By Michael Smith, North American Correspondent, MedPage Today
Published: June 22, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
The protease inhibitor, telaprevir (Incivek), markedly improved response rates in patients with difficult-to-treat hepatitis C virus (HCV) infection, compared with standard therapy, according to two studies reported in the June 23 issue of the New England Journal of Medicine.
The improvement was particularly dramatic among patients who had previously failed standard therapy, according to Stefan Zeuzem, MD, of Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, and colleagues.
In one arm of their REALIZE study, 88% of patients getting telaprevir, in combination with standard therapy, had a sustained virological response (SVR), defined as no detectable virus 24 weeks after the final treatment dose.
In contrast, just 24% of patients attempting standard therapy for a second time had a sustained response, Zeuzem and colleagues reported.
Only about 40% of patients with the most difficult-to-treat variety of HCV, the so-called genotype 1, respond to standard treatment with pegylated interferon alfa-2a and ribavirin.
But in the ADVANCE study, the second one in this issue of the journal, the rate of sustained virological response among treatment-naive patients was between 69% and 75%, depending on the exact regimen, according to Ira Jacobson, MD, of the Weill Cornell Medical College in New York City, and colleagues.
In contrast, just 44% of patients who got standard therapy had a sustained response, the researchers reported.
When the FDA approved the drug in May, a company spokesman told MedPage Today, the agency used a slightly different method of calculating SVR rates. As a result, the labeling for the drug says that in treatment-naive patients the best SVR rate is 79%.
Telaprevir is the second protease inhibitor to be approved for hepatitis C; earlier in May, the FDA okayed boceprevir (Victrelis).
In the REALIZE trial, researchers enrolled 663 patients with genotype 1 hepatitis C who had either not responded, had a partial response, or had relapsed after an initial response to standard therapy.
They were randomly assigned to three groups, Zeuzem and colleagues reported.
In the so-called T12PR48 group, patients got telaprevir for 12 weeks, along with peginterferon plus ribavirin, followed by peginterferon plus ribavirin alone for a total of 48 weeks of therapy.
In the "lead-in group" patients started with four weeks of peginterferon plus ribavirin followed by the T12PR48 regimen.
In the control group -- dubbed PR48 – patients were treated with peginterferon and ribavirin for 48 weeks.
The researchers found:
SVR rates among patients who had a previous relapse were 83% in the T12PR48 group, 88% in the lead-in group, and 24% in the control group.
Among those who had a previous partial response, the rates were 59%, 54%, and 15%, respectively.
In those who had not responded to their first therapy, the rates were 29%, 33%, and 5%, respectively.
The comparisons were all significant at P<0.001.
Grade three adverse events were mainly anemia, neutropenia, and leukopenia and were reported by 37% of patients in the telaprevir groups, compared with 22% in the control group.
But the most common side effects, reported by more than 25% of patients, were fatigue, pruritus, rash, nausea, influenza-like illness, anemia, and diarrhea.
The researchers were especially concerned about rash, because there have been reported cases of Stevens-Johnson syndrome among telaprevir patients. In this study, grade three rash, any skin event resulting in permanent discontinuation of study drugs, or any skin event defined as a serious adverse event occurred in 5% of patients in the two telaprevir groups, as compared with none in the control group.
The ADVANCE study, in 1,088 treatment-naive patients, also had a three-arm design, Jacobson and colleagues reported, although it was slightly more complicated.
As in the other trial, the control group was assigned to get peginterferon and ribavirin for 48 weeks, but with the addition of a placebo for the first 12 weeks.
In one active arm – dubbed T12PR – patients got all three drugs for 12 weeks, followed by peginterferon/ribavirin alone for 12 weeks if the virus was undetectable at weeks four and 12 or for 36 weeks if it was found at either point.
In the other arm, called T8PR, patients got all three drugs for eight weeks, followed by a placebo and peginterferon/ribavirin for four weeks. This was followed by either 12 or 36 weeks of peginterferon/ribavirin, based on the same criteria used in the T12PR group.
Jacobson and colleagues found:
SVR rate in the control group was 44%, comparable with rates previously seen with standard therapy.
SVR rate in the T12PR group was 75%, while the rate in the T8PR group was 69%. Both differences were significant from the control group at P<0.001.
58% of telaprevir patients responded early enough so that the treatment could be truncated to 24 weeks in total.
The researchers said the rates of nausea, diarrhea, pruritus, rash, and anemia were at least 10 percentage points higher in each of the telaprevir groups than in the control group.
Development of a rash caused 7% of patients in the T12PR group and 5% in the T8PR group to stop telaprevir, and 1.4% and 0.5%, respectively, to stop all treatment, Jacobson and colleagues reported.
Rashes were primarily eczema and were reversible with discontinuation of telaprevir, they said, noting that one case of Stevens–Johnson syndrome occurred about 11 weeks after the patient's last dose of telaprevir.
Both studies were supported by Tibotec and Vertex Pharmaceuticals. Several authors in both cases are employees of one of the companies.
Jacobson reported financial links with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Human Genome Sciences, Novartis, Pharmasset, Pfizer, Roche–Genentech, sanofi-aventis, Schering-Plough (now part of Merck), Tibotec, Vertex Pharmaceuticals, and ZymoGenetics,
Zeuzem reported financial links with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Human Genome Sciences, iTherX, Novartis, Pfizer, Pharmasset, Roche–Genentech, Santaris Pharma, Schering-Plough (Merck), Tibotec, and Vertex Pharmaceuticals.
Primary source: New England Journal of Medicine
Source reference:
Jacobson IM, et al "Telaprevir for previously untreated chronic hepatitis C virus infection" N Engl J Med 2011; 364: 2405-2416.
Additional source: New England Journal of Medicine
Source reference:
Zeuzem S, et al "Telaprevir for retreatment of HCV infection" N Engl J Med 2011; 364: 2417-2428.
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