Interim Efficacy and Resistance Data from a Phase II Study of Telaprevir (VX-950) Plus Pegylated Interferon and Ribavirin in Previously Untreated Patients with Hepatitis C

By Liz Highleyman

Telaprevir (formerly VX-950) is an HCV protease inhibitor being developed by Vertex. The PROVE 1 study (also known as VX05-950-104) is an ongoing randomized, placebo-controlled Phase II study of telaprevir plus pegylated interferon alpha-2a (Pegasys) and ribavirin in people who have not previously been treated for hepatitis C.

Results from a planned interim analysis of PROVE 1, as well as preliminary HCV sequencing data, were presented this week at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago.

In this study, 263 treatment-naive participants with genotype 1 HCV were randomized into 4 groups. The first 3 groups all received 750 mg tipranavir every 8 hours plus 180 mcg/week pegylated interferon plus 1000-1200 mg/day ribavirin for 12 weeks. This was followed by either 0 (n=20), 12 (n=80), or 36 (n=82) weeks of pegylated interferon plus ribavirin without telaprevir. A control group (n=81) received standard therapy with pegylated interferon plus ribavirin for 48 weeks.

The interim analysis was performed when all treated subjects had completed 12 weeks of dosing. Samples were collected for viral sequencing at baseline and at each HCV viral load assessment.

Results

• The proportion of subjects with undetectable HCV RNA (limit of detection 10 IU/mL) at Week 4 was 79% in the combined telaprevir/pegylated interferon/ribavirin arms, compared with 11% in the control group (P<0.001).

• At Week 12, the corresponding percentages were 70% and 39%, respectively (P<0.001).

• In the telaprevir combination therapy groups, 12 of 175 subjects experienced virological breakthrough (defined as an increase of > 1 log above with the HCV RNA nadir) and had evidence of previously described telaprevir-resistant variants.

• In the group receiving 12 weeks of telaprevir, 6 of 9 subjects (66%) with rapid virological response (RVR) at Week 4 who completed 12 weeks of therapy had undetectable HCV RNA 20 weeks after the end of treatment (sustained virological response is typically measured 24 weeks after the end of treatment).

• 3 subjects experienced viral relapse after completion of treatment and also had telaprevir resistant variants.

• Discontinuations due to adverse events were more frequent in the telaprevir combination therapy arms compared with the standard therapy control group (11% vs 3%).

• Rashes, gastrointestinal symptoms, and anemia were more common - and rashes were more severe - in the telaprevir groups.

Conclusion

"Significantly more subjects receiving a telaprevir-based regimen achieved undetectable HCV RNA at Weeks 4 and 12," the investigators concluded. "Viral breakthrough and relapse are associated with the selection of telaprevir resistant variants."

They added that, "Shorter treatment durations appear feasible for genotype 1 HCV in a subset of patients achieving RVR."

Johns Hopkins University, Baltimore, MD; Duke University Clinical Research Institute, Durham, NC.

09/18/07

Reference
MS Sulkowski and JG McHutchison. Interim Analysis Results and Preliminary Viral Variant Evaluation from a Phase 2 Study of Telaprevir with Peginterferon alfa-2A and Ribavirin in Treatment-Naïve Subjects with Hepatitis C. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, September 17-20, 2007. Abstract V-1383.