Telaprevir-based Therapy for HCV May Shorten Treatment Duration from 48 to 24 Weeks for Some Genotype 1 Patients

By Ronald Baker, PhD

Preliminary data were presented at a late-breaker session at the 42nd Annual Meeting of the European Association for the Study of the Liver last week in Barcelona, Spain, suggesting that treatment which includes the HCV protease inhibitor telaprevir (VX-950) may be able to significantly shorten the duration of therapy in treatment-naive, genotype 1 patients with chronic hepatitis C virus (HCV) infection.

Telaprevir is an experimental oral HCV protease inhibitor in Phase IIb development by Vertex Pharmaceuticals in collaboration with Tibotec Therapeutics for the treatment of patients with chronic hepatitis C.

Vertex is conducting 3 large, ongoing trials of telaprevir in approximately 1000 patients at medical centers in the U.S., Canada, and Europe. Among other objectives, the 3 studies (PROVE 1, PROVE 2, and PROVE 3) are evaluating the safety and efficacy of various durations of telaprevir-based regimens in treatment-naive genotype 1 patients, as well as patients who have failed prior anti-HCV therapy. The goal of these studies is to determine optimal telaprevir-based regimens and treatment durations.

The information in this report, describing data from the PROVE 1 study, is drawn from an announcement released by Vertex on April 14, 2007. Following are excerpts from that document:

Summary of PROVE 1 Results

•A total of 250 patients were enrolled in PROVE 1 and received at least 1 dose of telaprevir or placebo in addition to pegylated interferon alfa-2a (Pegasys) + ribavirin.

• A total of 175 patients received at least 1 dose of telaprevir in 3 study arms (Arms B, C, D), and 75 received at least 1 dose of placebo (Arm A).

• 3 groups were randomly assigned to receive telaprevir 750 mg every 8 hours, Pegasys 180 mcg/week, and ribavirin 1000-1200 mg/day for 12 weeks, followed by 0, 12, or 36 weeks of Pegasys plus ribavirin (telaprevir/peg/ribavirin groups).

• The control group was randomly assigned to receive up to 48 weeks of Pegasys/ribavirin plus telaprevir-matched placebo for the first 12 weeks.

• This planned interim analysis was performed when the first 80 enrolled subjects had completed 12 weeks of dosing.

• All subjects in the telaprevir groups received the same treatment through Week 12; these groups were pooled for this analysis.

• 88% and 79% of patients receiving telaprevir achieved rapid virological response (RVR), defined as plasma HCV RNA < 30 IU/mL and < 10 IU/mL, respectively, at Week 4.

• 6 out of 9 patients (67%) in one treatment arm who completed 12 weeks
of therapy, and who achieved RVR as defined by the study protocol (< 10 IU/mL), continued to have undetectable HCV RNA 20 weeks after stopping all treatment ("SVR20"). [Note: sustained virological response (SVR) is typically measured 24 weeks after completion of therapy.]

• Skin rash was more common, and in some cases more severe, in the telaprevir/peg/ribavirin group, while gastrointestinal (GI) events were more common than in the placebo arm.

• The treatment discontinuation rate due to adverse events through 12 weeks was 11% in telaprevir arms and 3% in the placebo arm.

Conclusion

PROVE 1 is the first study to evaluate therapy of short duration using the HCV PI telaprevir in combination with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C patients.

The interim results of this study showed a high RVR rate in the telaprevir-treated groups and a low rate of on-treatment virological breakthrough. Patients receiving telaprevir/pegylated interferon/ribavirin had a higher frequency of undetectable HCV RNA than pegylated interferon/ribavirin without telaprevir.

The adverse event profile was similar overall in types of events, but rash and GI events were more common in the telaprevir/peg/ribavirin groups. The most common reason for treatment discontinuation in the telaprevir arms was rash (7 patients), and the median time to discontinuation in these patients was 64 days.

Analysis of PROVE 1 Patients Who Finished Treatment at 12 Weeks

According to the study protocol, patients in Arm D were eligible to stop all treatment at week 12 if they met on-treatment criteria, including achievement of RVR (< 10 IU/mL at Week 4) and maintenance of this virological response at Week 10 of treatment.

In this arm, 9 of 17 patients met these criteria and stopped therapy at 12 weeks; 6 of these patients continued to have undetectable HCV RNA at Week 20 of post-treatment follow-up. Of the remaining 8 patients enrolled in this arm, 4 discontinued due to adverse events prior to Week 12, and 4 did not achieve RVR.

Adverse Events

In the telaprevir arms, the incidence of treatment discontinuations due to adverse events through 12 weeks was 11% (19 of 175 patients), compared to 3% (2 of 75 patients) in the control arm. The difference between the 2 groups is due to the greater number of discontinuations due to rash, gastrointestinal symptoms, and anemia in the telaprevir arms compared to the control arm.

Overview of Interim Results

Treatment with telaprevir resulted in a high proportion of patients achieving RVR at 4 weeks. At the time of the interim analysis, all patients had either completed 12 weeks of therapy or discontinued from the study prior to Week 12. Available 4-week and 12-week results are detailed in the following table:

Commentary

John McHutchison, MD, Principal Investigator for the PROVE 1 study and Director of Gastroenterology and Hepatology Research at Duke Clinical Research Institute, stated, "The high rates of RVR observed in the telaprevir groups in PROVE 1, and the fact that some patients have remained persistently viral negative 20 weeks after stopping the 12 weeks of telaprevir-based therapy, suggest that we may be able to shorten the treatment duration in genotype 1 HCV patients."

Further, Dr. McHutchison remarked, "These interim results are encouraging and suggest that high sustained viral response (SVR) rates may be achieved with regimens that are 24 weeks in total duration. We look forward to 24 week follow-up data from the initial group of patients who stopped treatment at 12 weeks, and follow-up data from patients in the study who received 24 weeks of treatment."

Implications for Clinical Development of Telaprevir

In addition to the interim results of PROVE 1, Vertex also included in their announcement a statement about the potential implications the new information has for future clinical development of telaprevir.

Vertex stated its intention to consider evaluation of treatment regimens that include telaprevir in combination with pegylated interferon alfa-2a and ribavirin, and depending on data from PROVE 2, regimens that may exclude ribavirin. Vertex expects to focus on treatment durations of no more than 24 weeks.

Vertex and Tibotec are planning to meet with regulatory authorities in mid-2007 to discuss the design of Phase III trials, and are planning to initiate Phase III clinical development in the fourth quarter of this year. The registration strategy and timing of an NDA filing will be dependent on discussions with these authorities.

04/17/07

Sources

J G McHutchison, G T Everson, S Gordon, and others. Results of an Interim Analysis of a Phase 2 Study of Telaprevir (VX-950) with Peginterferon Alfa-2a and Ribavirin in Previously Untreated Subjects with Hepatitis C. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11 - 15, 2007, Barcelona, Spain.

Vertex Pharmaceuticals. Interim Results Presented at EASL from PROVE 1 Clinical Trial of Investigational Drug Telaprevir in Patients with Genotype 1 Hepatitis C. Press Release. April 14, 2007.

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