Status: 505(b)(2) follow-on protein NDA approved in Jan. 2008

Organizations involved:

Cangene Corp. – Manuf.; R&D; Tech.; World mark.

Apotex Holdings Inc. – R&D; Parent

Cross ref.: See the Somatropin (hGH) Products entry, and other somatropin product entries.

Description: Accretropin is an aqueous formulation of recombinant somatropin (hGH) expressed by transformed E. coli bacteria. This is intended to be a biogeneric, biosimilar, follow-on protein, etc. version of somatropin. The hGH in Accretropin has an amino acid sequence identical to that of human growth hormone of pituitary origin. This product is intended for subcutaneous injection.

Accretropin is packaged in vials as a liquid solution containing 1 mL of a 5 mg/mL solution of rhGH (15 IU/mL). Accretropin in vials is a liquid solution containing 1 mL of a 5 mg/mL solution of growth hormone (15 IU/mL). The formulation also contains 0.75% NaCl, 0.34% phenol (as preservative), 0.2% Pluronic F-68 (a non-ionic surfactant), and 10 mM NaPO4 buffer (final pH is 6.0).

The reference product, i.e., the product for which adequate similarities in biological and pharmacokinetic activities supported abbreviated testing and approval, was Humatrope from Eli Lilly & Co. (see related entry).

Nomenclature: Somatropin, rDNA/Cangene [BIO]; Accretropin [TR]; Somatropin (rDNA origin) for Injection [FDA]; somatropin [USAN INN]; somatropin (human) [CAS]; 12629-01-5 [CAS RN]; human growth hormone, recombinant [SY]; hGH [SY]; rhGH [SY]; 60492-0162-1 [NDC]

Companies.: Accretropin was developed by Cangene Corp. in collaboration with Apotex, the majority shareholder of Cangene, and the largest Canadian generic pharmaceutical company. It is manufactured and will be marketed in the U.S. and Canada by Cangene Corp. The product is manufactured in Cangene’s facility in Winnipeg, Manitoba, Canada. Accretropin was developed under a research and development agreement with the Apotex Group, Cangene’s majority shareholder. Accretropin is manufactured at the Cangene facility in Winnipeg, Manitoba, Canada. Howeer, the NDA was granted to the Chesapeake Biological Labs. subsidiary of Cangene.

Manufacture: Upon expression in E. coli, the protein has a N-terminal L-methionine. This is later removed to yield a protein that is chemically, immunologically and physicochemically identical to pituitary derived human growth hormone, consisting of 191 amino acids in a single polypeptide chain.

FDA class: Drug NDA (21-538)

Approvals: Date = 20080123; NDA (no. 21-538) under 505(b)(2)

Indications: [full text of the "Indications and USAGE" section of product insert, from FDA, 8/28/2008]:

Accretropin (somatropin) is indicated for: treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone; treatment of short stature associated with Turner Syndrome in pediatric patients whose epiphyses are not closed.

Status: The NDA for Accretropin was accepted by FDA for filing on July 17, 2006 for the treatment of short stature in children with growth hormone deficiency and girls with Turner Syndrome. The original PDUFA date was March 10, 2007. This was an abbreviated (biogeneric) 505(b)(2) application. Cangene has three products already approved by the FDA, but this will the first of its recombinant biogeneric products to be filed in the U.S.

On March 12, 2007, FDA issued an approvable letter requesting additional support data regarding the manufacture of Accretropin. This did not require any new clinical trials.

As of late Aug. 2008, despite its approval, the product had not yet been launched in the U.S. (and no product insert was available).

Medical: Like other immediate-release rhGHs or somatropins it is administered daily as subcutaneous injections six times per week. The recommended dosage is 0.18 mg to 0.3 mg/week (for children with growth hormone deficiency) and 0.36 mg/kg/week (for children with Turner syndrome) divided into equal daily subcutaneous doses.

Trials: The Accretropin clinical program consisted of three clinical studies: a Phase I bioequivalence study (Study GA-002) and two Phase III clinical Trials: one conducted in pediatric patients with growth hormone deficiency (Study GA-005/5A) and one in girls with short stature due to Turner syndrome (Study GA-007/7A). Both Phase III clinical trials were non-randomized, single-arm, open-label studies and included patients with severe short stature. Study GA-005/5A was conducted in 4 centers in Poland and Hungary and enrolled 44 patients. Study GA-007/7A was conducted in a single center in Poland and enrolled 37 patients. Since there was no control group in either Phase III study, proof of efficacy was based on comparisons with “historical” height data obtained from normally growing children or untreated girls with Turner syndrome.

Market: Accretropin sales are presumed to be relatively small, probably significantly less than the ~$30 million/year sales of Omnitrope marketed by a major international pharmaceutical company (Sandoz/Novartis), longer on the market and with very substantial discounts compared to leading somatropins.