November 9, 2011 (San Francisco, California) — An interferon-free regimen for the treatment of infection with hepatitis C virus (HCV) might soon be available, according to data from the ELECTRON trial, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.
In ELECTRON — 1 of 2 phase 2 studies of the investigational compound
PSI-7977 (Pharmasset) reported here — an interferon-free regimen of
PSI-7977 plus ribavirin achieved a 100% sustained viral response (SVR)
at 12 weeks in all study subjects. The second study, PROTON, was also reported here.
"PSI-7977 has the potential to dramatically change the treatment
paradigm for HCV," said lead study investigator Edward Gane, MD, from
Auckland City Hospital in New Zealand.
PSI-7977 is a uridine nucleotide analog polymerase inhibitor that is
administered once daily with or without food. It has demonstrated
robust activity in patients infected with HCV genotype 1 when used in
combination with pegylated-interferon and ribavirin after a 12-week
Activity with this agent used as a monotherapy has also been reported.
"The aim of the ELECTRON trial was to determine the shortest duration
of interferon, if any, required to achieve SVR when PSI-7977 plus
ribavirin are administered for 12 weeks," Dr. Gane explained.
ELECTRON investigators recruited 40 patients who were randomized to 1
of 4 treatment groups: PSI-7977 400 mg plus ribavirin for 12 weeks
plus interferon for 0, 4, 8, or 12 weeks.
Patients were treatment-naïve, noncirrhotic, infected with HCV
genotype 2 or 3, and stratified by interleukin (IL)28B single-nucleotide
polymorphisms (SNP) and HCV RNA levels. Mean age was 47 years and mean
baseline HCV RNA was 6.49 log10 IU/mL, with 42.5% exhibiting the CC genotype at the IL28B SNP.
"We selected a genotype 2/3 population because this represents a
population that would be more easily rescued with interferon in the
event of virologic breakthrough," Dr. Gane explained.
Results after treatment initiation were dramatic. "All patients
achieved a rapid virologic response, with over 80% being nondetectable
at 2 weeks," reported Dr. Gane.
All patients had undetectable HCV at 3 weeks; furthermore, all
patients achieved end-of-treatment response. No cases of treatment
resistance were observed.
"Even following cessation of interferon, or with no interferon, there
were no virologic breakthroughs on treatment." Also encouraging was
the fact that all patients in the study experienced a rapid
normalization of alanine aminotransferase.
There were no serious adverse events, and the mild to moderate events
observed were attributed to either interferon or ribavirin.
Significant improvements in safety and tolerability were seen in the
interferon-free treatment group. No safety signals for PSI-7977 were
observed, and there were no treatment-related discontinuations.
Results of the 12-week analysis prompted study investigators to add
an exploratory treatment group of open-label PSI-7977 monotherapy for 12
weeks (n = 10). "The response was the same as with combination
treatment with ribavirin," said Dr. Gane. Although this study is
ongoing, 6 of 10 patients have achieved SVR at 4 weeks.
"These data clearly demonstrate that PSI-7977 exhibits high potency
and has a high barrier to resistance," Dr. Gane said, noting that the
drug is being advanced in phase 3 investigations in all HCV genotypes.
Too Good to be True?
Michael Bernstein, MD, director of the hepatitis clinic at the Coney
Island Hospital, Brooklyn, New York, has doubts about PSI-7977. "If you
use it with ribavirin and no interferon, you get a 100% SVR; if you
use it alone, you get a 100% SVR."
Dr. Bernstein accepts the efficacy of PSI-7977 for the moment, but is
concerned that ELECTRON isn't powered to say much about the
tolerability or resistance profiles of the drug.
"What we've found with most of these [polymerase inhibitors] is that
if you use them by themselves, you get resistance; if you don't, they
can be very difficult to tolerate," said Dr. Bernstein. "There was a
drug being investigated at Mount Sinai — a polymerase inhibitor, NM286 —
and those patients got severe diarrhea and could not tolerate it.
According to the ELECTRON study, everything was perfect — no
gastrointestinal issues, no apparent adverse events of any kind, and it
worked 100% of the time without interferon, or ribavirin.... If it's true, it will be great. The holy grail is to try to rid HCV treatment regimens of interferon."
Although sincerely impressed, Dr. Bernstein, who has seen many drugs
come and go, suspects that as larger phase 3 trials of PSI-7977 are
conducted, polymerase-associated adverse events, tolerability issues,
and treatment resistance patterns will emerge.
Dr. Gane reports advisory board
relationships with Pharmasset, Gilead, Roche, Janssen-Cilag, and
Boehringer-Ingelheim. Dr. Bernstein has disclosed no relevant financial