Pharmasset trial results from AASLD liver Meeting

I know people have posted on this trial before but I wanted to provide the latest info as there are a couple on interesting points regarding the trial because it mentions but Pros and Cons.
* 100% effective in patients with the interleukin (IL)28B T/T mutation all became HCV-negative by week 3
* Phase 2 trial with generally healthy patients. Little fibrosis man IL28B CC patients 41%
* Further phase 3 trials will revel the true efficacy of the drug.
* Mauricio Lisker-Melman, MD, director of the hepatology program at the University of Washington, St. Louis, Missouri says interferon free treatment could be available with 5 years.
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"New Once-daily HCV Drug Overcomes Poor Interferon Response"

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.

Cheers!
Hector

[printze]

Interesting, I hope they get it soon , for eveyone with this disease throw in a c=vaccine while they are at it .

[sandysf]

Very encouraging news!

[curiouslady1]

Thank you very much for this Hector.  I wish we had a special place on this forum for information like this so that people would be able to compare trials and study results easily without getting themselves confused moving about the forum and the internet (also because sometimes search elements don't work?)

[UKgirl55]

I agree. I find this forum very confusing and difficult to navigate.

[Aquisi]

Thank you Hector, exciting news for people that can wait for tx. You provide wonderful service for us on this forum.

[susan400]

Thank-you Hector, I've been keeping my eye on the Pharmasset, hoping it continues on through later phase w/o any set backs.  I'm hoping to be able to get into a later trial, if they can agree to allow protease inhibitor failure patients to participate.  Susan400