Biopharmecuticals: Approval Trends in 2006 - Thirteen biopharmaceuticals gained marketing authorization - BioPharm International

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Biopharmecuticals: Approval Trends in 2006
Thirteen biopharmaceuticals gained marketing authorization


BioPharm International
Volume 21, Issue 9

Preotact (parathyroid hormone) is a recombinant form of human parathyroid hormone produced in an engineered E. coli cell line. The 9.4 kDa, 84 amino acid hormone is identical in sequence to the native human molecule and is devoid of disulfide bonds or a glycocomponent. It gained approval in the EU in 2006 and is indicated for the treatment of osteoporosis in postmenopausal women at high risk of fractures.

Postmenopausal osteoporosis is characterized by low bone mass with resultant increase in bone fragility and hence increased risk of fracture. Parathyroid hormone functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high affinity cell surface receptors for the hormone. It also increases intestinal absorption of calcium.

The manufacture of Preotact involves initial (1100-L scale) fermentation of the producer E. coli (cell line PAL 1000). The cells contain an expression plasmid (pJT42) housing a synthetic gene coding for human PTH fused to a 21 amino acid E. coli outer membrane protein A signal peptide. As a result, the fusion product is secreted into the culture medium, with automatic removal of the leader sequence from the fusion product by an E. coli signal peptidase. Following fermentation, the cells are removed from the product stream by a combination of centrifugation and filtration, followed by an ultrafiltration or diafiltration step. Purification includes five chromatographic steps, with addition of mannitol, sodium chloride, and citric acid as excipients, followed by lyophilization. The final product is presented as a dual chamber cartridge, with the second chamber containing the reconstitution solvent (WFI, containing metacresol as a preservative). The recommended administration schedule entails once daily abdominal subcutaneous injection of 100 g active ingredient.

The major clinical study underpinning product approval was an 18-month, double blind, placebo-controlled trial involving more than 2,500 post menopausal women. The trial demonstrated no significant difference in the incidence of non-vertebral clinical fractures, but demonstrated a 61% relative reduction of vertebral fracture (3.37% versus 1.32%) associated with product administration. Preotach treatment also increased the mineral density of the spine as well as hip bone. The most common side effects noted included increased serum and urine calcium levels (hypercalcemia and hypercalciuria) as well as nausea. The biologically active substance is manufactured by SynCo BioPartners (Amsterdam, the Netherlands) and it is marketed by Nycomed (Roskilde, Denmark).

Tysabri (natalizumab) is a recombinant, 149 kDa humanized IgG4 monoclonal antibody produced in engineered murine myeloma cells. In 2006 it was approved for resumed marketing in the US and approved for the first time in the EU. It is indicated as a monotherapy for the treatment of the relapsing forms of multiple sclerosis (MS) under certain conditions.

Initial accelerated approval had been granted by the FDA in November 2004 on the basis of the substantial benefit recorded to MS sufferers as revealed by initial trials. At that stage, the most serious adverse events noted were acceptable infections and hypersensitivity reactions, but approval was contingent upon continuing the trials for an additional year. Marketing and its use in ongoing clinical trials was subsequently halted in February 2005 when the studies revealed two cases of fatal progressive multifocal leukoencephalopathy (PML, a rare viral infection of the brain) in patients receiving Tysabri in conjunction with interferon therapy. The FDA allowed resumption of a clinical trial in February 2006 and the product subsequently gained approval under more limited conditions (e.g., it must be used as a monotherapy only, and it is made available under a restricted distribution program).

The manufacture of Tysabri entails initial culture of the producer cells in a 15,000-L bioreactor, using media devoid of serum or animal-derived components. Cells are then removed from the antibody-containing media by membrane filtration and the product is purified by a combination of protein A affinity, anion exchange, and hydrophobic interaction chromatography. Additional (viral clearance) steps undertaken during downstream processing include low pH treatment and nanofiltration. The final product is formulated in the presence of sodium chloride, polysorbate 80, and sodium phosphate buffer components as excipients and is presented as a 15 mL-concentrate (20 mg active/mL) in glass vials.

The recommended dosage regimen includes initial dilution of the concentrate in 100 mL saline, followed by once monthly administration via IV infusion over one hour.

Tysabri binds specifically to selected integrins found on the surface of most white blood cells (with the exception of neutrophils). These integrins serve as recognition docking markers, allowing binding to vascular endothelial cells, and thereby facilitating leukocyte migration across the endothelium. Tysabri administration blocks this interaction and increases the numbers of circulating leukocytes in the blood by inhibiting transmigration out of the vascular space.


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