Alferon N Injection (Interferon Alfa-N3) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

General --Interferons are naturally occurring proteins with antiviral, antiproliferative, and immunoregulatory properties. They are produced and secreted in response to viral infections and to a variety of other synthetic and biological inducers. Four major families of interferons have been identified: alpha, beta, gamma, and omega. The interferon alpha family contains 13 different non-allelic molecular species. Their molecular weights range from 16,000 to 27,000 daltons.

Interferons bind to specific membrane receptors on cell surfaces. Interferon alfa-n3 has been shown to bind to the same receptors as Interferon alfa-2b. The receptors have a high degree of selectivity for the binding of human but not mouse interferon. This correlates with the high species specificity found in laboratory studies.

Binding of interferon to membrane receptors initiates a series of events including induction of protein synthesis. These actions are followed by a variety of cellular responses, including inhibition of virus replication and suppression of cell proliferation. Immunomodulation, including enhancement of phagocytosis by macrophages, augmentation of the cytotoxicity of lymphocytes and enhancement of human leukocyte antigen expression occurs in response to exposure to interferons. One or more of these activities may contribute to the therapeutic effect of interferon.

Pharmacokinetics --In a study of intralesional use of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] for the treatment of condylomata acuminata, plasma concentrations of interferon were below the detection limit of the assay, i.e., </= 3 IU/ml. Minor systemic effects (e.g., myalgias, fever, and headaches) were noted, indicating that some of the injected interferon entered the systemic circulation (See ADVERSE REACTIONS).

Condylomata Acuminata --Condylomata acuminata (venereal or genital warts) are associated with infections of human papilloma virus (HPV), especially HPV type-6 and possibly type-11. Given the antiviral and antiproliferative activities of interferons and the viral etiology of condylomata, a placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of intralesional injection of Alferon N Injection® in the treatment of condylomata acuminata.

In a multicenter, randomized, double-blind, placebo-controlled, clinical trial, intralesional administration of Alferon N Injection® was an effective treatment for condylomata acuminata. ^1-4 One hundred fifty-six (156) patients were evaluable for efficacy (81 Alferon N Injection® patients and 75 placebo patients). Patients had a mean of five warts (range was 2-14) and all warts were treated. Patients were injected intralesionally with a mean of 225,000 IU of Alferon N Injection® per wart 2 times a week for up to 8 weeks.

Overall, 80% (⁶⁵/₈₁) of patients treated with Alferon N Injection® had a complete or partial resolution of warts compared with 44% (³³/₇₅) of placebo-treated patients (p < 0.001). Alferon N Injection® was significantly more effective than placebo in producing a complete resolution of warts (p < 0.001), as shown by Table 1.

Of the patients who had a complete resolution of warts, approximately half (²¹/₄₄) the patients had complete resolution of warts by the end of treatment, and half (²³/₄₄) had complete resolution of warts during the three months after the cessation of treatment. Patients with complete resolution of warts were followed for a median of 48 weeks. Overall, 76% (³¹/₄₁) of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)]-treated patients who achieved complete resolution of warts remained clear of all treated lesions during follow-up, while 79% (¹¹/₁₄) of the placebo-treated patients remained clear of all treated lesions during follow-up.

A total of 762 evaluable warts were injected in this trial. Of the 407 Alferon N Injection®-treated warts, 73% (²⁹⁷/₄₀₇) completely resolved, as compared to 35% (¹²⁵/₃₅₅) of the placebo-treated warts (p < 0.0001). Alferon N Injection® was effective in treating lesions of all sizes, and there was no difference in resolution for perianal, penile, or vulvar lesions.

There was no difference in resolution for patients who had received prior treatment of their warts and for those who had not. Among patients with recalcitrant warts (i.e., warts that were refractory to previous treatment or recurring), 82% (⁵⁸/₇₁) of the evaluable patients had complete or partial resolution of warts due to intralesional administration of Alferon N Injection® as compared to 43% (²⁹/₆₇) of placebo patients (p <0.001). Fifty-four percent (³⁸/₇₁) of the evaluable Alferon N Injection® patients had complete resolution of warts as compared to 18% (¹²/₆₇) of placebo patients (p < 0.001). Patients with primary occurrence of genital warts (i.e., no prior treatment of warts) had a similar resolution rate compared to the patients with recalcitrant warts: 70% (⁷/₁₀) had complete or partial resolution of warts due to Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] treatment and 60% (⁶/₁₀) had complete resolution of warts, as compared to 50% (⁴/₈) of placebo recipients who had complete or partial resolution of warts and 38% (³/₈) who had complete resolution. Overall, 83% (⁵/₆) of Alferon N Injection®-treated patients with primary occurrence, who achieved complete resolution of warts, remained clear of all treated lesions during a median follow-up of 52 weeks. Because the number of patients with primary occurrence of warts was small (10 Alferon N Injection® recipients and 8 placebo recipients), the difference between Alferon N Injection® and placebo treatment was not statistically significant. However, when the resolution of primary warts was examined, 75% (³³/₄₄) of the Alferon N Injection®-treated primary warts resolved completely as compared to 39% (¹¹/₂₈) of the placebo-treated primary warts (p = 0.003).

In an open clinical trial using a once-a-week treatment schedule for up to 16 weeks, 28 patients were evaluable for efficacy. Eighty-nine percent (²⁵/₂₈) of patients had a complete or partial resolution of warts following treatment with Alferon N Injection®. The condylomata acuminata resolved completely in 46% (¹³/₂₈) of the patients. Of the 154 warts treated, 77% (¹¹⁸/₁₅₄) resolved completely.

After injections of Alferon N Injection®, side effects were minor and transient. After 4 weeks of treatment, the frequency of adverse reactions was similar in Alferon N Injection® and placebo treatment groups. The most frequent side effects were myalgias, fever, and headache (See ADVERSE REACTIONS).

ANTIGENICITY

1. Alferon N Injection®
   One hundred five (105) patients treated with Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] during clinical trials were tested for the presence of anti-interferon antibodies using three different antibody assays: Immunoradiometric Assay (IRMA), Enzyme Linked Immunosorbent Assay (ELISA), and neutralization by the Cytopathic Effect Assay (CPE). To date, no antibodies to Interferon alfa-n3 have been detected in any of the patients.
2. Mouse Proteins
   No hypersensitivity reactions to the components in Alferon N Injection® have been observed. Alferon N Injection® uses a murine monoclonal antibody in one of the purification procedures. A possibility exists that patients treated with Alferon N Injection® may develop hypersensitivity to the mouse proteins. However, none of the patients receiving Alferon N Injection® during clinical trials developed antibodies or hypersensitivity to mouse proteins (See CONTRAINDICATIONS).
3. Egg Protein
   The initial stage in the manufacture of Alferon N Injection® uses Sendai virus which was grown in chicken-embryonated eggs as the specific Interferon alfa-n3 inducer. Although no egg protein (ovalbumin) has been detected in the initial stage of interferon manufacture using an ELISA (sensitivity of 16 ng/ml), a possibility exists that patients treated with Alferon N Injection® may develop hypersensitivity to egg protein (See CONTRAINDICATIONS).