Boceprevir clinical studies

# Clinical Studies
The efficacy of VICTRELIS as a treatment for chronic hepatitis C (genotype 1) infection was assessed 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 1600 mg orally three times daily in combination with PR  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 (less than or equal to 400,000 IU per mL vs. more than 400,000 IU per mL) to one of the following three treatment arms:
- PegIntron + REBETOL for 48 weeks (PR48).
- PegIntron + REBETOL for four weeks followed by VICTRELIS 1600 mg three times daily + PegIntron + REBETOL for 24 weeks. The subjects were then continued on different regimens based on Treatment Week (TW) 8 through TW24 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 24 weeks of therapy with VICTRELIS.
Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with PegIntron + REBETOL for an additional 20 weeks, for a total treatment duration of 48 weeks.
- Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and remained undetectable through TW24 discontinued therapy and entered follow-up at the TW28 visit.
- Subjects with detectable HCV-RNA at TW8 or any subsequent treatment week but subsequently achieving undetectable HCV-RNA (Target Not Detected) at TW24 (late responders) were changed in a blinded fashion to placebo at the TW28 visit and continued therapy with PegIntron + REBETOL for an additional 20 weeks, for a total treatment duration of 48 weeks.
- PegIntron + REBETOL for four weeks followed by VICTRELIS 1600 mg three times daily + PegIntron + REBETOL for 44 weeks (boceprevir-PR48).
All subjects with detectable HCV-RNA in plasma at TW24 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL 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% in arms containing VICTRELIS 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 who received the combination of VICTRELIS with PegIntron and REBETOL were 42% to 53% in a predefined analysis (see Table 10).
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 boceprevir-RGT arm and 56% (204/366) of subjects in the boceprevir-PR48 arm had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 17% (60/363) of subjects in the PR48 arm.
Among subjects with detectable HCV-RNA at TW8 who had attained undetectable HCV-RNA (Target Not Detected) at TW24 and completed at least 28 weeks of treatment, the SVR rates were 66% (45/68) in boceprevir-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 boceprevir-PR48 arms (4 weeks of PegIntron and REBETOL then 44 weeks of VICTRELIS with PegIntron and REBETOL).

## Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy
RESPOND-2 was a randomized, parallel-group, double-blind study comparing two therapeutic regimens of VICTRELIS 1600 mg orally three times daily in combination with PR  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  or undetectable HCV-RNA at end of prior treatment with a subsequent detectable HCV-RNA in plasma ). 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:
- PegIntron + REBETOL for 48 weeks (PR48)
- PegIntron + REBETOL for 4 weeks followed by VICTRELIS 1600 mg three times daily + PegIntron + REBETOL for 32 weeks. The subjects were then continued on different treatment regimens based on TW8 and TW12 response-guided therapy (boceprevir-RGT). All subjects in this treatment arm were limited to 32 weeks of VICTRELIS.
Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with PegIntron + REBETOL for an additional 12 weeks, for a total treatment duration of 48 weeks.
- Subjects with undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) and TW12 completed therapy at TW36 visit.
- Subjects with a detectable HCV-RNA at TW8 but subsequently undetectable (Target Not Detected) at TW12 (late responders) were changed in a blinded fashion to placebo at the TW36 visit and continued treatment with PegIntron + REBETOL for an additional 12 weeks, for a total treatment duration of 48 weeks.
- PegIntron + REBETOL for 4 weeks followed by VICTRELIS 1600 mg three times daily + PegIntron + REBETOL for 44 weeks (boceprevir-PR48).
All subjects with detectable HCV-RNA in plasma at TW12 were discontinued from treatment. Sustained Virologic Response (SVR) was defined as plasma HCV-RNA less than 25 IU/mL 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% in arms containing VICTRELIS vs. 23% PR48 control) for randomized subjects who received at least one dose of any study medication (Full-Analysis-Set population) (see Table 12).
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 were relapsers or partial responders to previous interferon and ribavirin therapy. Forty-six percent (74/162) of subjects in the boceprevir-RGT arm and 52% (84/161) in the boceprevir-PR48 had undetectable HCV-RNA (Target Not Detected) at TW8 (early responders) compared with 9% (7/80) in the PR48 arm.
Among subjects with detectable HCV-RNA at TW8 who attained an undetectable HCV-RNA (Target Not Detected) at TW12 and completed at least 36 weeks of treatment, the SVR rates were 79% (27/34) in boceprevir-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 boceprevir-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. Subjects treated with VICTRELIS who demonstrated interferon responsiveness at TW4 achieved SVR rates of 81% (203/252) in boceprevir-RGT arm and 79% (200/254) in boceprevir-PR48 arm, compared to 52% (134/260) in subjects treated with PegIntron/REBETOL.
Subjects treated with VICTRELIS 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 boceprevir-RGT arm and 38% (36/95) in boceprevir-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 boceprevir-RGT arm and 30% (11/37) in boceprevir-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.
Previous Partial Responders and Relapsers to Interferon and Ribavirin Therapy
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. Subjects treated with VICTRELIS who demonstrated interferon responsiveness at TW4 achieved SVR rates of 74% (81/110) in boceprevir-RGT arm and 79% (90/114) in boceprevir-PR48 arm, compared to 27% (18/67) in subjects treated with PegIntron/REBETOL. Subjects treated with VICTRELIS 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 boceprevir-RGT arm and 34% (15/44) in boceprevir-PR48 arm, compared to 0% (0/12) in subjects treated with PegIntron/REBETOL.

## Prior Null Responders to Interferon and Ribavirin Therapy
PROVIDE is an ongoing, open-label, single-arm study of VICTRELIS 1600 mg orally three times daily in combination with peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600  1,400 mg per day orally divided twice daily) in adult subjects with chronic hepatitis C (HCV) genotype 1 infection who did not achieve SVR while in the peginterferon alfa/ribavirin control arms of previous Phase 2 and 3 studies of combination therapy with VICTRELIS. Subjects who enrolled in PROVIDE within 2 weeks after the last dose of peginterferon alfa/ribavirin in the parent study received VICTRELIS 1600 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks. Subjects who were not able to enroll in this study within 2 weeks received PegIntron/REBETOL lead-in for 4 weeks followed by VICTRELIS 1600 mg three times daily + peginterferon alfa-2b + ribavirin for 44 weeks.
Among the subjects who were null responders in the peginterferon alfa/ribavirin control arm of the parent study that received the 4-week PegIntron/REBETOL lead-in treatment followed by VICTRELIS 1600 mg three times daily + PegIntron/REBETOL for 44 weeks, 38% (20/52) achieved SVR, and the relapse rate was 14% (3/22).

## Use of Ribavirin Dose Reduction versus Erythropoiesis Stimulating Agent (ESA) in the Management of Anemia in Previously Untreated Subjects
A randomized, parallel-arm, open-label study was conducted to compare two strategies for the management of anemia (use of ESA versus ribavirin dose reduction) in 687 subjects with previously untreated CHC genotype 1 infection who became anemic during therapy with VICTRELIS 1600 mg orally three times daily plus peginterferon alfa-2b 1.5 micrograms per kg per week subcutaneously and weight-based ribavirin (600  1,400 mg per day orally divided twice daily). The study enrolled subjects with serum hemoglobin concentrations of less than 15 g per dL. Subjects were treated for 4 weeks with peginterferon alfa-2b and ribavirin followed by up to 44 weeks of VICTRELIS plus peginterferon alfa-2b and ribavirin. If a subject became anemic (serum hemoglobin of approximately less than or equal to 10 g per dL within the treatment period), the subject was randomized in a 1:1 ratio to either ribavirin dose reduction (N=249) or use of erythropoietin 40,000 units subcutaneously once weekly for the management of the anemia (N=251). If serum hemoglobin concentrations continued to decrease to less than or equal to 8.5 g per dL, subjects could be treated with additional anemia interventions, including the addition of erythropoietin (18% of those in the ribavirin dose reduction arm) or ribavirin dose reduction (37% of those in the ESA arm).
Mean age of subjects randomized was 49 years. The racial distribution of subjects was as follows: 77% White, 19% Black, and 4% other. The distribution of subjects by gender was 37% men and 63% women.
The overall intent-to-treat SVR rate for all enrolled subjects (including those subjects who were not randomized to RBV dose reduction or ESA for the management of anemia) was 63% (431/687). The SVR rate in subjects randomized who received ribavirin dose reduction was 71% (178/249), similar to the SVR rate of 71% (178/251) in subjects randomized to receive an ESA. The relapse rates in subjects randomized to receive ribavirin dose reduction or an ESA were 10% (19/196) and 10% (19/197), respectively.