Biopharmaceuticals: Approval Trends in 2008 - Ten biopharmaceuticals gained marketing authorization in the US or EU in 2008, although only four were new approvals. - BioPharm International


Biopharmaceuticals: Approval Trends in 2008
Ten biopharmaceuticals gained marketing authorization in the US or EU in 2008, although only four were new approvals.

BioPharm International
Volume 22, Issue 10

Arcalyst is manufactured and distributed by Regeneron Pharmaceuticals (New York, NY). Manufacture entails initial cell culture of the CHO producer cells, followed by chromatographic purification. The product is marketed in a lyophilized form and contains histidine, arginine glycine, sucrose, and polyethylene glycol as excipients.

Cimzia (certolizumab pegol) is a recombinant humanized anti-TNF-α antigen-binding (Fab') fragment covalently linked to a 40kDa polyethylene glycol. The 91 kDa antibody fragment is expressed in E. coli and is composed of a 214 amino acid light-chain and a 229 amino acid heavy-chain fragment. The FDA approved the product in April 2008 for the treatment of Crohn's disease in adult patients who have not responded adequately to conventional therapy.

Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract. Characteristic symptoms can include abdominal pain, diarrhea, vomiting, or weight loss. The condition is characterized by overactive T cell activity, including the overproduction of proinflammatory cytokines—most notably tumor necrosis factor-α (TNF-α). Cimzia brings about its therapeutic effect by binding (mopping up) TNF-α, thereby reducing the pro-inflammatory effect. Unlike additional full-length antibody-based therapies for Chron's disease (Remicade and Humira), Cimzia is devoid of the antibody Fc component, and therefore, cannot trigger Fc-mediated functions, such as complement fixation or antibody-dependant cell-mediated cytotoxicity. The PEG moiety extends the product's plasma half-life (antibody fragments are characterized by substantially shorter half-lives than intact antibodies), allowing an initial dosage regimen of once fortnightly subcutaneous injection, with subsequent once monthly maintenance dosages.

Product safety and efficacy was primarily established in two double-blind, randomized placebo-controlled studies with a combined population of over 1,000 Crohn's sufferers. Overall, the studies confirmed a statistically significant improvement in product-treated patients as compared to the placebo group. The most common—and potentially life threatening—adverse reactions were increased risk of infection, with tuberculosis, invasive fungal, and other opportunistic infections, all being observed in Cimiza-treated patients.

Manufacture entails chromatographic purification subsequent to product recovery from E. coli-based fermentation and the final product is formulated in a lyophilized form, containing sucrose, lactic acid, and polysorbate as excipients.

Filgrastim ratiopharm (filgrastim) is a recombinant form of the 174 amino acid native human granulocyte colony stimulating factor (G-CSF) expressed in E. coli. Compared to native G-CSF the product is nonglycosylated and contains an extra N-terminal methione reside, both modifications reflecting the recombinant expression system used. Approved for general medical use throughout the EU in September 2008, Filgrastim ratiopharm is a biosimilar product and the reference product against which it was compared was Amgen's Neupogen (also produced in E. coli, also nonglycosylated and of an identical amino acid sequence).

Filgrastim ratiopharm is indicated for reducing duration or incidence of neutropenia associated with certain conditions, including cancer therapeutic regimes, advanced HIV infection, and congenital neutropenia. Neutropenia is a condition triggered by a significant decrease in blood neutrophil (white blood cells capable of ingesting and destroying bacteria) levels and is characterized by the occurrence of frequent and usually serious infections. G-CSF functions as a growth and differentiation factor for neutrophils and their precursor cells, and activates mature neutrophils. Clinical comparability to Neupogen was investigated in one main trial involving 348 breast cancer patients suffering from severe chemotherapy-associated neutropenia and with follow-up safety assessments in patients with non-Hodgkin's lymphoma and lung cancer. Safety and efficacy were comparable to the reference medicine, with muscoskeletal pain representing the most common side effect recorded.

The active substance is manufactured by SICOR Biotech (Vilnius, Lithuania) with Ratiopharm (Ulm, Germany) holding the marketing licence. Manufacture entails initial fermentation of the producing E. coli, induction of product synethesis, and subsequent recovery of product-containing inclusion bodies from the harvested cells. The inclusion bodies are dissolved using a chaotrophic agent, with protein refolding then undertaken in a reducing–oxidizing system. The product is then purified to homogeniety by column chromatography. The final product contains sorbitol, polysorbate, and sodium acetate buffer components as excipients and it is presented in solution in prefilled syringes.

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