Daniel M. Keller, PhD
April 30, 2012 (Barcelona, Spain) — In 3 phase 2 trials of GS-7977, there was a concordance between the sustained virologic response (SVR) 4 weeks after the end of therapy (SVR4) and SVRs at 12 and 24 weeks after therapy (SVR12 and SVR24) in treatment-naive patients infected with hepatitis C virus (HCV) genotypes 1, 2, or 3.
No patient relapsed after posttreatment week 12, and 99% of patients with SVR4 for whom posttreatment week 12 data were available achieved SVR12, Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas, reported here at the International Liver Congress 2012.
GS-7977 (formerly PSI-7977) is a specific nucleotide analogue inhibitor of HCV NS5B RNA polymerase and is taken orally once daily. Previous reports have shown that it has broad antiviral activity against HCV genotypes 1, 2, and 3, with or without interferon, in treatment-naive patients, and has a high barrier to the development of viral resistance.
The aim of the study was to evaluate concordance between SVR4 and SVR12 or SVR24 among treatment-naive patients taking GS-7977 400 mg daily in the PROTON (n = 144), ELECTRON (n = 120), and ATOMIC (n = 332) phase 2 clinical trials. The trial protocols differed somewhat, but in general were various combinations and durations of GS-7977, pegylated interferon (Peg-IFN), and ribavirin.
In the PROTON and ATOMIC trials, depending on viral genotype, patients received GS-7977 plus Peg-IFN/ribavirin for 12 weeks followed by Peg-IFN for 12 weeks, Peg-IFN/ribavirin alone for 48 weeks, GS-7977 plus Peg-IFN/ribavirin for 12 or 24 weeks, GS-7977 plus PegIFN/ribavirin for 12 weeks followed by 12 weeks of GS-7977 alone or by GS-7977 plus ribavirin.
In the ELECTRON trial, some patients with genotypes 2 or 3 virus received similar combinations but only out to 12 weeks. Other patients with genotypes 1, 2, or 3 received GS-7977 plus ribavirin for 12 weeks.
The analysis involved only patients treated with GS-7977 400 mg in combination with interferon, ribavirin, or both for at least 4 weeks who had SVR4 plus SVR12 or SVR4 plus SVR24 data available. Of the 596 patients in the 3 studies, 259 (43%) were eligible for analysis.
At baseline in all treatment groups, mean age ranged from 43 to 52 years, and most patients were white, male, had similar body mass indices (mean, 26 to 28 kg/m²), and had interleukin-28B genotype non-CC. Mean baseline HCV RNA levels were mainly in the range of 6.3 to 6.7 log10 IU/mL.
Dr. Lawitz presented results for virologic response at the end of therapy and for SVR4, SVR12, and SVR24.
"If we look at all regimens and look at the concordance between SVR4 and SVR12, we can see that 249 of the 251 [patients] were concordant between SVR4 and SVR12 — a concordance rate of 99%," he said. "If we look at concordance between SVR4 and SVR24, we can see that although the numbers are smaller, there is complete concordance — all 107 patients who had an SVR4 achieved an SVR24.... The concordance held, irrespective of the presence or absence of interferon. However, the dataset is fairly small in the noninterferon arm, limiting conclusions."
Dr. Lawitz concluded that "much of the concordance is due to the high response rates observed across all treatment groups. To date, relapse after week 4 is infrequent and was only observed in patients who received a peg-interferon-containing regimen."
Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital, in Athens, Greece, and a member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that GS-7977 "is a very interesting, very promising molecule. It seems to be rather safe and very effective, even in combination with ribavirin." Dr. Papatheodoridis was not involved in any of the studies.
In terms of new drugs to treat HCV, he said, "some of the new molecules are very genotype-specific.... Most of the protease inhibitors are developed to work only for genotype 1; some of them work for genotype 2, but not 3 and 4. The nucleoside polymerase inhibitors seem to work better across almost all genotypes, so this is the only class [of drug] that is not that genotype-specific."
Dr. Papatheodoridis wondered about the use of SVR4 as a standard efficacy measure. "I don't think that SVR4 will and should be the standard for SVR," he told Medscape Medical News. "Of course, we know that the FDA and most of the physicians have now accepted SVR12. So probably...SVR12 is going to be the standard for reporting trials in the near future. Still, with all these combinations, patients should have at least 1 examination, maybe 6 months or 12 months after SVR12, so we can be sure that this SVR remains over time. I think that SVR12 is going to be the standard from now on, but the patients treated with the new regimens should be followed for a bit longer."
He admitted that SVR4 looks predictive of later sustained responses. "You expect most of the patients to relapse soon after stopping treatment [if they are going relapse]. Of course, SVR4 is reasonable; we know and we expect that it is going to be associated with SVR12 and SVR24. There is no rush to decide the SVR just 4 weeks after treatment.... We should be sure that we eradicated the virus," he cautioned.
Dr. Lawitz reports financial relationships with Abbott, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, sanofi-aventis, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics. Dr. Papatheodoridis has disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 7. Presented April 19, 2012.