AASLD: Rapid Response for Once-Daily Protease Inhibitor
By Kristina Fiore , Staff Writer,
MedPage TodayPublished:
November 02, 2010
Reviewed by Robert Jasmer, MD;
Associate Clinical Professor of Medicine,
University of California, San Francisco.
MedPage TodayPublished:
November 02, 2010
Reviewed by Robert Jasmer, MD;
Associate Clinical Professor of Medicine,
University of California, San Francisco.
BOSTON -- The vast majority of patients with hepatitis C virus infection respond rapidly to a novel, once-daily protease inhibitor that may also mitigate the effects of a mutation predicting worse response to standard combination therapy, researchers reported here.
In an interim analysis of a phase IIb, five-arm trial, genotype 1 hepatitis C patients taking various doses of TMC435 in addition to peginterferon and ribavirin had significantly greater responses at four weeks than those on combination therapy plus placebo (68% to 79% versus 5%), according to Michael Fried, MD, of the University of North Carolina Chapel Hill, and colleagues.
The drug also appeared to enhance response to treatment among those with the CT and TT variants of the IL28B genotype, which are associated with diminished response to interferon and ribavirin therapy.
Fried presented the findings during a late-breaking session at the American Association for the Study of Liver Diseases meeting here.
"All treatment groups had a rapid and steep decline [in hepatitis C virus RNA] during the first four weeks that was maintained through weeks 12 and 24," Fried said.
He added that researchers are "encouraged that regimens containing TMC435 will mitigate the effects of IL28 genotype."
The compound is given once a day -- an easier regimen than that of the two protease inhibitors closest to market, boceprevir and telaprevir, which are administered thrice daily.
To evaluate the drug's safety and efficacy, the researchers conducted the five-arm, phase-IIb PILLAR study in 386 treatment-naive patients with genotype 1 disease.
Patients were randomized to one of five groups:
75 mg or 150 mg of TMC435 daily along with peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin only for another 12 weeks;
75 mg or 150 mg of TMC435 daily along with peginterferon and ribavirin for 24 weeks; or
Standard combination therapy plus placebo for 48 weeks.
They were allowed to stop treatment at week 24 if their HCV RNA levels were under 25 IU/mL at week four and then again at weeks 12, 16, and 20.
If they didn't meet that criteria, they were continued on standard combination therapy until week 48.
The endpoint was response at 72 weeks, and secondary endpoints included viral breakthrough, relapse, and tolerability.
Fried reported the results of an interim analysis at week 24.
All treatment arms had significant responses after four weeks compared with the placebo group (68% to 79% versus 5%), and continued to have "potent antiviral activity" over 12 and 24 weeks, Fried said.
At week 12, response rates fell between 91% and 97% for the four drug arms, compared with 58% for the placebo group.
Through 24 weeks of treatment, response levels somewhat converged but were still greater in the drug groups (94% to 97% versus 82%).
Between 79% and 86% of patients in the drug arms ended therapy at week 24 as per protocol-defined response criteria.
Viral breakthrough was comparable across all five arms, occurring in 2.5% to 7.8% of patients across the different treatment arms, compared with 3.9% for placebo.
The researchers also found that TMC435 increased response rates among those with IL28B variants known to diminish response to interferon and ribavirin therapy.
Those with genotype CT and TT appeared to have comparable responses to those with genotype CC if they were taking the drug, Fried said.
There were no differences in adverse events, including rash, anemia, or gastrointestinal events, and the most common effects were headache and fatigue, which were comparable across all groups.
Discontinuation rates were similar across all groups as well.
There were, however, "small and transient" elevations in bilirubin levels for patients in the 150-mg dose groups, which Fried said resolved after treatment ended.
"We see some increase in bilirubin, but it's completely reversible," he said, adding the effects are "clearly related to a transporter mechanism as opposed to hepatotoxicity."
He added that despite these effects, "in my opinion, the 150-mg dose is probably the way to go."
Douglas LaBrecque, MD, of the University of Iowa, who moderated the session at which the data were presented, told MedPage Today that the findings are hopeful, but are still in very preliminary stages.
"We just don't have enough data yet," he said.
Drugmaker Tibotec is currently planning phase III trials for the compound.
Fried reported relationships with Tibotec, Roche, Vertex, Merck/Schering, Pharmasset, Bristol-Myers Squibb, Anadys, Conatus, and Human Genome Sciences.
LaBrecque said he had no disclosures.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Fried MW, et al "Efficacy and safety of TMC435 in combination with peginterferon alpha-2a and ribavirin in treatment-naive genotype 1 HCV patients: 24-week interim results of the PILLAR study" AASLD 2010; Abstract LB-5.
In an interim analysis of a phase IIb, five-arm trial, genotype 1 hepatitis C patients taking various doses of TMC435 in addition to peginterferon and ribavirin had significantly greater responses at four weeks than those on combination therapy plus placebo (68% to 79% versus 5%), according to Michael Fried, MD, of the University of North Carolina Chapel Hill, and colleagues.
The drug also appeared to enhance response to treatment among those with the CT and TT variants of the IL28B genotype, which are associated with diminished response to interferon and ribavirin therapy.
Fried presented the findings during a late-breaking session at the American Association for the Study of Liver Diseases meeting here.
"All treatment groups had a rapid and steep decline [in hepatitis C virus RNA] during the first four weeks that was maintained through weeks 12 and 24," Fried said.
He added that researchers are "encouraged that regimens containing TMC435 will mitigate the effects of IL28 genotype."
The compound is given once a day -- an easier regimen than that of the two protease inhibitors closest to market, boceprevir and telaprevir, which are administered thrice daily.
To evaluate the drug's safety and efficacy, the researchers conducted the five-arm, phase-IIb PILLAR study in 386 treatment-naive patients with genotype 1 disease.
Patients were randomized to one of five groups:
75 mg or 150 mg of TMC435 daily along with peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin only for another 12 weeks;
75 mg or 150 mg of TMC435 daily along with peginterferon and ribavirin for 24 weeks; or
Standard combination therapy plus placebo for 48 weeks.
They were allowed to stop treatment at week 24 if their HCV RNA levels were under 25 IU/mL at week four and then again at weeks 12, 16, and 20.
If they didn't meet that criteria, they were continued on standard combination therapy until week 48.
The endpoint was response at 72 weeks, and secondary endpoints included viral breakthrough, relapse, and tolerability.
Fried reported the results of an interim analysis at week 24.
All treatment arms had significant responses after four weeks compared with the placebo group (68% to 79% versus 5%), and continued to have "potent antiviral activity" over 12 and 24 weeks, Fried said.
At week 12, response rates fell between 91% and 97% for the four drug arms, compared with 58% for the placebo group.
Through 24 weeks of treatment, response levels somewhat converged but were still greater in the drug groups (94% to 97% versus 82%).
Between 79% and 86% of patients in the drug arms ended therapy at week 24 as per protocol-defined response criteria.
Viral breakthrough was comparable across all five arms, occurring in 2.5% to 7.8% of patients across the different treatment arms, compared with 3.9% for placebo.
The researchers also found that TMC435 increased response rates among those with IL28B variants known to diminish response to interferon and ribavirin therapy.
Those with genotype CT and TT appeared to have comparable responses to those with genotype CC if they were taking the drug, Fried said.
There were no differences in adverse events, including rash, anemia, or gastrointestinal events, and the most common effects were headache and fatigue, which were comparable across all groups.
Discontinuation rates were similar across all groups as well.
There were, however, "small and transient" elevations in bilirubin levels for patients in the 150-mg dose groups, which Fried said resolved after treatment ended.
"We see some increase in bilirubin, but it's completely reversible," he said, adding the effects are "clearly related to a transporter mechanism as opposed to hepatotoxicity."
He added that despite these effects, "in my opinion, the 150-mg dose is probably the way to go."
Douglas LaBrecque, MD, of the University of Iowa, who moderated the session at which the data were presented, told MedPage Today that the findings are hopeful, but are still in very preliminary stages.
"We just don't have enough data yet," he said.
Drugmaker Tibotec is currently planning phase III trials for the compound.
Fried reported relationships with Tibotec, Roche, Vertex, Merck/Schering, Pharmasset, Bristol-Myers Squibb, Anadys, Conatus, and Human Genome Sciences.
LaBrecque said he had no disclosures.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Fried MW, et al "Efficacy and safety of TMC435 in combination with peginterferon alpha-2a and ribavirin in treatment-naive genotype 1 HCV patients: 24-week interim results of the PILLAR study" AASLD 2010; Abstract LB-5.
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