Neil Canavan

November 10, 2011

November 10, 2011 (San Francisco, California) — The new once-daily oral medication PSI-7977 (Pharmasset), in combination with the standard regimen of pegylated interferon and ribavirin for patients infected with hepatitis C virus (HCV), cut the time for complete viral clearance in half, compared with interferon and ribavirin alone. In addition, the investigational agent was 100% effective in patients with the interleukin (IL)28B T/T mutation that has been associated with a poor response to interferon. These findings, from the PROTON trial, were presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.

PROTON was 1 of 2 phase 2 studies of this investigational compound reported here

PSI-7977 plus interferon/ribavirin shows "a rapid and complete suppression in 95% of patients," said PROTON lead investigator Eric Lawitz, MD, from Alamo Medical Research in San Antonio, Texas.

PSI-7977, a uridine nucleotide analog polymerase inhibitor that is administered once daily with or without food, has previously shown activity in a broad range of HCV patient genotypes. There have been no drug-related viral breakthroughs reported to date, demonstrating a high barrier to resistance.

PROTON was a double-blind placebo-controlled dose-ranging phase 2 study that enrolled 121 treatment-naïve patients with HCV genotype 1. Participants were 18 years or older, with an HCV RNA level of at least 50,000 IU/mL, a platelet count above 90,000/mm3, a hemoglobin level of at least 11 g/dL, and no evidence of cirrhosis.

Subjects were randomized in a 2:2:1 ratio to 1 of 3 treatment groups: 12 weeks of interferon/ribavirin plus PSI-7977 200 mg, PSI-7977 400 mg, or placebo. All patients then received 12 weeks of interferon/ribavirin, and those who had still not achieved a rapid viral response received another 24 weeks of interferon/ribavirin.

"Duration of therapy was response-guided," said Dr. Lawitz. "Those who achieved rapid viral response discontinued therapy at 24 weeks, and those who did not continued for a total of 48 weeks." The control group consisted of the interferon/ribavirin standard combination for 48 weeks.

At baseline, median age was 51 years, 15% self-identified as black and 10% as Hispanic, median HCV load was 6.6 log IU/mL, median body mass index was 28 kg/m2, roughly 95% had mild fibrosis (F0 to F2), and 41% of the cohort had the IL28B C/C genotype.

Results showed a dramatic improvement with the triple drug combination, compared with placebo.

"The rapid viral response for the 200 mg dose was 98%, with an end-of- treatment response at 24 weeks of 91%," reported Dr. Lawitz. The same response rate was seen with the 400 mg dose. In the placebo group, the rapid viral response was 19%, and end-of-treatment response was 50%. The reported sustained viral response at 12 weeks was 88% for the 200 mg group, 91% for the 400 mg group, and roughly 40% for the placebo group (an estimate because observation is ongoing).

Significantly, a subanalysis of patients with the difficult-to-treat IL28B T/T mutation (n = 13) showed that "all had a rapid response and all became HCV-negative by week 3," said Dr. Lawitz.

These cohorts went on to achieve a 100% sustained viral response.

There were several failures reported. In the 200 mg group, 3 patients experienced viral breakthrough during the 12 weeks of interferon/ribavirin treatment immediately after the discontinuation of PSI-7977, and 1 patient relapsed at the end of treatment. "In contrast, in the 400 mg arm, there were no breakthroughs, suggesting that the 400 mg dose achieved a deeper viral suppression," said Dr. Lawitz. "There was 1 failure prior to [a sustained viral response at 4 weeks], but this was not due to any S282T resistance mutation."

The adverse events reported in the PROTON trial were typical of those seen with interferon/ribavirin treatment, with the single exception of a modest increase in the incidence of insomnia in the PSI-7977 treatment groups. No serious hematologic events were reported, and no dose-related changes in event rates were observed.

Optimism for the Novel Drug, With Caveats

"Part of the problem of working with a new product is all the unanswered questions due to the size of early trials," said Mauricio Lisker-Melman, MD, director of the hepatology program at the University of Washington, St. Louis, Missouri. What are the potential adverse effects of this medication that will only emerge with a larger dataset? How do these data translate into the community setting?

"There is a significant group of patients in my practice who have cirrhosis that may be more prone to develop some of the side effects," said Dr. Lisker-Melman, noting that patients with cirrhosis were excluded from PROTON.

"We should be very careful, especially when we analyze effects on the bone marrow — anemia, thrombocytopenia, and other complications related to these new targeted inhibitors," Dr. Lisker-Melman cautioned. "That's why analyzing different subgroups of patients is so important."

Dr. Lisker-Melman is also concerned that the racial make-up of PROTON did not reflect what he and others see in the clinic; responses to HVC medications have been found to vary widely by race.

"Don't get me wrong — it's a great study, a great beginning. The sister study, ELECTRON, just presented here, suggested that we can even be successful without the use of interferon. That offers a lot of hope," he said.

With these data and the results from other drugs in development for HCV infection, Dr. Lisker-Melman predicts that an interferon-free HCV regimen is less than 5 years away.

Dr. Eric Lawitz reports relationships with Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Meyers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck & Co, Novartis, Pharmasset, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec, Vertex Pharmaceuticals, ViroChem Pharma, and Zymogenics. Dr. Mauricio Lisker-Melman has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting: Abstract 225. Presented November 8, 2011.

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