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

Exubera (insulin, human recombinant) is identical in amino acid sequence to native human insulin. It is produced by recombinant means in an engineered E. coli K 12 strain, and gained approval for general medical use in 2006 both in the EU and US. Unlike formerly approved insulins, which are administered parenterally, Exubera is administered via the pulmonary route using a specially designed inhaler. It is indicated for the treatment of adults with diabetes mellitus, for the control of hyperglycemia. The inhaled insulin is absorbed more quickly than subcutaneously administered regular human insulin and has an onset of action that is similar to subcutaneously administered rapid-acting engineered insulin analogues, such as insulin lispro.

After its absorption from the lung into the blood Exubera promotes a decrease in blood, glucose levels (and its other characteristic effects) in the normal manner, via interaction with the insulin receptor.

The manufacture of Exubera consists of 16 steps. After initial fermentation, the E. coli cells are harvested via centrifugation, with subsequent cell disruption and recovery of the insulin-containing fusion pro-product. Downstream processing includes a concentration step, a step to release free insulin from the pro-product and multiple chromatographic purification steps. Excipients then added include mannitol (a stabilizing and bulking agent) as well as glycine and sodium citrate (buffering and stabilizing agents). The product is spray dried, allowing its subsequent storage at room temperature. Product particles display a mean particle diameter of approximately 3 m, which facilitates aerosol delivery to the deep lung. The finished product is filled into unit dose blisters containing 1 mg or 3 mg of active substance. These fit a manually operated, reusable inhaler device.

Exubera has a duration of action comparable to subcutaneously injected regular human insulin and longer than rapid-acting insulin. It is administered immediately before food consumption and in regimens that include a longer acting insulin. When administered to healthy volunteers, the onset of (glucose lowering) activity was observed within 10 minutes with maximum effect noted after two hours and a total duration of about six hours.

Clinical studies underpinning safety and efficacy were conducted using 2,500 adult patients with type 1 or type 2 diabetes, and the primary efficacy parameter monitored was invariably glycemic control. Like other insulin preparations, hypoglycemia represented the most commonly reported adverse event. Product administration was also found to cause a greater decline in lung function than controls and, as a consequence, the product is contraindicated in patients who smoke or who have poorly controlled or unstable lung disease. Exubera is distributed by Pfizer (New York City, NY) and licensed from Nektar (San Carlos, CA).

Gardasil (human papillomavirus vaccine, types 6,11,16,18, recombinant), also marketed as Silgard in the EU, is a multivalent vaccine preparation containing the purified recombinant major surface capsid (L1) protein of human papillomavirus (HPV) types 6,11,16, and 18, produced separately in engineered strains of S. cerevisiae. The product gained approval in 2006 in both the US and EU and is used to vaccinate girls and women (9–26 years of age) against cervical and vaginal cancer and genital warts caused by the HPV types listed. HPV infection represents the most common sexually transmitted disease worldwide, with some 50% of young women being infected within five years of becoming sexually active. Native papillomavirions are approximately 60 nm in diameter. These double-stranded DNA viruses display an icosahedral symmetry made by 72 pentamers of the L1 caspid protein. Some 40 different HPV strains preferentially infect the genitals and 13 of these are highly carcinogenic. They are believed to be the primary cause of cervical cancer, which is the second most common type of cancer causing deaths in women worldwide. Types 6,11,16, and 18 are the most commonly occurring HPVs and these are believed to cause the vast majority of cancers and genital wart growth.

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