PEGINTRON Powder and solvent for solution for injection Ref.[9681] Active ingredients: Peginterferon alpha-2b

Pharmacotherapeutic group: Immunostimulants, Interferons
ATC code: L03AB10

Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at an average degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 31,300 daltons of which the protein moiety constitutes approximately 19,300.

Mechanism of action

In vitro and in vivo studies suggest that the biological activity of PegIntron is derived from its interferon alfa-2b moiety. Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virusinfected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell.

Pharmacodynamic effects

PegIntron pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5'-oligoadenylate synthetase (2’5'-OAS), as well as white cell and neutrophil counts. Subjects treated with PegIntron showed mild dose-related elevations in body temperature. Following single doses of PegIntron between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of PegIntron.

Clinical efficacy and safety – Adults

Tritherapy with PegIntron, ribavirin and boceprevir

Refer to the SmPC for boceprevir.

Monotherapy with PegIntron and bitherapy with PegIntron and ribavirin

Naïve patients

Two pivotal trials have been conducted, one (C/I97-010) with PegIntron monotherapy; the other (C/I98-580) with PegIntron in combination with ribavirin. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (>30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

In the PegIntron monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with PegIntron (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that PegIntron was superior to interferon alfa-2b (Table 8).

In the PegIntron combination trial, 1,530 naïve patients were treated for one year with one of the following combination regimens:

• PegIntron (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n=511).
• PegIntron (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) + ribavirin (1,000/1,200 mg/day), (n=514).
• Interferon alfa-2b (3 MIU three times a week) + ribavirin (1,000/1,200 mg/day) (n = 505).

In this trial, the combination of PegIntron (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly in patients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with PegIntron or interferon alfa-2b. In those patients that received >10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received ≤10.6 mg/kg ribavirin (Table 9), while response rates in patients that received >13.2 mg/kg ribavirin were even higher.

Table 8. Sustained virological response (% patients HCV negative):

P 1.5 PegIntron 1.5 micrograms/kg
P 1.0 PegIntron 1.0 microgram/kg
P 0.5 PegIntron 0.5 microgram/kg
I Interferon alfa-2b 3 MIU
P 1.5/R PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)
P 0.5/R PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)
I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)
* p<0.001 P 1.5 vs. I
** p=0.0143 P 1.5/R vs. I/R

Table 9. Sustained response rates with PegIntron + ribavirin (by ribavirin dose, genotype and viral load):

P 1.5/R PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)
P 0.5/R PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)
I/R Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

In the PegIntron monotherapy study, the Quality of Life was generally less affected by 0.5 microgram/kg of PegIntron than by either 1.0 microgram/kg of PegIntron once weekly or 3 MIU of interferon alfa-2b three times a week.

In a separate trial, 224 patients with genotype 2 or 3 received PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with ribavirin 800 mg–1,400 mg p.o. for 6 months (based on body weight, only three patients weighing >105 kg, received the 1,400 mg dose) (Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell ¾).

Table 10. Virologic response at end of treatment, Sustained Virologic Response and relapse by HCV Genotype and viral load*:

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5% vs. 14%, for dose modification 18% vs. 49%.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (<600,000 IU/ml) received PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50%. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92% (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48). Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/ribavirin regimens [PegIntron 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 11).

*Table 11. Virologic response at treatment week 12, end of treatment response, relapse rate and Sustained Virologic Response (SVR):

* (HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml)
Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a <2 log₁₀ reduction from baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with PegIntron (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to PegIntron 1 µg/kg dose. At the PegIntron 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load >600,000 IU/ml, and in patients >40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24%.

Predictability of sustained virological response – Naïve patients: Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA. Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 12).

Table 12. Predictive value of in-treatment Virologic Response while on PegIntron 1.5 µg/kg/ribavirin 800-1,400 mg combination therapy:

* Genotype 1 receive 48 weeks treatment
** Genotype 2, 3 receive 24 weeks treatment
*** The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12.
^† These criteria were used in the protocol: If week 12 HCV-RNA is positive and <2log₁₀ decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥2log₁₀ from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

The negative predictive value for sustained response in patients treated with PegIntron in monotherapy was 98%.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 13. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either PegIntron (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either PegIntron (100 or 150 µg/week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load <800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

Table 13. Sustained virological response based on genotype after PegIntron in combination with Ribavirin in HCV/HIV Co-infected patients:

MIU = million international units; TIW = three times a week.
^a p value based on Cochran-Mantel Haenszel Chi square test.
^b p value based on chi-square test.
^c subjects <75 kg received 100 µg/week PegIntron and subjects ≥75 kg received 150 µg/week PegIntron.
^d ribavirin dosing was 800 mg for patients <60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients >75 kg.
¹ Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
² Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response: Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51%). Both the Metavir score and Ishak grade decreased among subjects treated with PegIntron in combination with ribavirin. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

PegIntron/ribavirin retreatment of prior treatment failures

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 14).

Table 14. Rates of response to retreatment in prior treatment failures:

NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment.
Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory
* Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.

Overall, approximately 36% (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56% (463/823) sustained virological response rate. For patients with prior failure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59% and 50%, respectively. Among 480 patients with >2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12%.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin (12.4% vs. 28.6%). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response.

Long-term efficacy data-Adults

A large long-term follow-up study enrolled 567 patients after treatment in a prior study with PegIntron (with or without ribavirin). The purpose of the study was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. 327 patients completed at least 5 years of long-term follow-up and only 3 out of 366 sustained responders relapsed during the study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 99% (95% CI: 98-100%). SVR after treatment of chronic HCV with PegIntron (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical “cure” from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Clinical efficacy and safety – paediatric population

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus PegIntron 60 μg/m² once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52% were female, 89% Caucasian, 67% with HCV Genotype 1 and 63% <12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of PegIntron with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 15.

Table 15. Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects n=107:

^a Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment lower limit of detection=125IU/ml
^b n = number of responders/number of subjects with given genotype, and assigned treatment duration.
^c Patients with genotype 3 low viral load (<600,000 IU/ml) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (≥600,000 IU/ml) were to receive 48 weeks of treatment.

Long-term efficacy data – paediatric population

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85% (80/94) of all enrolled subjects and 86% (54/63) of sustained responders completed the study. No paediatric subjects with SVR had relapsed during the 5 years of follow-up.