By Michael Smith , North American Correspondent, MedPage Today
Published: November 02, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
BOSTON -- Combining the direct anti-viral agent telaprevir with standard hepatitis C care can sharply improve response rates and shorten the treatment period, researchers reported.
The findings -- from two major phase III trials encompassing more than 1,500 patients -- suggest that treatment of hepatitis C, which affects about two million Americans, is about to undergo a dramatic change, observers here said.
With standard care -- 48 weeks of ribavirin and pegylated interferon -- about 45% of patients with the most refractory form of the disease can expect a "sustained virologic response," defined as undetectable virus six months after the end of treatment.
But with the addition of the protease inhibitor telaprevir, that number can rise as high as 75%, according to the trial results, presented at the annual meeting of the American Association for the Study of Liver Diseases.
Moreover, in many cases, so-called "response-guided therapy" can cut the treatment period to 24 weeks, sharply reducing the exposure to interferon, which causes difficult and sometimes intolerable side effects.
The high response rates are "incredible, when you think about the time when we only had a 5% response rate (with interferon alone)," commented Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond, Va., who was not part of either study.
Sanyal, president of the AASLD, said other reports presented here suggest that a sustained virologic response is essentially a cure for the disease -- so that higher response rates make the battle against hepatitis C "winnable."
He told MedPage Today one of the barriers to that goal is diagnosis -- some 80% of people infected with hepatitis C are not aware of their condition.
The two clinical trials presented at the AASLD meeting had slightly different goals:
• The ILLUMINATE study compared two telaprevir-based regimens of 24 and 48 weeks duration, with the goal of showing the noninferiority of the shorter course. It was an open-label trial and all patients also got standard treatment with ribavirin and peginterferon.
• The ADVANCE study compared two telaprevir regimens -- of eight and 12 weeks -- with standard care alone; its goal was to show that either regimen would be as good as the other and could shorten the treatment period. The trial was randomized, double-blinded, and placebo-controlled during the telaprevir phases.
Telaprevir is a protease inhibitor aimed at the NS3-4A enzyme, which is needed for the hepatitis C virus to replicate. The drug is still not approved.
Illuminating Study Results
In the ILLUMINATE study, 540 patients new to treatment and infected with genotype 1 hepatitis C were treated with telaprevir, ribavirin, and peginterferon for 12 weeks, according to Kenneth Sherman, MD, PhD, of the University of Cincinnati College of Medicine, who presented the study at a late-breaker session.
Patients then had eight more weeks of ribavirin and peginterferon and, at week 20, those who had demonstrated undetectable virus at weeks four and 12 (a so-called "extended rapid virologic response") were re-randomized to get either four or 28 more weeks of the two drugs.
Patients who didn't have an extended rapid virologic response were also given an additional 28 weeks of standard therapy combining ribavirin and peginterferon, Sherman said.
Overall, 72% of the patients, on an intent-to-treat basis, had a sustained virologic response, Sherman reported.
But 65% of the patients also had an extended rapid virologic response and were randomized to a shorter or longer treatment course, he said. In that population, 92% of those treated for 24 weeks had a sustained virologic response, compared with 88% of those who had the longer course.
The difference was within a preset noninferiority margin, Sherman said.
The results were similar even after Sherman's team analyzed patient data according to the severity of disease or race and ethnicity, he said.
The most common adverse events were fatigue, pruritus, nausea, anemia, headache, and rash, and 17% of patients stopped all study drugs because of adverse events.
The ILLUMINATE study shows there's no clinical benefit in extending treatment with the three drugs -- as long as patients have an early and sustained virologic response, Sherman concluded.
The data "are certainly showing the best responses we've seen today for type 1 patients," said 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.
"It's another step forward," he told MedPage Today, "but it's not 100%."
LaBrecque also commented that the regimen does not do away with the use of interferon. "It's triple therapy, without question, but it's still a significant step forward," he said.
Advancing Hep C Treatment
The ADVANCE study also enrolled treatment-naive, genotype 1 patients, but they were randomized to three arms:
• Arm One patients were treated with telaprevir, ribavirin and peginterferon for 12 weeks, followed by 12 weeks of ribavirin and peginterferon alone. Those with an extended rapid virologic response stopped therapy, while lack of such a response meant another 24 weeks of ribavirin and peginterferon.
• Arm Two patients had eight weeks of triple therapy, followed by four weeks of placebo, ribavirin, and peginterferon. Again, an extended rapid virologic response stopped therapy, while lack of such a response meant another 24 weeks of standard care.
• Arm Three was the control arm. Patients were given standard treatment for 48 weeks, with a placebo to maintain blinding for the first 12.
The primary endpoint of ADVANCE was a sustained virologic response six months after the last planned dose, according to Ira Jacobson, MD, of the Weill Cornell Medical Center in New York City.
Overall, Jacobson and colleagues reported sustained virologic response rates among the more than 1,000 patients enrolled in the trial were as follows:
• 44% among control patients
•69% among those in Arm Two, who got eight weeks of telaprevir
• And 75% among those in Arm One, who got 12 weeks of telaprevir
• Both results were significantly different from controls at P<0.0001
In both telaprevir arms, slightly more than half of the ADVANCE patients (58% and 57%) had an extended rapid virologic response and were eligible to stop therapy at 24 weeks, Jacobson said.
Among those patients, he said, the sustained virologic response rates were 89% for the 12-week regimen and 83% for the eight-week course. In contrast, among those who took the full 48-week course, the rates were 54% and 50% respectively.
Among controls who had an extended rapid virologic response, 97% went on to have a sustained virologic response, Jacobson noted, but there were only 29 such patients. Among the 332 controls who did not have an early response, the sustained virologic response rate was 39%, he said.
As in the ILLUMINATE study, the researchers found high response rates among telaprevir patients regardless of severity of disease, race, or ethnicity, Jacobson said. The adverse event profile was also similar.
Telaprevir improved response rates compared with placebo, Jacobson concluded, but the 12-week regimen was slightly better. A majority of patients, he noted, were able to finish treatment in 24 weeks.
Both studies were co-sponsored by Vertex and Tibotec, which are developing telaprevir.
Sherman reported financial links with Anadys, Bristol-Myers Squibb, Merck, Roche, Schering-Plough, Valeant, and Vertex.
Jacobson reported financial links with Abbott, Roche, Genentech, Tibotec, Bristol-Myers Squibb, Novartis, Gilead, Progenics, Pfizer, GlobeImmune, Human Genome Sciences, Schering-Plough, March, Boehringer Ingelheim, Pharmasset, Zymogenetics, Vertex, and Anadys.
LaBrecque made no disclosures.
Sanyal reported financial links with Takeda, Salix, Ikaria, Exhalenz, Bayer Onyx, Norgine, Gore, Gilead, Intercept, Roche, and Astellas.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Sherman KE, et al "Telaprevir in combination with peginterferon alfa2a and ribavirin for 24 or 48 weeks in treatment-naïve genotype 1 HCV patients who achieved an extended rapid viral response: Final results of phase 3 ILLUMINATE study" AASLD 2010; Abstract LB-2.
Additional source: American Association for the Study of Liver Diseases
Source reference:
Jacobson IM, et al "Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study" AASLD 2010; Abstract 211.
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