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

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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

Advate production incorporates modifications to the original Recombinate procedure to increase product safety. Alterations include elimination of human- and animal-derived raw materials and excipients. Cell culture media is adapted to be serum-free, and human serum albumin is no longer used as an excipient. The purification process has been modified to include a viral inactivation step with a solvent-detergent (1% Triton-X-100, 0.3% polysorbate 80, and 0.3% tri-N-butylphosphate). The purification process consists of immunoaffinity chromatography, cation exchange and anion exchange steps as well as the solvent-detergent step. Final product is presented in lyophilized form and is available in four different strengths. Trials confirmed its efficacy and comparability to Recombinate.

Dukora (oral cholera vaccine) contains inactivated Vibrio cholerae serotype O1 strains along with recombinant cholera toxin B subunit (CTB). The European Commission approved the vaccine in April 2004. It is indicated for active immunization against disease caused by V. cholerae serogroup O1 in adults and children set to visit indemic and epidemic geographical regions. Dukoral contains both killed bacterial cells and the cholera toxin subunit, thereby incorporating all the most important disease-related antigens. The marketing authorization holder is SBL Vaccin AB. The product has been available in Sweden since 1993.

The relevant serogroup O1 cells are cultured in 550-L fermentors, harvested, concentrated and inactivated, either by heat (560C) or formalin (0.5%). The recombinant cholera toxin B subunit, a 102-amino acid polypeptide, is produced by an engineered V. cholerae strain. Precipitation (using sodium hexametaphosphate) and hydroxyapatite chromatography represent the principle purification steps. The finished product is formulated in phosphate buffered saline solution, and is intended for oral administration. A bicarbonate buffer is co-administered to protect the CTB from stomach acid.

The efficacy of Dukoral has been demonstrated in three randomized placebo-controlled trials. It was found to be immunogenic in both children and adults, and an overall protective efficacy of 85 percent after six months was recorded. Commonly reported adverse events were gastrointestinal related, including abdominal discomfort and diarrhea.

Zevalin (ibritumomab tiuxetan) is a murine monoclonal antibody produced in an engineered CHO cell line and administered in radiolabelled form. The product is indicated for refractory or Rituximab-relapsed CD 20+ follicular B-cell non-Hodgkin's lymphoma. The Zevalin antibody specifically binds to the human CD 20 antigen, expressed on the surface of both normal and malignant B-lymphocytes. Cell death is induced by the Y90 derived high-energy beta radiation. Treatment is normally in combination with Rituximab (trade names MabThera in EU and Rituxan in US).

Zevalin gained marketing authorization in the EU in January 2004, although it was first approved in the US in 2002. It is manufactured by IDEC pharmaceuticals and the EU marketing authorization holder is Schering AG.

Manufacture starts with cell culture and product recovery, followed by multiple chromatographic steps, and then vital inactivation and removal steps. The antibody is chemically conjugated to a chelator (tiurexan) and formulated as a solution for injection. Immediately prior to its administration, it is chelated to the radionucleotide yttrium-90 (Y90), which is not supplied with the product.

The dossier submitted to the EMEA was supported by six clinical trials (306 patients in total). A post-treatment response rate of 75 to 80 percent was observed in patients no longer responsive to plain Rituximab or to chemotherapy. Adverse effects included a severe reduction in white blood cell and platelet counts, and gastrointestinal and respiratory complications.

Erbitux (cetuximab) is a chimeric monoclonal antibody directed against the human epidermal growth factor receptor (EGFR) and is produced by an engineered murine myeloma cell line. It is usually used in combination with irinotecan. Erbitux binds specifically to the extracellular ligand-binding domain of the EGFR found on a range of normal cells (e.g. epithelial cells) as well as a proportion of colorectal and other tumor cells. The product acts as a competitive antagonist, preventing binding of native EGF to its receptor, thereby blocking EGFR activation and signal transduction. This in turn inhibits cell growth and triggers apoptosis.

It was approved in 2004 both in the EU and US for the treatment of (EGFR-expressing) metastatic colorectal cancer in patients refractory to irinotecan-based chemotherapy. Manufactured by ImClone Systems and Boehringer Ingelheim, it is marketed by Bristol-Myers Squibb in the US and by Merck in the EU.


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