Daniel M. Keller, PhD
May 2, 2012 (Barcelona, Spain) — Twelve weeks of GS-7977 (Gilead Sciences) plus pegylated interferon (pegIFN) and ribavirin was as effective as 24 weeks of treatment in eliminating hepatitis C virus (HCV) genotype 1.
In the phase 2 ATOMIC trial, the drug was found to be safe and well tolerated, according to Kris Kowdley, MD, director of the Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, and clinical professor of medicine at the University of Washington in Seattle, who reported the interim results here at the International Liver Congress 2012.
GS-7977 is a potent oral nucleotide analogue inhibitor of HCV NS5B RNA polymerase that has a high barrier to the development of viral resistance. In another trial (PROTON), 12 weeks of GS-7977 in combination with pegIFN/ribavirin followed by 12 weeks of pegIFN/ribavirin was associated with a sustained virologic response (SVR) rate of 91% at 12 (SVR12) and 24 weeks (SVR24) after the end of therapy in patients infected with HCV genotype 1. In light of those results, the aim of the ATOMIC trial was to see if only 12 weeks of therapy could achieve similar results.
In the ATOMIC trial, treatment-naive patients chronically infected with HCV genotype 1 were randomly assigned to 1 of 3 treatment groups: GS-7977 plus pegIFN/ribavirin for 12 weeks (n = 52), GS-7977 plus pegIFN/ribavirin for 24 weeks (n = 125), or GS-7977 plus pegIFN/ribavirin for 12 weeks followed by 12 weeks of GS-7977 alone (n = 75) or in combination with pegIFN/ribavirin (n = 75).
Participants were predominantly white, male, about 50 years of age, had HCV RNA levels of at least 50,000 IU/mL, and had adequate hematologic values. The treatment groups were generally well matched for baseline characteristics.
Drug Combination Yields Rapid and Sustained Virologic Response
In all treatment groups, there was rapid viral suppression over the first 2 weeks of therapy, regardless of interleukin-28B genotype. At the end of treatment, 98% to 99% of patients in each group had achieved HCV RNA levels below the limits of detection, and 92% to 94% achieved a sustained virologic response at 4 weeks (SVR4).
An SVR12 of 90% was achieved in all treatment groups. At the time of the presentation, SVR12 data were available for only some of the patients treated with GS-7977 plus pegIFN/ribavirin for 12 weeks, When only those patients were included, an SVR12 of 94% was achieved, "suggesting that this is a very effective and successful combination," Dr. Kowdley said.
"In fact, when we examined the reasons for failure to achieve an SVR, in most cases it was because of a lack of follow-up rather than because of virologic failure or relapse," he reported. Only 4 patients in the 3 groups experienced a relapse at the SVR4 time point. In the 4 patients who relapsed, no S282T resistance mutations have been detected in the viral NS5B RNA polymerase.
GS-7977 plus pegIFN/ribavirin was generally well tolerated. Less than 5% of patients discontinued the study because of adverse effects related to GS-7977. Most adverse effects were constitutional symptoms generally associated with pegIFN/ribavirin. Neutrophil and lymphocyte counts and hemoglobin and alanine aminotransferase levels quickly improved after pegIFN/ribavirin was discontinued.
Dr. Kowdley concluded that 12 weeks of GS-7977 in combination with pegIFN/ribavirin appears to be as effective as 24 weeks of the same therapy.
Session moderator Mark Thursz, MBBS, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the European Association for the Study of the Liver, who was not involved in the ATOMIC trial, said during a news conference that SVR24, an absence of viremia for 6 months after the end of treatment, has been the standard definition of cure until recently. Now, "we've started to become used to SVR12 as an end point. I understand that the FDA [US Food and Drug Administration] is now interested in SVR12 if it can be subsequently established as meaning a cure," he said.
"Now the companies are coming to us with SVR4 data.... SVR4 certainly predicts the final outcome. It may not be quite the same as the cure rate, the SVR24 rate, but it's pretty close and gives us a very good indication," Dr. Thursz explained. The implication is that when abstracts are submitted to meetings, "SVR4 is something that we have to take seriously...whereas previously we would regard [the results] as merely interim data," he said.
He told Medscape Medical News that the program for the development of GS-7977 is "progressing very rapidly. I know that Gilead [the drug's manufacturer] is looking at what the best option is" to get the drug approved and available to patients as quickly as possible. He said that some reports suggest that Gilead could file for approval with the FDA in late 2013, with the potential for approval in 2014.
Dr. Kowdley reports being a consultant/advisor for Novartis, Vertex, Pharmasset, Merck, and Abbott; and receiving grants and research support from BMS, Intercept, Abbott, Pharmasset, Merck, Gilead, GSK, Mochida, Conatus, Boeringer Ingelheim, and Genentech. Dr. Thurzs has disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 1. Presented April 19, 2012.