Biopharmacetiucal Approval Trends in 2009 - Biotech approvals were up last year. Is it a sign of a new trend? - BioPharm International

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Biopharmacetiucal Approval Trends in 2009
Biotech approvals were up last year. Is it a sign of a new trend?


BioPharm International
Volume 23, Issue 10

Products Other Than Antibodies

Kalbitor (ecallantide) is a 60 amino acid polypeptide produced by recombinant means in the yeast P. pastoris. It is the first approved biopharmaceutical to be produced in this particular recombinant system. Kalbitor was approved in December 2009 by the FDA for the treatment of acute attacks of hereditary angioedema (HAE). This genetic disorder is caused by mutations to the gene coding for the C1 esterase inhibitor, which plays a role in controlling the coagulation cascade in blood clotting, the complement cascade, and elements of the inflammatory process. The C1 esterase inhibitor is a major inhibitor of plasma kallikrein. The absence of active esterase inhibitor results in the overproduction of bradykinin. Bradykinin is a vasodilator believed to be primarily responsible for the episodes of painful swelling in various body tissues (usually lasting for several days) that characterize hereditary angioedema. Kalbitor functions by inhibiting plasma kallikrein, the plasma protease responsible for the production of bradykinin. The safety and efficacy of Kalbitor was primarily evaluated by two randomized, double-blind trials involving 143 HAE patients. The primary endpoints measured related to patient-assessed symptom severity and response scales, with Kalbotir scoring significantly better than the placebo. The most common adverse reactions noted included headache, nausea, and upper respiratory tract infection, while the most serious was the risk of anaphylaxis. Kalbitor is manufactured by Dyax Corporation (Cambridge, MA).

Victoza (liragutide) is a glucagon-like peptide 1 (GLP-1) receptor agonist produced by recombinant means in S. cerevisiae. It was approved in Europe in June 2009 for the treatment of type 2 diabetes (and has subsequently been approved in the US in January 2010). The product has an amino acid sequence identical to native GLP-1, with one exception: lysine34 is substituted with an arginine. A 16 carbon fatty acid also has been attached to lysine26, by a glutamic acid spacer. This increases the molecule's plasma half-life from approximately 2 min to 13 h, allowing once daily administration by subcutaneous injection. The product potentiates glucose-dependent insulin secretion. The efficacy and safety were assessed in five double blind, randomized controlled clinical trials involving almost 4,000 type 2 diabetics. The primary endpoint measured was the level of glycosylated haemoglobin (HbA1c; an indicator of long-term blood glucose levels) present in the blood after 6 and 12 months. Victoza treatment, alone or in combination with additional diabetic therapies, resulted in mean decreases of HbA1c levels by 0.5–1.5%. The common side effects included hypoglycemia. Victoza is manufactured by Novo Nordisk (Bagsvaerd, Denmark).

Biopoin and Eporatio (epoetin theta) are tradenames of a recombinant human erythropoietin (EPO) produced in a CHO cell line. The 165 amino acid 30.6 kDa glycosylated product displays an identical amino acid sequence to native human EPO and, like the native molecule, displays 3 N-linked and 1 O-linked oligosaccharide side chains. The EPO is manufactured by Merckle Biotech (Ulm, Germany) and is marketed as Biopoin by CT Arzneimittel (Berlin, Germany) and as Eporatio by Ratiopharm (Ulm, Germany). It is approved under both tradenames for the treatment of anemia associated with chronic renal failure and chemotherapy in adults. It is marketed in prefilled syringes and can be administered subcutaneously or intravenously. The dosage regimes typically entail thrice weekly administration for several weeks ("correction" phase), followed by a "maintenance" phase entailing once, twice, or three times weekly administration. The exact dosage levels may have to be experimentally determined for individual patients. The safety and efficacy was assessed in four main studies of chronic renal failure patients (842 patients in total), as well as three studies (586 participants) of nonmyeloid cancer patients receiving chemotherapy. The changes in hemoglobin levels represented the primary endpoint assessed, with product administration being associated with appropriate mean increases. The most common side effect noted during trials was clot formation in some patients on dialysis.

Fertivid (follitropin beta) is a recombinant follicle stimulating hormone produced in CHO cells. Schering Plough gained marketing approval (with the agreement of Organon, see below) for the product from the EU in March 2009. It is manufactured by Organon (Oss, the Netherlands) and the product, along with its indications, is identical to Organon's Puregon. The product is used to treat certain forms of female infertility, as well as deficient spermatogenesis in the male and its approval was based on the regulatory data on Puregon.

Zarzio and Filgrastim Hexal (filgrastim) are trade names of a recombinant form of human G-CSF (granulocyte colony stimulating factor) produced in E. coli. The product is manufactured by Sandoz. Sandoz also markets the product as Zarzio, while Hexal markets it as filgrastim hexal. This filgrastim product differs from the endogenous molecule only in that it contains an additional N-terminal methionine residue (a consequence of the recombinant expression system used), and in that it is not glycosylated (the endogenous molecule contains a single O-linked oligosaccharide side chain). It is a biosimilar product, approved in Europe since February 2009, with Amgen's Neupogen having acted as the reference medicine. Its indication is identical to that of Neupogen—the treatment of neutropenia associated with chemotherapy and selected additional conditions such as advanced HIV infection. The administration usually is subcutaneous or by daily infusion over several days. The clinical comparability to the reference medicine was established over four studies involving 146 healthy volunteers, and both products achieved similar increases in blood neutrophil counts. The most common side effect was musculoskeletal pain.

Opgenra (eptotermin alfa) is a recombinant form of osteogenic protein-1 produced in CHO cells, manufactured by Howmedica International (Limerick, Ireland). It gained regulatory approval in Europe in February 2009 and is similar to a previously approved Stryker product (Osigraft/OP-1 implant), containing the same active ingredient. In addition to the osteogenic protein, the product contains bovine collagen and carmellose (carboxymethylcellulose). Opgenra is indicated for posterolateral lumbar spinal fusion in adults suffering from spondylolisthesis (vertebral displacement) when autograft has failed or is contraindicated, and the product is administered by direct surgical implant around the affected vertebrae. The active substance then initiates bone formation directly at the implanted site by recruitment and activation of bone forming chondroblast and osteoblast cells. The collagen provides an appropriate support scaffold for these cells, while the carmellose generates a putty-like consistency, aiding product implanting. The safety and efficacy were assessed primarily in one main study involving 336 patients, and treatment with Opgenra was compared to direct bone autograft. Opgenera treatment was judged successful in 39% of patients, as compared to a 49% success rate in the case of autograft. Despite the lower efficacy, the product was approved for the treatment of individuals when autograft has failed or is contraindicated. The most common side effect associated with Opgenra application was bone formation outside of the fusion area.

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


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