May 28, 2013

Milestones and Moderate Progress in 2012 Drug Approvals


Voraxaze is a relatively large (83 kDa) homodimeric bacterial carboxypeptidase enzyme expressed in E. coli. It is approved for treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. Methotrexate is an anti-folate antimetabolite widely used as a chemotherapeutic agent, but which itself exhibits a number of potential toxic side effects. It is excreted predominantly via the kidneys, with a typical half-life of 15 hours. Voraxaze, by hydrolyzing the carboxy-terminal glutamate residue from the methotrexate program, inactivates the latter, thereby alleviating potential toxicities in patients with impaired methotrexate clearance. 

Jetrea and NovoThirteen are both produced in yeast-based systems. Jetrea contains a 27 kDa proteolytic enzyme and is used to treat vitreomacular adhesion. The condition is characterized by abnormal adherence of the vitreous gel within the eye to the retina, potentially leading to distortion or loss of vision. The adherence is mediated by vitreous proteins including laminin, fibronectin, and collagen, which are targeted by the product. NovoThirteen contains the A subunit of blood factor XIII and is used to treat congenital factor XIII A subunit deficiency. 

Perjeta contains a humanized mAb that targets the extracellular dimerization domain of the human epidermal growth factor 2 protein (HER 2), found in association with a significant proportion of breast tumours. It binds to a different element of the HER-2 protein than does the previously approved Herceptin, and the product is used in combination with Herceptin (and docetaxel) in the treatment of HER-2 positive metastatic breast cancer.
The final product listed in Table I is Zaltrap, a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions derived from VEGF receptors 1 and 2, fused to the Fc portion of a human IgG. The resultant 115 kDa dimeric glycoprotein acts as a soluble receptor for human VEGF, thereby preventing/reducing the biological activity of the latter. Zaltrap is approved for treatment of colorectal cancer, and the active ingredient is also marketed in a different formulation as Eylea, approved in 2011 for the treatment of age-related macular degeneration. 

Gary Walsh, Industrial Biochemistry Program, Dept. of Chemical and Environmental Sciences and the Materials and Surface Science Institute, University of Limerick, Limerick City, Ireland, Gary.walsh@ul.ie

REFERENCES
1. G. Walsh, Biopharm Int., 25 (6), 34-36 (2012).
2. G. Walsh, Biopharm Int., 23 (10), 30-41 (2010).
3. G. Walsh, Biopharm Int., 22 (10), 68-77 (2009).
4. G. Walsh, BioPharm Int., 21 (10), 52-65 (2008).
5. S. Pearson, H.P., Jai, and K. Kandachi, Nat. Biotechnol. 22, (1), 3-4, (2004).
6. M.P. Ryan and G. Walsh, Trends in Biotechnol. 30, (12) 615-620, (2012).
7. EMA, Positive opinion on the marketing authorisation of Glybera (alipogene tiparvovec) (July 19, 2012).

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Tags: wumike, approval, FDA, Mab, regulatory