By Michael Smith, North American Correspondent, MedPage TodayPublished: November 08, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.
Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Explain that PSI-7977, an investigational drug with direct antiviral activity in hepatitis C virus (HCV) infection, was found to suppress virus in treatment-naive infected patients when combined only with ribavirin, leaving the usual pegylated interferon out of the regimen.
Note that the interferon-free group only included 10 patients and that all of the patients had the easier to treat HCV genotypes 2 and 3 rather than genotype 1.
SAN FRANCISCO -- Treatment with an investigational hepatitis C drug allowed investigators to dispense with an old stand-by -- pegylated interferon-alpha.
The compound, dubbed PSI-7977, is a nucleotide analog that directly targets viral polymerase and has yielded good responses in patients with all three major genotypes of hepatitis C, according to Edward Gane, MD, of Auckland City Hospital in Auckland, New Zealand.
In previous studies, it has been tested – as with most of the new direct antiviral agents – in combination with pegylated interferon and ribavirin, Gane reported here at the annual meeting of the American Association for the Study of Liver Diseases.
Results have been promising, with sustained virologic response rates above 90%, and observers are watching the compound with great interest as it moves into more advanced clinical trials.
But in a small phase II study conducted in New Zealand, Gane and colleagues asked whether interferon was actually necessary. To find out, they enrolled 40 patients with genotype 2 and 3 virus and randomly assigned them to one of four arms in which the duration of interferon treatment varied from 12 weeks – the full length of the trial – to none at all.
The other component of standard therapy – ribavirin – was given to all patients throughout the 12-week trial.
The researchers selected genotypes 2 and 3 because they are easier to treat than genotype 1, offering the possibility of "rescue" with interferon and ribavirin if the treatment failed, Gane said.
The primary endpoint was sustained virologic response – undetectable hepatitis C RNA -- at week 12.
But, regardless of the length of interferon treatment, the researchers found that 100% of the patients reached a sustained virologic response at week 12, Gane said. Moreover, all of the patients who have been followed for 24 weeks continue to show a 100% response rate.
The combination of interferon and ribavirin was standard of care for several years; the drugs were thought to work by stimulating the immune system, rather than attacking the virus itself. But interferon is associated with a range of adverse events, including flu-like symptoms and neutropenia, which make the standard treatment difficult.
Recently, new agents have been developed, which target aspects of the virus itself, but the two that are approved – telaprevir (Incivek) and boceprevir (Victrelis) – are only used against the difficult-to-treat genotype 1 and are given in combination with interferon and ribavirin.
As a result of the study, Gane said PSI-7977 will be moved into phase III trials in combination only with ribavirin, leaving interferon on the shelf.
Gane said leaving interferon out resulted in improvements in safety and tolerability. In particular, there were no hematologic abnormalities in the interferon-free arm, there was a minimal impact on hemoglobin, and liver enzymes became normal within three weeks of taking PSI-7977 without interferon.
The drug is being watched with "great enthusiasm" as it moves into phase III trials, according to Joseph Lim, MD, of Yale University, who was not part of the study but who was one of the moderators of the session at which it was presented.
PSI-7977 is "one of the most potent compounds studied to date" for the treatment of hepatitis C, Lim told MedPage Today, "and it clearly has the potential to transform the treatment paradigm, not only for genotype 1 but for all genotypes."
It has – at least according to studies conducted so far – some very attractive properties as an agent that acts directly on the virus, he said: it works on all genotypes, it has a high barrier to resistance, and so far there have been no signs of virologic breakthrough when it's used.
But Lim cautioned that the study Gane presented has an "incredibly small" sample size so that few conclusions can be drawn about efficacy and safety. Among other things, he noted, researchers remember that earlier compounds in the same class faltered in larger studies because of serious liver toxicity and neutropenia.
Another study of the drug presented here showed similar results in patients with the hard-to-treat genotype 1 of the virus, although, in this case, PSI-7977 was given in combination with both peg-interferon and ribavirin.
The proportion of patients achieving a sustained virologic response at week 12 was 91%, according to Eric Lawitz, MD, of Alamo Medical Research in San Antonio, Texas, and the safety profile of the drug was similar to that of interferon and ribavirin alone.
The studies were supported by Pharmasset. Gane reported financial links with the company , as well as with Gilead, Riche, Janssen-Cilag, and Boehringer-Ingelheim. Lawitiz reported financial links with Abbott Laboratories, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers 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 ZymoGenetics.
Lim reported financial links with Bristol-Myers Squibb, Vertex, Merck, Tibotec, GlobeImmune, GSK, and Zymnogenetics.
Primary source: Hepatology
Source reference:
Gane EJ, et al "Once daily PSI -- 7977 plus RBV: pegylated interferon -- ALFA not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3" Hepatology 2011; 54(4): Abstract 34.
http://www.medpagetoday.com/MeetingCoverage/AASLD/29518
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