AASLD: Two New HCV Drugs Need Old Hands' Help
By Michael Smith , North American Correspondent,
MedPage TodayPublished: November 02, 2010
BOSTON -- Two direct anti-viral agents showed robust activity against hepatitis C in treatment-naive patients with the most refractory form of the virus, a researcher said here.
But the two drugs needed the standard medications -- ribavirin and pegylated interferon -- to get high response rates, according to Stefan Zeuzem, MD, of J.W. Goethe University Hospital in Frankfurt, Germany.
The findings come from a phase II randomized trial that tested the two drugs over a four-week period, followed by 44 weeks of ribavirin and interferon, Zeuzem told a late-breaker session at the annual meeting here of the American Association for the Study of Liver Diseases.
The hope has been that the direct-acting agents -- which target viral replication -- might allow physicians to avoid the use of interferon, which modulates the immune system and has unpleasant and often intolerable side effects.
But the research presented here doesn't support that hope, according to Douglas LaBrecque, MD, of the University of Iowa in Iowa City, Iowa, who was not part of the study but who moderated the session at which the data were presented.
The combination "didn't show a major promise of eliminating the standard two drugs," he told MedPage Today. "It's not the holy grail."
The two drugs are GS-9256, a protease inhibitor, and GS-9190, a polymerase inhibitor. Both showed significant reductions in hepatitis RNA in phase I studies, Zeuzem said.
To extend the findings, Zeuzem and colleagues enrolled 46 patients with genotype 1 -- the most difficult to treat -- and randomized them to get the two drugs alone, with ribavirin, or with ribavirin and peginterferon for four weeks.
All patients then got ribavirin and peginterferon for 44 weeks, followed by six months of follow-up. Zeuzem presented efficacy and safety data for the first four weeks, where a "rapid virologic response" was defined as 25 or fewer international units of hepatitis C RNA per milliliter of serum.
At 28 days, the researchers found:
One of 15 patients getting the two drugs alone had a rapid virologic response.
Five of 13 patients getting both drugs, with the addition of ribavirin, had a rapid virologic response.
All 14 patients getting the two drugs, as well as ribavirin and peginterferon, had a rapid virologic response.
Zeuzem said the two direct-acting agents led to a rapid drop in hepatitis C RNA levels, but most patients rebounded within two weeks. But when ribavirin was added, the same rapid drop was observed and only a handful rebounded, while the addition of the fourth drug meant all patients responded, after a similar quick decline.
A key difference, he said, was that in the four-drug arm patients had such low levels of virus that it was impossible to perform the sequencing needed to identify resistance mutation against the two agents. In the three-drug arm, the same was true in 11 of 13 patients and the other two patients each had at least one resistance mutation.
On the other hand, 11 patients in the two-drug arm had two or more resistance mutations, two had a single mutation, and only two had virus levels so low that resistance sequencing was not possible.
Adverse effects were low in the two- and three-drug arms, but the addition of peginterferon introduced the gamut of side effects associated with the drug, Zeuzem said. Only one patient stopped therapy because of adverse events, he said.
There were two serious adverse events but only one -- a vasovagal collapse attributed to gastroenteritis -- was thought to be possibly linked to the study drug, in this case the four-drug regimen, he said.
Overall, the data are promising but need "much longer follow-up," LaBrecque told MedPage Today.
"It's too early to make too many conclusions," he told, especially when the main focus of the report was four-week data.
The study was supported by Gilead. Zeuzem reported financial links with Gilead, Intermune, Roche, Merck, Vertex, Human Genome Sciences, Abbott, BMS, Tibotec, Bayer, and Anadys.
Labrecque had no disclosures.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Zeuzem S, et al. "Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment naïve, genotype 1 HCV subjects" AASLD 2010; Abstract LB-1.
http://www.medpagetoday.com/MeetingCoverage/AASLD/23107
By Michael Smith , North American Correspondent,
MedPage TodayPublished: November 02, 2010
BOSTON -- Two direct anti-viral agents showed robust activity against hepatitis C in treatment-naive patients with the most refractory form of the virus, a researcher said here.
But the two drugs needed the standard medications -- ribavirin and pegylated interferon -- to get high response rates, according to Stefan Zeuzem, MD, of J.W. Goethe University Hospital in Frankfurt, Germany.
The findings come from a phase II randomized trial that tested the two drugs over a four-week period, followed by 44 weeks of ribavirin and interferon, Zeuzem told a late-breaker session at the annual meeting here of the American Association for the Study of Liver Diseases.
The hope has been that the direct-acting agents -- which target viral replication -- might allow physicians to avoid the use of interferon, which modulates the immune system and has unpleasant and often intolerable side effects.
But the research presented here doesn't support that hope, according to Douglas LaBrecque, MD, of the University of Iowa in Iowa City, Iowa, who was not part of the study but who moderated the session at which the data were presented.
The combination "didn't show a major promise of eliminating the standard two drugs," he told MedPage Today. "It's not the holy grail."
The two drugs are GS-9256, a protease inhibitor, and GS-9190, a polymerase inhibitor. Both showed significant reductions in hepatitis RNA in phase I studies, Zeuzem said.
To extend the findings, Zeuzem and colleagues enrolled 46 patients with genotype 1 -- the most difficult to treat -- and randomized them to get the two drugs alone, with ribavirin, or with ribavirin and peginterferon for four weeks.
All patients then got ribavirin and peginterferon for 44 weeks, followed by six months of follow-up. Zeuzem presented efficacy and safety data for the first four weeks, where a "rapid virologic response" was defined as 25 or fewer international units of hepatitis C RNA per milliliter of serum.
At 28 days, the researchers found:
One of 15 patients getting the two drugs alone had a rapid virologic response.
Five of 13 patients getting both drugs, with the addition of ribavirin, had a rapid virologic response.
All 14 patients getting the two drugs, as well as ribavirin and peginterferon, had a rapid virologic response.
Zeuzem said the two direct-acting agents led to a rapid drop in hepatitis C RNA levels, but most patients rebounded within two weeks. But when ribavirin was added, the same rapid drop was observed and only a handful rebounded, while the addition of the fourth drug meant all patients responded, after a similar quick decline.
A key difference, he said, was that in the four-drug arm patients had such low levels of virus that it was impossible to perform the sequencing needed to identify resistance mutation against the two agents. In the three-drug arm, the same was true in 11 of 13 patients and the other two patients each had at least one resistance mutation.
On the other hand, 11 patients in the two-drug arm had two or more resistance mutations, two had a single mutation, and only two had virus levels so low that resistance sequencing was not possible.
Adverse effects were low in the two- and three-drug arms, but the addition of peginterferon introduced the gamut of side effects associated with the drug, Zeuzem said. Only one patient stopped therapy because of adverse events, he said.
There were two serious adverse events but only one -- a vasovagal collapse attributed to gastroenteritis -- was thought to be possibly linked to the study drug, in this case the four-drug regimen, he said.
Overall, the data are promising but need "much longer follow-up," LaBrecque told MedPage Today.
"It's too early to make too many conclusions," he told, especially when the main focus of the report was four-week data.
The study was supported by Gilead. Zeuzem reported financial links with Gilead, Intermune, Roche, Merck, Vertex, Human Genome Sciences, Abbott, BMS, Tibotec, Bayer, and Anadys.
Labrecque had no disclosures.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Zeuzem S, et al. "Dual, triple, and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PegIFN/RBV for up to 28 days in treatment naïve, genotype 1 HCV subjects" AASLD 2010; Abstract LB-1.
http://www.medpagetoday.com/MeetingCoverage/AASLD/23107
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