Biopharmaceuticals: Approval Trends in 2005 - - BioPharm International


Biopharmaceuticals: Approval Trends in 2005

BioPharm International
Volume 19, Issue 8

Efficacy was monitored using clinical attachment-level measurements and radiographic bone measurements over a six-month period, with significantly increased endpoint values reported for the GEM 21S group. No serious adverse events attributable to the product were reported, although standard events associated with periodontal grafting procedures (e.g., pain, swelling, and bleeding) were noted. GEM 21S is manufactured by BioMimetic Pharmaceuticals (Franklin, TN) and is distributed by Osteohealth, a division of Luitpold Pharmaceuticals (both in Shirley, NY).

Hylenex (hyaluronidase recombinant human), as its generic name suggests, is a purified preparation of recombinant human hyaluronidase. It is a 447-amino-acid glycoprotein of approximate molecular mass 61 kDa. The FDA approved it in 2005 as an adjuvant to increase the absorption and dispersion of other injected drugs, as well as for hypodermoclysis (subcutaneous-based fluid replacement) and as an adjuvant in subcutaneous urography for improving resorption of radiopaque agents.

Hyaluronidases are enzymes that degrade hyaluronan, a high-molecular mass, linear-structural polysaccharide consisting of repeating disaccharide units of D-glucuronic acid linked to N-acetyl D glucosamine. The enzyme is widely distributed in the extracellular matrix, vitreous humor, cartilage, and several other tissues of higher animals. Subcutaneous administration of hyaluronidase increases the permeability of the local connective tissue via hyaluronan degradation.

The enzyme therefore can act as a spreading agent, facilitating more rapid diffusion of subcutaneously coadministered fluids or localized transudates or exudates, facilitating their more rapid systemic absorption. Bovine and ovine hyaluronidase directly extracted from native tissue traditionally has been used for cosmetic and pharmaceutical purposes in orthopedics, ophthalmology, and general medicine.

The advent of bovine spongiform encephalitis has all but halted commercial use of the bovine enzyme. Production via recombinant means largely overcomes potential accidental pathogen transmission. Upstream processing entails cell culture of the producer CHO cell line with multistep chromatographic purification after initial product recovery. Final product is formulated as a solution for subcutaneious administration. It contains 150 USP units of recombinant enzyme/mL, sodium chloride, sodium phosphate buffer components, human serum albumin, calcium chloride, and edentate disodium as excipients.

Enhanced absorption and distribution of drugs are usually achieved by subcutaneous coadministration of 150 IU hyaluronidase activity. The most frequently reported adverse reactions occur at the local injection site and sometimes allergic reactions occur. Hylenex is manufactured by Baxter Healthcare Corporation (Deerfield, IL) and distributed by Baxter and Halozyme Therapeutics (San Diego, CA).

Increlex (mecasermin) is a recombinant form of human insulin-like growth factor-1 (rhIGF-1) produced in E. coli. The 7.6 kDa, 70-amino-acid, single-chain polypeptide displays an amino acid sequence identical to that of the native human growth factor. It is characterized by the presence of three intrachain disulphide linkages. The product was approved for general medical use by the FDA last year and is indicated for the long-term treatment of growth failure in children with primary IGF-1 deficiency or growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH (see also IPLEX entry below).

IGF, as its name suggests, bears a strong structural resemblance to proinsulin. IGF-1 is synthesized primarily in the liver, and then released into the bloodstream. Its cell surface receptors are found on a wide variety of cell types in the body. Transcription of the IGF-1 gene is strongly initiated when GH binds to its hepatic receptor, and most of the growth-promoting effects of GH are actually mediated by IGF-1. Direct injection of IGF-1 into animals whose pituitary gland (and hence source of GH) have been removed stimulated longitudinal bone growth, as well as growth of various organs, including the kidneys, spleen, and thymus.

Increlex manufacture is initiated by fermentation of the producer E. coli cells. After initial product recovery, it is subject to a number of high resolution chromatographic steps. Excipients added are sodium acetate buffer components, sodium chloride benzyl alcohol, and polysorbate 20. After filter sterilization, the product (10 mg/mL active) is aseptically filled into multidose glass vials (40 mg active/vial).

Increlex is generally administered twice daily by subcutaneous injection at a starting dose of 40–80μg/kg. Long-term product dosage levels are individualized for each patient. Bioavailability following subcutaneous administration is close to 100% and mean terminal serum half life in pediatric patients is estimated at 5.8 hours.

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