INTRONA Solution for injection or infusion Ref.[8706] Active ingredients: Interferon, alfa-2b

Pharmacotherapeutic group: interferon alfa-2b
ATC code: L03AB05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b protein corresponding to 2.6 × 10⁸ IU. International Units are determined by comparison of the activity of the recombinant interferon alfa-2b with the activity of the international reference preparation of human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or various synthetic and biological inducers. Three major classes of interferons have been identified: alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain several different molecular species of interferon. More than 14 genetically distinct human alpha interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species specificity. Studies with other interferons have demonstrated species specificity. However, certain monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

The results of several studies suggest that, 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 virus-infected 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 has exhibited antiproliferative effects in studies employing both animal and human cell culture systems as well as human tumour xenografts in animals. It has demonstrated significant immunomodulatory activity in vitro.

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.

Chronic hepatitis B

Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity and mortality has been observed.

Interferon alfa-2b (6 MIU/m² 3 times a week for 6 months) has been given to children with chronic active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of depression were observed.

Chronic hepatitis C in adult patients

In adult patients receiving interferon in combination with ribavirin, the achieved sustained response rate is 47%. Superior efficacy has been demonstrated with the combination of pegylated interferon with ribavirin (sustained response rate of 61% achieved in a study performed in naïve patients with a ribavirin dose >10.6 mg/kg, p<0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (>100 copies/mL), a liver biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were followed for an additional 6 months after the end of treatment for the determination of sustained virologic response. Sustained virologic response rates for treatment groups treated for one year with IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. The increased response rate to the combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients who received IntronA in combination with ribavirin and received 80% of their treatment had a higher sustained response 6 months after 1 year of treatment than those who took <80% of their treatment (56% vs. 32% in trial C/I98-580).

Table 3. Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by genotype and viral load:

I IntronA (3 MIU 3 times a week)
I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, patients who received IntronA plus ribavirin, were less likely to respond than patients who received pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is presented in Table 4. 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 pegylated interferon alfa-2b (1.5 μg/kg/week) plus ribavirin (800 mg/day) or IntronA (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 pegylated interferon alfa-2b (100 or 150 μg /week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (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 4. Sustained virological response based on genotype after IntronA in combination with ribavirin versus pegylated interferon alfa-2b 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 pegylated interferon alfa-2b and subjects ≥75 kg received 150 µg/week pegylated interferon alfa-2b.
^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.

Relapse patients

A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic hepatitis C (48.6% vs. 4.7%). This enhancement in efficacy included loss of serum HCV (<100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was sustained when measured 6 months after the end of treatment.

Long-Term efficacy data

In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic response and assess the impact of continued viral negativity on clinical outcomes. 462 patients completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 492 relapsed during this study. The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97% with a 95% Confidence Interval of [95%, 99%]. SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (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).

Chronic hepatitis C in children and adolescent population

Three clinical trials have been conducted in children and adolescents; two with standard interferon and ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received IntronA 3 MIU/m² 3 times a week plus ribavirin 15 mg/kg per day for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57% male, 80% Caucasian, and 78% genotype 1,64% 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5. Sustained virological response in previously untreated children and adolescents:

* Number (%) of patients
^a Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

Long-term efficacy data

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75% (42/56) 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 of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98% [95% CI: 95%, 100%] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98% (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit. SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with 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).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin

In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m² plus ribavirin 15 mg/kg per day 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 peginterferon alfa-2b with ribavirin needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs section 4.4). The study results are summarized in Table 6.

Table 6. Sustained virological response rates (n^a,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects:

^a Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of detection=125 IU/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.