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

Nplate (romiplostim) is a dimeric fusion product. Each of its two constituent polypeptides consists of two thrombopoietin receptor-binding domains linked to a human IgG-1 Fc fragment. It is expressed in E. coli. Approved by the FDA in August 2008, Nplate is indicated for the treatment of thrombocytopenia (low platelet count and hence impaired blood clotting ability) in patients with chronic idiopathic thrombocytopenic purpura (ITP) who display insufficient response to the alternative potential treatments of corticosteroids, immunoglobulins, or splenectomy. ITP is an autoimmune condition characterized by the destruction of platelets (thrombocytes) and megakaryocytes (the platelet-producing cells).

Thrombopoietin (TPO) is the primary physiological (stimulatory) regulator of platelet production. Nplate, by its thrombopoietin receptor-binding domains, binds to and activates TPO cell surface receptors in a manner analogous to endogenous TPO. The resultant increase in platelet production counterbalances platelet destruction by the immune system. Nplate's IgG Fc component serves to increase the product's serum half-life, facilitating its once weekly subcutaneous administration.

Safety and efficacy were largely assessed by two double-blind, placebo-controlled clinical studies and one open-label extension study involving 124 patients with chronic ITP. A clear overall increase in platelet production was observed in response to Nplate administration. The most common adverse effects noted included joint, stomach and shoulder pain, dizziness, and insomnia. However, several more serious effects were also reported, including a risk of bone marrow fibrosis and worsened thrombocytopenia after cessation of therapy.

Nplate is manufactured and distributed by Amgen (Thousand Oaks, CA). Subsequent to post-fermentation recovery and chromatographic purification, mannitol, sucrose, histidine, and polysorbate are added as excipients, and the final product is lyophilized.

Recothrom (thrombin, topical, recombinant) is a recombinant version of human thrombin produced in an engineered CHO cell line. It was approved by the FDA for controlling minor bleeding during surgery. The product is applied topically, directly on the surface of the bleeding or oozing tissue only. Thrombin (activated blood coagulation factor II, i.e., factor IIa) is a serine protease that functions at the terminal stage of the normal blood-clotting process. Its inactive circulating xymogen (prothrombin, i.e., factor II) is a 582 amino acid, 72.5 kDa glycoprotein containing six γ-carboxyglutamate residues toward its N-terminal end. It is proteolytically activated during the blood coagulation cascade by factor Xa and the active thrombin molecule consists of two polypeptides linked by a single disulfide linkage. The smaller polypeptide contains 49 amino acids while the larger contains 259 amino acids. [Physiologically thrombin then proteolytically activates fibrinogen (blood factor I), yielding fibrin, which forms the structural basis of a blood clot]. The recombinant thrombin displays an identical amino acid sequence to that of the native molecule.

The primary clinical evaluation undertaken was a multisite, randomized, double-blind study involving 411 surgical patients, who were treated with either recothrom or bovine thrombin. Efficacy was evaluated by the incidence of hemostasis 10 minutes post-product application, and no difference in efficacy between both treatment groups was recorded (95.4% versus 95.1%). The recombinant product, however, has a much reduced likelihood of triggering an immune response and the risk of accidental transmission of blood-bourne pathogens is also minimized. The most common side effect noted was complications at the incision site.

The recombinant molecule is synthesized and released from the producing CHO cell line in zymogen form. Downstream processing steps include its proteolytic activation, multiple chromatographic purification steps, and a solvent-detergent treatment step, as well as nanofiltration as viral clearance steps. No additives of human or animal origin are used in the manufacturing process. Histidine, mannitol, sucrose, sodium, and calcium chloride, as well as polyethylene glycol are added as excipients and the final product is lyophilized.

Gary Walsh, PhD, is an associate professor in the Industrial Biochemistry Program at the University of Limerick, Ireland. He is also a member of BioPharm International's editorial advisory board, 353.61.202664,


1. Walsh G. Biopharmaceuticals: approvals and approval trends in 2004. Biopharm Int. 2005;18,58-65.

2. Walsh G. Biopharmaceuticals: approval trends in 2005. BioPharm Int. 2006;9:58-68.

3. Walsh G. Biopharmaceuticals: approval trends in 2006. BioPharm Int. 2007;20:40-48.

4. Walsh G. Biopharmaceuticals: approval trends in 2007. BioPharm Int. 2008;21:52-65.

5. Raider RA. Low FDA approvals of new biopharmaceuticals continued in 2008. Available from:

6. Hoffman H, Yasothan U, Kirkpatrick P. Rilonacept. Nature reviews drug discovery. 2008;7:385-386.

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