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


Accretropin (somatropin) is a recombinant form of human growth hormone (hGH), expressed in E. coli. Native hGH is a 191 amino acid, 22kDa polypeptide hormone synthesized in the anterior pituitary and Accretropin is identical to the native molecule in amino acid sequence. Accretropin is a biosimilar-type product. It was approved in January 2008 under section 505 (b) of the food, drug, and cosmetic act—a similar route under which Sandoz's hGH product, Omnitrope, gained approval in 2006.

Accretropin is indicated for the treatment of pediatric patients displaying growth failure because of inadequate secretion of endogenous hGH and for short stature associated with Turner syndrome (a chromosomal disorder) in pediatric patients whose epiphyses (the rounded end of long bones) are not closed. Dosage regimes should be individualized for each patient, but normally entail daily subcutaneous administration of 0.18–0.36 mg/kg body weight. Safety and efficacy were assessed in two trials containing 44 patients with growth hormone deficiency and 37 patients with Turner syndrome, respectively. Clinical results confirmed accelerated growth (height velocity) and the most common adverse reactions related to injection site events including erythema, edema, and brusing.

Product manufacture is initiated by fermentation of the engineered E. coli. As initially synthesized, the recombinant product displays an additional N-terminal methionine residue, a consequence of the expression construct used. Subsequent to product recovery the additional methionine is cleaved, yielding a product identical in sequence to the native hormone. Additional downstream processing entails multistep chromatographic purification and sterile filtration. Final formulation entails the addition of NaCl, phenol, pluronic F-68 surfactant, and phosphate buffer constituents as excipients, and the product is presented in liquid solution (1 mL of a 5 mg/mL solution in glass vials). Accretropin is manufactured by Cangene corporation (Winnipeg, Canada) and is marketed in the US by Apotex, Cangene's majority shareholder.

Arcalyst (rilonacept) is an engineered dimeric fusion protein with each of its two constituent polypeptides consisting of the ligand-binding domains of the human interleukin-1 receptor (IL-R1) and interleukin 1 receptor accessory protein (IL-1RacP), linked to the constant (Fc) portion of human IgG1. The 251 kDa glycosylated product is expressed in an engineered CHO cell line. It was approved in February 2008 by the FDA for the treatment of cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), in persons 12 years and older.

Autoinflammatory syndromes are usually underlined by aberrant regulation of cytokine signaling. CAPS (including FCAS and MWS) encompass one such group of rare autoinflammatory conditions, representing a spectrum of one disease manifesting with varying degrees of severity. The conditions are linked to mutations in a gene coding for a protein known as cryopyrin, which plays a role in generating free biologically active interleukin-1 (IL-1β). As a result, overproduction of IL-1β occurs, driving inflammation. General features of these conditions include recurrent fevers, rash, and joint pain.

The discovery of the molecular basis of this disease group suggested the blocking of IL-1β activity as a potential treatment. Some CAPS patients were thus treated with Kineret (anakinra, an IL-1 receptor antagonist approved for the treatment of rheumatoid arthritis since 2001), although that product's short half-life necessitated daily injections. Arcalyst also brings about its therapeutic effect by acting as a decoy receptor, binding excess free IL-1β, and hence, preventing it from interacting with cell-surface receptors. The product's antibody Fc portion confers on it an extended half-life, supporting once weekly injections.

Arcalyst's safety and efficacy profiles were established by a randomized, double-blind, placebo-controlled study involving 47 CAPS patients. Participants rated primary signs and symptoms of CAPS (joint pain, fever or chills, rash, eye pain or redness, and fatigue) on a scale of severity from 1–10, with Arcalyst-treated patients reporting a mean reduction in symptom severity of –2.4. Moreover, mean symptom scores subsequently increase when patients were withdrawn to placebo. The most common adverse reactions reported were injection-site reaction and an increased susceptibility to infections.

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