By Michael Smith, North American Correspondent, MedPage Today
Published: April 29, 2013
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania
AMSTERDAM – A four-drug regimen was effective in hard-to-treat hepatitis C (HCV) patients who had previously failed therapy, a researcher said here, but the drug combination is not being further developed.
In a phase II study, 70% of patients had undetectable HCV virus 12 weeks after ending the so-called "quad regimen," according to Gregory Everson, MD, of the University of Colorado in Aurora.
The drug protocol consisted of an NS5A inhibitor dubbed ledipasvir and a protease inhibitor, GS-9451, along with pegylated interferon and ribavirin.
Among those who responded to the four-drug regimen quickly and persistently, the rate was even higher at 87%, Everson reported at the meeting of the European Association for the Study of the Liver.
But despite the promise of what he called a "re-treatment protocol," Everson said further development of the regimen is not in the cards.
He did not immediately respond to an email from MedPage Today seeking clarification, but other experts here suggest it may have to do with the perception that pegylated interferon and ribavirin are on the way out.
Meanwhile, ledipasvir and GS-9451 remain in clinical development, according to a spokesman for the developer, Gilead Sciences of Forest City, Calif.
The results of the trial "are not entirely unexpected," commented Heiner Wedemeyer, MD, of Hannover Medical School in Hannover, Germany, who was not involved with the study.
"This specific regimen is not being further developed," he said, but what investigators "learned is that if we add more potent drugs, we can treat more difficult patients. We confirmed that concept."
It seems likely, he said, that the two drugs will continue to be developed for use without interferon and perhaps ribavirin. "The question will be whether we can shorten treatment," Wedemeyer said.
Until 2011, standard therapy for HCV genotype 1 was 48 weeks of pegylated interferon with ribavirin, a regimen regarded as difficult to tolerate with a substantial proportion of treatment failures.
Current standard therapy adds a third drug, one of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis), but those medications have their own side effects and risks.
Patients who fail standard treatment – either relapsing or not responding in the first place – need better options, Everson said here.
He and colleagues tested the four drugs (ledipasvir, GS-9451, pegylated interferon, and ribavirin) in a response-guided fashion, enrolling 163 patients, including 52 who had not responded to previous therapy, 28 who had a partial response, and 83 who either relapsed or had viral breakthrough on treatment.
Patients who had undetectable viral RNA at weeks four through 20 of treatment stopped therapy after 24 weeks, while the others stopped ledipasvir and GS-9451 but continued the other two drugs for another 24 weeks.
The 70% rate of undetectable virus 12 weeks after the end of therapy (SVR12) indicated a "fairly robust antiviral effect," Everson said, and response during therapy was "highly predictive " of treatment success.
Among those who had a so-called extended rapid virologic response – no detectable virus from weeks four through 20 – the SVR12 rate was 87%, compared with just 28% among those who did not have such a response.
Everson said that patients with genotype 1b did better than those with genotype 1a, while those with the favorable CC variant of the IL-28B gene did better than those with other versions.
He added that 5% of patients had a serious adverse event during the study and 7.3% stopped treatment because of adverse events, all attributed to the interferon or ribavirin.
The overall pattern of adverse events, he said, was "typical" of what is seen with the two older drugs.
The study was supported by Gilead. Everson reported financial links with the company as well as BMS, Abbott, Roche/Genentech, Vertex, Merck/Schering-Plough Novartis, Janssen/Tibotec, GSK, Eisai, and BioTest.
Wedemeyer reported financial links with Abbott, Achillion, Biolex, BMS, Gilead, Janssen-Cilag, Merck, Novartis, Roche, Siemens, Transgene, and ViiV.
Primary source: European Accociation For the Study of the Liver
Everson GT, et al "Combination of the NS5A inhibitor, GS-5885, the NS3 protease inhibitor, GS-9451, and pegylated interferon plus ribavirin in treatment experienced patients with genotype 1 hepatitis C infection" EASL 2013; Abstract 13.