Milestones and Moderate Progress in 2012 Drug Approvals

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BioPharm International, BioPharm International-04-01-2013, Volume 26, Issue 4

First gene therapy and plant-based expression vector products approved in 2012.

In terms of product approvals, the past year can be considered reasonably successful. Twelve biopharmaceutical marketing applications were approved in the United States and/or the European Union in 2012 (see Table I). Approval numbers for the past year are in line with those recorded over the previous five years (1-4), which reveal a statistical average of 12.2 approvals annually (see Figure 1).

Figure 1: Biopharmaceutical approval numbers in European Union and/or United States over the past five years.

Products approved included three enzymes, three antibodies, and two fusion proteins, as well as a gene therapy product, a regulatory peptide, a blood product, and a colony stimulating factor. Three products are indicated against cancer and a further two against genetic diseases, while the remainder target a wide range of medical conditions.

In terms of expression systems used, 5 of the 11 protein-based products approved are produced using mammalian (mainly CHO) cell lines, three are expressed in E. coli, two in yeast-based systems (one each in S. cerevisiae and P. pastoris), and one product is produced in an engineered plant-based system. These figures once again reflect the ongoing dominance of mammalian-based expression systems in terms of biopharmaceutical manufacture.

Digging a little deeper reveals that the majority of approvals (10 of the 12) were first-time approvals in 2012. Two of the products (Adcetris and Eylea), although newly approved in one region last year, had gained approval in 2011 in the other region (Table I). Elelyso, moreover, is not the first glucocerebrosidase approved, nor is Tbo-filgrastim the first G-CSF-based product to come on the market.

Table I: Biopharmaceuticals (recombinant proteins, monoclonal antibody, or nucleic acid-based products) approved in the USA and/or European Union in 2012. Abbreviations: r = recombinant; rh = recombinant human; VEGF = vascular endothelial growth factor; AAV1 = adeno-associated virus, serotype 1; G-CSF = granulocyte colony stimulating factor; LPL = lipoprotein lipase.

Several of the newly approved products are particularly noteworthy in terms of technological or medical innovation, and it is those products that are discussed in most detail below. As Adcetris and Eylea were included in last year's review (1), they are not considered further herein.



The first gene therapy trials date from the late 1980s. In the intervening years, more than 1800 such trials have been approved/initiated world wide. Until 2012, no gene therapy-based product had gained approval for human use in the western world, although a small number of such products have been approved in China (5) and four gene therapy-based drugs/vaccines have been approved for veterinary use in the West (6).

A significant milestone for gene therapy was achieved on Oct. 25, 2012, with the approval of Glybera (alipogene tiparvovec) by the European Commission for use in the treatment of lipoprotein lipase deficiency within the EU. Lipoprotein lipase (LPL) deficiency is a rare genetic condition, affecting 1 in 500,000 individuals and, therefore, the approved product has orphan status. The condition is characterized by absence/near absence of lipoprotein lipase, an enzyme central to dietary-derived lipid metabolism and distribution in the body. The enzyme is expressed primarily by muscle cells and adipocytes and is central to the processing of circulating triglyceride-rich lipoproteins.

Glybera is a replication-deficient adeno-associated viral vector housing a human lipoprotein lipase gene. The product is administered intramuscularly, and the resultant transduction of the surrounding muscle cells results in functional LPL expression, leading to an anticipated positive therapeutic outcome. The vector genome persists in the nucleus of transduced cells as episomes, leading to long-term expression of the transgene. It is anticipated that treatment will be a once-off series of intramuscular injections into the legs. Treatment will certainly not be inexpensive, with as estimated cost in the region of $1.6 million (€1.2 million) per patient.

Despite its eventual approval, European Medicines Agency (EMA) evaluators had some reservations about the product. The Committee for medicinal products for human use (CHMP) considered the Glybera application—and adopted a negative opinion—on two previous occasions in 2011 (7). The committee appeared initially to have a number of product quality-related and efficacy-related concerns, and final product approval is restricted to a subset of LPL-deficient patients suffering the most serious condition-related effect, that of severe or multiple pancreatitis attacks.


The approval of Elelyso (taliglucerase alfa) by FDA in May 2012 represents another technological milestone, in that it is the first product approved for human use that is produced using a plant-based expression vector. Glycoprotein production in plant-based systems generally results in the formation of hyperglycosylated product containing various sugar moieties immunogenic in man. The sugar chains are devoid of sialic acid caps, which can negatively influence their serum half-life.

Elelyso is a recombinant human glucocerebrosidase used as a replacement therapy to treat Gaucher disease, a rare lysosomal storage disorder. The recombinant protein displays terminal mannose residues in its glycocomponent, facilitating direct product uptake by macrophages (the target cell type) via cell surface mannose receptors.

Interestingly, a parallel marketing authorization application for Elelyso submitted to the EMA was refused. However, the grounds for European refusal was not scientific in nature, but was due to the existence of a 10-year marketing exclusivity granted to a substantially similar product (trade name Vpriv), approved by the European Commission in August 2010.


Among the additional products approved in 2012 is Raxibacumab injection, a human monoclonal antibody (mAb) approved by FDA for the prophylaxis and treatment of inhalational anthrax. The anthrax causative agent is the spore-forming Bacillus anthracis, and the infection can present as cutaneous, gastrointestinal, or inhalation formats, depending upon the route of infection. Inhalational anthrax is generally the most commonly fatal and would likely be the form of most concern in terms of bioterrorism. Raxibacumab specifically targets (neutralizes) the B. anthracis protein toxin.

The approval of three products produced in engineered E. coli cells (Gattex, Tbo-filgrastim, and Voraxaze) illustrates the continued utility of this prototypic expression system. Gattex (Revestive in Europe) is a short (33 amino acid) single-chain Glucagon Like Peptide 2 (GLP-2) analogue devoid of post-translational modifications. GLP-2 is known to promote increased intestinal blood flow, enhanced absorption of nutrients and maintenance of the small intestinal mucosa, hence the basis of product development as a treatment for short bowel syndrome caused by congenital defect, surgery, or disease associated loss of intestinal function.

Tbo filgrastim is another recombinant granulocyte colony stimulating factor used to treat neutropenia. The product is already marketed in Europe as Tevagrastim where it is classified as a biosimilar (to Amgen's recombinant G-CSF, Neupogen). However, it was assessed and approved in the US as an original biologics license application (BLA), because a biosimilar pathway was not available to the sponsor at the time of submission to the regulators.

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,


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).