Natural alpha interferon (DB05258) Approved and Investigational Drug Chemical Formula: ---- Molecular Weight: 19.3-22.1 kDa Natural interferon alpha or Multiferon is obtained from the leukocyte fraction of human blood following induction with Sendai virus. Interferon alfa contains several naturally occurring IFN-α subtypes and is purified by affinity chromatography. Interferon alpha proteins are mainly involved in innate immune response against viral infection. They come in 13 subtypes that are called IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21. Multiferon consists of the 6 major subtypes are IFN-α1, IFN-α2, IFN-α8, IFN-α10, IFN-α14 and IFN-α21. Of these, IFN-α2 and IFN-α14 are glycosylated. Indication/Usage Investigated for use/treatment in hepatitis (viral, C), leukemia (lymphoid), leukemia (myeloid), leukemia (unspecified), and melanoma.)

Mechanism of Action Metabolism Route of Elimination Targets Natural alpha interferon offers multiple subtypes of interferon which may work together as a 'cocktail-in-one', while recombinant versions only exhibit a single subtype." Viragen offers MultiferonT at a cost which is competitive with recombinant interferon regimens. Natural alpha interferon contains the multiple subtype composition that is characteristic of interferon produced by the human body. It is believed that this results in a broader spectrum of specific anti-viral and immunoregulatory activity with the subtypes acting synergistically to give a wide-ranging response. Metabolism Proteolyzed by endogenous proteases. Route of Elimination Reticulo-endothilial system, kidneys and liver. Targets Interferon alpha/beta receptor 1 General References Yonezawa A, Morita R, Takaori-Kondo A, Kadowaki N, Kitawaki T, Hori T, Uchiyama T: Natural alpha interferon-producing cells respond to human immunodeficiency virus type 1 with alpha interferon production and maturation into dendritic cells. J Virol. 2003 Mar;77(6):3777-84. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/12610152 Brands Multiferon

Multifereon Formulation The human genome consists of 13 functional genes that code for interferon-alpha.  Multiferon® is a human multi-subtype leukocyte interferon-alpha consisting of 6 alpha interferon subtypes released by human leucocytes in contrast to recombinant interferon-alpha with only one interferon subtype alpha 2a/b. The interferon-alpha subtypes are purified from the supernatant of a culture medium of primary human leukocytes challenged with Sendai virus. Multiferon is administered subcutaneously using a disposable injection syring Formulation Each pre-filled syringe contains 3 million IU interferon-alpha per 0.5 ml as a solution for injection, ready for use. Pack size: 6 x 0.5 ml (0.5 ml = 3 million IU) Used/Prescribed for Malignant melanoma: Adjuvant treatment of high-risk patients with cutaneous melanoma, stages IIb-III, after 2 initial cycles of dacarbazine (DTIC). Other indications: Treatment of patients who initially respond to recombinant interferon-alpha, but for whom treatment subsequently fails, most likely as the result of neutralising antibodies. Dosage Adjuvant treatment of malignant melanoma: 3 million IU three times weekly for 6 months after 2 initial cycles of DTIC 850 mg/m2 (intravenous). DTIC should be administered once every 3 weeks, as well as 3 weeks prior to starting interferon-alpha. Contraindications None

Stadler R. Acta Oncologica, 2006;45:389-399. Multiferon SPC. Side- effects The most frequently reported were fever, chills, sweating, fatigue, arthralgia, myalgia, headache, anorexia and nausea. Fever and fatigue are dose-related and are reversible within 72 hours of interruption or cessation of treatment. These acute side effects can ordinarily be alleviated or eliminated by concomitantly administering paracetamol. They tend to subside with continued treatment or dosage adjustment, although ongoing treatment can cause lethargy, weakness and persistent fatigue. Drug Interactions No information provided References Stadler R. Acta Oncologica, 2006;45:389-399. Multiferon SPC. Foster GR, Finter NB. Are all type I interferons equivalent? J Viral Hepatitis 1998;5:143-52