By Liz Highleyman

Given the unimpressive response rate and difficult side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection, researchers have increasingly focused on oral antiviral agents that directly target the viral lifecycle.

One of the most promising such therapies is telaprevir (previously known as VX-950), an experimental HCV NS34A protease inhibitor being developed by Vertex Pharmaceuticals and Tibotec.

Two research groups at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) this week in Milan presented data from the Phase 2 PROVE studies, looking at telaprevir plus pegylated interferon and ribavirin in previously untreated patients with hard-to-treat genotype 1 HCV.

The PROVE1 trial included 250 treatment-naive genotype 1 chronic hepatitis C patients in the U.S. Participants were randomly assigned to 4 regimens:

• 750 mg telaprevir every 8 hours plus 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin for 12 weeks (n = 17);

• The same regimen followed by pegylated interferon/ribavirin without telaprevir for 12 weeks (n = 79);

• The same regimen followed by pegylated interferon/ribavirin without telaprevir for 36 weeks (n = 79);

• Standard therapy with pegylated interferon/ribavirin (no telaprevir) for 48 weeks (n = 75).

Results

• Patients in all telaprevir arms were significantly more likely to achieve rapid virological response (RVR), or undetectable HCV RNA (< 10 IU/mL) at week 4, compared with the standard therapy control group (79% vs 11%, respectively).

• The same was also true for early virological response at week 12 (70% vs 39%, respectively).

• During the first 12 weeks, 91% of patients in the telaprevir arms achieved undetectable HCV RNA, compared with 43% in the standard therapy group.

• At the end of treatment, the proportion of patients with undetectable HCV RNA was significantly higher in the 48 week telaprevir group compared with the 48 week standard therapy group (65% vs 45%).

• 6 months after completion of therapy, the SVR rate was substantially higher in the 24 week telaprevir arm compared with the 12 week telaprevir arm (61% vs 35%, respectively).

• Among patients who experienced RVR, the relapse rate was 33% in the 12 week telaprevir group compared with 2% in the 24 week telaprevir group.

• Adverse events leading to treatment discontinuations were more frequent in the telaprevir arms than in the standard therapy group (13% vs 3%, respectively).

• Skin rashes, gastrointestinal events, and anemia were more common, and rashes were more severe, in the telaprevir arms.

• "Serious" adverse events were reported by 11% of patients in the telaprevir arms compared with 5% in the standard therapy group.

Conclusion

"Compared with current treatment, telaprevir-based therapy resulted in a high rate of RVR and subsequent on-treatment response rate," the investigators concluded.

"These results suggest potential for higher SVR rates with shorter duration of therapy in subjects with genotype 1," they added.

In a related presentation, researchers described results from PROVE2, which included 323 patients in Europe. The study design was similar to PROVE1, but there was also an arm that received telaprevir plus pegylated interferon without ribavirin.

Overall results were generally similar to those of PROVE1. Here, too, telaprevir plus with pegylated interferon and ribavirin produced significantly greater virological response than standard therapy at 4, 12, and 24 weeks. However, patients who received telaprevir/pegylated interferon without ribavirin were less likely to achieve HCV RNA suppression and more likely to relapse than those who received triple combination therapy.

Among participants who experienced a rash, 7% discontinued in the 12 and 24 week triple therapy arm compared with 3% in the telaprevir/pegylated interferon arm without ribavirin and none in the standard therapy group.

Taken together, these studies indicate that telaprevir is a promising therapy that may allow for shorter treatment for chronic hepatitis C. However, shortening therapy too much - to less than 24 weeks - substantially increased the risk of relapse, as did the omission of ribavirin.

4/25/08

References

JG Mchutchison, GT Everson, SC Gordon, and others. PROVE1: Results from a Phase 2 Study of Telaprevir with Peginterferon Alfa-2a and Ribavirin in Treatment-Naive Subjects With Hepatitis C. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

GM Dusheiko, C Hezode, S Pol, and others. Treatment of Chronic Hepatitis C with Telaprevir (TVR) in Combination with Peginterferon-Alfa-2a with or without Ribavirin: Further Interim Analysis Results of the PROVE2 Study. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.