Peginterferon-α-2a (40kD)

Peginterferon-α-2a (40kD) is a new ‘pegylated’ subcutaneous formulation of interferon-α-2a that has been developed to improve on the pharmacokinetic profile and therapeutic efficacy of interferon-α-2a. Peginterferon-α-2a (40kD) is produced by the covalent attachment of recombinant interferon-α-2a to a branched mobile 40kD polyethylene glycol moiety, which shields the interferon-α-2a molecule from enzymatic degradation, reduces systemic clearance and enables once-weekly administration.

Peginterferon-α-2a (40kD) was significantly more effective than interferon-α-2a in interferon-α therapy-naive adults with chronic hepatitis C in three non-blind, randomised, multicentre trials. Virological responses (intention-to-treat results) were achieved in 44 to 69% of patients with or without cirrhosis after 48 weeks of treatment with peginterferon-α-2a (40kD) 180 μg/week; sustained virological responses 24 weeks after the end of treatment occurred in 30 to 39% of patients. Virological responses at the end of treatment and at long-term follow-up were significantly higher than those achieved with interferon-α-2a. Peginterferon-α-2a (40kD) was significantly more effective than interferon-α in patients with or without cirrhosis infected with HCV genotype 1.

Sustained biochemical responses achieved with peginterferon-α-2a (40kD) 180 μg/week ranged from 34 to 45% and were significantly higher than with interferon-α-2a. Recipients of peginterferon-α-2a (40kD) also experienced histological improvements; 24 weeks after discontinuation of treatment with peginterferon-α-2a (40kD) 180 μg/week, 54 to 63% of patients had a ≥2-point improvement in histological activity index score. Peginterferon-α-2a (40kD) produced histological responses in patients (with or without cirrhosis) with or without a sustained virological response.

Peginterferon-α-2a (40kD) produced better results than interferon-α-2a alone or interferon-α-2b plus oral ribavirin on various measures of quality of life in patients with chronic hepatitis C.

The tolerability profile of peginterferon-α-2a (40kD) is broadly similar to that of interferon-α-2a in patients with chronic hepatitis C with or without cirrhosis. Headache, fatigue and myalgia are among the most common adverse events.

The interferons are naturally occurring proteins with nonspecific regulatory activity. These cytokines are secreted by many mammalian cells and influence cell growth and differentiation, modulate the immune response and inhibit the replication of a number of viruses including hepatitis B and C. The antiviral activity of interferon-α is achieved by its ability to alter interactions between the host and virus in a complex manner.

When administered as a drug, interferon-α-2a induces a nonspecific antiviral state in the virus-infected cell which results in the inhibition of HCV replication. The drug also has immunomodulatory effects that intensify specific host immune responses against the virus. These effects include activation of macrophages, natural killer cells and cytotoxic T lymphocytes and stimulation of the production of type 1 T-helper cells. The anti-inflammatory properties of interferon-α-2a are achieved via inhibition of the production of tumour necrosis factor α, interleukin (IL)-1 and IL-8 and stimulation of the production of IL-10.

The pharmacological activity of interferon-α-2a is augmented by pegylation. The activity of 2′,5′-oligoadenylate synthetase (OAS), a key effector protein synthesised in response to interferon-α stimulation, increased with dose in volunteers who received single 45, 135 or 270μg subcutaneous doses of peginterferon-α-2a (40kD), or single 3 or 18MU subcutaneous doses of interferon-α-2a. Maximum serum OAS activity occurred approximately 48 hours after administration and remained at about this level for up to 168 hours (1 week) in the peginterferon-α-2a (40kD) [≥135μg] treatment groups.

Preliminary results of a small randomised comparative trial indicate that peginterferon-α-2a (40kD) treatment (180 μg/week for 48 weeks; n = 14) produces more robust HCV-specific CD4+ T helper 1 immune responses than interferon-α-2a (6MU three times a week for 12 weeks then 3MU three times a week for 36 weeks) in therapy-naive patients with chronic hepatitis C (with weak or no HCV-specific CD4+ responses before treatment).

The rate of viral decline was HCV genotype-dependent in patients treated with peginterferon-α-2a (40kD) or interferon-α-2a. The first and second phases of viral decline were significantly faster in patients infected with HCV non-1 genotypes than in those infected with HCV genotype 1 receiving treatment with peginterferon-α-2a (40kD) 180μg weekly.

Peginterferon-α-2a (40kD) is well absorbed after single subcutaneous doses in healthy volunteers or multiple subcutaneous doses in patients with chronic hepatitis C.

Three to 8 hours after a single 180μg dose of the drug, ‘substantial’ concentrations (values not reported) of peginterferon-α-2a (40kD) were detected in the serum of 10 healthy volunteers. Peginterferon-α-2a (40kD) was delivered to the systemic circulation at a sustained rate; the mean maximum serum concentration (Cmax) of peginterferon-α-2a (40kD) was 14.2 μg/L and was reached in mean time (tmax) of 78 hours. After single 180μg doses of peginterferon-α-2a (40kD), serum peginterferon-α-2a (40kD) concentrations were sustained for longer than concentrations of interferon-α-2a in healthy volunteers.

In 16 patients with chronic hepatitis C who received multiple doses of peginterferon-α-2a (40kD) 180 μg/week, the peginterferon-α-2a C_max was 25.6 μg/L and the t_max 45 hours. After single 180μg doses (n = 14), C_max and t_max values were 15.4 μg/L and 80 hours, respectively; steady-state concentrations of the drug were attained 5 to 8 weeks after initiation of the once-weekly regimen in these patients.

Peginterferon-α-2a (40kD) is cleared by both the liver and kidney and the liver plays an important role in the metabolism of the drug. Because of its large size and branched nature, peginterferon-α-2a (40kD) undergoes reduced renal clearance compared with that of standard interferon-α, thus prolonging hepatic exposure to the pegylated interferon. Pegylation resulted in a >100-fold reduction in the renal clearance of interferon-α-2a in 10 volunteers who received a single 180μg dose of peginterferon-α-2a (40kD). Metabolic products of peginterferon-α-2a (40kD) are eliminated via the kidneys. However, clearance via the kidneys does not appear to be extensive as the pharmacokinetics of the drug in patients with chronic renal impairment (creatinine clearance values ≥20 ml/min; ≥1.2 L/h) are not appreciably different from those in patients with normal renal function. In patients with chronic hepatitis C and cirrhosis, the terminal half-life of peginterferon-α-2a (40kD) was 70 to 90 hours.

Peginterferon-α-2a (40kD) showed no significant effects on drug metabolism mediated by CYP2C9, 2C19, 2D6 and 3A4 isoenzymes in healthy nonsmoking male volunteers. However, as documented with interferon-α, the clearance of theophylline (metabolised by CYP1A2) was significantly reduced (compared with baseline) in volunteers receiving multiple doses of peginterferon-α-2a (40kD).

The therapeutic efficacy of peginterferon-α-2a (40kD) has been investigated in 3 nonblind, randomised, multicentre, comparative trials that enrolled a total of 961 patients with chronic hepatitis C with or without cirrhosis who had not been previously treated with interferon-α. One of these trials was a dose-finding trial and the other two were large multinational comparative trials enrolling patients with or without cirrhosis (typical of a general population of patients with hepatitis C) or patients with cirrhosis or bridging fibrosis. Peginterferon-α-2a (40kD) was administered as a subcutaneous injection once weekly for 48 weeks in all three trials. The virological and biochemical efficacy of study medication was assessed at the end of treatment and after a 24-week treatment-free follow-up period, to establish the durability of responses. The efficacy of various dosages of peginterferon-α-2a (40kD) was compared with interferon-α-2a, administered at a dosage of either 6MU three times a week for 12 weeks, then 3MU three times a week (6/3MU three times a week), or 3MU three times a week.

Overall, virological responses (undetectable HCV RNA in the plasma) [intention-to-treat results] were achieved in 44 to 69% of patients with or without cirrhosis after 48 weeks of treatment with peginterferon-α-2a (40kD) 180 μg/week. At the 24-week follow-up evaluation, sustained virological responses in the peginterferon-α-2a (40kD) 180μg groups ranged from 30 to 39%. Virological responses both at the end of treatment and at long-term follow-up were significantly higher than those achieved with interferon-α (6/3MU or 3MU three times a week) at the end of treatment (12 to 28%) and at the 24-week follow-up evaluation (3 to 19%).

Peginterferon-α-2a (40kD) was significantly more effective than interferon-α in patients with or without cirrhosis infected with HCV genotype 1, achieving sustained virological responses in 28% of patients compared with 7% of interferon-α-2a recipients. As in patients with less advanced disease, sustained virological responses in patients with cirrhosis infected with HCV genotype 1 tended to be higher in patients treated with peginterferon-α-2a (40kD) 90 (5%) and 180 μg/week (13%) than in recipients of interferon-α-2a (2%). In patients with a histological diagnosis of cirrhosis at baseline, virological responses were about 4-fold higher in the patients treated with peginterferon-α-2a (40kD) 180 μg/week (32%) than in the interferon-α-2a treatment group (7%).

Across the three trials, end-of-treatment biochemical responses (defined as the reduction of previously elevated ALT levels to levels at or below the normal level) were achieved in 38 to 46% of patients in the peginterferon-α-2a (40kD) 180 μg/week treatment groups and in 15 to 39% of patients in the interferon-α-2a groups (intention-to-treat results); sustained biochemical responses in the peginterferon-α-2a (40kD) 180 μg/week groups ranged from 34 to 45% and were significantly higher than sustained responses in the interferon-α-2a treatment groups (9 to 25%).

Peginterferon-α-2a (40kD) also produced beneficial effects on liver histology. At the end of the follow-up period, between 54 and 63% of patients (with paired liver biopsies) treated with peginterferon-α-2a (40kD) 180 μg/week had a ≥2-point improvement in histological activity index scores in the three trials.

Peginterferon-α-2a (40kD) achieves superior results, during and after treatment, on various measures of quality of life in patients with chronic hepatitis C (including patients with cirrhosis) compared with interferon-α-2a alone or interferon-α-2b plus oral ribavirin, according to preliminary data reported in abstracts.

Peginterferon-α-2a (40kD) was associated with a more marked increase in self-assessed health improvement [as measured by the standardised 36-question short form (SF-36) Health Survey] than interferon-α-2a in patients with chronic hepatitis C and cirrhosis.

Apooled analysis of data from 1441 patients who participated in 3 randomised multinational comparative trials showed significant improvements in measurements of fatigue (using the Fatigue Severity Scale) and SF-36 scores among patients with a sustained virological response.

Peginterferon-α-2a (40kD) 180 μg/week produced significantly less impairment in quality of life and less fatigue than interferon-α-2a 6/3MU three times weekly during the first 12 weeks of treatment (evaluated patients were participants in a large multinational comparative trial).

Within the first 12 weeks of treatment, therapy-naive recipients of peginterferon-a-2a experienced significantly better quality of life than recipients of interferon-α-2b plus oral ribavirin in a large comparative multicentre trial. Assessments were made using the Hepatitis Quality of Life Questionnaire.

The tolerability profile of subcutaneous peginterferon-α-2a (40kD) is broadly similar to that of subcutaneous interferon-α-2a in patients with chronic hepatitis C. Types of adverse events were similar in patients in the peginterferon-α-2a (40kD) and interferon-α-2a treatment groups in the 2 large multinational comparative trials. Adverse events in recipients of peginterferon-α-2a (40kD) were not dose-related in noncirrhotic patients (with the exception of rigors) or in patients with more advanced liver disease.

In the largest comparative trial conducted in patients with chronic hepatitis (most of whom showed no histological evidence of cirrhosis or bridging fibrosis at baseline), headache, fatigue, pyrexia, myalgia, rigors and alopecia were the most common adverse events reported in patients receiving peginterferon-α-2a (40kD) 180 μg/week.

In patients with chronic hepatitis C and cirrhosis, the most common adverse events in recipients of peginterferon-α-2a (40kD) 180 μg/week were fatigue, headache, myalgia, rigors, pyrexia and nausea. Incidences of these adverse events were generally similar in recipients of peginterferon-α-2a (40kD) 180μg or 90 μg/week or interferon-α-2a 3MU three times a week.

Interferon-a may produce undesirable adverse effects on bone marrow, thus limiting the use of the drug in some patients. In the trial that enrolled patients with cirrhosis or bridging fibrosis, marked decreases in both neutrophil and platelet counts often occurred in recipients of peginterferon-α-2a (40kD) or interferon-α-2a. Nevertheless, these effects were effectively managed by a reduction in dose.

Dosages of subcutaneously administered peginterferon-α-2a (40kD) evaluated in adult patients with chronic hepatitis C (with or without cirrhosis) in clinical trials ranged from 45 to 270 μg/week. The optimal dosage of the drug was found to be 180μg once weekly. Data are limited on the efficacy and tolerability of peginterferon-α-2a (40kD) in patients with chronic hepatitis C aged <18 years or >60 years.