- Category: Approved HCV Drugs
- Published on Tuesday, 28 June 2011 06:53
- Written by Liz Highleyman
The recently approved HCV protease telaprevir added to standard therapy increased cure rates for both previously untreated people and prior non-responders.
Direct-acting antiviral agents that target different steps of the hepatitis C virus (HCV) lifecycle signal a new paradigm in treatment for chronic hepatitis C, especially for people with difficult-to-treat HCV genotype 1 and those who did not achieve sustained response to prior treatment attempt.
The first 2 direct-acting drugs -- Merck's boceprevir (Victrelis) and Vertex's telaprevir (Incivek) -- were approved by the U.S. Food and Drug Administration (FDA) last month.
Pivotal clinical trials with both treatment-naive and previously treated patients showed that adding the new drugs to standard therapy consisting of pegylated interferon plus ribavirin increased the likelihood of achieving sustained virological response (continued undetectable HCV RNA after completion of treatment); furthermore, many people could receive a shorter course of therapy.
Telaprevir data from the treatment-naive ADVANCE trial and the treatment-experienced REALIZE trial were published in the June 23, 2011, New England Journal of Medicine. (Boceprevir findings from the treatment-naive SPRINT-2 and treatment-experienced RESPOND-2 trials appeared in the March 31, 2011 issue of the same journal.)
Ira Jacobson from Weill Cornell Medical College and a large international team of collaborators evaluated the safety and efficacy of telaprevir plus standard therapy for previously untreated patients. The Phase 3 ADVANCE study included 1088 treatment-naive participants with chronic genotype 1 hepatitis C.
Participants were randomly assigned to receive 750 mg 3-times-daily telaprevir or placebo along with 180 mcg/week pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin. Patients received telaprevir for either 8 or 12 weeks; duration of pegylated interferon/ribavirin (up to 48 total weeks) was determined using a response-guided strategy based on HCV RNA declines at weeks 4 and 12.
Investigators measured HCV viral load levels at various points after starting treatment, including week 4 (rapid virological response or RVR), week 12 (early virological response or EVR), end of treatment, and 24 weeks after completion of treatment (sustained virological response or SVR).
- Significantly more participants who took telaprevir for 8 or 12 weeks achieved SVR compared with those taking standard therapy alone (75% and 69%, respectively, vs 44%).
- Virological treatment failure occurred more often in the 8-week telaprevir group.
- 58% of patients treated with telaprevir were eligible to stop all treatment after 24 weeks using the response-guided strategy.
- Telaprevir was generally safe and well-tolerated, with mostly mild-to-moderate side effects.
- Adverse events that occurred more often in the telaprevir group than in the standard therapy group included anemia, gastrointestinal symptoms, and skin rash.
- 10% of patients taking telaprevir for 12 weeks and 7% taking standard therapy discontinued treatment prematurely due to side effects.
Based on these findings, the study authors wrote, "Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients."
"Patients in the [8-week telaprevir] group, as compared with those in the [12-week telaprevir] group, had a lower rate of response, and also a slightly lower rate of discontinuation of telaprevir," they elaborated in their discussion. "The lower rate of virologic failure during treatment in the [12-week] group as compared with the [8-week] group and the more frequent emergence of wild-type and lower-level resistant variants beyond week 12 in the [8-week] group than in the [12-week] group are probably attributable to more efficient elimination of these viral strains as a result of the additional 4 weeks of telaprevir therapy in the [12-week] group."
The researchers also noted that SVR rates "were substantially improved with the addition of telaprevir in patients with negative predictive factors for a response to peginterferon-ribavirin treatment, such as bridging fibrosis or cirrhosis, older age, diabetes, and HCV RNA levels of 800,000 IU per milliliter or more. An increase in sustained virologic response by a factor of more than 2 occurred with telaprevir in black patients, in whom low response rates to interferon have been reported."
"The significant improvement in the rates of sustained virologic response with telaprevir-based therapy and the capacity for response-guided therapy to shorten the duration of exposure to peginterferon-ribavirin among patients who have a rapid response represent important advances in the treatment of patients with HCV genotype 1 infection," they concluded.
Stefan Zeuzem from J.W. Goethe University in Frankfurt and fellow investigators looked at the safety and effectiveness of telaprevir in previously treated people in the REALIZE study, another large international Phase 3 trial.
This study included 663 genotype 1 chronic hepatitis C patients who had no response or partial response to previous therapy, or who relapsed after an initial response.
Again, participants were randomly assigned to receive 750 mg 3-times-daily telaprevir or placebo along with weekly pegylated interferon alfa-2a and daily weight-adjusted ribavirin. However, everyone in this harder-to-treat patient population received telaprevir for 12 weeks and pegylated interferon/ribavirin for 48 weeks. Some started with a 4-week pegylated interferon/ribavirin lead-in period before starting telaprevir.
- SVR rates were significantly higher in the 2 telaprevir groups compared with the standard therapy control group:
- Prior relapsers: 83% with concurrent start and 88% with lead-in, vs 24% in the standard therapy group;
- Prior partial responders: 59%, 54%, and 15%, respectively;
- Prior null responders: 29%, 33%, and 5%, respectively.
- SVR rates did not differ significantly in the telaprevir concurrent start and lead-in arms.
- The most common side effects overall (reported by > 25% of patients) were fatigue, pruritis or itching, rash, nausea, flu-like symptoms, anemia, and diarrhea.
- The most common serious side effects were blood cell deficiencies (anemia, neutropenia, leukopenia).
- Serious (grade 3) adverse events were significantly more frequent in the telaprevir groups compared with the standard therapy group (37% vs 22%).
- 5% of patients in the telaprevir arms experienced grade 3 rash, skin events leading to drug discontinuation, or serious skin-related adverse events, compared with none in the standard therapy group.
These findings led the investigators to conclude, "Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase."
"Among patients who have had no response or a partial response to previous therapy, those with a high baseline viral load and advanced liver fibrosis have disease that is particularly difficult to cure," they explained in their discussion. "In our study, more than 85% of patients had a high baseline viral load (i.e., above 800,000 IU per milliliter), 26% had liver cirrhosis, and 22% had bridging fibrosis. No specific safety and tolerability issues were associated with the use of telaprevir in patients with an advanced stage of liver fibrosis, and in such patients the rates of sustained virologic response were higher in the telaprevir groups than in the control group."
"Overall, virologic failure rates during therapy were lower in patients who had a previous relapse or a partial response than in patients who had no response to previous therapy," they continued. "Selection and persistence of drug-resistant variants is a common concern in the use of direct-acting antiviral agents...strict application of stopping rules may help to avoid the selection and long-term persistence of HCV variants with telaprevir resistance."
For more information about telaprevir, including full Prescribing Information, see www.Incivek.com.
IM Jacobson, JG McHutchison, G Dusheiko, et al (ADVANCE Study Team). Telaprevir for previously untreated chronic hepatitis C virus infection.
New England Journal of Medicine 364(25):2405-2416 (abstract). June 23, 2011.
S Zeuzem, P Andreone, S Pol, et al (REALIZE Study Team). Telaprevir for retreatment of HCV infection. New England Journal of Medicine 364(25):2417-2428 (abstract). June 23, 2011.
Vertex Pharmaceuticals. New England Journal of Medicine Publishes Data From Two Phase 3 Studies of Incivek (telaprevir) in Hepatitis C. Press release. June 22, 2011.