Biopharmaceuticals: Approvals and Approval Trends in 2004 - Twelve biopharmaceuticals gained marketing approval in the US and EU in 2004. Antibody-based products represented the single largest product

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Biopharmaceuticals: Approvals and Approval Trends in 2004
Twelve biopharmaceuticals gained marketing approval in the US and EU in 2004. Antibody-based products represented the single largest product category.


BioPharm International
Volume 18, Issue 5

The European Commission approved the product for the treatment of diabetes mellitus in June, 2004. It is used as a basal insulin preparation in combination with meal-related, rapid-acting insulin products. The marketing authorization holder is Novo Nordisk.

Manufacture entails an initial fermentation step, followed by product recovery, an ion exchange-based concentration step and two crystallization steps. The insulin is then extensively purified via several chromatographic steps, followed by product acylation. Final polishing purification and precipitation follow, and the product is formulated as a solution for subcutaneous administration. Clinical trials illustrated the product's efficacy in maintaining glycemic control and a low within-patient variability. Common side effects were episodes of hypoglycaemia and injection site reactions.

Apidra (insulin glulisine) is a rapid- acting insulin analog produced in an engineered E. coli strain. It was approved in 2004 for the treatment of diabetes mellitus in both the US and EU and is manufactured and marketed by Aventis.

Apidra differs from native human insulin in that lysine replaces asparagine at position 3 of the insulin B chain (B3) and glutamic acid replaces the B29 lysine residue. The amino acid substitutions characteristic of Apidra reduce the interchain interaction between individual insulin molecules within the insulin hexamer. As a result, the hexameric species dissociates rapidly at the site of injection, facilitating more rapid product entry into the bloodstream.

Manufacture is initiated by culture of the producer E. coli cell line. Product accumulates intracellularly in the form of inclusion bodies (IB). The product is chromatographically purified after cell harvest, IB recovery, and solubilization. Downstream processing also incorporates enzyme-based excision of the final insulin from a fusion protein precursor. Product is formulated as a solution intended for SC administration. Clinical data clearly illustrated product safety as well as efficacy in terms of glycemic control. Negative effects included the potential to trigger hypoglycemia as well as local or systemic allergic reactions.

Kepivance (palifermin) is a recombinant, truncated form of human keratinocyte growth factor (KGF), produced in engineered E. coli cells. It was approved by FDA in December 2004, and is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving chemotherapy in preparation for bone marrow transplants. It is manufactured and marketed by Amgen.

Mucositis (ulcers in the lining of the mouth) represent a prominent, common, and sometimes very severe side effect of high-dose chemotherapy or radiotherapy. The KGF receptor is present on epithelial cells in many tissues including the tongue and buccal mucosa, and binding of KGF to its receptor triggers the proliferation and differentiation of these epithelial cells. It is by this means the product is believed to bring about its effect.

Manufacture entails initial E. coli fermentation, product recovery, chromatographic purification, and formulation. Final product is supplied in lyophilized form, intended for IV injection after reconstitution with WFI. Kepivance is a 16.3 kDa, 140-amino acid polypeptide, differing from native KGF only in that it is devoid of the first 23 N-terminal amino acid residues.

The truncated form retains the biological activity of the parent molecule while displaying improved stability. Clinical trials involving patients with leukemia and lymphoma established the product's safety and efficacy. Ninety-eight percent of patients receiving a placebo developed serious mucositis, whereas only 63 percent of KGF-treated patients did. Median duration of mucositis was also reduced, from nine (placebo group) to three days (treated group). The most frequently noted adverse effect was a skin rash.

NeutroSpec (fanolesomab) is a murine IgM monoclonal antibody produced by suspension culture of hybridoma cells. It is indicated for the imaging of patients with equivocal signs and symptoms of appendicitis. Fanolesomab specifically binds the CD15 antigen expressed on the surface of polymorphonuclear neutrophils (PMNs), eosinophils, and monocytes (all white blood cells). Of these, PMNs represent the greatest proportion found in circulation. These cells migrate to the site of active infections in the body such as those underpinning appendicitis.

Approved in July, 2004 by FDA, the product was developed by Palatin Technologies. It is contract manufactured for Palatin by Ben Venue Laboratories and is distributed by Mallinckrodt Inc.

Product manufacture includes initial cell culture, product recovery, and multi-step chromatographic purification. It is presented in lyophilized form, intended for reconstitution immediately prior to use in a Tc99m-containing solution. The Tc99m radionucleotide complexes with the antibody. Localization of (gamma radiation emitting) radiolabelled NeutroSpec in the appendix is easily detectable using a gamma camera and is indicative of an active infection characteristic of true appendicitis.


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