Biopharmaceuticals: Approval Trends in 2005 - - BioPharm International


Biopharmaceuticals: Approval Trends in 2005

BioPharm International
Volume 19, Issue 8

Product safety and efficacy were assessed by a total of five clinical studies conducted in 71 pediatric patients, with treatment supporting mean height velocities (cm growth per year) ranging from 2.8–8.0 over several years. Adverse events included hypoglycemia. The product is contraindicated in the presence of active or suspected neoplasia, because of the potential stimulatory effect on cancer cell growth. Increlex is manufactured by Baxter and distributed by Tercica (Brisbane, CA).

IPLEX (mecasermin rinfabate) contains a protein complex of rhIGF-1 and rhIGF-binding protein 3 (rhIGFBP-3), both of which are produced in (separate) E. coli strains. rhIGF-1 is a single-chain, 70-amino-acid polypeptide (see Increlex entry). RhIGFBP-3 is a single-chain, 264-amino-acid, 28.7 kDa polypeptide containing 18 cysteine residues, all of which participate in disulphide bond formation. Both recombinant polypeptides present in IPLEX display amino acid sequences identical to the native human proteins. Naturally occurring IGFBP-3 is glycosylated, while the recombinant version is devoid of this post-translational modification, a consequence of expression in E. coli. When mixed together, the two molecules form a 1:1 molar ratio complex of overall molecular mass 36.4 kDa. The product gained approval in the US in 2005 and is indicated for the treatment of growth failure in children with primary IGF-1 deficiency or with GH gene deletion who have developed neutralizing antibodies to GH.

As described in the context of Increlex, most of the growth-promoting effects of GH are actually mediated by IGF-1. The growth factor promotes linear growth, as well as additional anabolic effects. In serum, IGF is invariably complexed to an IFGBP, of which there are six (IGFBP-1 to IGFBP-6). Individual IGFBPs display differing amino acid sequences and molecular masses, although they generally exhibit in the region of 50% homology to each other. The bulk of serum IGF-1 is found as an equimolar (1:1:1) complex, with IGFBP-3 and an acid-labile polypeptide. IGFBPs most likely fulfill several biological functions, including stabilization and protection of IGF-1 from proteolysis in the serum, increasing serum half-life, and modulating IGF-1 function locally at the surface of IGF-1 sensitive cells. This includes modulating their potential to induce hypoglycemia. Free IGF-1 can interact with the insulin receptor, although relatively weakly, and it consequently displays about 5% of the hypoglycemic potential of insulin.

Product manufacture entails separate fermentation and purification procedures of both recombinant proteins. After mixing, the final product is formulated to a concentration of 36 mg/0.6 mL filled in a single-use glass vial. The final product contains sodium acetate buffer components and sodium chloride as excipients.

Pharmacokinetic studies indicate that the mean serum half-life of IGF-1 when complexed to its binding protein is 13 hours, which supports its once daily subcutaneous administration. Exact dosage levels may be individualized for each patient but starting doses are typically 0.5 mg/kg, increased to 1–2 mg/kg.

Product approval was largely granted based on results from a single, open-label, multicenter study in 36 prepubertal subjects. Eighty-nine percent (32 subjects) had primary GH receptor deficiency (Laron syndrome), while three individuals (8%) had GH gene deletion with neutralizing antibodies to GH. After six months of treatment, annualized height velocity (cm/year) was almost doubled (from 3.4 to 7.4) upon treatment with 1 mg product/kg daily, while treatment with 2 mg/kg daily increased annualized height velocity levels to a mean of 8.8 cm. Adverse reactions sometimes associated with the product include hypoglycemia and lymphoid tissue hypertrophy. The product is contraindicated in the presence of active or suspected neoplasia. IPLEX is manufactured and marketed by Insmed (Glen Allen, VA).

Naglazyme (galsulfase) is a recombinant version of the human enzyme N-acetylgalactosamine 4-sulfatase produced by an engineered CHO cell line. The 495-amino-acid, 56 kDa enzyme, also contains six asparagine-linked (N-linked) glycosylation sites, carrying a mixture of complex high-mannose and phosphorylated high-mannose oligosaccharides. A second, post-translational modification characteristic of the enzyme is the conversion (within the endoplasmic reticulum of producing cells) of cysteine 53 into a formylglycine residue. This modification is essential for catalytic activity.

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