Somatropin (rDNA origin) for Injection - Norditropin; Norditropin SimpleXx; human growth hormone, recombinant
Status - approved; marketed
Organizations involved:
Novo Nordisk A/S – Manuf.; R&D; Tech.; Intl. Mark.; Parent
Novo Nordisk Pharmaceuticals, Inc. – USA mark.; Patent dispute
Serono Laboratories Inc. – Patent dispute
Astellas Pharma Inc. – Japan mark.
Yamanouchi Pharmaceutical Co., Ltd. – Former
GlaxoSmithKline plc – Europe mark.
Genentech, Inc. – Tech.; Patent dispute
City of Hope National Medical Center – Tech.; Patent dispute
Savient Pharm., Inc. – Patent dispute; Tech.
Teva Pharm. Ind. Ltd. – Patent dispute; Tech.
Cross ref.: See Somatotropin (hGH) Products entry, and other somatropin product entries.
Description: Somatropin (rDNA origin) for Injection or Norditropin refers to aqueous and lyophilized powder formulations of recombinant somatropin protein expressed by transformed Escherichia coli (E. coli). Norditropin is a lyophilized (freeze-dried) powder formulation, and Norditropin SimpleXx is a reconstituted (dissolved) liquid formulation containing the same recombinant somatropin (hGH). The recombinant hGH is composed of 191 amino acids having the same primary sequence and molecular weight (about 22 kDa) as that of endogenous human growth hormone (and other recombinant hGH products, except for somatrem). Norditropin SimpleXx was the first liquid growth hormone product approved in the U.S., and may be used in autoinjector devices.
Norditropin, the lyophilized formulation, is packaged in vials containing 4 mg or 8 mg, along with diluent for reconstitution and subcutaneous injection; and in cartridges for use with the NordiPen autoinjector device. The 4 mg vial contains 4 mg (12 IU) of somatropin, 8.8 mg glycine, 1.3 mg disodium phosphate dihydrate (NaH2P04.2H2O), and 44 mg mannitol. The 8 mg vial contains 8 mg (24 IU) of somatropin, and twice the amounts of excipients at the same concentrations. The vials contains no preservatives. The supplied 2 mL diluent vial contains Sterile Water for Injection with 1.5% benzyl alcohol (preservative). Norditropin may also be reconstituted with plain Sterile Water for Injection, if patients are sensitive/allergic to benzyl alcohol. After reconstitution of the dry powder with the 2 mL of supplied diluent, the 4 mg vial provides a solution containing 2 mg/mL somatropin per mL, and the 8 mg vial provides a concentration of 4 mg/mL. Norditropin should be stored at 2-8˚C (refrigerated).
Norditropin SimpleXx may be used in various autoinjector devices, e.g., NordiPen. Between its various delivery systems, over 100 different dosing options are now available. The premixed Norditropin cartridge and NordiPen delivery systems were introduced in the U.S. in 2000. The NordiPen 5 delivery system and and the NordiPenMate auto-insertion device were launched in 2001. NordiPen was designed for fine-tuned dosing for children, with dosing in 0.05 mg increments up to a maximum dose of 1.25 mg. The Norditropin NordiFlex injection system was approved in Oct. 2004. This is a fully integrated delivery system for hGH. The disposable Norditropin NordiFlex is prefilled, so there is no loading of cartridges. Fine dosing increments are available in a 5 mg/1.5 mL pen that delivers doses from 0.025 to 1.50 mg, and a 15 mg/1.5 mL pen that delivers doses from 0.075 to 4.5 mg. A new 10 mg Nordipen was added in early 2006.
In March 2010, FDA approved Norditropin FlexPro, a pre-filled injection pen to be used by children and adults with growth hormone disorders. Norditropin FlexPro is available in 5 mg/1.5 mL, 10 mg/1.5 mL and 15 mg/1.5 mL pens. After first use, the 5 mg/1.5 mL and 10 mg/1.5 mL pens may be left at room temperature for up to three weeks without risk of spoilage.
Norditropin is designed to offes storage flexibility.Norditropin products must be refrigerated prior to use. After initial use, Norditropin NordiFlex 5 mg/1.5 mL and 10 mg/1.5 mL delivery pens can either be stored outside of the refrigerator (at up to 77ºF) for use within 3 weeks, or in the refrigerator (between 36°F and 46°F) for use within 4 weeks. These storage flexibility guidelines also apply to Norditropin cartridge 5 mg/1.5 mL. Norditropin NordiFlex 15 mg/1.5 mL delivery pen must always be refrigerated (between 36º-46ºF)—both prior to and after the initial injection—for use within 4 weeks. These guidelines for continuous refrigerated storage also apply to Norditropin cartridge 15 mg/1.5 mL.
Nomenclature: Somatropin, rDNA/Novo [BIO]; Norditropin [TR]; Norditropin SimpleXx [TR for liquid formulation]; Dial-A-Dose Somatropin Delivery Devices [TR]; NordiPen [TR for delivery device]; Somatropin (rDNA origin) for injection [FDA]; 12629-01-5 [CAS RN]; human growth hormone, recombinant [SY]; somatotropin [SY]; hGH [SY]; somatomammotropin [SY]; Norditropine [TR in France]; Norditropin S-chu [TR in Japan]; NDC 0169-7774-11; NDC 0169-7774-12 [NDC]
Companies.: Norditropin was developed and is manufactured by Novo Nordisk A/S (Bagsvaerd, Denmark; according to the product insert). Other sources indicate the product is manufactured at company facilities in Clayton, NC.
Norditropin is marketed in the U.S. by Novo Nordisk Pharmaceuticals Industries, Inc. and internationally by Novo Nordisk A/S affiliates. The product was launched in the U.S. on Feb. 20, 1997. The product is marketed in over 70 countries, including most European countries, Japan, Australia, Korea and other countries. It is marketed by Yamanouchi Pharmaceutical Ltd. (became Astellas Pharma Inc. in spring 2005) in Japan and in the U.K by GlaxoSmithKline plc.
Manufacture: As described in U.S. 5,633,352, concerning recombinant hGH manufacture by E. coli using cleavable fusion expression technology, a fusion protein of hGH with an N-terminal amino acid sequence with an even number of amino acids is expressed and subsequently cleaved to hGH (not N-met-hGH) using dipeptidyl aminopeptidase I (DAP I; cathepsin C; EC 3.4.14.1). hGH is produced using this “cleavable fusion expression,” rather than direct expression methods. A plasmid containing: a cDNA fragment for hGH codons 24-191; a genomic DNA fragment containing hGH codons 1-23; and DNA encoding certain additional cleavable amino acids. The plasmid is inserted into the E. coli host, which expresses a fusion protein consisting of hGH molecule and the additional amino acids, which are subsequently enzymatically cleaved, leaving hGH product of 191 amino acids.
FDA class: Drug NDA
Approvals: Date = 19950508, first approval, NDA(no. 21-148); orphan designation (expired 5/2002); Indication = for the long-term treatment of children who have growth failure due to inadequate secretion of endogenous growth hormone
Date = 19990900; NDA supplement; Indication = approval of Norditropin SimpleXx, a liquid formulation of Norditropin, primarily for use with a dedicated delivery system, NordiPen
Date = 20000720; full/original NDA; ; Indication = approval of Norditropin Cartridges, 5mg/1.5mL, 10mg/1.5mL, and 15mg/1.5mL (ready-to-inject solutions) used with the new NordiPen 5, NordiPen 10, and NordiPen 15 (Dial-A-Dose Somatropin Delivery Devices) reuseable injection devices
Date = 20010402; NDA supplement; Indication = approval of NordiPenMate, a durable auto-insertion device (autoinjector; reducing pain compared to manual injection) using NovoFine 30 thin-walled disposable needles
Date = 20041008; NDA supplement; Indication = approval of the NordiFlex pen injection system for the long-term treatment of children with growth failure due to inadequate secretion of endogenous growth hormone
Date = 20041101; NDA supplement; Indication = approval for treatment of adults with growth hormone deficiency
Date = 20060111; NDA supplement; Indication = approval of 5 mg and 10 mg prefilled, multi-dose, disposable pen to be kept unrefrigerated after initial use; approval of NordiFlex pen containing 10 mg
Date = 20070603; NDA supplement; Indication = for treatment of short stature in children with Noonan syndrome
Date = 200810051; NDA supplement; Indication = for the treatment of short stature in children born Small for Gestational Age (SGA) with no catch-up growth by age 2-4 years.
Date = 20080921; NDA supplement; Indication = for treatment of children with short stature associated with Turner syndrome
Date = 20100303; NDA supplement; Indication = approval of Norditropin FlexPro, a pre-filled injection pen to be used by children and adults with growth hormone disorders
Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling, 5/19/2009]:
1.1 Pediatric Patients
Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone (GH).
Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with short stature associated with Noonan syndrome.
Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with short stature associated with Turner syndrome.
Norditropi® [somatropin (rDNA origin) injection] is indicated for the treatment of children with short stature born small for gestational age (SGA) with no catch-up growth by age 2–4 years.
1.2 Adult Patients
Norditropin® [somatropin (rDNA origin) injection] is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD) who meet either of the following two criteria:
• Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
• Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
According to current standards, confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
Status: Norditropin was approved by FDA in May 1995, but was delayed in entering the U.S. market until Feb. 1997 due to a complex patent dispute. See the Tech. transfer section for further information.
The Norditropin Cartridges NDA was filed on Sept. 29, 1999 and approved on July 24, 2000; approval time = ~10 months (.83 year). Norditropin Cartridge (refills) and the accompanying NordiPen, the only dedicated pen-type delivery system for premixed growth hormone, were launched in the U.S. on Oct. 2, 2000. The new Norditropin NordiFlex was launched in the U.S. on Jan. 26, 2005.
Novo Nordisk filed for European Union (EU) approval of Norditropin SimpleXx on July 22, 1998, and received approval in Sept. 1999. On July 1, 2003, the EU granted approval for treatment of growth disturbance in short children born small for gestational age (SGA), primarily due to intrauterine growth retardation (IUGR), and who have failed to show spontaneous catch-up growth. Approval in Japan was granted on March 20, 2000.
Norditropin is currently available in most countries worldwide.
With the Jan. 2006 supplemental approval for the first time in the U.S., patients taking Norditropin NordiFlex in the 5 mg pen or the new 10 mg pen have the option to store their somatropin pens at room temperature (<77˚F) for three weeks after initial use or in the refrigerator for use within four weeks. Previously, all growth hormone pens had to be stored in the refrigerator after initial use. These flexibile storage guidelines also apply to the Norditropin cartridge 5 mg/1.5 mL. Norditropin NordiFlex 15 mg delivery pen must still be refrigerated both prior to and after the initial injection.
Tech. transfer: Orange Book reports relevant patents are
5,849,700 and 5,849,704, expiring in Dec. 2015;
6004297 and 6235004, expiring in Jan. 2019; and
RE41956, concerning the cartridge injection device, expiring in Jan. 2021.
Novo Nordisk holds (although modified by court ruling; see below) a composition-of-matter patent, U.S. 5,633,352, broadly covering recombinant human growth hormone manufacture by E. coli using cleavable fusion expression technology, involving expression as a fusion protein (hGH with an N-terminal amino acid sequence with an even number of amino acids to form) and subsequent cleavage to hGH (not N-met-hGH). Cleavage is achieved using dipeptidyl aminopeptidase I (DAP I; cathepsin C; EC 3.4.14.1), but the claims do not cite (restrict the patent to) this or any other specific enzyme. The Orange Book reports this patent as expiring May 27,2014.
On Oct. 6, 1997, Novo Nordisk filed a patent infringement suit in U.S. District Court alleging that other recombinant hGH U.S. marketers– Genentech, Inc., Eli Lilly & Co., Pharmacia & Upjohn Co., and Serono Laboratories, Inc. – each infringe its patent. In the same complaint, Novo Nordisk asserted two additional hGH-related patents against Eli Lilly. The trade names of the products affected were Nutropin, Nutropin AQ, Humatrope, Genotropin, Serostim and Saizen (see related entries).
In August 2004, in a separate case, the U.S. District Court of Delaware ruled that Novo Nordisk A/S’ patent, 5,633,352, was invalid and unenforceable due to inequitable conduct. Savient Pharmaceuticals filed this suit in connection with its efforts to marketing of its hGH product, Tev-Tropin (see related entry), in the U.S. Novo Nordisk appealed this decision.
In early 2005, Teva and Savient (hGH product acquired by Ferring BV in mid-2005) 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, Teva and Savient’s patents have now been licensed to Novo Nordisk, and vice versa. However, an interference proceeding in the U.S. patent office will continue.
In May 1998, Serono Laboratories, Inc. announced an out-of-court settlement with Novo Nordisk concerning its manufacture and marketing of Saizen and Serostim in the U.S. Terms of the settlement were not be disclosed. In Nov. 2000, Pharmacia Corp. (now merged into Pfizer) announced an out-of-court settlement of Novo Nordisk’s patent infringement suit. Financial and other terms of these settlements were not disclosed, but Novo Nordisk reported that there would be no significant impact on the company’s financial results. Novo Nordisk is presumably continuing to press its disputes against the other recombinant hGH manufacturers, or the other companies have settled with Novo Nordisk.
In 1996, Genentech filed suit in U.S. District Court alleging that Novo Nordisk was infringing its U.S. patent 4,601,980. The court granted a preliminary injunction barring Norditropin from entering the U.S. market. Novo Nordisk appealed. In March 1997, the Court of Appeals for the Federal Circuit (CAFC) ruled in favor of Novo Nordisk, finding that Genentech failed to established a likelihood of proving infringement of the “980” patent, because that finding was based on an improper construction of claim 2 of the patent. The claim used referred to hGH and processes for directly expressing either hGH or met-hGH, while Novo Nordisk’s method of manufacture involves direct expression of a fusion protein and subsequent cleavage to hGH. The CAFC ruled that no one was able to produce any human protein by use of Genentech’s cleavage fusion expression method at the time of patent application filing, and for nearly a year afterwards. The case also involved interpretation of claim 2 with the definition of hGH at issue. Novo Nordisk alleging the method of claim 2 covered only manufacture of N-met-hGH using a cleavable fusion protein. Genentech contended that claim 2 covers both the direct expression and cleavable fusion expression of hGH, and that it defined hGH in the patent to include both N-met-hGH and hGH.
Genentech later went back to the district court and charged Novo Nordisk with infringement of its newly issued U.S. Patent 5,424,199. This patent has the same specification as the “980” patent and contains a single claim concerning somatropin expression methods, differing from the claim in the prior case in reciting that the encoded (fusion) protein has an additional amino acid sequence and includes the step of cleaving this conjugate protein. This process of expressing a DNA encoding a conjugate/fusion protein and using an enzyme to cleave off an undesired portion of that protein is generally known as cleavable fusion expression. Both parties agreed that Novo uses cleavable fusion expression to produce hGH. Based on this, the court again granted Genentech an injunction barring sales of Norditropin.
Novo Nordisk appealed. Novo argued that mere generic statement of the possibility of cleavable fusion expression, along with the DNA sequence encoding hGH, a single enzyme (trypsin) for cleaving undisclosed conjugate proteins, and a statement of that enzyme’s cleavage sites as being potential amino acid extensions conjugated to hGH is not an enabling disclosure commensurate in scope with the claim. The CAFC ruled in favor of Novo Nordisk, allowing U.S. marketing of Norditropin, which was launched on Oct. 2, 2000.
In Feb. 2005, Novo, Savient and Teva entered into a settlement agreement, granting each other cross-licenses to their patents covering somatropin. That month, Savient and Teva also launched Tev-Tropin, and dropped their claims for attorneys’ fees and damages for wrongful injunction. However, the appeals concerning patent validity and ownership continued.
In Oct. 2005, Novo Nordisk lost its challenge in the U.S. Court of Appeals for the Federal Circuit (CAFC) to overturn a lower court ruling that claim 1 of Novo’s 5,633,352 patent was invalid and unenforceable due to inequitable conduct (i.e., Novo Nordisk’s patent was ruled invalid). Thus, even though Novo Nordisk had partially settled its lawsuit with defendants Savient and Teva Pharmaceutical, this ruling apparently opens the door for generic (biogeneric, biosimilar, biocomparable, follow-on protein, etc.) versions of Norditropin. The CAFC upheld the first part of the 2004 District Court ruling, which stated that one of Novo’s patent claims was invalid because the information necessary to make somatropin had been published in an earlier article (“anticipated” in a December 1981 article by Dr. G. Pavlakis, published in Biochemistry). The CAFC, however, vacated the lower court’s ruling of invalidity for the second claim in the patent. The CAFC agreed that the patent claim was unenforceable, because Novo was not able to produce somatropin by the process it described in its patent. The CAFC also agreed that the patent was invalid because of inequitable conduct. Novo Nordisk had failed to disclose that it had never actually produced somatropin by the process described in its 1983 application. Novo’s ‘352 patent was based on its ‘856 application, which was based on its earlier 1983 application. However, the ‘856 and 1983 applications name two different processes to produce somatropin, one using LAP enzyme and one using dipeptidyl aminopeptidase I (DAP I) enzyme. Only the process described in the later ‘856 application, using DAP I enzyme, was actually able to produce “ripe somatropin protein.” Novo acknowledged that its scientists were not able to actually create somatropin for five months after they submitted their 1983 application, until they accidentally used a batch of LAP contaminated with DAP I.
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. Genentech appealed to the California State Supreme Court, but did not prevail.
Disease: The prevalence of Noonan syndrome has not been determined accurately to date, but most authors report 1 in 1,000-2,500 live births, affecting males and females equally. Based on the U.S. population, prevalence may range anywhere from 125,000 to 300,000 live births. However, fetal loss can occur in Noonan syndrome so actual incidence of the disorder may be higher than its prevalence. Noonan syndrome is a heterogeneous genetic condition in which the clinical features are quite variable. Short stature, which can be severe, is one of the most common characteristics.
Market: Total 2011 sales were about $890 milllion, 2010 sales were about 887 million; 2009 worldwide Norditropin sales were $804 million; ~$724 million in 2008; ~$600 million in 2007; ~$583 million in 2006; $449 million in 2005; $398 million in 2004; and $377 million in 2003.
In 2012, Novo Nordisk was the second-largest supplier in the global growth hormone market with a 24% share measured in volume.
In 2009, Norditropin was reported to have 15% market share among somatropin products, holdign the 3rd largest market share. [Note, presuming total hGH sales of $2.75-$3.0 billion/year, this does not agree with actual reported sales data]. Japan has been Novo’s largest single market for hGH.
The 2007 Average Wholesale Price (AWP) is $310.46/5 mg vial; $931.38/15 mg vial (Red Book, 2007). The 2005 AWP was $278.94/5 mg vial ($264.39 in 2004); and $931.38/15 mg vial ($793.19 in 2004).
In Aug. 2010, Novo Nordisk in the U.S. launched NordiFlex 30 mg/3 mL, the only prefilled, preloaded pen that allows children who need a dose of growth hormone larger than 4.5 mg to take one injection instead of two. The pen holds twice the volume of, and has a higher maximum dose than, the 15 mg Norditropin NordiFlex pen, offering a more convenient option for patients who require a growth hormone dose up to 6.0 mg.
Companies involvement:
Full monograph
253 Somatropin, rDNA/Novo
Nomenclature:
Somatropin, rDNA/Novo [BIO]
Norditropin [TR]
Norditropin SimpleXx [TR (for liquid formulation)]
Dial-A-Dose Somatropin Delivery Devices [TR]
Nordipen [TR for delivey device]
Somatropin (rDNA origin) for injection [FDA]
somatropin (human) [CAS]
12629-01-5 [CAS RN]
hGH [SY]
human growth hormone, recombinant [SY]
rhGH [SY]
somatotropin [SY]
somatomammotropin [SY]
Norditropin S-chu [TR in Japan]
Norditropine [TR in France]
NDC 0169-7774-11; NDC 0169-7774-12 [NDC]
molecular weight (kDa) = 22
FDA Class: Drug NDA
Year of approval (FDA) = 1995
Date of 1st FDA approval = 19950508
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2021, based on RE41956, concerning the cartridge injection device (Orange Book); otherwise, patents expired |
U.S. Patent Expiration Year: | 2014 |
U.S. Biosimilars Data Exclusivity Expiration: | 2007 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2002 |
U.S. Biosimilars Launchability Year: | 2021 |
U.S. Biobetters Launchability Year: | 2021 |
Biosimilars/biobetters-related EU Patents: | 2022, based on EP1250167, apparently the equivalent of US RE41956 |
EU Patent Expiration Year: | 2022 |
EU Biosimilars Data Exclusivity Expiration: | 2009 |
EU Biosimilars Orphan Exclusivity Expiration: | 2009 |
EU Biosimilars Launchability Year: | 2022 |
EU Biobetters Launchability Year: | 2022 |
Index Terms:
biopharmaceutical products
Biorex-70 resin
exempt from CBER lot release requirements
growth hormones
hormones
recombinant DNA
bacterial culture <!-- bacterialculture -->
citric acid
dipalmitoylphosphatidylcholine (DPPC)
Escherichia coli (E. coli)
exempt from CBER lot release requirements
fusion proteins, recombinant
benzyl alcohol
disodium phosphate
glycine
lyophilized (freeze-dried)
mannitol
Sterile Water for Injection
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
BHK-21 (C-13)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US US777
EM001 Marketed Product in EU
Copyright© 2020, Biotechnology Information Institute