Pharmasset's PSI 7977

Terms used in these reports:

• RVR (Rapid virological response)= No virus detected at week 4
• eRVR(Extended rapid virological response) = No virus detected at week 4 and week 12
• EVR (Early Virological Response) — 2 log drop of HCV RNA after 12 weeks.
• cEVR = Complete Early Virological Response — No virus detected after 12 Weeks.
• SVR12 (Sustained virological response) = No virus detected at 12 weeks after completion of treatment.
• SVR24 = No virus detected at 24 weeks after completion of treatment.

Pharmasset are developing a new drug for the treatment of hepatitis C that may be taken without Interferon. This would mean an all oral (in the form of pills) treatment that would be taken with Ribavirin. The drug is a polymerase inhibitor and its development name is PSI – 7977. The latest research is very promising and is seeing a 100% success rate within 12 weeks in patients with genotypes 2 and 3.

Research is also being conducted to discover its effectiveness in patients with genotype 1. This is being done with Interferon and Ribavirin and current research is showing a 91% cure rate.

As with all drugs it will have to go through rigorous research and safety procedures before it is licensed but if it is successful we are hoping to see availability of this drug possibly in 2014.

A copy of a press release for PSI -7977 that was unveiled at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) is below.

An all-oral dual regimen containing Pharmasset's hepatitis C virus (HCV) polymerase inhibitor PSI-7977 plus ribavirin produced 100% sustained response at 12 weeks in previously untreated people with HCV genotypes 2 or 3, according to findings from the ELECTRON study reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) in San Francisco.

With the approval in spring 2011 of the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek), direct-acting antiviral agents (DAAs) have begun to revolutionise hepatitis C treatment. Until recently, however, most clinical trials have combined investigational DAAs with pegylated interferon/ribavirin standard therapy, which has suboptimal effectiveness and causes side effects that lead many potential patients to delay or refuse therapy.

But several companies are now studying interferon-free oral regimens that combine DAAs that target different steps of the viral lifecycle; some also include ribavirin.

PSI-7977, a uridine nucleotide analog HCV polymerase inhibitor, has previously demonstrated promising safety and antiviral activity alone and in combination with standard therapy in people with HCV genotypes 1, 2, and 3.

Edward Gane from the New Zealand Liver Transplant Unit in Aukland and colleagues sought to determine whether and for how long pegylated interferon should be taken with PSI-7977 and ribavirin to produce the best outcomes.

A total of 40 participants with chronic hepatitis C received 400 mg PSI-7977 once-daily plus ribavirin for 12 weeks. In addition, they were randomly assigned to take pegylated interferon alfa-2a (Pegasys) for 4, 8, or 12 weeks, or not at all.

Because the researchers were uncertain whether the 2 oral drugs alone would work, they chose a population of relatively easy-to-treat patients who could be most easily "rescued" if the experimental regimen failed: treatment-naive people with HCV genotypes 2 (about one-third) or 3 (about two-thirds), and no cirrhosis; about 40% also had the favorable IL28B CC genotype. A majority were men, most were white, and the average age was about 48 years; concurrent use of methadone maintenance was allowed.

Results

• By week 4, all participants receiving PSI-7977 achieved HCV suppression below the limit of detection (15 IU/mL), regardless of pegylated interferon duration
• All patients maintained undetectable HCV viral load at the end of PSI-7977 administration at week 12.
• All participants went on to achieve sustained virological response -- or continued undetectable HCV after the end of therapy -- at both 12 and 24 weeks post-treatment (SVR12 and SVR24, respectively).
• HCV viral kinetics did not differ between people receiving and not receiving pegylated interferon.
• No viral breakthrough was observed in any group, confirming that PSI-7977 has a high barrier to resistance.
• All participants receiving the PSI-7977 interferon-free regimen experienced ALT normalisation.
• PSI-7977 plus ribavirin was general well-tolerated.
• Serious adverse events were most frequent in the 12-week pegylated interferon arm and least frequent in the interferon-free arm (72% vs 40%, respectively.
• No serious (grade 3 or 4) laboratory abnormalities, including blood cell deficiencies, were reported in the interferon-free arm.
• Use of ribavirin was still associated with anaemia, but less so in the interferon-free arm.

"Potency, high barrier to resistance, and safety/tolerability allows interferon-free cures," the researchers concluded. "PSI-7977 has the potential to dramatically change the treatment paradigm for HCV in all genotypes and populations."

Gane noted that Pharmasset is now enrolling additional cohorts to look at interferon-free PSI-7977/ribavirin regimens in prior non-responders with genotypes 2 or 3, treatment-naive people with genotype 1, and prior null responders with genotype 1.

In light of these findings, the researchers asked what is the role of ribavirin. In an exploratory analysis, 10 patients received open-label PSI-7977 monotherapy. In this group HCV viral kinetics were "identical" with or without ribavirin, Gane said. No viral breakthrough was observed and 6 had sustained response up to 4 weeks after completing treatment. PSI-7977 monotherapy studies are also underway.

Pharmasset and Bristol-Myers Squibb announced this week that they are adding new trial arms looking at various 12-week, once-daily dual regimens combining PSI-7977 plus the investigational NS5A inhibitor daclatasvir (BMS-790052).

Investigator affiliations New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand; Gastroenterology Department, Christchurch Hospital, Christchurch, New Zealand; Pharmasset, Inc, Princeton, NJ.

11/8/11

The genotype 1 analysis included 121 treatment-naive patients. Approximately half were men, the median age was about 50 years, about 75% were white, 20% were black, and 10% were Hispanic. About 75% had HCV subtype 1a and about 40% had the favorable IL28B CC gene pattern; people with liver cirrhosis were excluded.

Participants were randomly assigned to receive 200 mg or 400 mg once-daily PSI-7977 plus pegylated interferon/ribavirin for 12 weeks, continuing on pegylated interferon/ribavirin alone for another 12 weeks. At that point, those with extended rapid virological response (eRVR) stopped treatment, while non-eRVR patients continued on a pegylated interferon/ribavirin "tail" through week 48. A control arm received pegylated interferon/ribavirin standard therapy for 48 weeks.

Results

• All participants receiving either dose of PSI-7977 experienced rapid HCV viral load suppression.
• Rapid virological response (RVR), undetectable HCV RNA at week 4:
• 98% of patients receiving 200 mg PSI-7977 + pegylated interferon/ribavirin;
• 98% of patients receiving 400 mg PSI-7977 + pegylated interferon/ribavirin;
• 19% of patients receiving pegylated interferon/ribavirin alone.

End-of-treatment response at week 12:

• 91% of patients receiving 200 mg PSI-7977 + pegylated interferon/ribavirin;
• 91% of patients receiving 400 mg PSI-7977 + pegylated interferon/ribavirin;
• 50% of patients receiving pegylated interferon/ribavirin alone.

SVR12:

• 88% of patients receiving 200 mg PSI-7977 + pegylated interferon/ribavirin;
• 91% of patients receiving 400 mg PSI-7977 + pegylated interferon/ribavirin;
• Patients receiving pegylated interferon/ribavirin standard therapy are still undergoing follow-up for SVR.
• The SVR12 rate reached 98% among patients who received at least 8 weeks of 400 mg PSI-7977.
• All but 1 patient in the 2 PSI-7977 arms qualified for 24 total weeks of treatment according to response-guided therapy.
• No PSI-7977 recipients experienced viral breakthrough while on PSI-7977, but 3 people in the 200 mg group did so while on the pegylated interferon/ribavirin tail.
• 1 person each in the 200 mg and 400 mg groups experienced post-treatment relapse, none of whom showed evidence of the S282T resistance mutation.
• PSI-7977 was generally well-tolerated with an adverse events profile similar to that of pegylated interferon/ribavirin standard therapy.
• Insomnia was more common in the 400 mg PSI-7977 arm (15% vs 8% in control arm and 4% in 200 mg PSI-7977 arm).
• There were no treatment discontinuations due to adverse events related to PSI-7977
  The researchers noted that the high SVR rate among HCV genotype 1 patients was independent of predictors of poor interferon response.
  Lawitz elaborated that among the 13 PROTON participants with the unfavorable IL28B TT pattern, all had a "brisk response" and all achieved SVR12.