PEGASYS Solution for injection Ref.[9686] Active ingredients: Peginterferon alpha-2a

Pharmacotherapeutic group: Immunostimulants, interferons
ATC code: L03AB11

Mechanism of action

The conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms a pegylated interferon alfa-2a (Pegasys). Pegasys possesses the in vitro antiviral and antiproliferative activities that are characteristic of interferon alfa-2a.

Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of substitution of one mole of polymer/mole of protein. The average molecular mass is approximately 60,000 of which the protein moiety constitutes approximately 20,000.

Pharmacodynamic effects

HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 micrograms Pegasys. The first phase of decline occurs 24 to 36 hours after the first dose of Pegasys and is followed by the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Ribavirin had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of ribavirin and pegylated interferon alfa-2a or interferon alfa.

Clinical efficacy and safety

Chronic hepatitis B

Predictability of response

A patient-level meta-analysis of 9 Pegasys clinical studies (n=1,423) in CHB HBeAg positive and HBeAg-negative patients demonstrated that HBsAg and HBV DNA levels at Week 12 of treatment, are predictive of final treatment outcome at Week 24 post-treatment in certain genotypes. Operating characteristics of these biomarkers are presented in Table 11. No single biomarker with a cut-off can be identified to optimize all the operating characteristics (negative predictive value [NPV], sensitivity, specificity) and practical characteristics (simplicity, convenience). Consideration for early treatment discontinuation should be evaluated in the context of a particular clinical situation.

For HBeAg-positive patients with HBV genotype B and C infection, HBsAg >20,000 IU/mL or HBV DNA >8 log₁₀ IU/mL at Week 12 following commencement of treatment is associated with high likelihood of failure to achieve HBeAg seroconversion and HBV-DNA <2,000 IU/mL at 24 week post-treatment (NPV >90%). For HBV genotype A and D, subgroup size was insufficient to be analyzed.

For HBeAg-negative patients with HBV genotype D infection, HBsAg >20,000 IU/mL or HBV DNA >6.5 log₁₀ IU/mL at Week 12 following commencement of treatment is associated with high likelihood of failure to achieve HBV-DNA <2,000 IU/mL and ALT normalization at Week 24 post treatment. HBV genotype A subgroup size was insufficient to be analyzed. No biomarker can be identified with acceptable performance for HBeAg-negative patients with HBV genotype B or C infection.

Other published on-treatment biomarkers that are predictive of the final outcome of Pegasys treatment may be considered.

Table 11. Performance of individual biomarkers at Week 12 of therapy in CHB HBeAg-positive and HBeAg-negative patients according to genotype:

NPV= negative predictive value; Sensitivity = % of all responders not meeting the stopping rule; Specificity = % of all non-responders meeting stopping rule
^a Treatment response for HBeAg-positive patients was defined as HBeAg seroconversion (defined as loss of HBeAg and presence of anti-HBe) + HBV DNA <2,000 IU/mL at 6 months post-treatment and treatment response for HBeAg-negative patients was defined as HBV DNA <2,000 IU/mL + ALT normalization at 6 months posttreatment.

All clinical trials recruited patients with CHB who had active viral replication measured by HBV DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240 recruited patients who were positive for HBeAg, while study WV16241 recruited patients who were negative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks, with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasys plus lamivudine vs lamivudine alone. No HBV-HIV co-infected patients were included in these clinical trials.

Response rates at the end of follow-up for the two studies are presented in Table 12. In study WV16240, the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 105 copies/ml. In study WV16241, the primary efficacy endpoints were ALT normalisation and HBVDNA below 2 × 10⁴ copies/ml. HBV-DNA was measured by the COBAS AMPLICOR HBV MONITOR Assay (limit of detection 200 copies/ml).

A total of 283/1351 (21%) of patients had advanced fibrosis or cirrhosis, 85/1351 (6%) had cirrhosis. There was no difference in response rate between these patients and those without advanced fibrosis or cirrhosis.

Table 12. Serological, virological and biochemical responses in chronic hepatitis B:

* For HBeAg-positive patients: HBV DNA <10⁵ copies/ml
For HBeAg-negative/anti-HBe-positive patients: HBV DNA <2 × 10⁴ copies/ml
^# p-value (vs. lamivudine) <0.01 (stratified Cochran-Mantel-Haenszel test)

Histological response was similar across the three treatment groups in each study; however, patients showing a sustained response 24 weeks after the end of treatment were significantly more likely to also show histological improvement.

All patients who completed the phase III studies were eligible for entry into a long-term follow-up study (WV16866). Among patients from study WV16240, who received Pegasys monotherapy and entered the long-term follow-up study, the rate of sustained HBeAg seroconversion 12 months after the end of therapy was 48% (73/153). In patients receiving Pegasys monotherapy in study WV16241, the rate of HBV DNA response and ALT normalisation 12 months after end of treatment were 42% (41/97) and 59% (58/99), respectively.

Chronic hepatitis C

Predictability of response

Please refer to section 4.2, in Table 2.

Dose-response in monotherapy

In a direct comparison with 90 micrograms, the 180 micrograms-dose was associated with superior sustained virological response in patients with cirrhosis, but in a study in non-cirrhotic patients very similar results were obtained with doses of 135 micrograms and 180 micrograms.

Confirmatory clinical trials in adult treatment-naïve patients

All clinical trials recruited interferon-naïve patients with CHC confirmed by detectable levels of serum HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsy consistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histological diagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 21). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.

For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see Tables 13, 14, 15 and Table 21, respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after end of therapy.

Table 13. Virological response in CHC patients:

* 95% CI for difference: 11% to 33% p-value (stratified Cochran-Mantel-Haenszel test) = 0.001
** 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003

The virological responses of HCV monoinfected patients treated with Pegasys and ribavirin combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype, pre-treatment viral load and rapid virological response at week 4 are summarised in Table 14 and Table 15, respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype, baseline viral load and virological response at week 4 (see Tables 1, 14 and 15).

The difference between treatment regimens was in general not influenced by presence/absence of cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline characteristic.

Table 14. Sustained virological response based on genotype and pre-treatment viral load after Pegasys combination therapy with ribavirin in CHC patients:

Low viral load = ≤800,000 IU/ml; High viral load = >800,000 IU/ml
* Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 800 mg, 48 w: Odds Ratio (95% CI) = 1.52 (1.07 to 2.17), P-value (stratified Cochran-Mantel-Haenszel test) = 0.020
* Pegasys 180 mcg & ribavirin 1000/1200 mg, 48 w vs. Pegasys 180 mcg & ribavirin 1000/1200 mg, 24 w: Odds Ratio (95% CI) = 2.12 (1.30 to 3.46), P-value (stratified Cochran-Mantel-Haenszel test) = 0.002.

The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 15).

Table 15. Sustained virological response based on rapid viral response at week 4 for genotype 1 and 4 after Pegasys combination therapy with ribavirin in CHC patients:

Low viral load = ≤800,000 IU/ml; High viral load = >800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24

Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 16).

Table 16. Relapse of virological response at the end of treatment for rapid virological response population:

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on a sustained virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 17).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received Pegasys 180 mcg sc qw and a ribavirin dose of 800 mg and were randomised to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p<0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 17).

Table 17. Sustained virological response overall and based on rapid viral response by week 4 for genotype 2 or 3 after Pegasys combination therapy with ribavirin in CHC patients:

Low viral load = ≤800,000 IU/ml; High viral load = >800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4

It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 18).

Table 18. Relapse of virological response after the end of treatment in genotype 2 or 3 patients with a rapid viral response:

Low viral load = ≤800,000 IU/ml; High viral load = >800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4

Superior efficacy of Pegasys compared to interferon alfa-2a was demonstrated also in terms of histological response, including patients with cirrhosis and/or HIV-HCV co-infection.

Adult chronic hepatitis C prior treatment non-responder patients

In study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments:

• Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks
• Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks
• Pegasys 180 mcg/week for 72 weeks
• Pegasys 180 mcg/week for 48 weeks

All patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 19.

Table 19. Week 12 virological response (VR) and sustained virological response (SVR) in patients with virological response at week 12 after treatment with Pegasys and ribavirin combination therapy in nonresponders to peginterferon alfa-2b plus ribavirin:

High viral load = >800,000 IU/ml, low viral load = ≤800,000 IU/ml.
^a Patients who achieved viral suppression (undetectable HCV RNA, <50 IU/ml) at week 12 were considered to have a virological response at week 12. Patients missing HCV RNA results at week 12 have been excluded from the analysis.
^b Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up were
considered to be non-responders.

In the HALT-C study, patients with CHC and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa monotherapy or in combination therapy with ribavirin were treated with Pegasys 180 mcg/week and ribavirin 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen; see Table 20.

Table 20. Sustained virological response in HALT-C by previous treatment regimen in nonresponder population:

HIV-HCV co-infected patients

The virological responses of patients treated with Pegasys monotherapy and with Pegasys and ribavirin combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV coinfected patients are summarised below in Table 21.

Table 21. Sustained virological response based on genotype and pre-treatment viral load after Pegasys combination therapy with ribavirin in HIV-HCV co-infected patients:

Low viral load = ≤800,000 IU/ml; High viral load = >800,000 IU/ml
* Pegasys 180 mcg & ribavirin 800 mg vs. Interferon alfa-2a 3 MIU & ribavirin 800 mg: Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001
* Pegasys 180 mcg & ribavirin 800 mg vs. Pegasys 180 mcg: Odds Ratio (95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001
* Interferon alfa-2a 3 MIU & ribavirin 800 mg vs. Pegasys 180 mcg: Odds Ratio (95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0084

A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using Pegasys 180 mcg/week and either ribavirin 800 mg or 1000 mg (<75 kg)/1200 mg (≥75 kg) daily for 48 weeks. The study was not powered for efficacy considerations. The safety profiles in both ribavirin groups were consistent with the known safety profile of Pegasys plus ribavirin combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose ribavirin arm.

HCV patients with normal ALT

In study NR16071, HCV patients with normal ALT values were randomised to receive Pegasys 180 micrograms/week and ribavirin 800 milligrams/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or no treatment for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.

Paediatric population

Chronic hepatitis B

Study YV25718 was conducted in previously untreated paediatric patients aged 3 to 17 years (51% <12 years old) with HBeAg positive CHB and ALT > ULN but <10 x ULN in two blood samples taken ≥14 days apart during the 6 months before the first dose of study drug. Patients with cirrhosis were not enrolled in this study. A total of 151 patients without advanced fibrosis were 2:1 randomized to Pegasys (group A, n=101) or untreated control (group B, n=50), respectively. Patients with advanced fibrosis were assigned to Pegasys treatment (group C, n=10). Patients in groups A and C (n=111) were treated with Pegasys once weekly for 48 weeks according to BSA categories, whereas patients in group B were observed for a period of 48 weeks (principal observation period). Patients in group B had the choice to switch to treatment with Pegasys after Week 48 of the principal observation period. All patients were followed up for 24 weeks post-treatment (groups A and C), or post-principal observation period (group B). After the Week 24 follow-up visit, patients from group A, B and C entered a long-term follow-up period (lasting for 5 years after end of treatment). Response rates in groups A and B at the end of 24 weeks follow-up are presented in Table 22. Efficacy response in group C to Pegasys treatment was in line with that seen in group A. For paediatric patients, efficacy has not been established in HBV genotypes other than genotypes A-D.

Table 22. Serological, virological and biochemical responses in paediatric patients with chronic hepatitis B:

* Similar to end point of HBV DNA <10⁵ copies/mL. COBAS AMPLICOR HBV MONITOR: HBV-DNA (IU/mL) = HBV-DNA (copies/mL) / 5.26)
** Patients switched to Pegasys treatment post-principal observation period and before Week 24 follow-up were counted as non-responders.
¹ Cochran-Mantel-Haenszel test, stratified by genotype (A vs. non-A) and baseline ALT (<5 × ULN and ≥ 5 × ULN)
² Fisher’s Exact Test

The response rate of HBeAg seroconversion was lower in patients with HBV genotype D, also in patients with no to minimal increase in ALT level at baseline (see Table 23).

Table 23. HBeAg seroconversion rates (%) by HBV genotype and baseline ALT levels:

* Subgroup of patients with genotype D had a higher proportion with baseline ALT <1.5x ULN (13/31) compared to other genotype groups (16/70).
** Patients switched to Pegasys treatment post-principal observation period and before Week 24 follow-up were counted as non-responders.

Exploratory analyses based on limited data show paediatric patients with greater decline in HBV-DNA at week 12 of therapy were more likely to achieve HBeAg seroconversion at 24 weeks of follow-up (Table 24).

Table 24. HBeAg seroconversion rates (%) by HBV-DNA decline from baseline to week 12 of Pegasys treatment in paediatric patients:

Chronic hepatitis C

In the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with Pegasys 100 mcg/m² sc once weekly and ribavirin 15 mg/kg/day for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.

In the NV17424 (PEDS-C) study, previously untreated paediatric patients 5 to 17 years of age (55% <12 years old) with compensated CHC and detectable HCV RNA were treated with Pegasys 180 mcg x BSA/1.73 m² once weekly for 48 weeks with or without ribavirin 15 mg/kg/day. All patients were followed for 24 weeks post-treatment. A total of 55 patients received initial combination treatment of Pegasys plus ribavirin, of whom 51% were female, 82% were Caucasian, and 82% were infected with HCV genotype 1. The study efficacy results for these patients are summarised in Table 25.

Table 25. Sustained virological response in the NV17424 study:

* 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.