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Pegasys

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Pegasys

CLINICAL PHARMACOLOGY

Mechanism of Action

Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune response [see Microbiology].

Pharmacodynamics

PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5'-oligoadenylate synthetase.

Pharmacokinetics

Maximal serum concentrations (Cmax) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mcg of PEGASYS. Maximal serum concentrations (Cmax) occur between 72 to 96 hours post-dose.

Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON®-A). The mean terminal half-life after subcutaneous dosing in subjects with chronic hepatitis C was 160 hours (range 84 to 353 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A.

Special Populations

Gender and Age

PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng·h/mL in subjects older than 62 years taking 180 mcg PEGASYS, but peak concentrations were similar (9 vs. 10 ng/mL) in those older and younger than 62 years.

Pediatric Patients

In a population pharmacokinetics study, 14 children 2 to 8 years of age with CHC received PEGASYS based on their body surface area (BSA of the child x 180 mcg/1.73 m²). The clearance of PEGASYS in children was nearly 4-fold lower compared to the clearance reported in adults.

Steady-state trough levels in children with the BSA-adjusted dosing were similar to trough levels observed in adults with 180 mcg fixed dosing. Time to reach the steady state in children is approximately 12 weeks, whereas in adults, steady state is reached within 5 to 8 weeks. In these children receiving the BSA adjusted dose, the mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing.

Renal Impairment

A clinical trial evaluated 50 CHC subjects with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). Subjects with moderate renal impairment receiving PEGASYS 180 mcg once weekly dose exhibited similar peginterferon alfa-2a plasma exposures compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of PEGASYS. No PEGASYS dose adjustment is required for patients with mild or moderate renal impairment [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

For subjects with severe renal impairment, peginterferon alfa-2a apparent clearance was 43% lower as compared to subjects with normal renal function. A reduced dose of 135 mcg once weekly PEGASYS is recommended in patients with severe renal impairment. This dose may result in 30% higher peginterferon alfa2a exposure compared to that of the recommended dose for patients with normal renal function. Signs and symptoms of interferon toxicity should be closely monitored in patients with severe renal impairment and the dose reduced to 90 mcg once weekly as appropriate [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

In 18 subjects with ESRD receiving chronic HD, PEGASYS was administered at a dose of 135 mcg once weekly. The apparent clearance of peginterferon alfa-2a was similar between subjects with ESRD and subjects with normal renal function. Despite a lower exposure to peginterferon alfa-2a with the 135 mcg dose, subjects with ESRD had a high rate of adverse events and discontinuations of PEGASYS in the trial. Therefore, a dose of 135 mcg once weekly should be used for patients with ESRD on HD. However, the potential for reduced efficacy and increased interferon toxicity in patients with ESRD receiving chronic HD should be closely monitored. The dose may be reduced to 90 mcg once weekly as appropriate [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Microbiology

Mechanism of Action

The biological activity of PEGASYS is derived from its recombinant human interferon α-2a moiety. Peginterferon α-2a binds to the human type 1 interferon receptor leading to receptor dimerization. Receptor dimerization activates multiple intracellular signal transduction pathways initially mediated by the JAK/STAT pathway. Given the diversity of cell types that respond to interferon α-2a, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon α-2a is expected to have pleiotropic biological effects in the body.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV RNA replication with an effective concentration (EC50) value of 11-21 mcm. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC50 value of 0.1-3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance

Cross-resistance between IFN-α and ribavirin has not been observed.

Clinical Studies

Chronic Hepatitis C Studies 1, 2, and 3: PEGASYS Monotherapy

The safety and effectiveness of PEGASYS for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All subjects were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All subjects received therapy by subcutaneous injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

In Study 1 (n=630), subjects received either ROFERON-A (interferon alfa-2a) 3 MIU three times a week, PEGASYS 135 mcg once weekly or PEGASYS 180 mcg once weekly. In Study 2 (n=526), subjects received either ROFERON-A 6 MIU three times a week for 12 weeks followed by 3 MIU three times a week for 36 weeks or PEGASYS 180 mcg once weekly. In Study 3 (n=269), subjects received ROFERON-A 3 MIU three times a week, PEGASYS 90 mcg once weekly or PEGASYS 180 mcg once each week.

In all three studies, treatment with PEGASYS 180 mcg resulted in significantly more subjects who experienced a sustained response (defined as undetectable HCV RNA [less than 50 IU/mL] using the COBAS AMPLICOR® HCV Test, version 2 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In Study 1, response to PEGASYS 135 mcg was not different from response to 180 mcg. In Study 3, response to PEGASYS 90 mcg was intermediate between PEGASYS 180 mcg and ROFERON-A.

Table 11 : Sustained Response to Monotherapy Treatment

  Study 1 Study 2 Study 3
Roferon-A 3 MIU
(N=207)
PEGASYS 180 mcg
(N=208)
Diff* (95% CI) Roferon-A 6/3 MIU†
(N=261)
PEGASYS 180 mcg
(N=265)
Diff* (95% CI) Roferon-A 3 MIU
(N=86)
PEGASYS 180 mcg
(N=87)
Diff* (95% CI)
Combined Virologic and Biologic Sustained Response¶ 11% 24% 13 (6, 20) 17% 35% 18 (11, 25) 7% 23% 16 (6, 26)
Sustained Virologic Response 11% 26% 15 (8, 23) 19% 38% 19 (11, 26) 8% 30% 22 (11, 33)
*Percent difference between PEGASYS and ROFERON-A treatment.
†An induction dose of 6 million international units (MIU) three times a week for the first 12 weeks followed by 3 million international units three times a week for 36 weeks given subcutaneously.
¶ Defined as undetectable HCV RNA [less than 50 IU/mL] using the COBAS AMPLICOR®HCV Test, version 2 and normalization of ALT on or after study week 68.

Matched pre-and post-treatment liver biopsies were obtained in approximately 70% of subjects. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups.

Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log10 drop in HCV RNA titer from baseline by 12 weeks of PEGASYS 180 mcg therapy, 2% (3/156) achieved a sustained virologic response [see DOSAGE AND ADMINISTRATION].

Averaged over Study 1, Study 2, and Study 3, response rates to PEGASYS were 23% among subjects with viral genotype 1 and 48% among subjects with other viral genotypes. The treatment response rates were similar in men and women.

Chronic Hepatitis C Studies 4, 5, and 6: PEGASYS/COPEGUS Combination Therapy

Adult Patients

The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of subjects in both studies had compensated cirrhosis (Child-Pugh class A). Subjects coinfected with HIV were excluded from these studies.

In Study 4, subjects were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS 180 mcg once weekly with COPEGUS 1000 mg by mouth (body weight less than 75 kg) or 1200 mg by mouth (body weight greater than or equal to 75 kg) or Rebetron® (interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth). All subjects received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table 12). In all treatment arms, subjects with viral genotype 1, regardless of viral load, had a lower response rate.

Table 12 : Sustained Virologic Response to Combination Therapy (Study 4)

  Interferon alfa-2b + Ribavirin 1000 mg or 1200 mg PEGASYS + Placebo PEGASYS + COPEGUS 1000 mg or 1200 mg
All subjects 197/444 (44%)* 65/224 (29%) 241/453 (53%)*
Genotype 1 103/285 (36%) 29/145 (20%) 132/298 (44%)
Genotypes 2-6 94/159 (59%) 36/79 (46%) 109/155 (70%)
*Difference in overall treatment response (PEGASYS/COPEGUS – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).

In Study 5 (see Table 13), all subjects received PEGASYS 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight less than 75 kg/greater than or equal to 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Subjects with genotype 1 and high viral titer (defined as greater than 2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

HCV Genotypes

HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg COPEGUS.

HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS (see Table 13).

The numbers of subjects with genotype 5 and 6 were too few to allow meaningful assessment.

Table 13 : Sustained Virologic Response as a Function of Genotype (Study 5)

  24 Weeks Treatment 48 Weeks Treatment
PEGASYS + COPEGUS 800 mg
(N=207)
PEGASYS + COPEGUS 1000 mg or 1200 mg*
(N=280)
PEGASYS + COPEGUS 800 mg
(N=361)
PEGASYS + COPEGUS 1000 mg or 1200 mg*
(N=436)
Genotype 1 29/101
(29%)
48/118
(41%)
99/250
(40%)
138/271
(51%)
Genotypes 2, 3 79/96
(82%)
116/144
(81%)
75/99
(76%)
117/153
(76%)
Genotype 4 0/5
(0%)
7/12
(58%)
5/8
(63%)
9/11
(82%)
*1000 mg for body weight less than 75 kg; 1200 mg for body weight greater than or equal to 75 kg.

Other Treatment Response Predictors

Treatment response rates are lower in subjects with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in subjects older than 40 years (50% vs. 66%), in subjects with cirrhosis (47% vs. 59%), in subjects weighing over 85 kg (49% vs. 60%), and in subjects with genotype 1 with high vs. low viral load (43% vs. 56%). African-American subjects had lower response rates compared to Caucasians.

Paired liver biopsies were performed on approximately 20% of subjects in studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups.

In studies 4 and 5, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of subjects who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of subjects who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

Pediatric Patients

Previously untreated pediatric subjects 5 through 17 years of age (55% less than 12 years old) with chronic hepatitis C, compensated liver disease and detectable HCV RNA were treated with COPEGUS approximately 15 mg/kg/day plus PEGASYS 180 mcg/1.73 m² x body surface area once weekly for 48 weeks. All subjects were followed for 24 weeks post-treatment. Sustained virological response (SVR) was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of 114 subjects were randomized to receive either combination treatment of COPEGUS plus PEGASYS or PEGASYS monotherapy; subjects failing PEGASYS monotherapy at 24 weeks or later could receive open-label COPEGUS plus PEGASYS. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of COPEGUS plus PEGASYS and 59 received PEGASYS plus placebo; in the overall intent-to-treat population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are summarized in Table 14.

Table 14 : Sustained Virologic Response (NV17424 -Study 6)

  PEGASYS 180 mcg/1.73 mē x BSA + COPEGUS 15 mg/kg
(N=55)*
PEGASYS 180 mcg/1.73 mē x BSA + Placebo*
(N=59)
All HCV genotypes** 29 (53%) 12 (20%)
  HCV genotype 1 21/45 (47%) 8/47 (17%)
  HCV non-genotype 1*** 8/10 (80%) 4/12 (33%)
*Results indicate undetectable HCV-RNA defined as HCV RNA less than 50 IU/mL at 24 weeks post-treatment using the AMPLICOR HCV test v2.
**Scheduled treatment duration was 48 weeks regardless of the genotype
***Includes HCV genotypes 2, 3 and others

Chronic Hepatitis C and Coinfection with HIV (CHC/HIV) Study 7: PEGASYS Monotherapy and PEGASYS/COPEGUS Combination Therapy

In Study 7, subjects with CHC/HIV were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly plus an oral placebo, PEGASYS 180 mcg once weekly plus COPEGUS 800 mg by mouth daily or ROFERON-A (interferon alfa-2a), 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All subjects received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS treatment arms. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Subjects also had CD4+ cell count greater than or equal to 200 cells/mm³ or CD4+ cell count greater than or equal to 100 cells/mm³ but less than 200 cells/mm³ and HIV-1 RNA less than 5,000 cells/mm³, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in Table 15.

Table 15: Sustained Virologic Response in Subjects with Chronic Hepatitis C Coinfected with HIV (Study 7)

  ROFERON-A + COPEGUS 800 mg
(N=289)
PEGASYS + Placebo
(N=289)
PEGASYS + COPEGUS 800 mg
(N=290)
All subjects 33 (11%) 58 (20%) 116 (40%)
Genotype 1 12/171 (7%) 24/175 (14%) 51/176 (29%)
Genotypes 2, 3 18/89 (20%) 32/90 (36%) 59/95 (62%)

Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.

Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and COPEGUS combination therapy, 2% (2/85) achieved an SVR.

In CHC subjects with HIV coinfection who received 48 weeks of PEGASYS alone or in combination with COPEGUS treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

Chronic Hepatitis B Studies 8 and 9: PEGASYS Monotherapy

The safety and effectiveness of PEGASYS for the treatment of chronic hepatitis B were assessed in controlled clinical trials in HBeAg positive (Study 8) and HBeAg negative (Study 9) subjects with chronic hepatitis B.

Subjects were randomized to PEGASYS 180 mcg subcutaneous once weekly, PEGASYS 180 mcg subcutaneous once weekly combined with lamivudine 100 mg once daily by mouth or lamivudine 100 mg once daily by mouth. All subjects received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of PEGASYS or no PEGASYS was not masked.

All subjects were adults with compensated liver disease, had chronic hepatitis B virus (HBV) infection, and evidence of HBV replication (serum HBV greater than 500,000 copies/mL for Study 8 and greater than 100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR® HBV Assay). All subjects had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic hepatitis.

The results observed in the PEGASYS and lamivudine monotherapy groups are shown in Table 16.

Table 16 : Percentage of Subjects with Serological, Virological, Biochemical, and Histological Response

  Study 8 HBeAg positive Study 9 HBeAg negative
Lamivudine
N = 272
PEGASYS
N = 271
Lamivudine
N = 181
PEGASYS
N = 177
EOT1 EOF2 EOF2 EOT1 EOF2 EOF2
HBeAg Seroconversion (%) 20 19 32 NA NA NA
HBV DNA Response (%)3 62 22 32 85 29 43
ALT Normalization (%) 62 28 41 73 44 59
HBsAg Seroconversion (%) 0 0 3 1 0 3
  N = 184 N = 207 N = 125 N = 143
Histological Improvement (%)4 ND 40 41 ND 41 48
Changes in Ishak fibrosis score compared to baseline (%):
-Improved5 ND 32 25 ND 31 32
-Unchanged 20 25 23 30
-Worsened5 16 26 15 19
1End of Treatment (week 48)
2End of follow-up – 24 weeks post-treatment (week 72)
3Less than 100,000 copies/mL for HBeAg positive and less than 20,000 copies/mL for HBeAg negative subjects
4Greater than or equal to 2 point decrease in Ishak necro-inflammatory score from baseline with no worsening of the Ishak fibrosis score. Not all subjects provided both initial and end of follow-up biopsies (missing biopsy rates: 19% to 24% in the PEGASYS and 31% to 32% in the lamivudine arms)
5Change of 1 point or more in Ishak fibrosis score

PEGASYS co-administered with lamivudine did not result in any additional sustained response when compared to PEGASYS monotherapy.

Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.

Last reviewed on RxList: 7/12/2013
This monograph has been modified to include the generic and brand name in many instances.

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