PSI-7977 plus ribavirin -A 'Newer' Era of HCV Therapy Begins?

Related Dec 16th--Experimental Hepatitis C Drug PSI-938 Halted In Clinical Trial
--Use of PSI-938 halted in clinical trial due to liver-related abnormalities
--Studies of lead hepatitis C candidate, PSI-7977, continue


A 'Newer' Era of HCV Therapy Begins?

Dawning of Another New Era
In an editorial appearing in the New England Journal of Medicine ^[1] in March of this year, Jensen suggested that a new era of therapy for hepatitis C virus (HCV) infection was dawning with the development of 2 effective protease inhibitors -- telaprevir and boceprevir. These direct-acting antiviral (DAA) agents, used in combination with peginterferon and ribavirin, were shown to be effective in patients infected with HCV genotype 1. Now an even newer era may be on the horizon!

New Compounds, New Hope

Several investigational drug trials were presented at The Liver Meeting 2011 -- the annual meeting of the American Association for the Study of Liver Diseases. Two groups reported the apparently remarkable preliminary results of an investigational agent for the treatment of infection with HCV.^[2,3] An interferon-free regimen of PSI-7977 plus ribavirin achieved strikingly high rates of sustained viral response (SVR); this drug offers the potential solution to a long sought after goal -- the ability to delete noisome interferon injections from treatment strategies.
PSI-7977 is a uridine nucleotide analog polymerase inhibitor that is administered orally once daily. This agent has previously demonstrated robust activity in patients infected with HCV genotype 1 when used in combination with pegylated-interferon and ribavirin, and activity when used as a monotherapy has also been reported.
Promising Antiviral Activity

Two phase 2 studies of this investigational compound were presented at The Liver Meeting 2011.
The aim of the first (ELECTRON) trial was to determine the shortest duration of interferon, if any, that was required to achieve SVR when PSI-7977 plus ribavirin are coadministered.^[2] Forty treatment-naive, noncirrhotic patients infected with HCV genotype 2 or 3were randomly assigned to receive PSI-7977 400 mg plus ribavirin for 12 weeks -- this was combined with either no interferon or interferon for 4, 8, or 12 weeks. All patients achieved a rapid virologic response (RVR); more then 80% had nondetectable HCV RNA at 2 weeks and all patients had undetectable levels at 3 weeks. All patients achieved an end-of-treatment (ETR) response and normalization of alanine aminotransferase levels. No serious adverse events were attributed to PSI-7977, and as expected, safety and tolerability were highest in the interferon-free treatment group. Buoyed by these results, the investigators carried out a small trial of open-label PSI-7977 monotherapy for 12 weeks; the response rates were similar to the combination therapy results.
A similar study (PROTON), a double-blind, placebo-controlled, dose-ranging study of PSI-7977, enrolled 121 treatment-naive patients with HCV genotype 1.^[3] Patients were randomly assigned to receive either 12 weeks of interferon/ribavirin plus PSI-7977 (200 mg or 400 mg), or placebo. Duration of therapy was response guided. The control group received the interferon/ribavirin standard combination for 48 weeks. The RVR for the 200 mg and the 400 mg dose was 98%, with an ETR at 24 weeks of 91%. The RVR in the placebo group was 19%, and the ETR was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3 and 100% went on to achieve an SVR.
The studies suggest that PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes and has a high barrier to resistance; the agent reduced the duration of therapy for HCV clearance in half. The impact may be significant -- offering a shorter, interferon-free regimen that is effective even in difficult-to-treat patients. A newer era indeed!
The potent antiviral efficacy in association with a promising safety profile, support the continued exploration of PSI-7977 with abbreviated interferon duration, as monotherapy, or with other DAA in patients with all HCV genotypes. These further studies will hopefully confirm this optimism and document the spectrum of potential adverse effects of this drug.

References

1. Jensen DM. A new era of hepatitis C therapy begins. N Engl J Med. 2011;364:1272-1274.
2. Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: pegylated interferon-ALFA not required for complete rapid viral response in treatment-naïve patients with HCV GT2 or GT3. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, MA. Abstract 34.
3. Lawitz E, Lalezar JP, Hassanein T, et al. Once-daily PSI-7977 plus Peg/RBV in treatment-naïve patients with HCV GT1: robust end of treatment response rates are sustained post-treatment. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, MA. Abstract 225.

Source-Medscape