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


Biopharmecuticals: Approval Trends in 2006
Thirteen biopharmaceuticals gained marketing authorization

BioPharm International
Volume 21, Issue 9

Gardasil manufacture requires separate fermentation of four engineered S. cerevisiae strains, each housing the gene coding for the P1 capsid protein of one of the HPV strains listed. Following fermentation, the cells are recovered by microfiltration and the recombinant protein is released via homogenization. In each case, the recombinant capsid proteins spontaneously self-assemble into large virus-like particles (VLPs), rendering their subsequent purification— via size-based membrane filtration, ultrafiltration, and chromatography—relatively straightforward. The purified antigen (VLP) is then absorbed onto amorphous aluminium hydroxyphosphate sulphate, which acts as an adjuvant. Also added are sodium chloride, histidine, polysorbate 80, and sodium borate buffer as excipients. The product is presented as single use, 0.5 mL-doses in either vials or prefilled syringes with each dose containing 20 g of type 6 L1 protein and 40 g of each of the other L1 proteins. The administration schedule usually entails intramuscular injection of an initial dose, with subsequent doses delivered at months two and six.

Clinical trials assessing product safety and efficacy involved more than 20,000 females and clearly showed a protective effect. The most common side effects noted were pyrexia (fever) and reaction site injections. Gardasil is manufactured (and distributed in the US) by Merck (Whitehouse Station, NJ) and is marketed in the EU by Sanofi Pasteur (Lyon, France). It is also marketed in the EU as Silgard by Merck Sharp & Dohme (Hertfordshire, UK).

Lucentis (ranibizumab) is a 48 kDa humanized MAb antigen-binding fragment (Fab fragment) consisting of a 214 amino acid light- chain fragment linked by an interchain disulfide bond to a 231 amino acid heavy-chain fragment. Produced in E. coli, the fragment binds vascular endothelial growth factor A (VEGF-A) with high affinity. It was first approved in the US in 2006, and subsequently in the EU (in January 2007). It is indicated for the treatment of neovascular (wet) age-related macular degeneration (wet AMD), a condition characterized by the formation of abnormal, leaky blood vessels under the macula (the central part of the retina). This condition can result in the lifting of the retina and hemorrhage in the subretinal space. As a progressive, degenerative disease, central vision is gradually blurred and the condition is most common in persons aged 75 years and older.

VEGF-A, via binding to its endothelial cell surface receptors, is believed to be a major driving force for abnormal blood vessel formation. Binding of Lucentis to VEGF-A prevents interaction with the receptor, thereby reducing abnormal blood vessel growth.

The manufacturing process of Lucentis involves initial fermentation of the E. coli producer cell which carries cDNAs encoding variable light and variable heavy antibody chains fused to human constant light and constant heavy (CH1) domains. The light and heavy chains fold into their native conformation after their secretion into the periplasm. Soluble product is fully released from the E. coli via initial homogenization and a subsequent heating step that precipitates cellular debris. High-resolution purification is achieved by a combination of four subsequent chromatographic steps, followed by the addition of trehalose, histidine, and polysorbate 20 as excipients.

Lucentis is administered by direct intravitreal injection (0.5 mg active in a final volume of 0.05 mL) once monthly, and usually for an initial period of 3 months, with subsequent administration being dependent upon results from routine visual monitoring.

The clinical efficacy and safety of Lucentis was assessed primarily in three randomized, double blind studies over a period of 24 months using a total of 1,323 patients (879 of which received Lucentis, with 444 untreated controls). The primary efficacy endpoint was either the proportion of patients who maintained vision (defined as losing fewer than 15 letters of visual acuity) compared with baseline or the mean change in visual acuity. The studies showed that Lucentis administration resulted in an increase in mean change in visual acuity as compared with continuous deterioration in the case of controls. The most common adverse reactions noted were conjunctival hemorrhage, eye pain, vitreous floaters, increased ocular pressure, and inflammation. Lucentis is manufactured by Genentech (San Francisco, CA) and is marketed in Europe by Novartis Europharm (Sussex, UK).

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