HCV Protease Inhibitor Telaprevir Demonstrates Good Efficacy in Both Treatment-experienced and Treatment-naive Patients

		SUMMARY: Vertex's experimental hepatitis C virus (HCV) protease inhibitor telaprevir (formerly known as VX-950) -- which, along with Schering-Plough's boceprevir is the most advanced of the directly targeted oral anti-HCV drugs in development -- continues to demonstrate good efficacy with acceptable tolerability, according to data presented last week at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) in Boston. Final results from the PROVE3 trial showed that patients with prior treatment failure can be successfully treated with a telaprevir-based regimen, while Study C208 indicated that twice-telaprevir works as well as 3-times-daily dosing.

By Liz Highleyman

PROVE Studies

John McHutchison and colleagues presented final data from the Phase 2 PROVE3 trial; the researchers previously presented interim 36-week data at last year's AASLD meeting.

The study included 453 genotype 1 chronic hepatitis C patients who were non-responders, partial responders, or relapsers following a prior course of interferon plus ribavirin. Two-thirds were men, about 90% were white, 9% were black, and the median age was about 50 years. Most (92%) had baseline HCV RNA > 800,000 IU/mL. About 40% had bridging fibrosis or compensated cirrhosis. About 60% were prior non-responders (never achieved undetectable HCV RNA) and about 30% were relapsers (undetectable HCV RNA during treatment, but viral load recurred after completing therapy).

Participants were randomly allocated to 4 arms, receiving 750 mg 3-times-daily telaprevir plus 180 mcg/week pegylated interferon alfa-2a (Pegasys), with or without 1000-1200 mg/day weight-adjusted ribavirin. One group received all 3 drugs for 12 weeks followed by Pegasys plus ribavirin without telaprevir for 12 additional weeks (T12/PR24). A second group received all 3 drugs for 24 weeks, followed by Pegasys plus ribavirin for 24 additional weeks (T24/PR48). A third group took telaprevir plus Pegasys without ribavirin for 24 weeks (T24/P24). Finally, a control arm received standard therapy using Pegasys plus ribavirin for 48 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 24 weeks after completion of therapy (sustained virological response, or SVR); telaprevir recipients who achieved SVR were tested again 48 weeks after completing treatment. The study protocol included a stopping rule that required patients to discontinue treatment if they did not achieve a response by week 4 or 12, or if they experienced viral breakthrough.

Results

	About half the participants completed their assigned treatment.
	Proportions discontinuing treatment due to meeting the defined stopping rule were 15% in the T12/PR24 arm, 23% in the T24/PR48 arm, and 37% in the T12/P24 arm, compared with 59% in the standard therapy arm.
	Proportions discontinuing therapy due to adverse events were 10%, 25%, 9%, and 4%, respectively.
	Overall SVR rates were 51% in the T12/PR24 arm, 53% in the T24/PR48 arm, 24% in the T12/P24 arm, and 14% in the standard therapy arm, but varied according to type of prior failure:
	Prior non-responders: 39%, 38%, 11%, and 9%, respectively. Prior relapsers: 69%, 76%, 42%, and 20%, respectively. Prior viral breakthough while on treatment: 57%, 63%, 36%, and 40%, respectively.
	Rates of viral breakthrough during treatment were 13% in the T12/PR24 arm, 12% in the T24/PR48 arm, 32% in the T12/P24 arm, and 3% in the standard therapy arm
	Overall relapse rates during the 24-week post-treatment follow-up period were 30%, 13%, 53%, and 53%, respectively.
	Among patients who completed their assigned regimen, relapse rates were 28%, 4%, 53%, and 52%, respectively.
	No late relapses were observed during the longer 48-week post-treatment follow-up period for telaprevir recipients.
	Adverse events occurring with greater frequency in the telaprevir compared with standard therapy arms included fatigue, nausea, diarrhea, headache, skin rash, pruritus (itching), anemia, insomnia, fever, chills, and hair loss.
	Rash leading to treatment discontinuation occurred in 4%, 6%, 5%, and 0% of patients in the T12/PR24, T24/PR48, T24/P24, and standard therapy arms, respectively.
	Anemia leading to discontinuation occurred in 0%, 2%, 1%, and 1%, respectively.

Based on these findings, the researchers stated, "SVR rates in all treatment groups receiving [telaprevir plus pegylated interferon plus ribavirin] regimens were significantly higher than with [pegylated interferon plus ribavirin]. Other than 1 patient lost to follow-up, all patients who completed [a telaprevir] regimen and achieved SVR maintained virologic response 48 weeks after the end of treatment."

Participants who did not include ribavirin in their regimen were about half as likely to achieve SVR as those who used all 3 drugs, demonstrating the importance of ribavirin in preventing relapse. Overall, prior relapsers and those who previously experienced viral breakthrough during treatment had better sustained response rates than prior non-responders. For prior non-responders, SVR rates were similar in the 24-week and 48-week treatment arms, although prior relapsers and breakthroughs tended to respond better with longer treatment.

"Patients who failed prior [pegylated interferon plus ribavirin] therapy can successfully be treated with a telaprevir-based regimen and maintain SVR 1 year after the end of treatment," the investigators concluded.

In addition, Gregory Everson and colleagues presented a poster describing findings from a sub-analysis of "difficult-to-cure" patients in the Phase 2b PROVE1 and PROVE2 trials. These trials included treatment-naive genotype 1 chronic hepatitis C patients. Final PROVE1 results were reported at the 2008 EASL meeting and final PROVE2 findings presented last year at AASLD.

The present analysis pooled data from PROVE1 and PROVE2 participants who received the T12/PR24 regimen or standard therapy. Overall SVR rates were 65% and 44%, respectively, in these arms. In a logistic regression analysis, lower baseline HCV RNA (< 800,000 IU/mL), younger age (< 45 years), and white race were predictors of SVR. The investigators concluded that, "Telaprevir-based triple therapy improved SVR rates in patients predicted to have low virologic response to the current standard treatment."

Study C208

Study C208 was an open-label, Phase 2 trial conducted by Tibotec in Europe. This trial included 161 previously untreated genotype 1 chronic hepatitis C patients. About half were men, about 90% were white, the mean age was about 45 years, and about 20% had fibrosis.

Participants were randomly allocated to 4 treatment arms, received telaprevir at doses of either 750 mg 3-times-daily (every 8 hours) or 1125 mg twice-daily (every 12 hours). Each dose was combined with either Pegasys or pegylated interferon alfa-2b (PegIntron) plus ribavirin. Patients took telaprevir for 12 weeks, followed by pegylated interferon/ribavirin for at least an additional 12 weeks.

In a response-guided design, patients who achieved RVR at week 4 and maintained undetectable viral load (< 25 IU/mL) through week 20 could stop all treatment at 24 weeks; they were then followed for 6 months post-treatment to evaluate SVR. The study protocol required that patients who did not meet these criteria receive pegylated interferon plus ribavirin for a total of 48 weeks.

Results

	18% of patients across all treatment arms were required to continue treatment through week 48.
	In an intent-to-treat analysis, similar proportions of patients in the 3-times-daily and twice daily arms -- as well as those receiving Pegasys vs PegIntron -- achieved SVR, not a statistically significant difference:
	85% taking 3-times-daily telaprevir plus Pegasys; 81% taking 3-times-daily telaprevir plus PegIntron; 83% taking twice-daily telaprevir plus Pegasys; 82% taking twice-daily telaprevir plus PegIntron.
	Looking only at patients who achieved RVR, the SVR rates were 91%, 93%, 91%, and 92%, respectively.
	Among patients who completed their assigned regimen, 3% experienced viral relapse during post-treatment follow-up.
	6% of patients experienced viral breakthrough during telaprevir treatment.
	Safety and tolerability were similar with 3-times-daily and twice-daily regimens.
	The most common adverse events were pruritis, nausea, rash, anemia, flu-like illness, fatigue, and headache, occurring with similar frequency in the both arms.
	5% of participants permanently discontinued therapy due to serious adverse events, mostly rash (3%) and anemia (2%).

Based on these findings, the researchers concluded that "treatment with telaprevir [every 8 hours] or [every 12 hours] in combination with [pegylated interferon/ribavirin] yielded high and comparable rates of virological response at week 12, independent of baseline viral load or viral subtype.

"With high SVR rates and similar safety outcomes between the twice-daily and 3-times-daily treatment groups, the results from this exploratory study support the future evaluation of telaprevir-based regimens dosed twice daily," Dr Marcellin said in a press release issued by Vertex. "These results also highlight the potential future role for response-guided therapy with the goal of improving treatment outcomes and potentially shortening the duration of therapy for the majority of patients."

11/10/09

References

JG McHutchison, MP Manns, A Muir, and others. PROVE 3 Final Results and 1-Year Durability of SVR with Telaprevir-Based Regimen in Hepatitis C Genotype 1-Infected Patients with Prior Non-response, Viral Breakthrough or Relapse to Peginterferon-Alfa-2a/b and Ribavirin Therapy. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 66.

GT Everson, GM Dusheiko, P Ferenci, and others. Telaprevir, Peginterferon Alfa-2a and Ribavirin Improved Rates of Sustained Virologic Response (SVR) in "Difficult-to-Cure" Patients With Chronic Hepatitis C (CHC): a Pooled Analysis From the PROVE 1 and PROVE 2 Trials. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1565.

P Marcellin, X Forns, T Goeser, and others. Virological Analysis of Patients Receiving Telaprevir Administered q8h or q12h with Peginterferon-Alfa-2a or -Alfa-2b and Ribavirin in Treatment-Naïve Patients with Genotype 1 Hepatitis C: Study C208. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 194.

Other sources

Vertex Pharmaceuticals. More than 80% of Hepatitis C Patients Treated in Study C208 Achieved an SVR with Telaprevir-Based Regimens. Press release. October 31, 2009.