By Liz Highleyman

Given the suboptimal efficacy, side effects, and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection, investigators have explored several novel drugs that directly target various steps of the viral lifecycle -- an approach dubbed "STAT-C."

At the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers presented the latest data on the STAT-C agent furthest along in the development pipeline: telaprevir (VX-950), an HCV protease inhibitor being developed by Vertex Pharmaceuticals and Tibotec.

PROVE 2 Final Results

Telaprevir has been studied in a series of related Phase 2b trials. Data from the PROVE 1 and PROVE 2 studies were presented earlier this year at the annual meeting of the European Association for the Study of the Liver (EASL). Final results from PROVE 2 were presented at AASLD.

In PROVE 2, a total of 323 treatment-naive patients with genotype 1 chronic hepatitis C were randomized to receive 1 of the following regimens:

• 750 mg telaprevir every 8 hours + 180 mcg/week pegylated interferon alfa-2a (Pegasys) for 12 weeks (T12/P12);

• Telaprevir + Pegasys at the same doses + 1000-1200 mg/day weight-adjusted ribavirin for 12 weeks (T12/PR12);

• Telaprevir + Pegasys + ribavirin for 12 weeks, followed by Pegasys + ribavirin without telaprevir for 12 additional weeks (T12/PR24).

• Standard therapy with Pegasys + ribavirin (+ telaprevir placebo) for 48 weeks (PR48).

A majority of participants (about 60%) were men, 94% were white, and the median age was 45 years. Most (nearly 90%) had HCV RNA > 600,000 IU/mL at baseline and about 7% had advanced liver fibrosis.

Results

• In the final intent-to-treat analysis, proportions of patients who achieved sustained virological response (SVR) 24 weeks after completion of therapy were as follows:

• 69% of patients in the T12/PR24 arm;
• 60% in the T12/PR12 arm;
• 46% in the standard therapy PR48 arm;
• 30% in the T12/P12 (no ribavirin) arm.

• 14% of patients receiving a 24-week telaprevir regimen discontinued therapy due to adverse events, compared with 7% in the 48-week standard therapy arm.

• 7% of patients across all telaprevir arms discontinuation due to skin rash.

Based on these findings, the researches concluded that, "Telaprevir in combination with [pegylated interferon/ribavirin] demonstrated significantly higher SVR rates compared with the control group in patients infected with HCV genotype 1, with the potential to shorten the overall treatment duration by half in most patients."

While telaprevir improved response, however, it still appears that ribavirin is needed to reduce the risk of relapse and increase the likelihood of sustained response.

Dept of Internal Medicine I, JW Goethe University Hospital, Frankfurt a.M., Germany; AP-HP Henri-Mondor Hospital & University of Paris 12, Créteil, France; Medical University of Vienna, Vienna, Austria; Royal Free Hospital, London, UK; Medicines Development Group, Vertex Pharmaceuticals, Inc., Cambridge, MA.

PROVE 3

John McHutchison and colleagues presented results from a 36-week planned interim analysis of PROVE 3, which included 453 genotype 1 chronic hepatitis C patients who were null responders, partial responders, or relapsers following a previous course of treatment with interferon plus ribavirin.

Two-thirds of study participants were men, about 90% were white, and the median age was about 50 years. About 60% had HCV genotype 1a, 30% had 1b, and the rest were undetermined. About 25% had bridging fibrosis and about 15% had compensated cirrhosis. About 60% were prior non-responders (never achieved undetectable HCV RNA), about 30% were relapsers (undetectable HCV RNA at the end of treatment but relapsed during follow-up and did not achieve SVR), and the remainder experienced virological breakthrough while still on therapy.

Participants were randomly assigned to receive 1 of the following regimens:

• 750 mg telaprevir every 8 hours + 180 mcg/week Pegasys + 1000-1200 mg/day ribavirin for 12 weeks, followed by Pegasys + ribavirin without telaprevir for 12 additional weeks (T12/PR24);

• All 3 drugs at the same doses for 24 weeks, followed by Pegasys + ribavirin alone for 24 additional weeks (T24/PR48).

• Telaprevir + Pegasys without ribavirin for 24 weeks (T24/P24);

• Standard therapy with Pegasys + ribavirin for 48 weeks (+ telaprevir placebo for the first 24 weeks) (PR48).

HCV RNA was measured at week 4 (rapid virological response, or RVR), week 12 (early virological response, or EVR), end of treatment (EOT), and 12 months after completion of therapy for the 2 groups treated for 24 weeks (SVR12; standard sustained virological response is ascertained 24 weeks after competing treatment.) Stopping rules required patients to discontinue treatment if they did not achieve a response by week 4 or 12, or if they experienced viral breakthrough.

Results

• In an intent-to-treat analysis at week 4, no patients in the PR48 arm, 61% in the T12/PR24 arm, 47% in the T24/P24 (no ribavirin) arm, and 50% in the T24/PR48 arm achieved undetectable HCV RNA.

• At week 12, the corresponding percentages were 8%, 75%, 53%, and 66%.

• At week 24, the percentages were 33%, 70%, 48%, and 56%, respectively.

• In the 2 groups whose treatment ended at 24 weeks, SVR12 rates were 52% in the T12/PR24 arm and 21% in the T24/P24 arm:

• 41% vs 11% for prior non-responders;
• 73% vs 46% for prior relapsers;
• 44% vs 20% for those with prior viral breakthrough.

• In the longer treatment groups, 30% in the PR48 arm and 46% in the T24/PR48 arm achieved undetectable HCV RNA at 36 weeks, but they were still receiving therapy.

• In the telaprevir arms, viral breakthrough occurred more often in patients with genotype 1a compared with 1b.

• A total of 224 patients discontinued therapy prior to week 24:

• Due to stopping rules: 72% in the PR48 arm, 28% in the T12/PR24 arm, 50% in the T24/P24 arm, and 49% in the T24/PR48 arm;

• Due to adverse events (AEs): 4%, 7%, 8%, and 22%, respectively.

• Gastrointestinal symptoms were significantly more frequent in the telaprevir arms.

Based on these findings, the investigators stated, "In a population of patients who have failed previous [pegylated interferon/ribavirin] treatment, response rates 12 weeks after end of treatment were 52% overall in the T12/PR 24 arm: 73% in prior relapsers, 41% in prior non-responders."

AEs reported more frequently in the tipranavir arms compared with the standard therapy arm were gastrointestinal symptoms, headache, anemia, and skin symptoms (rash and pruritis, or itching).

"Other AEs were similar in type and frequency to those seen with [pegylated interferon/ribavirin]," they noted. Treatment discontinuation rates at week 36 were 16% in the telaprevir arms and 4% in the standard therapy arm.

"Data from Phase 2 telaprevir clinical studies in genotype 1 HCV patients are encouraging as responses were seen in treatment-naive patients, as well as in those who had previously failed treatment with the current standard of care regimen," McHutchison stated in a press release issued by Vertex. "PROVE 3 data showed that a telaprevir regimen produced a 52% SVR12 in treatment-failure subjects, which is noteworthy as patients who have failed therapy are very difficult to manage due to limited available treatment options and are at greater risk for developing progressive liver disease."

PROVE 3 is ongoing, and will report SVR outcomes for patients in the 48-week treatment arms at a later date.

Duke Clinical Research Institute, Durham, NC; McGuire DVAMC, Fairfax, VA; University of California, San Francisco, CA; Medizinische Hochschule Hannover, Hannover, Germany; St Louis University, St Louis, MO; Weill Medical College of Cornell University, New York, NY; Beth Israel Deaconess Medical Center, Boston, MA; University of Toronto, Toronto, Ontario, Canada; Saarland University Hospital, Homburg/Saar, Germany; University of Amsterdam, Amsterdam, Netherlands; Vertex Pharmaceuticals, Inc., Cambridge, MA.

Telaprevir in Black and Latino Patients

Numerous studies have shown that African-American and Latino patients have lower SVR rates than white when using interferon-based therapy, but it remains to be determined whether this is also the case with STAT-C agents.

In the PROVE 1 trial, treatment-naive genotype 1 patients were randomized to receive telaprevir for 12 weeks + Pegasys for either 12, 24, or 48 weeks, or else standard therapy with Pegasys + ribavirin for 48 weeks. Out of 250 total participants, nearly 75% were white and about 10% each were black and Latino.

Viral decline at 1 week was significantly different in the white and African-American subgroups receiving Pegasys/ribavirin standard therapy, but not in the groups that added telaprevir. SVR rates in patients receiving telaprevir appeared higher compared with standard therapy across all racial/ethnic groups:

• 62% vs 41% for whites;

• 44% vs 11% for African-Americans;

• 65% vs 33% for Latinos.

"This sub-analysis suggests that telaprevir-based regimens enhance early viral responses and subsequently lead to improved viral responses in African-Americans, Latinos, and Caucasians," the researchers concluded. "Given the burden of disease among African-Americans and Latinos, it is imperative these results be confirmed in larger phase 3 clinical trials."

Duke Clinical Research Institute, Duke University, Durham, NC; Alamo Medical Research, San Antonio, TX; Henry Ford Hospital, Detroit, MI; Weill Medical College of Cornell University, New York, NY; Vertex Pharmaceuticals, Boston, MA; Fundacion de Investigacion de Diego, Ponce School of Medicine, San Juan, Puerto Rico.

Twice-daily Dosing

Finally, the open-label Study C208 is assessing the efficacy and safety of telaprevir at a dose of 1125 twice-daily (every 12 hours) versus the three-times-daily (every 8 hours) dose used in the PROVE trials. Telaprevir at each dose level was combined with either Pegasys or pegylated interferon alfa-2b (Pegintron) + ribavirin

• In an interim analysis of data from 161 treatment-naive genotype 1 chronic hepatitis C patients, the following percentages achieved undetectable HCV RNA:

• Telaprevir every 8 hours + Pegasys/ribavirin: 80% at week 4, 93% at week 12;

Telaprevir every 8 hours + PegIntron/ribavirin: 69% and 93%, respectively;

Telaprevir every 12 hours + Pegasys/ribavirin: 83% and 83%, respectively;

Telaprevir every 12 hours + PegIntron/ribavirin: 67% and 85%, respectively.

• Treatment discontinuation rates were 10%, 5%, 10%, and 8%, respectively, in the 4 study arms.

• 3%, 7%, 5%, and 8%, respectively, experienced virologic breakthrough.

In the context of the two currently available standard-of-care regimens," the researchers concluded, "telaprevir 750 mg [every 8 hours] or 1125 mg [every 12 hours] in combination with [pegylated interferon/ribavirin] yielded high rates of virological response and low viral breakthrough at week 4."

Liver Unit, University of Barcelona, Barcelona, Spain; Hôpital Beaujon, Clichy, France; Klinikum der Universität zu Köln, Köln, Germany; Medical University of Vienna, Vienna, Austria; University Hospital Gasthuisberg, Leuven, Belgium; Clinic of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc., Yardley, PA.

11/11/08

References

S.. Zeuzem, C Hezode, P Ferenci, and others. Telaprevir in Combination with Peginterferon-Alfa-2a with or without Ribavirin in the Treatment of Chronic Hepatitis C: Final Results of the PROVE2 Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 243.

JG McHutchison, ML Shiffman, N Terrault, and others. A Phase 2b Study of Telaprevir with Peginterferon-Alfa-2a and Ribavirin in Hepatitis C Genotype 1 Null and Partial Responders and Relapsers Following a Prior Course of Peginterferon-Alfa-2a/b and Ribavirin Therapy: PROVE3 Interim Results. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 269.

AJ Muir, EJ Lawitz, JG McHutchison, and others. Viral Responses in African-Americans, Latinos and Caucasians in the US Phase 2 Study (PROVE1) of Telaprevir with Peginterferon Alfa-2a and Ribavirin in Treatment-Naïve Genotype 1-infected Subjects with Hepatitis C. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1846.

X Forns, P Marcellin, T Goeser, and others. Phase 2 Study of Telaprevir Administered q8h or q12h with Peginterferon-Alfa-2a or -Alfa-2b and Ribavirin in Treatment-Naïve Subjects with Genotype 1 Hepatitis C: Week 4 Interim Results. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1854.

Other source
Vertex Pharmaceuticals. New Clinical Data Support Broad Profile for Telaprevir in Patients with Genotype 1 Hepatitis C Virus (HCV) Infection. Press release. November 2, 2008.