Pharmacology Update

Telaprevir Film-Coated Tablets (Incivek™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship relevant to this field of study.

A second NS3/4A protease inhibitor has been approved by the FDA for the treatment of chronic hepatitis C (HCV) genotype 1, joining the recently approved boceprevir (Victrelis™). Telaprevir is marketed by Vertex Pharmaceuticals as Incivek.

Indications

Telaprevir is indicated, in combination with peginterferon and ribavirin, for the treatment of genotype 1 chronic hepatitis C in adult patients.1 This includes treatment-naïve patients, those with compensated liver disease including cirrhosis, or those who are treatment-experienced with interferon-based treatment. The latter group may be relapsers, partial responders, or null responders.

Dosage

The recommended dose for treatment-naïve and prior relapsers is 750 mg (two 375 mg tablets) taken three times a day (7-9 hours apart) with food.1 Telaprevir should be taken with peginterferon and ribavirin (triple therapy) for 12 weeks followed by a response-guided regimen.1 If virus is undetectable at week 4 and 12, peginterferon/ribavirin (PR) therapy is continued for an additional 12 weeks. If virus is detected at week 12, an additional 36 weeks of PR therapy is recommended. For prior partial or null responders, 36 weeks of dual therapy is recommended after 12 weeks of triple therapy. Treatment should be discontinued if HCV-RNA is equal to or greater than 1000 IU/mL at treatment week 4 or 12, or detectable at treatment week 24.

Telaprevir is available as 375 mg tablets.

Potential Advantages

The addition of telaprevir to peginterferon alfa-2a/ribavirin significantly improved sustained virologic response (SVR) compared to peginterferon/ribavirin alone in both treatment-naïve and previously treated patients with chronic hepatitis C genotype 1.1,2

Potential Disadvantages

Most common adverse events associated with telaprevir (compared to peginterferon/ribavirin) are rash (56% vs 34%), pruritus (47% vs 28%), nausea (39% vs 28%), anemia (36% vs 17%), and diarrhea (26% vs 17%).1 Telaprevir is an inhibitor of CYP3A and p-glycoprotein. Concomitant administration with drugs that are metabolized by CYP3A or substrates of p-glycoprotein may increase the plasma levels of these drugs.

Comments

The safety and efficacy of telaprevir was evaluated in three randomized clinical trials (ADVANCE, ILLUMINATE, and REALIZE).1,2 In ADVANCE, treatment-naïve patients were randomized to telaprevir for 12 weeks (T12PR) (n = 363) or 8 weeks plus 4 weeks of placebo (T8PR) (n = 364) in combination with peginterferon alfa-2a (180 mcg/week) and ribavirin (800 mg/day or 1200 mg/day based on whether weight was equal to or less than or greater than 75 kg) followed by PR for 24 or 48 weeks. Patients who achieved undetectable virus at weeks 4 and 12 received 24 weeks of therapy and those with detectable virus received 48 weeks. The control group was peginterferon/ribavirin for 48 weeks (PR48) (n = 361). The primary efficacy endpoint was SVR, defined as HCV-RNA less than 25 IU/mL at 24 weeks after the planned end of treatment. SVR rates were 75% for T12PR, 69% for T8PR, and 44% for PR48. Most common adverse events were fatigue, pruritus, nausea, anemia, and headache.

ILLUMINATE was designed to evaluate whether it was beneficial to extend therapy from 24 to 48 weeks in patients who had achieved undetectable virus at weeks 4 and 12 weeks. SVR rates were 92% (149/162) for T12/PR24 and 88% (140/160) for T12/PR48. Relapse rates were 5.7% (9/159) and 1.9% (3/154), respectively.3 The findings suggest no real overall added advantage with 48 weeks of therapy.1-3 However, a small subset of patients with cirrhosis achieved a higher SVR with 48 weeks of therapy 92% (11/12) compared to 67% (12/18).

REALIZE included patients who were partial or null responders or relapsers. These patients were randomized 2:2:1 to: 1) 12 weeks of telaprevir with PR, 4 weeks of placebo plus PR, and 32 weeks of PR (T12PR48); 2) 4-week lead-in with PR followed by 12 weeks of telaprevir plus PR, and PR for 32 weeks; or 3) PR for 48 weeks. The overall SVR rates for telaprevir/PR were 86% for prior relapsers, 59% for prior partial responders, and 32% for prior null responders compared to 22%, 15%, and 5% for PR only. Relapse rates for telaprevir were 24% for prior null responders, 20% for partial responders, and 3% for prior relapsers. Skin reactions (rash and pruritus) and anemia were more likely associated with telaprevir compared to peginterferon/ribavirin.

Clinical Implications

Telaprevir is the second protease inhibitor approved for the treatment of HCV genotype 1 infection. Both boceprevir and telaprevir have improved SVR by roughly 60% to 70% compared to peginteferon and ribavirin alone. There are no direct comparisons between telaprevir and boceprevir. In addition, telaprevir is combined with peginterfon alpha-2a while boceprevir was used with peginterferon alpha-2b, doses of ribavirin were slightly different, and treatment schedules differ. Initial selection may be based on simplicity of the dosing schedule and cost.

References

1. Incivek Prescribing Information. Cambridge, MA: Vertex Pharmaceuticals Incorporated; May 2011.

2. Pawlotsky JM. The results of Phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: A new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterology 2011;140:746-760.

3. http://www.businesswire.com/news/home/20100810005477/en/Phase-3-ILLUMINATE-Study-Supports-24-Week-Telaprevir-Based. Accessed May 29, 2011.