Somatrem for Injection - Protropin; N-L-methionyl-human growth hormone, recombinant; N-met-hGH
Status - discontinued in 2004
Organizations involved:
Genentech, Inc. – Manuf.; R&D; Tech.; World mark.; Former
Columbia University – Tech.; Patent dispute
City of Hope National Medical Center – Tech.; Patent dispute
Cross ref.: See the Somatropin (hGH) Products entry, and the entries above for other somatropin products (which lack the extra amino acid of this product). Genentech also markets Nutropin and Nutropin Depot containing recombinant hGH.
Description: Somatrem for Injection or Protropin is a lyophilized (freeze-dried) formulation of a recombinant human growth hormone (somatropin; hGH) mutein (modified form) protein expressed by Escherichia coli (E. coli) bacteria. Somatrem comprises the identical sequence of 191 amino acids constituting pituitary-derived human growth hormone (and most other recombinant hGH products) with an additional amino acid, methionine (met), on the N-terminus of the molecule (from the E. coli secretion signal sequence). Protropin has 192 amino acid residues, a molecular weight of ~ 22,256.39 Daltons (22.26 kDa), and an empirical formula of C995-H1537-B263-O301-S8. [Note, most other recombinant hGH products have the N-terminal methionine residue removed].
Protropin was the first recombinant pharmaceutical to be manufactured and marketed by a biotechnology company (Genentech). Clinical trials began in 1981. In vitro, preclinical, and clinical testing have shown that Protropin is functionally and therapeutically equivalent to pituitary-derived human growth hormone (and other recombinant hGH products). The product was discontinued in 2004.
Protropin was packaged in vials containing either 5 mg (~5 IU) or 10 mg (~30 IU) of somatrem along with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), for reconstitution and either intramuscular or subcutaneous injection. Each carton of two 5 mg vials and each carton of two 10 mL vials includes one 10 mL multiple-dose vial of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) for reconstitution. Each 5 mg vial contains 5 mg (~15 IU) of somatrem, with 40 mg mannitol, and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic). Each 10 mg vial contains 10 mg (~30 IU) of somatrem, with 80 mg mannitol, and 3.4 mg sodium phosphates (0.2 mg sodium phosphate monobasic and 3.2 mg sodium phosphate dibasic). Phosphoric acid may be added for pH adjustment. The Bacteriostatic Water for Injection, USP, contains 0.9 percent benzyl alcohol per mL as an antimicrobial preservative at pH of 4.5-7.0. The product is stored at 2-8˚C, (36-46˚F; refrigerated).
Nomenclature: Somatropin, met-, rDNA [BIO]; Protropin [TR]; Somatrem [FDA USAN INN BAN JAN]; somatropin (human), N-L-methionyl- [CAS]; growth hormone, N-L-methionyl- [CAS]; 82030-87-3 [CAS RN]; Somatotropin, recombinant [SY]; human growth hormone, recombinant [SY]; hGH [SY]; met-hGH [SY]; somatomammotropin [SY]; Somatonorm [TR foreign]; NDC 50242-016-20 [NDC]
Companies.: Protropin was developed, and is manufactured by Genentech, Inc. (S. San Francisco, CA). It was marketed worldwide by Genentech and affiliates. Development of Protropin was at least partially funded through Genentech Limited Partners, L.P.
FDA class: Drug NDA
Approvals: Date = 19851017, first approval, NDA; orphan designation (granted 12/09/1985; expired 10/2002)
Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling]:
Protropin (somatrem for injection) is indicated only for the long-term treatment of children who have growth failure due to a lack of adequate endogenous growth hormone secretion. Other etiologies of short stature should be excluded.
Status: Protropin (and also Nutropin Depot) was discontinued by Genentech in 2004, with Genentech now concentrating on promoting Nutropin (see related entry).
Tech. transfer: U.S. 4,658,021 (div of 4,601,980), “Methionyl human growth hormone,” assigned to Genentech, has only one claim, “Methionyl human growth hormone.” and describes recombinant constructs and methods for expression of N-L-methionyl-somatropin. This patent expired on April 14, 2004.
See the Nutropin entry for further information about Genentech’s hGH patents. In 1995, Genentech and Eli Lilly settled all patent infringement and breach of contract suits and related claims, ending a long-standing dispute regarding recombinant human growth hormone products. Most insulin-related patents disputes concerned manufacture of hGH, not N-met-hGH, although a few manufacturers produce hGH via an N-met-hGH intermediate.
Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was seeking royalties, which Genentech and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
As discussed in the Recombinant DNA Product entry (#100), Genentech appealed a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent licensing dispute involving COH developing basic cloning technology for Genentech, including use for manufacture of somatropin.
Medical: Treatment of children lacking adequate endogenous growth hormone with Protropin results in an increase in growth rate and an increase in insulin-like growth factor-I levels similar to that seen with pituitary-derived hGH. The recommended total weekly dosage of 0.30 mg/kg (approximately 0.90 IU/kg) of body weight is administered by daily intramuscular or subcutaneous injection.
Market: Genentech did not report sales for Protropin. As other growth hormone products became available, competition prevented significant sales and market share growth, and the product was abandoned. Genentech now concentrates on marketing Nutropin.
The Average Wholesale Price (AWP) was $264.38/5 mg vial and $528.74/10 mg vial (Red Book, 2004).
Companies involvement:
Full monograph
258 Somatropin, met-, rDNA
Nomenclature:
Somatropin, met-, rDNA [BIO]
Protropin [TR]
Somatrem [FDA USAN INN BAN JAN]
growth hormone (human), N-L-methionyl- [CAS ]
Growth hormone (human), N-L-methionyl- [CAS]
Somatropin (human), N-L-methionyl- [CAS ]
82030-87-3 [CAS RN]
hGH [SY]
human growth hormone, recombinant [SY]
met-hGH [SY]
rhGH [SY]
Somatotropin, recombinant [SY]
somatomammotropin [SY]
Somatonorm [TR foreign]
NDC 50242-016-20 [NDC]
molecular weight (kDa) = 22.3
FDA Class: Drug NDA
Year of approval (FDA) = 1985
Date of 1st FDA approval = 19851017
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2004, based on 4,658,021 (div of 4,601,980); product withdrawn in 2004, so no biosimilars possible |
U.S. Patent Expiration Year: | |
U.S. Biosimilars Data Exclusivity Expiration: | 1997 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1992 |
U.S. Biosimilars Launchability Year: | |
U.S. Biobetters Launchability Year: | 2004 |
Biosimilars/biobetters-related EU Patents: | expired - 2004 arbitrarily used as EU patent expiration date; product withdrawn in 2004; No approval, so no biosimilars possible |
EU Patent Expiration Year: | 2004 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2004 |
EU Biobetters Launchability Year: | 2004 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
hormones
recombinant DNA
bacterial culture <!-- bacterialculture -->
cell proliferation bioassay
Escherichia coli (E. coli)
Bacteriostatic Water for Injection
benzyl alcohol
lyophilized (freeze-dried)
mannitol
phosphoric acid
sodium phosphate, dibasic
sodium phosphate, monobasic
apheresis (hemapheresis)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
orphan status
EU003 EU application withdrawn
UM999 Not Available/Not Marketed in US
US011 Approved Formerly in US/withdrawn
EM999 Not Available/Not Marketed in EU
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