Biopharmaceuticals: Approval Trends in 2005 - - BioPharm International


Biopharmaceuticals: Approval Trends in 2005

BioPharm International
Volume 19, Issue 8

The remainder of this article provides detailed information about the products approved in 2005. Data was gathered from regulatory sources,4,5 as well as the web sites of sponsoring companies. Details about Levemir, Kepivance, and Avastin were included in the May 2005 issue of BioPharm International,6 so are not repeated below.


Fortical (calcitonin-salmon, recombinant) is a 32-amino-acid, single- chain, polypeptide hormone produced by recombinant means in E. coli. It gained approval in the US in 2005 for the treatment of postmenopausal osteoporosis. Calcitonin is secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. The hormone increases the amount of calcium and phosphate in bones and also reduces serum calcium levels.

Salmon calcitonin is 30 times more potent in humans when compared with the endogenous human hormone, hence its application in medicine. Chemically synthesized calcitonin of both human and salmon sequence has been used for over 20 years and recombinant salmon calcitonin (Forcaltonin) was approved in the EU in 1999 for the treatment of the bone disorder Paget's disease. After fermentation of the producer microorganism, Fortical is chromatographically purified and formulated with citric acid, sodium chloride, phenylethyl and benzyl alcohol, and polysorbate as excipients. It is presented as a metered dose solution (3.7 mL), with an associated pumping mechanism for nasal delivery. A single spray delivers 200 IU calcitonin activity in a volume of 0.09 mL. The recommended dosage schedule is one intranasal spray daily. Mean product bioavailability is 3% (with a range of 0.3–30% reported), and absorption through the nasal mucosa is rapid.

Postmenopausal osteoporosis is characterized by low bone mass and increased bone fragility, caused by a disproportionate rate of bone reabsorption, compared with bone formation. Consequently, there is an increased risk of fracture, particularly of the vertebrae, hip, and distal forearm. Calcitonin inhibits the bone reabsorption process. Intranasally administered product increases spinal bone mass in postmenopausal women with established osteoporosis as demonstrated by two randomized placebo controlled trials involving 325 women. Adverse reactions were generally mild to moderate, with nasal-related problems, such as irritation and soreness most commonly reported. Fortical is manufactured by Unigene Laboratories and distributed by Upsher-Smith Laboratories (Maple Grove, MN).

GEM 21S (growth-factor-enhanced matrix), approved by FDA last year, is classified as a medical device. It consists of two components, tricalcium phosphate and recombinant human platelet-derived growth factor-BB (rhPDGF-BB). It is indicated for the treatment of specific defects of the tissue supporting the teeth (periodontal defects).

The product is supplied as a kit consisting of a cup containing 0.5 mL of tricalcium phosphate and a syringe containing 0.5 mL of rhPDGF-BB (0.3 mg/mL). The two constituents are aseptically mixed immediately before use, allowed to stand for 10 minutes, and directly applied to the damaged area. The tricalcium phosphate generates a sponge-like porous scaffold for the PDGF, provides a framework for bone ingrowth, and helps stabilize the surrounding soft tissue. The PDGF exerts potent mitogenic and chemotactic effects on bone and periodontal ligament-derived cells, thereby accelerating periodontal healing.

Native human PDGF is a dimer, with two constituent polypeptides identified (A and B) and three active isoforms: AA, AB, and BB. The BB isoform is glycosylated, with the two 109-amino-acid polypeptides held together by interchain disulphide bonds. The product is produced in engineered S. cerevisiae, followed by multistep chromatographic purification. The same active ingredient (but formulated as a gel and applied topically) has been on the market since the late 1990s under the tradename Regranex, for the treatment of diabetic ulcers.

Initial animal studies show that PDGF promotes the regeneration of periodontal tissues including bone, cementium, and periodontal ligament. The safety and efficacy of GEM 21S in humans were primarily demonstrated via a multicenter, double-blinded, randomized, controlled, prospective clinical trial involving 180 patients who required surgical intervention to treat periodontal defects.

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