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Approval of Victrelis (Boceprevir), a Direct-Acting Antiviral Drug to Treat Hepatitis C Virus

May 15, 2011

On May 13, 2011, FDA approved VICTRELISTM (boceprevir), a hepatitis C virus (HCV) protease inhibitor, which works by binding to the virus and preventing it from multiplying. Boceprevir is the first direct acting antiviral drug against the hepatitis C virus to be approved.

VICTRELIS is indicated for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy

The following points should be considered when initiating VICTRELIS for treatment of chronic hepatitis C infection:

DOSAGE AND ADMINISTRATION

VICTRELIS must be administered in combination with peginterferon alfa and ribavirin. The dose of VICTRELIS is 800 mg (four 200-mg capsules) three times daily (every 7-9 hours) with food [a meal or light snack] (see Table 1). Refer to the peginterferon alfa and ribavirin Package Inserts for instructions on dosing.

The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials. Response-Guided Therapy (RGT) is recommended for most individuals, but longer dosing is recommended in targeted subgroups (e.g., patients with cirrhosis).

VICTRELIS Combination Therapy: Patients Without Cirrhosis Who Are Previously Untreated or Who Are Previous Partial Responders or Relapsers to Interferon and Ribavirin therapy

Table 1
Duration of Therapy Using Response-Guided Therapy (RGT) Guidelines in Patients Without Cirrhosis Who Are Previously Untreated or Who Are Previous Partial Responders or Relapsers to Interferon and Ribavirin Therapy

 ASSESSMENT* (HCV-RNA Results†) RECOMMENDATION
 At Treatment Week 8 At Treatment Week 24
Previously Untreated Patients Undetectable Undetectable Complete three-medicine regimen at TW28.
Detectable Undetectable
  1. Continue all three medicines and finish through TW36; and then
  2. Administer peginterferon alfa and ribavirin and finish through TW48.
Previous Partial Responders or Relapsers Undetectable Undetectable Complete three-medicine regimen at TW36.
Detectable Undetectable
  1. Continue all three medicines and finish through TW36; and then
  2. Administer peginterferon alfa and ribavirin and finish through TW48.
*TREATMENT FUTILITY

If the patient has HCV-RNA results greater than or equal to 100 IU/mL at TW12, then discontinue three-medicine regimen.
If the patient has confirmed, detectable HCV-RNA at TW24, then discontinue three-medicine regimen.

† In clinical trials, HCV-RNA in plasma was measured using a Roche COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. See Warnings and Precautions (5.5) for a description of HCV-RNA assay recommendations.

Response-Guided Therapy was not studied in subjects who had less than a 2-log10 HCV-RNA decline by treatment week 12 during prior therapy with peginterferon alfa and ribavirin. If considered for treatment, these subjects should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily (every 7-9 hours) in combination with peginterferon alfa and ribavirin. In addition, consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW4) with 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of VICTRELIS 800 mg orally three times daily (every 7-9 hours) in combination with peginterferon alfa and ribavirin in order to maximize rates of SVR [see Clinical Studies (14)].

VICTRELIS Combination Therapy: Patients with Cirrhosis
Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed by 44 weeks VICTRELIS 800 mg (four 200-mg capsules) three times daily (every 7-9 hours) in combination with peginterferon alfa and ribavirin.

Dose Modification
Dose reduction of VICTRELIS is not recommended.
If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin Package Inserts for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

Discontinuation of Dosing Based on Treatment Futility
Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 100 IU/mL at TW12; or 2) confirmed detectable HCV-RNA levels at TW24.

CLINICAL TRIAL RESULTS

The approval of Victrelis is based on safety and efficacy data in approximately 1500 adult subjects who were previously untreated (SPRINT-2) or who had failed previous peginterferon alfa and ribavirin therapy (RESPOND-2) in Phase 3 clinical studies

Previously Untreated Subjects
SPRINT-2 was a randomized, double-blind, placebo-controlled study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [PegIntron 1.5 µg/kg/week subcutaneously and weight-based dosing with REBETOL (600-1400 mg/day orally divided twice daily)] to PR alone in adult subjects who had chronic hepatitis C (HCV genotype 1) infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy. Subjects were randomized in a 1:1:1 ratio within two separate cohorts (Cohort 1/non-Black and Cohort 2/Black) and were stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load (=400,000 IU/mL vs. >400,000 IU/mL) to one of the following three treatment arms:

All subjects with detectable HCV-RNA in plasma at TW24 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA undetectable at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.

Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 82% White, 14% Black, and 4% others. The distribution of subjects by gender was 60% men and 40% women.

The addition of VICTRELIS to PegIntron and REBETOL significantly increased the SVR rates compared to PegIntron and REBETOL alone in the combined cohort (63% to 66% VICTRELIS-containing arms vs. 38% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population). SVR rates for Blacks in a predefined analysis who received the combination of VICTRELIS with PegIntron and REBETOL were 42% to 53% (see Table 10).

Table 10
Sustained Virologic Response (SVR)*, † and Relapse Rates‡ for Previously Untreated Subjects

Study Cohorts VICTRELIS-RGT VICTRELIS-PR48 PR48
Cohort 1 Plus Cohort 2 (all subjects) n=368 n=366 n=363
SVR† % 63 66 38
Relapse‡ %
(n/N)
9
(24/257)
9
(24/265)
22
(39/176)
Cohort 1 Plus Cohort 2 (subjects without cirrhosis)      
SVR†,§ %
(n/N)
65
(228/352)
68
(232/342)
38
(132/350)
Cohort 1 (non-Black) n=316 n=311 n=311
SVR† % 67 68 40
Relapse‡ % (n/N) 9
(21/232)
8
(18/230)
23
(37/162)
Cohort 2 (Black) n=52 n=55 n=52
SVR† % 42 53 23
Relapse‡ % (n/N) 12
(3/25)
17
(6/35)
14
(2/14)

*The Full Analysis Set (FAS) consisted of all randomized subjects (N=1097) who received at least one dose of any study medication (PegIntron, REBETOL, or VICTRELIS).

†Sustained Virologic Response (SVR): reported as plasma HCV-RNA < 25 IU/mL at follow-up week (FW) 24. The last available HCV-RNA value in the period at or after FW24 was used. If HCV-RNA value at FW24 was missing, the FW12 value was carried forward.

‡Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA (≥ 25 IU/mL) at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data.

§Includes subjects with missing baseline data regarding cirrhosis as diagnosed by liver biopsy.

In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of VICTRELIS with PegIntron and REBETOL for 44 weeks after lead-in therapy with PegIntron and REBETOL (10/24, 42%) compared to those who received RGT (5/16, 31%).

Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
Table 11 presents sustained virologic response based on TW8 HCV-RNA results in previously untreated subjects. Fifty-seven percent (208/368) of subjects in the VICTRELIS-RGT arm and 56% (204/366) of subjects in the VICTRELIS-PR48 arm had undetectable HCV RNA at TW8 (early responders) compared with 17% (60/363) of subjects in the PR48 arm.

Table 11
Sustained Virologic Response (SVR) by HCV-RNA Detectability at TW8 in Previously Untreated Subjects in the Combined Cohort

  VICTRELIS-RGT VICTRELIS-PR48 PR48
SVR by TW8 Detectability, % (n/N)* N=337 N=335 N=331
Undetectable 88 (184/208) 90 (184/204) 85 (51/60)
Detectable 36 (46/129) 40 (52/131) 30 (82/271)
*Denominator included only subjects with HCV-RNA results at TW8.

Among subjects with detectable HCV-RNA at TW8 who had attained undetectable HCV-RNA at TW24 and completed at least 28 weeks of treatment, the SVR rates were 66% (45/68) in VICTRELIS-RGT arm (4 weeks of PegIntron and REBETOL then 24 weeks of VICTRELIS with PegIntron and REBETOL followed by 20 weeks of PegIntron and REBETOL alone) and 75% (55/73) in VICTRELIS-PR48 arms (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).

Subjects Who Failed Previous Therapy with Peginterferon Alfa and Ribavirin
RESPOND-2 was a randomized, parallel-group, double-blind study comparing two therapeutic regimens of VICTRELIS 800 mg orally three times daily in combination with PR [PegIntron 1.5 µg/kg/week subcutaneously and weight-based ribavirin (600-1400 mg/day orally divided twice daily)] compared to PR alone in adult subjects with chronic hepatitis C (HCV genotype 1) infection with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral load greater than or equal to 2-log10 by Week 12, but never achieved SVR [partial responders] or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma [relapsers]). Subjects with less than 2-log10 decrease in HCV-RNA by week 12 of previous treatment (prior null responders) were not eligible for enrollment in this trial. Subjects were randomized in a 1:2:2 ratio and stratified based on response to their previous qualifying regimen (relapsers vs. partial responders) and by HCV subtype (1a vs. 1b) to one of the following treatment arms:

All subjects with detectable HCV-RNA in plasma at TW12 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA undetectable at Follow-up Week 24. Plasma HCV-RNA results at Follow-up Week 12 were used if plasma HCV-RNA results at Follow-up Week 24 were missing.

Mean age of subjects randomized was 53 years. The racial distribution of subjects was as follows: 85% White, 12% Black, and 3% others. The distribution of subjects by gender was 67% men and 33% women.

The addition of VICTRELIS to the PegIntron and REBETOL therapy significantly increased the SVR rates compared to PegIntron/REBETOL alone (59% to 66% VICTRELIS-containing arms vs. 23% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population) (see Table 12).

Table 12
Sustained Virologic Response (SVR)*, † and Relapse‡ Rates for Subjects Who have Failed Previous Therapy with Peginterferon Alfa and Ribavirin

  VICTRELIS-RGT VICTRELIS-PR48 PR48
  N=162 N=161 N=80
SVR† % 59 66 23
Relapse‡ %
(n/N)
14
(16/111)
12
(14/121)
28
(7/25)
SVR (subjects without cirrhosis) §
(n/N)
62
(90/145)
65
(90/139)
26
(18/70)
SVR by Response to Previous Peginterferon and Ribavirin Therapy
Previous Response Relapser, % (n/N) 70 (73/105) 75 (77/103) 31 (16/51)
Partial responder, % (n/N) 40 (23/57) 52 (30/58) 7 (2/29)

*The Full Analysis Set (FAS) consisted of all randomized subjects (N=403) who received at least one dose of any study medication (PegIntron, REBETOL, or VICTRELIS).

†Sustained Virologic Response (SVR): reported as plasma HCV-RNA < 25 IU/mL at follow-up week (FW) 24. The last available HCV RNA value in the period at or after FW24 was used. If HCV RNA value at FW24 was missing, the FW12 value was carried forward.

‡Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA (≥ 25 IU/mL) at End of Follow-up (EOF) among subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data.

§Includes subjects with missing baseline data regarding cirrhosis as diagnosed by liver biopsy.

Previous Partial Responder = subject who failed to achieve SVR after at least 12 weeks of previous treatment with PegIntron/REBETOL, but demonstrated a ≥2-log10 reduction in HCV-RNA by Week 12.

Previous Relapser = subject who failed to achieve SVR after at least 12 weeks of previous treatment with PegIntron/REBETOL, but had undetectable HCV-RNA at the end of treatment.

In subjects with cirrhosis at baseline, sustained virologic response was higher in those who received treatment with the combination of VICTRELIS with PegIntron and REBETOL for 44 weeks after 4 weeks of lead-in therapy with PegIntron and REBETOL (17/22, 77%) compared to those who received RGT (6/17, 35%).

Sustained Virologic Response (SVR) Based on TW8 HCV-RNA Results
Table 13 presents sustained virologic response based on TW8 HCV-RNA results in subjects who have failed previous therapy. Forty-six percent (74/162) of subjects in the VICTRELIS-RGT arm and 52% (84/161) in the VICTRELIS-PR48 had undetectable HCV RNA at TW8 (early responders) compared with 9% (7/80) in the PR48 arm.

Table 13
Sustained Virologic Response (SVR) by HCV-RNA Detectability at TW8 in Subjects Who Have Failed Previous Therapy

  VICTRELIS-RGT VICTRELIS-PR48 PR48
SVR by TW8 Detectability, % (n/N)* N=146 N=154 N=72
Undetectable 88 (65/74) 88 (74/84) 100 (7/7)
Detectable 40 (29/72) 43 (30/70) 14 (9/65)
*Denominator included only subjects with HCV-RNA results at TW8.

Among subjects with detectable HCV-RNA at TW 8 who attained an undetectable HCV-RNA at TW12 and completed at least 36 weeks of treatment, the SVR rates were 79% (27/34) in VICTRELIS-RGT arm (4 weeks of PegIntron and REBETOL then 32 weeks of VICTRELIS with PegIntron and REBETOL followed by 12 weeks of PegIntron and REBETOL alone) and 72% (29/40) in VICTRELIS-PR48 arm (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).

Interferon Responsiveness during Lead-In Therapy with Peginterferon alfa and Ribavirin

Previously Untreated Subjects
In previously untreated subjects evaluated in SPRINT-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. VICTRELIS-treated subjects who demonstrated interferon responsiveness at TW4 achieved SVR rates of 81% (203/252) in VICTRELIS-RGT arm and 79% (200/254) in VICTRELIS-PR48 arm, compared to 52% (134/260) in subjects treated with PegIntron/REBETOL.
VICTRELIS-treated subjects who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4), achieved SVR rates of 28% (27/97) in VICTRELIS-RGT arm and 38% (36/95) in VICTRELIS-PR48 arm, compared to 4% (3/83) in subjects treated with PegIntron/REBETOL. Subjects with less than a 0.5-log10 decline in viral load at TW4 achieved SVR rates of 28% (13/47) in VICTRELIS-RGT arm and 30% (11/37) in VICTRELIS-PR48 arm, compared to 0% (0/25) in subjects treated with PegIntron/REBETOL. Subjects with less than a 0.5-log10 decline in viral load at TW4 with peginterferon alfa plus ribavirin therapy alone are predicted to have a null response (less than 2-log10 viral load decline at TW12) to peginterferon alfa and ribavirin.

Subjects Who Failed Previous Therapy with Peginterferon Alfa and Ribavirin
In subjects who were previous relapsers and partial responders evaluated in RESPOND-2, interferon-responsiveness (defined as greater than or equal to 1-log10 decline in viral load at TW4) was predictive of SVR. VICTRELIS-treated subjects who demonstrated interferon responsiveness at TW4 achieved SVR rates of 74% (81/110) in VICTRELIS-RGT arm and 79% (90/114) in VICTRELIS-PR48 arm, compared to 27% (18/67) in subjects treated with PegIntron/REBETOL. VICTRELIS-treated subjects who demonstrated poor interferon responsiveness (defined as less than 1-log10 decline in viral load at TW4) achieved SVR rates of 33% (15/46) in VICTRELIS-RGT arm and 34% (15/44) in VICTRELIS-PR48 arm, compared to 0% (0/12) in subjects treated with PegIntron/REBETOL.

CONTRAINDICATIONS

VICTRELIS combination treatment is contraindicated in:

WARNINGS AND PRECAUTIONS

The Warnings and Precautions for Victrelis include drug interactions and the following:

ADVERSE DRUG REACTIONS
The most commonly reported adverse reactions (>35% subjects of regardless of investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when VICTRELIS was used in combination with PegIntron and REBETOL.

During the four week lead-in period with PegIntron/REBETOL in the VICTRELIS-containing arms, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and 12% for subjects receiving PegIntron/REBETOL alone. Events resulting in discontinuation were similar to those seen in previous studies with PegIntron/REBETOL. Only anemia and fatigue were reported as events that led to discontinuation in >1% of subjects in any arm

USE IN SPECIAL POPULATIONS:

The complete label is available on the FDA website at Drugs@FDA, an online database where you can find drug labeling and other information related to product approval.

An FDA press release provides additional information about the approval.




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