Biopharmaceuticals: Approvals and Approval Trends in 2004 - Twelve biopharmaceuticals gained marketing approval in the US and EU in 2004. Antibody-based products represented the single largest product


Biopharmaceuticals: Approvals and Approval Trends in 2004
Twelve biopharmaceuticals gained marketing approval in the US and EU in 2004. Antibody-based products represented the single largest product category.

BioPharm International
Volume 18, Issue 5

Erbitux manufacture is initiated by batch culturing the producing cell line in serum-free media in 10,000-L and 12,000-L bioreactors. Multistep chromatographic purification is undertaken following initial recovery and concentration. Downstream processing also incorporates two specific viral inactivation and removal steps, and the final product is formulated as a sterile, 2-mg/mL-cetuximab solution, intended for administration via infusion.

Both in vitro and animal studies confirmed that Erbitux inhibits the growth and survival of tumor cells over-expressing EGFR. Clinical trials also showed that a combination of Erbitux and irinoectan outperformed Erbitux monotherpay in terms of objective response rate, disease control rate, and progression-free survival. Reported adverse events include severe infusion-related reactions, pulmonary complications, dermatological toxicity, and gastrointestinal disturbances.

Avastin (bevacizumab) is a humanized monoclonal antibody produced in an engineered CHO cell line. It binds specifically to human vascular endothelial growth factor (VEGF). Avastin brings about its therapeutic effect by inhibiting angiogenesis (the formation of new blood vessels), a process required to support tumor growth. Binding to VEGF prevents VEGF interaction with its cell surface receptor, a process central to the triggering of new blood vessel growth in both normal and diseased tissue.

FDA approved Avastin in 2004. It is indicated for first line of treatment for patients with metastatic carcinoma of the colon or rectum, in conjunction with specified small molecule chemotherapeutic agents (5 fluorouricil, folinic acid, and irinotecan). The product has subsequently also gained marketing approval in the EU (in January, 2005). It is manufactured by Genentech and marketed in the EU by Roche.

Production-scale manufacture entails culture of the CHO producer-cell line in 12,000-L fermentors using a serum-free growth media. Product purification is achieved via protein A affinity chromatography followed by sequential anion and cation exchange steps. Two viral inactivation steps are also included in the downstream processing protocol. The final product is concentrated via ultrafiltration and is formulated as a sterile solution for intravenous infusion.

Clinical trials confirmed the product's efficacy, with Avastin administration (in conjunction with the specified small molecule chemotherapeutics) resulting in a statistically significant increase in overall survival, higher objective response rates, and longer progression-free survival. Adverse effects that were noted included gastrointestinal perforations, hemorrhage and arterial thromboembolism.

Raptiva (efalizumab) is a humanized monoclonal antibody produced in an engineered CHO cell line. Approval by the European Commission was in September 2004 (and by FDA in 2003) for the treatment of adult patients with moderate to severe chronic plaque psoriasis who failed to respond to or were intolerant of other specified systemic therapies. Genentech manufactures the product but Serono markets it.

Psoriasis is a chronic inflammatory skin disorder caused by T-lymphocyte mediated stimulation of keratinocyte hyperproliferation. By preventing LFA-1/ICAM binding, the product inhibits several stages of this immunological disorder. Raptiva specifically binds lymphocyte function-associated antigen 1 (LFA-1), a leukocyte cell surface protein. Binding inhibits interaction of LFA-1 with intercellular adhesion molecules 1, 2 and 3 (ICAM-1, -2 and -3). LFA-1 is present on activated T lymphocytes, and ICAM-1 is up-regulated on endothelial cells and keratinocytes in psoriasis plaques.

Manufacture entails initial culture of producer CHO cells in suspension, followed by multiple chromatographic purification and viral inactivation/removal steps. The final product is presented in lyophilized form, intended for subcutaneous (SC) administration subsequent to reconstitution in water for injections (WFI).

Clinical trials confirmed that 12 weeks of treatment with Raptiva significantly improved the severity and area of psoriatic lesions. As an immunosuppressive agent however, the product has the potential to increase the risk of serious infections and malignancies.

Levemir (insulin detemir) is a long-acting insulin analogue produced in an engineered Saccharomyces cerevisiae cell line. The product differs from native human insulin in that the theronine residue at position 30 of the insulin B chain (B30) has been omitted and a myristic fatty acid (a C14 saturated fatty acid) has been attached (acylated) to the amino group of the lysine residue found at position B29. Albumin harbors three high-affinity, fatty-acid, binding sites and, as such, Levemir binds tightly but reversibly to albumin, both at the site of injection and in the blood. This in turn ensures a constant and prolonged release of free insulin, bestowing upon it an extended duration of action of up to 24 hours.

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