[转移贴]FDA真给力--两个HCV蛋白酶抑制药物同时上市

viruskiller

原贴由pumcpzg 发表于 2011-5-26 08:48

1. Incivek (telaprevir); Vertex; For the treatment of genotype 1 chronic hepatitis C, Approved May 2011
2. Victrelis (boceprevir); Merck; For the treatment of chronic hepatitis C genotype 1, Approved May 2011

1.
Drug Name: Incivek (telaprevir)
Company: Vertex
Approval Status: Approved May 2011
Treatment Area: genotype 1 chronic hepatitis C
General Information
Incivek (telaprevir) inhibits the hepatitis C protease NS3-4A, an enzyme that is essential for HCV viral replication.
Incivek is specifically indicated, in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C (CHC) in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment, including prior null responders, partial responders, and relapsers.
Invicek is supplied as a tablet for oral administration. The recommended dose is 750 mg (two 375-mg tablets) taken orally three times a day (7-9 hours apart) with food. Refer to the peginterferon alfa and ribavirin package inserts for instructions on dosing.
Clinical Results
FDA Approval
The FDA approval of Incivek was based on three clinical trials: two in treatment-naïve subjects and one in previously treated subjects (relapsers, partial responders, and null responders). In all three studies, Incivek was administered at a dosage of 750 mg every 8 hours; the peginterferon alfa-2a (Peg-IFN-alfa-2a) dose was 180 µg/week, and the ribavirin (RBV) dose was 1000 mg/day (subjects weighing less than 75 kg) or 1200 mg/day (subjects weighing greater than or equal to 75 kg).
Treatment-Naïve Adults
Study 108 (ADVANCE)
This randomized, double-blind, parallel-group, placebo-controlled, trial enrolled 1,088 subjects. Incivek was given for the first 8 weeks of treatment (T8/PR regimen) or the first 12 weeks of treatment (T12/PR regimen) in combination with Peg-IFN-alfa-2a/RBV for either 24 or 48 weeks. Subjects who had undetectable HCV-RNA at weeks 4 and 12 (extended Rapid Virologic Response [eRVR]) received 24 weeks of Peg-IFN-alfa-2a/RBV treatment, and subjects who did not have undetectable HCV-RNA at weeks 4 and 12 (no eRVR) received 48 weeks of Peg-IFN-alfa-2a/RBV treatment. In the T8/PR group, the overall SVR rate was 72%. The eRVR rate was 57% and the SVR rate for eRVR subjects was 87%. The SVR rate for no eRVR subjects was 52%. More subjects in the T8/PR group experienced virologic breakthrough after Week 12 while receiving peginterferon alfa and ribavirin alone, 16% compared to 10% in T12/PR group. In addition, in the T12/PR group, 21 subjects had cirrhosis at baseline and the overall SVR in these subjects was 62%. Among subjects with cirrhosis, 43% achieved an eRVR and of those 78% achieved SVR. Twenty-six subjects were African Americans. The overall SVR among this population was 62%. Among these subjects, 31% achieved an eRVR and of those 89% (8/9) achieved SVR.
Study 111 (ILLUMINATE)
This randomized, open-label trial was designed to compare SVR rates in 540 subjects achieving eRVR who were treated with Incivek for 12 weeks in combination with Peg-IFN-alfa-2a/RBV for either 24 weeks (T12/PR24 regimen) or 48 weeks (T12/PR48 regimen). The SVR rate for all subjects enrolled in the trial was 74%. A total of 352 (65%) subjects achieved eRVR and of those 322 (60%) were randomized to 24 weeks (T12/PR24, n=162) or 48 weeks (T12/PR48, n=160) of treatment. The SVR rates were similar at 92% (T12/PR24) and 90% (T12/PR48), respectively. Sixty-one (11%) of subjects had cirrhosis at baseline. Among these subjects, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 67% (12/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group. African Americans comprised 14% of study subjects. Thirty-four (47%) African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 94% (16/17), compared to 93% (246/265) for Caucasians.
Previously Treated Adults
Study C216 (REALIZE)
This randomized, double-blind, placebo-controlled, trial enrolled 662 prior relapsers and prior non-responders who were randomized to one of two Incivek combination treatment groups (with and without a Peg-IFN-alfa-2a/RBV lead-in) or a control group. The T12/PR48 group received Incivek and Peg-IFN-alfa-2a/RBV for 12 weeks (without a lead-in), followed by placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The T12(DS)/PR48 group had a lead-in (delayed start of Incivek) with placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by Incivek and Peg-IFN-alfa-2a/RBV for 12 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The Pbo/PR48 group received placebo and Peg-IFN-alfa-2a/RBV for 16 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. Among prior relapsers, 76% achieved an eRVR and of those 95% achieved an SVR. In an earlier, dose-finding clinical trial, 78% of prior relapsers achieved an eRVR and were treated with 24 weeks of peginterferon alfa and ribavirin (T12/PR24); of those 94% (49/52) achieved an SVR. Twenty-three percent of Incivek-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received Incivek combination treatment compared to Pbo/PR48 were: 87% compared to 13% for prior relapsers, 34% compared to 20% for prior partial responders, and 14% compared to 10% for prior null responders. Four percent of treatment experienced subjects who received Incivek combination treatment were African Americans; the SVR rate for these subjects was 63% compared to 65% for Caucasians.
Side Effects
Adverse events associated with the use of Incivek may include, but are not limited to, the following:
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•  rash
•  pruritus
•  anemia
•  nausea
•  hemorrhoids
•  diarrhea
•  anorectal discomfort
•  dysgeusia
•  fatigue
•  vomiting
•  anal pruritus
Mechanism of Action
Incivek is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication.



2.
Drug Name: Victrelis (boceprevir)
Company: Merck
Approval Status: Approved May 2011
Treatment Area: chronic hepatitis C genotype 1
General Information
Victrelis (boceprevir) is an inhibitor of the hepatitis C virus non-structural protein 3 (NS3) serine protease.
Victrelis is specifically indicated in combination with peginterferon alfa and ribavirin for adults with chronic hepatitis C genotype 1 infection with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Victrelis is supplied as a capsule for oral administration. The recommended dose of Victrelis is 800 mg (four 200-mg capsules) three times daily (every 7-9 hours) with food. Refer to the peginterferon alfa and ribavirin package inserts for instructions on dosing.
Clinical Results
FDA Approval
The FDA approval of Victrelis was based on two trials in 1500 adults who were previously untreated (SPRINT-2) or who had failed previous peginterferon alfa and ribavirin therapy (RESPOND-2).
SPRINT-2
This randomized, double-blind, placebo-controlled study enrolled subjects in two separate cohorts, one with non-African-American patients and the other with African-American patients. The trial evaluated 28- and 48-week regimens of boceprevir (800 mg three times daily (TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks. In the 28-week treatment arm, rapid viral response (RVR), defined as undetectable virus at 4 weeks of boceprevir treatment, (treatment week 8) was used to determine which boceprevir patients stopped all treatment at 28 weeks. The subjects who did not have RVR stopped boceprevir treatment at week 28 and continued PEGINTRON and REBETOL alone for an additional 20 weeks, for a total treatment duration of 48 weeks. In the 48-week treatment arm subjects received PEGINTRON and REBETOL plus boceprevir for a total treatment duration of 48 weeks. The subjects in any arm of the study with detectable virus at week 24 were considered treatment failures and treatment was discontinued. The primary endpoint was sustained virologic response (SVR). In the overall study population, 66% of subjects in the boceprevir 48-week treatment group and 63% of subejcts in the response-guided therapy group achieved SVR, compared to 38% of the control group (p<0.0001 for both, intent-to-treat analysis). Among the non-African-American patients in the boceprevir 48-week treatment group, 69% achieved SVR, and in the response-guided therapy group, 67% achieved SVR, compared to 40% in the control group (p<0.0001 for both, intent-to-treat analysis). Among the African-American patients, 53% of patients in the 48-week treatment group and 42% of patients in the response-guided therapy group achieved SVR, compared to 23% in the control group (p=0.004 and p=0.044, respectively, intent-to-treat analysis).
RESPOND-2
This randomized, double-blind, placebo-controlled study enrolled subjects who were either non-responders or relapsers to prior HCV therapy. The subjects received 36- and 48-week regimens of boceprevir (800 mg three times daily (TID) in combination with PEGINTRON (1.5 mcg/kg/week) and REBETOL (600-1400 mg/day) compared to a control of PEGINTRON and REBETOL alone for 48 weeks. In the 36-week treatment arm RVR criteria at 4 weeks of boceprevir treatment (treatment week 8) was used to determine which boceprevir patients were allowed to stop all treatment at 36 weeks. The subjects who did not meet the RVR criteria stopped boceprevir treatment at week 36 and continued on PEGINTRON and REBETOL alone for an additional 12 weeks, for a total treatment duration of 48 weeks. In the 48-week treatment arm subjects received PEGINTRON and REBETOL plus boceprevir for a total treatment duration of 48 weeks. Those subjects in any arm of the study with detectable virus at week 12 were considered treatment failures and discontinued treatment. The primary endpoint was sustained viral response (SVR). In the boceprevir 48-week treatment group, 66% of patients achieved SVR, and in the boceprevir response-guided therapy group, 59% of patients achieved SVR, compared to 21% of the control group (p<0.0001 for both, intent-to-treat analysis).
Side Effects
Adverse events associated with the use of Victrelis may include, but are not limited to, the following:
•        fatigue
•        anemia
•        nausea
•        headache
•        dysgeusia
Mechanism of Action
Victrelis (boceprevir) is an inhibitor of the hepatitis C virus non-structural protein 3 (NS3) serine protease.
Literature References
Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators Boceprevir for previously treated chronic HCV genotype 1 infection. New England Journal of Medicine 2011 Mar 31;364(13):1207-17
Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators Boceprevir for untreated chronic HCV genotype 1 infection. New England Journal of Medicine 2011 Mar 31;364(13):1195-206