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

 
 



DESCRIPTION

Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] is a sterile aqueous formulation of purified, natural, human interferon alpha proteins for use by injection. Alferon N Injection® consists of interferon alpha proteins comprising approximately 166 amino acids ranging in molecular weights from 16,000 to 27,000 daltons. The specific activity of Interferon alfa-n3 is approximately equal to, or greater than, 2 × 108 IU/mg of protein.

Alferon N Injection® is manufactured from pooled units of human leukocytes which have been induced by incomplete infection with a murine virus (Sendai virus) to produce Interferon alfa-n3. The manufacturing process includes immunoaffinity chromatography with a murine monoclonal antibody, acidification (pH 2) for 5 days at 4°C, and gel filtration chromatography.

Since Alferon N Injection® is manufactured using source leukocytes, human donor screening is performed to minimize the risk that the leukocytes could contain infectious agents. In addition, the manufacturing process contains steps which have been shown to inactivate known viruses. There has been no evidence of infection transmission to recipients in clinical trials (See WARNINGS).

The Alferon N Injection® manufacturing process was evaluated for quantitative removal or inactivation of model pathogenic viruses. The viruses were deliberately added to the leukocytes in amounts far exceeding those present in contaminated blood, i.e., >/= 109 infectious units per milliliter. The manufacturing process yielded a cumulative reduction of >/= 1014 of infectious HIV-1, i.e., >/= 106.5 removal by acid inactivation and >/= 107.9 removal by the purification process. In the validation studies, there was 108 reduction in the titer of hepatitis B virus as determined by HBsAg assay, and a 109 reduction in the infectious titer of herpes simplex virus-1 (HSV-1). Cultivation of Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] Purified Drug Concentrate with human indicator cells, i.e., MRC-5 cells, peripheral blood leukocytes in the presence of Cyclosporin A, and fetal cord blood cells, did not detect the presence of infectious viruses.

As part of a validation study, Alferon N Injection® was examined for the presence of the following viruses; Sendai virus (SV), HlV-1, HTLV-l, HBV, HSV-1, CMV, and EBV. Alferon N Injection® contained no detectable quantities of these viruses. In addition, other studies, i.e., Polymerase Chain Reaction (PCR) and Dot Blot Hybridization (DBH), have shown no detectable genetic material from these viruses in Alferon N Injection®. The sensitivity of the PCR was 10 copies for HlV-1 (env gene probe) and 10 copies for HBV (S/P gene probe). The sensitivity of the DBH was 1 pg for EBV, < 10 pg for CMV, < 10 pg for HSV-1, and < 2 pg for SV. Furthermore, sera from 105 patients treated with Alferon N Injection® (95 with condylomata acuminata and 10 with cancer) were tested for antibody to HlV-1 and HlV p24 antigen. There was no evidence to suggest transmission of HlV-1 by Alferon N Injection®. Sera from 135 patients with condylomata acuminata treated with Alferon N Injection® were tested to determine abnormal SGOT laboratory values. There was no evidence to suggest transmission of hepatitis by Alferon N Injection® based on both SGOT results and patient data collected during clinical trials.

Alferon N Injection® has been extensively purified using immunoaffinity chromatography with a murine monoclonal antibody, acidification (pH 2) for 5 days at 4°C, and gel filtration chromatography. Alferon N Injection® has been subjected to the acid treatment for five days during its manufacture in order to reduce the risk of viral transmission. Subsequent analyses of the Alferon N Injection® [Interferon alfa-n3 (human leukocyte derived)] Purified Drug Concentrate confirm the absence of detectable infectious or non-infectious viral particles.

The leukocyte nutrient medium contains the antibiotic neomycin sulfate at a concentration of 35 mg/L; however, neomycin sulfate is not detectable in the final product, i.e., < 0.64 µg/ml.

Murine immunoglobulin (IgG) is detected in the Alferon N Injection® Purified Drug Concentrate at levels below 0.15% of the Interferon alfa-n3 protein. This equates to levels less than 8 ng of murine IgG per million of IU Interferon alfa-n3 (range of 0.9 to 5.6 ng typically found).

Alferon N Injection® is available in an injectable solution containing 5 million IU Interferon alfa-n3 per vial for intralesional injection. The solution is clear and colorless. Each milliliter (ml) contains five million IU of Interferon alfa-n3 in phosphate-buffered saline (8.0 mg sodium chloride, 1.74 mg sodium phosphate dibasic, 0.20 mg potassium phosphate monobasic, and 0.20 mg potassium chloride) containing 3.3 mg phenol as a preservative and 1 mg Albumin (Human) as a stabilizer.

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.

Table 1
Degree of Resolution as Measured By Total Wart Volume per Patient
    Complete
Resolution
Percent of Patients with: Progression/
No change
Partial Resolution
(>/=50% resolution)
Minor Resolution
(<50% resolution)
Alferon
(n = 81)
54% 26% 15%   5%
Placebo
(n = 75)
20% 24% 13% 43%

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).

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