oct. 18. Anemia, nasopharyngitis, sore throat, bronchitis, headache, and urinary tract infection were among the common side effects associated with treatment, the statement said.

It will be marketed as Opsumit by Actelion Pharmaceuticals US. The approved indication is for the treatment of PAH, WHO Group I, to delay disease progression, which includes death, initiation of intravenous or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment, according to Actelion). The approved dose is 10 mg daily; it is an oral medication.

Like the other endothelin receptor blockers, macitentan’s label includes a boxed warning that it is a teratogen and should not be used in pregnant women, and that women can receive the drug only through a REMS (Risk Evaluation and Mitigation Strategy) program that will restrict the drug’s distribution. Under the Opsumit REMS, distribution of the drug will be restricted and prescribers will have to enroll in the REMS and become certified to prescribe the drug. Female patients will also need to be enrolled and must comply with pregnancy testing and contraception requirements before starting treatment. Pharmacies that dispense the drug will need to be certified and will dispense the drug only to authorized patients, the FDA said.

The study of 742 patients was SERAPHIN (Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), which compared treatment with 3 mg or 10 mg of macitentan once a day, or placebo, and were allowed to be treated with phosphodiesterase-5 inhibitors or oral or inhaled prostanoids, according to Actelion.

The primary end point, a composite of a PAH event or death from any cause, was reached by 38% of patients receiving 3-mg macitentan and 31% of those receiving 10-mg macitentan, compared with 46% of patients receiving placebo. The hazard ratios of 0.7 for the 3-mg dose and 0.55 for the 10-mg dose were statistically significant.

Macitentan is under review in Europe, Canada, Switzerland, Australia, Taiwan, Korea and Mexico, according to Actelion.

Actelion also markets bosentan (Tracleer), another endothelin receptor antagonist, which was approved for treating PAH in 2001. Ambrisentan (Letairis; Gilead), also an endothelin receptor antagonist, was approved in 2007.

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Another endothelin receptor blocker, macitentan, has been approved for treating pulmonary arterial hypertension, the Food and Drug Administration announced on Oct. 18.

In a study of 742 patients with pulmonary arterial hypertension (PAH), macitentan over an average of 2 years was "effective in delaying disease progression, a finding that included a decline in exercise ability, worsening symptoms of PAH or need for additional PAH medication," according to the FDA statement issued on Oct. 18. Anemia, nasopharyngitis, sore throat, bronchitis, headache, and urinary tract infection were among the common side effects associated with treatment, the statement said.

It will be marketed as Opsumit by Actelion Pharmaceuticals US. The approved indication is for the treatment of PAH, WHO Group I, to delay disease progression, which includes death, initiation of intravenous or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment, according to Actelion). The approved dose is 10 mg daily; it is an oral medication.

Like the other endothelin receptor blockers, macitentan’s label includes a boxed warning that it is a teratogen and should not be used in pregnant women, and that women can receive the drug only through a REMS (Risk Evaluation and Mitigation Strategy) program that will restrict the drug’s distribution. Under the Opsumit REMS, distribution of the drug will be restricted and prescribers will have to enroll in the REMS and become certified to prescribe the drug. Female patients will also need to be enrolled and must comply with pregnancy testing and contraception requirements before starting treatment. Pharmacies that dispense the drug will need to be certified and will dispense the drug only to authorized patients, the FDA said.

The study of 742 patients was SERAPHIN (Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), which compared treatment with 3 mg or 10 mg of macitentan once a day, or placebo, and were allowed to be treated with phosphodiesterase-5 inhibitors or oral or inhaled prostanoids, according to Actelion.

The primary end point, a composite of a PAH event or death from any cause, was reached by 38% of patients receiving 3-mg macitentan and 31% of those receiving 10-mg macitentan, compared with 46% of patients receiving placebo. The hazard ratios of 0.7 for the 3-mg dose and 0.55 for the 10-mg dose were statistically significant.

Macitentan is under review in Europe, Canada, Switzerland, Australia, Taiwan, Korea and Mexico, according to Actelion.

Actelion also markets bosentan (Tracleer), another endothelin receptor antagonist, which was approved for treating PAH in 2001. Ambrisentan (Letairis; Gilead), also an endothelin receptor antagonist, was approved in 2007.

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