Somatropin (rDNA origin) - Tev-Tropin; Bio-Tropin; Zomacton; human growth hormone, recombinant
Status - approved; marketed
Organizations involved:
Ferring BV – Manuf.; Tech.; Europe mark
Gate Pharmaceuticals – USA mark.
Teva Pharm. Ind. Ltd. – Mideast mark.; Parent
Savient Pharmaceuticals, Inc. – Manuf.; R&D.; Tech.; Former
Bio-Technology General Corp. – R&D; Tech.; Former
JCR Pharmaceuticals Co. Ltd. – Manuf. other; Japan mark.; China mark.
Dainippon Sumitomo Pharm Co., Ltd. – Japan mark.
Genentech, Inc. – Patent dispute
Novo Nordisk A/S – Patent dispute; Tech.
Antares Pharma, Inc. – Tech.; Former
Cross ref.: See the Somatropin (hGH) Products entry, and the other hGH product entries.
Description: Tev-Tropin is a lyophilized (freeze-dried) formulation of recombinant somatropin produced by Escherichia coli (E. coli) bacteria.
Tev-Tropin is packaged in vials for subcutaneous administration after reconstitution with supplied diluent; and is supplied in cartons of six vials. Each vial contains somatropin 5 mg (15 IU) and mannitol 30 mg. The diluent contains bacteriostatic 0.9% sodium chloride injection, USP, (normal saline), 0.9% benzyl alcohol as a preservative, and water for injection. Reconstituted solutions have a pH in the range of 7.0 to 9.0. Vials are stored at 2-8°C (refrigerated). Expiration dates are stated on the labels.
In Feb. 2010, Savient introduced the Tjet injector system, a needle-free device designed to deliver Tev-Tropin. The Tjet device uses a needle-free delivery system that releases the same amount of Tev-Tropin as a traditional syringe in two seconds. This is an attractive option for children disliking needles and injectons.
Nomenclature: Somatropin, rDNA/Savient [BIO]; Tev-Tropin [TR]; Bio-Tropin [TR in Japan and other countries]; Growject [TR in Japan]; Zomacton [TR in Europe]; human growth hormone, recombinant [SY]; hGH [SY]; rhGH [SY]
Companies.: Bio-Tropin was developed and manufactured by Bio-Technology General Corp. (BTG), which became Savient Pharmaceuticals, Inc., the biopharmaceutical business of which was acquired by Ferring BV in mid-2005. Recombinant hGH is manufactured at Ferring facilities in Israel (with patent infringement rulings precluding manufacture and marketing in the U.S.). Ferring now manufactures and markets the product in certain markets.
Teva Pharmaceutical Industries Ltd. has exclusive U.S. marketing rights, and markets Tev-Tropin in the U.S. through its GATE Pharmaceutical subsidiary.
Somatropin has been marketed by BTG/Savient, now Ferring, and licensees in >30 countries worldwide (where permitted by lack of patents or lack of patent infringement enforcement). Ferring Group held European marketing rights (prior to its acquisition of Savient), and continues to market rhGH (Zomacton) in 20 European countries.
Somatropin was originally marketed in Japan solely by JCR Pharmaceuticals Co. Ltd., (formerly Japanese Chemical Research). JCR manufactures finished product from bulk product supplied by BTG/Savient/Ferring. Since Jan. 1999, Sumitomo Ltd., now Dainippon Sumitomo Pharm Co., Ltd., also markets BTG/Savient/Ferring rhGH (after having lost its license to sell Genotropin from Pharmacia/Pfizer), purchasing finished product from JCR. In Jan. 1995, BTG granted JCR exclusive distribution rights in in China (PRC) for all hGH-related indications:.
Bio-Technology General (now Ferring) exclusively licensed needle-free injector technology for the U.S. human growth hormone market from Antares Pharma Inc. (Exton, PA) in 1999. In Feb. 2003, Antares reacquired these rights, and then licensed its Zomajet 2 Vision reusable needle-free device to Ferring Pharmaceuticals for use with Zomacton (European trade name).
FDA class: Drug NDA
Approvals: Date = 19950525; NDA (no. 19-774), original approval; Indication = approval of Bio-Tropin (then from BTG) for pediatric growth hormone deficiency, with each vial containing 4.8 mg hGH
Date = 19991103; NDA supplement; Indication = approval of a control supplement
Date = 19960909; NDA supplement; Indication = approval of a control supplement
Date = 19960829; NDA supplement; Indication = approval of a control supplemen
Date = 2000203; NDA supplement for a “Manufacturing Change or Addition;” Indication = presumably, this covered approval of Tev-Tropin, with each vial containing 5.0 mg hGH
Date = 20000817; NDA supplement; Indication = a labeling rrevision
Date = 20020214; NDA supplement; Indication = approval of a control supplement; Note, FDA Orange Book (inexplicably) reports this as the approval date for Tev-Tropin
Date = 20020409; NDA supplement; Indication = approval of a control supplement
Date = 20050316; a “Changes Being Effected” NDA supplement; Indication = revisions to the CONTRAINDICATIONS AND WARNINGS sections of the package insert regarding use in Prader-Willi patients
Date = 20070215; NDA supplement; Indication = harmonization of somatropin labeling, particularly involving the CONTRAindications: and WARNINGS sections of the package insert
Date = 20090625; NDA supplement; Indication = approval of a control supplement
Date = 20090629; NDA supplement; Indication = added “needle-free injection” to the insert.labeling, with Teva market a needle-free device (from Antares) as the Tev-Tropin Tjet Injector system
Indications: [full text of the “INDICATION AND USAGE” section of product insert/labeling]:
TEV-TROPIN is indicated only for the long-term treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Status: Bio-Tropin was originally approved by FDA in 1995, but was not launched in the U.S. until Feb. 11, 2005 as Tev-Tropin by Teva Pharmaceutical, due to long-runnning patent infringement and marketing disputes. See the Tech. transfer section.
Note, FDA reports Jan 4, 2002 (inexplicably, arbitrarily?) as the approval date for Tev-Tropin, with the new trade name perhaps adopted with this sNDA.
Ferring Group markets rhGH under the trade name Zomacton in over 20 European countries for treatment of pituitary growth hormone deficiency in children.
No European Union approval granted (country-by-country).
In April 1993, JCR Pharmaceuticals Co., Ltd. received Japanese approval for hGH (Biotropin) for the treatment of short stature, and began marketing in June 1993. In Dec. 2000, JCR received approval for Turner syndrome.
Tech. transfer:
Orange Book reports all relevant patents expired.
On June 28, 1995, a U.S. District Court issued a preliminary injunction against BTG restricting the company from marketing Bio-Tropin (BTG’s U.S. trade name at the time) in the U.S. This resulted from charges brought by Genentech, Inc. that Bio-Tropin infringed its U.S. patent 4,601,980 relating to methods for producing recombinant human growth hormone. See the Tech. transfer section of the Nutropin entry for further information. This ruling was upheld by the Court of Appears for the Federal Circuit (CAFC) on April 8, 1996. However, in Jan. 2000, Genentech’s U.S. patent 4,601,980 was ruled invalid. BTG/Savient claimed this recent ruling would open the way for U.S. sales of its Bio-Tropin rHGH, which received FDA approval in 1995. However, Genentech appealed, and the injunction against U.S. sales of Bio-Tropin remained in effect during the appeals process.
In May 2000, in a different case, a U.S. District Court ruled that BTG and its partner, Teva Pharmaceutical Industries Ltd., will be able to market Bio-Tropin in the U.S., pending resolution of litigation between BTG and Serono Laboratories Inc. (which markets its own recombinant hGH products in the U.S.; Serono merged with Merck KGaA in Jan. 2007 to form Merck Serono S.A.). Serono was contesting BTG’s 1999 termination of a 1998 agreement for U.S. co-promotion by both companies of Serono’s Saizen recombinant hGH (which would complicate, if not preclude, BTG’s own marketing of Bio-Tropin in the U.S), and Serono asserted that a non-compete provision of the agreement should continue in force. This has apparently been resolved satisfactorily for BTG/Savient.
Bio-Tropin was also the target of a patent (5,633,352) infringement suit filed by Novo Nordisk (see the Norditropin entry). A preliminary injunction against marketing of Bio-Tropin was granted by a U.S. District Court of Delaware in June 2002, but this was overturned by the U.S. Court of Appeals for the Federal Circuit (CAFC). In Dec. 2002, the CAFC confirmed that its dismissal of the injunction was not a comment on the strength of Novo Nordisk’s patents, and that the burden of proof of showing noninfringement falls on BTG/Savient. This case is continuing.
In August 2004, the U.S. District Court of Delaware ruled that Novo Nordisk A/S’ patent, 5,633,352, concerning recombinant hGH was invalid and unenforceable due to inequitable conduct. Savient asserted that this recent ruling would open the way for U.S. marketing of Tev-Tropin. Novo Nordisk is appealing this decision, so this dispute is continuing.
In early 2005, Teva and Savient reached a partial agreement on their patent disputes wth Novo Nordisk. All three parties cross licensed their patents, and Teva and Savient dropped their legal claims against Novo Nordisk. Thus, Novo Nordisk’s patents have now been licensed to Teva and Savient, and vice versa. This finally allowed BTG/Savient/Ferring’s hGH to be launched by as Tev-Tropin in the U.S. market. However, an interference proceeding in the US Patent and Trademark Office is continuing, so this aspect of the patent dispute is still not finally resolved.
BTG/Savient exclusively licensed needle-free injector technology from Antares Pharma, Inc. for use with somatropin in the U.S, in Dec. 1999. Antares reacquired this technology in Feb. 2002, and subsequently licensed it to Ferring Pharmaceuticals for use with Zomacton, its European brand of BTG/Savient/Ferring-Manufactured hGH.
Market: In 2009, Tev-Tropin was reported to have about 2% of the worldwide $2.75-$3.0 billion hGH market, or sales <$60 million).
Worldwide sales of hGH by Savient were $20.5 million in 2003; $20.6 million in 2002; and in 1997, 1998 and 1999 were ~$17 million. Note, these sales data do not include sales by Teva, JCR, or Ferring. Japan has accounted for ~65% of product sales. The author’ rough guess for total worldwide 2005 sales could be in the range $80-$120 million, including allowing for a larger market in Japan.
The 2007 Average Wholesale Price (AWP) is $213.51/5 mg vial, and $1,281.06 for six (Red Book, 2007).
Companies involvement:
Full monograph
256 Somatropin, rDNA/Ferring
Nomenclature:
Somatropin, rDNA/Ferring [BIO]
Bio-Tropin [TR]
Tev-Tropin [TR]
somatropin (human) [CAS]
12629-01-5 [CAS RN]
hGH [SY]
human growth hormone, recombinant [SY]
rhGH [SY]
Growject [TR in Japan]
Zomacton [TR in Europe]
molecular weight (kDa) = 22
FDA Class: Drug NDA
Year of approval (FDA) = 1995
Date of 1st FDA approval = 19950000
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | expired, including according to the Orange Book; 2004 arbitrarily used as expiration date; FDA's seemingly arbitrary use of the Jan. 2002 approval date is used as the approval date for Tev-Tropin (rather than the actual original approval of Bio-Tropin in 1995) |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 2012 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2008 |
U.S. Biosimilars Launchability Year: | 2012 |
U.S. Biobetters Launchability Year: | 2004 |
Biosimilars/biobetters-related EU Patents: | expired; 2004 arbitrarily used as expiration date |
EU Patent Expiration Year: | 2011 |
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
growth hormones
hormones
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
benzyl alcohol
lyophilized (freeze-dried)
mannitol
sodium chloride
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
UM001 Marketed Product in US
US200 Currently Approved in US
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