Biopharmecuticals: Approval Trends in 2006 - Thirteen biopharmaceuticals gained marketing authorization - BioPharm International


Biopharmecuticals: Approval Trends in 2006
Thirteen biopharmaceuticals gained marketing authorization

BioPharm International
Volume 21, Issue 9

Myozyme (alglucosidase alfa) is a recombinant form of the human lysosomal enzyme acid α-glucosidase (GAA). The 109 kDa glycoprotein is produced in an engineered CHO cell line. It has designated orphan status in both the US and EU and was approved in both regions in 2006. Myozyme is indicated for the treatment of Pompe disease, a rare genetic condition characterized by a deficiency of lysosomal GAA activity. The condition is also known as glycogen storage disease type II, glycogenosis type II, or acid maltase deficiency. GAA functions to degrade lysosomal glycogen via the hydrolysis of both the α-1-4 and α-1-6 glycosidic bonds characteristic of the molecule. Pompe disease is characterized by accumulation of lysosomal glycogen stores in various cell and tissue types, particularly cardiac, skeletal, and respiratory muscle cells, leading to dysfunction of the effected cell types.

The clinical presentation of the condition, which presumably is dependent on residual levels of catalytically active enzyme produced, ranges from a severe, rapidly fatal infant-onset form to a more slowly progressing late onset (juvenile or adult) form.

Myozyme manufacture includes cell culture, product recovery, chromatographic purification, and formulation. It is presented in lyophilized form in glass vials containing 50 mg active, as well as mannitol, polysorbate 80, and sodium phosphate as excipients. The recommended dosage regimen entails intravenous infusion, once every two weeks over approximately four hours, at a typical dosage level of 20 mg/kg body weight.

Product administration is followed by cellular uptake, likely through initial binding to cell surface mannose-6-phosphate receptors, with subsequent lysosomal delivery. Safety and efficacy were established primarily by two clinical trials involving a total of 39 Pompe disease patients ranging in age (at first treatment) from 1 month to 3.5 years. All were administered product and results were compared with historical data of (matched) untreated infantile-onset Pompe disease patients. Primary efficacy indicators included the proportion of patients who died or needed invasive ventilator support due to respiratory muscle failure. Both parameters were substantially improved with myozyme therapy. For example, historical control data indicated a mortality rate of 98% by 18 months of age compared with about 11% for the treatment group. The most common adverse effect noted is hypersensitivity reactions, including life-threatening anaphylactic reactions. Myozyme is manufactured and marketed by Genzyme (Cambridge, MA).

Omnitrope (somatropin) is a recombinant form of human growth hormone (hGH) produced in an engineered E. coli. Like the native molecule, Omnitrope is an unglycosylated, 191 amino acid single-chain polypeptide with a molecular mass of 22.1 kDa. It first gained approval within the EU in (April) 2006 as a similar biological medicinal product (a biosimiliar) and was subsequently approved in the US later that year. It is indicated for the treatment of children and adults with growth failure due to inadequate endogenous hGH secretion or also (in the EU) growth failure associated with chronic renal insufficiency, Turner syndrome, or Prader-Willi syndrome.

Omnitrope binds the native hGH cell surface receptor, thereby triggering the characteristic direct and indirect growth-promoting and related effects of this hormone.

The manufacture of Omnitrope is initiated by fermentation, during which the product accumulates intracellularly. Fermentation is followed by cell harvest and lysis, product recovery, and chromatographic purification. Glycine and phosphate buffer components are added as excipients and the final product is lyophilized in glass vials. Omnitrope is intended for daily subcutaneous administration with exact dosage levels being adjusted for individual patients.

As a biosimiliar application the clinical evidence needed to support approval in the EU required demonstration of the product's similarity to a reference medicine (i.e., an hGH product already approved) in terms of quality, safety, and efficacy. The reference medicine chosen was Genotropin, an hGH product that first gained approval in Europe in 1988. Therefore, as required by EU biosimiliar legislation, the applicant was required to submit a full quality module and reduced clinical and nonclinical modules. Efficacy was demonstrated largely by a nine-month clinical study involving 89 children lacking hGH. Treatment with either Omnitrope or Genotropin yielded similar increases in height and speed of growth (equivalent to approximately 10.7 cm/year). This and a second trial involving 51 children who were administered product for a year also underpinned safety data. Side effects associated with Omnitrope (transient local skin reactions and in adults, mild edema, and muscle or joint pain) were also similar in type and severity to those associated with the reference medicine.

The active ingredient is manufactured by Sandoz (Kundl, Austria), which also markets the product in both the EU and US.

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