Interferon Alfacon-1

Abstract

Interferon alfacon-1 (consensus interferon) is a non-naturally occurring, synthetic, type I interferon (IFN)α that is used for the treatment of patients with chronic hepatitis C. The efficacy of subcutaneously administered interferon alfacon-1 has been demonstrated in clinical trials during the treatment of IFN-naive patients (interferon alfacon-1 9μg 3 times a week for 24 weeks) and retreatment of nonresponders and relapsers to previous interferon therapy (interferon alfacon-1 15μg 3 times a week for up to 48 weeks). Higher and more frequent interferon alfacon-1 dosages have also been investigated. Results from a pivotal double-blind randomised trial in 704 patients with chronic hepatitis C showed that interferon alfacon-1 9μg 3 times a week achieved virological and biochemical response rates of 34.9 and 42.2%, respectively, at treatment end-point (week 24). Sustained virological and biochemical responses (week 48) were reported in 12.1 and 20.3% of the patients, respectively. In general, response rates in recipients of interferon alfacon-1 9μg 3 times a week were similar to those achieved with IFN-α2b 3 MIU 3 times a week. However, interferon alfacon-1 was more effective in the subgroup of patients infected with hepatitis C virus (HCV) genotype 1 at end-point (virological response, 24 vs 15 %; p < 0.05) and post-treatment observation period (8 vs 4%) although the difference between treatment groups was statistically significant only at treatment end-point. The sustained virological response rate achieved in patients with high baseline levels of serum HCV RNA receiving interferon alfacon-1 was statistically superior to that exhibited in the IFN-α2b treatment group (7 vs 0%; p < 0.05). Interferon alfacon-1 also showed efficacy during the retreatment of nonresponders and relapsers to previous IFN therapy in a large nonblind multicentre trial. Sustained virological response (week 72) was observed among 13 and 58% of nonresponders and relapsers, respectively, after 48 weeks of treatment with interferon alfacon-1 15μg 3 times a week. Interferon alfacon-1 has been generally well tolerated in clinical trials. As with other IFNs, adverse events were reported frequently but were usually considered of mild to moderate severity, decreased with time and caused a small percentage of patients to withdraw from the treatment. Fever, fatigue, arthralgia, myalgia, headache and rigors were the most frequently reported adverse events. Psychiatric adverse events appeared to be dose-related and caused the majority of treatment withdrawals. Conclusion: Interferon alfacon-1 is generally well tolerated and is an effective agent in the treatment of patients with chronic hepatitis C. Comparative data from a pivotal randomised trial indicate that the drug has at least equivalent efficacy to IFNα-2b, and a statistically significant advantage was demonstrated at treatment end-point in patients infected with HCV genotype 1. A number of ongoing trials with interferon alfacon-1 are evaluating issues such as the optimal dosage regimen and duration of therapy in an effort to improve sustained virological response to therapy, a goal for IFNs in general. There are not suitable cell culture systems or animal models for hepatitis C virus (HCV) replication. In vitro data have shown that interferon alfacon-1 has specific cytopathic activity superior to that of other interferon (IFN)α agents (≥3 x 10⁹ U/mg vs ≤2 × 10⁸ U/mg). Antiviral activity against encephalomyocarditis virus, vesicular stomatitis virus and herpes simplex virus type 1 and 2 in a series of mammalian cells was at least 10-fold higher with interferon alfacon-1 than IFNα-Ly, IFNα-2 and IFNα-2α1. Antiviral activity of interferon alfacon-1 was also observed against herpes simplex virus type 1 in golden Syrian hamsters in vivo. In most tumorous cell lines tested interferon alfacon-1 showed superior (1.9-to 260-fold) antiproliferative activity to IFNα (NAMALWA). This superiority was also evident when comparing interferon alfacon-1 with IFNα-2α and IFNα-2b. At concentrations of 0.01 μg/L interferon alfacon-1 and IFNα-2a inhibited the growth of Daudi cells by ≈85 and 30%, respectively, 72 hours after treatment. Compared with no treatment, interferon alfacon-1 inhibited the growth of AIDS-related Kaposi’s sarcoma-derived cells by 10 to 30% in a dose-dependent manner. In vivo interferon alfacon-1 suppressed tumour proliferation of human renal cancer cells transplanted below the skin of nude mice. Interferon alfacon-1 1 μg/mouse inhibited the growth of ACHN and OS-RC-2 cells by 78 and 33%, respectively. Natural killer (NK) cell activity in K562 and T98G was also ≥10-fold higher with interferon alfacon-1 than IFNα-Ly, IFNα-2 and IFNα-2α1. The NK cell activity exhibited by interferon alfacon-1 ng/ml against Eskol and K562 was greater than the NK cell activity of IFNα-2a and IFNα-2b 1 ng/ml (in Eskol cells ≈18 vs ≈7%, p < 0.05). A 10- to 20-fold lower concentration of interferon alfacon-1 than IFNα-2a induced a similar increase in the accumulation of 4 IFN-stimulated genes in Daudi and Eskol cells. In Daudi cells a similar increase of IRF-1 (IFN response factor 1) mRNA was induced by interferon alfacon-1 and IFNα-2a at concentrations of 3.3 and 33 ng/L, respectively. Similar differences between interferon alfacon-1 and other IFNα were observed during the induction of 2′-5′ oligoadenylate synthetase mRNA production in T98G cells. Interferon alfacon-1 bound to a higher number of receptors and low-affinity binding sites than IFNα-2b. Additionally, values of dissociation constant from IFN receptors indicated a higher binding affinity of interferon alfacon-1 than IFNα-2b...