Status - approved; marketed

Organizations involved:

Genentech, Inc. – Manuf.; R&D; Tech.; USA mark.

Ipsen S.A. – Intl. mark.

Kabivitrum AB – R&D; Tech.; Former

University of California – Patent dispute

Novo Nordisk Pharmaceuticals, Inc. – Patent dispute

Bio-Technology General Corp. – Patent dispute

Disetronics Medical Systems – Manuf. other

Meridian Medical Technologies – Manuf. other

Pharmacia Corp. – Former

Schwarz Pharma AG – Former

Sumitomo Pharm. Co., Ltd. – Former

Columbia University – Tech.; Patent dispute

City of Hope National Medical Center – Tech.; Patent dispute

Description: Nutropin refers to a lyophilized (freeze-dried) formulation and Nutropin AQ refers to an aqueous formulation (Nutropin AQ) of recombinant human growth hormone (hGH) expressed by Escherichia coli (E. coli) bacteria. Both the solid and liquid formulations of Nutropin have the same approved indications:. The amino acid sequence of the hGH in Nutropin/Nutropin AQ is identical to that of pituitary-derived human growth hormone, i.e., is composed of 191 amino acid residues, is terminal methionine-free (unlike somatrem/Protropin also from Genentech), and has a molecular weight of 22,125 Daltons (22.125 kDa). The recombinant somatropin in Nutropin/Nutropin AQ is identical to that in Nutropin Depot, an aqueous microencapsulated controlled-release formulation, also from Genentech (see the separate entry for Nutropin Depot). Nutropin AQ was the first liquid (aqueous) recombinant human growth hormone product available in the U.S.

Nutropin AQ is a sterile aqueous formulation of somatropin dissolved in water packaged in 2 mL vials intended for subcutaneous injection, and in prefilled cartridges for injection using the Nutropin AQ Pen device. Each 2 mL vial contains 10 mg (approximately 30 IU) somatropin formulated in 17.4 mg sodium chloride, 5 mg phenol, 4 mg polysorbate 20 (Tween 20), and 10 mM sodium citrate. The product is nearly isotonic with a concentration of 5 mg of somatropin/mL and pH of ~6.0. The sodium chloride improves the stability of somatropin, prevents development of globules, and enables adjustment of tonicity. Polysorbate 20 reduces the tendency for somatropin to aggregate in solution. Citrate buffer maintains a pH of 6, reducing the formation of deamidated proteins while maintaining solubility. Phenol is used as an antimicrobial preservative. No primary animal or human sourced materials are used in the manufacture of Nutropin AQ. However, a number of animal-derived raw materials (most likely culture media components) are used in the manufacture of Nutropin AQ, and the sources of these are well documented. Polysorbate 20 is plant-derived.

Nutropin is packaged in vials containing either 5 mg (~15 IU) or 10 mg (~30 IU) of somatropin powder per vial, along with Bacteriostatic Water for Injection, USP, for reconstitution and subcutaneous injection. The reconstituted product is nearly isotonic, with a somatropin concentration of 5 mg/mL and a pH of ~7.4. Each vial contains 5 mg somatropin, with 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg sodium phosphate monobasic and 1.3 mg sodium phosphate dibasic), and 1.7 mg glycine. The 10 mg vial contains twice these amounts at the same concentrations. Each 5 mg carton contains two vials of Nutropin (5 mg per vial) and one 10 mL multiple dose vial of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). Each 10 mg carton contains two vials of Nutropin (10 mg per vial) and two 10 mL multiple dose vials of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved).

The Nutropin AQ Pen injection device holds a single pre-filled 10 mg/2 ml cartridge containing liquid Nutropin AQ with a digital display of the dose to be delivered and a dial-back dose knob to correct over-dialing errors.

Nomenclature: Somatropin, rDNA/Genentech [BIO]; Nutropin [TR]; Nutropin AQ [TR]; Somatropin (rDNA origin) for Injection [FDA]; 12629-01-5 [CAS RN]; somatrem [SY]; human growth hormone, recombinant [SY]; somatomammotropin [SY]; Somatonorm [TR in U.K., Sweden, Switzerland, Japan and other countries]; hGH [SY]

Companies.: Nutropin (and Nutropin AQ) was developed, is manufactured, and is marketed in the U.S. and Canada by Genentech, Inc. Development of Nutropin and Nutropin AQ was at least partially funded through Genentech Limited Partners, L.P.

Nutropin was formerly marketed in many countries worldwide by Pharmacia Corp. (later became part of Pfizer). Sumitomo Pharmaceuticals Co., Ltd. (now Dainippon Sumitomo Pharma Co., Ltd.) formerly had exclusive Japanese rights (but now purchases a different recombinant insulin, Bio-Tropin, in bulk from Savient Pharmaceuticals, Inc., now Ferring BV) Dainippon Sumitomo now markets Nutropin Depot (see related entry) in Japan.

In June 2001, Schwarz Pharma AG returned to Genentech exclusive development and marketing rights (acquired in 1999) in Europe and certain other countries outside the U.S., Canada, China and Japan for Nutropin AQ (and Nutropin Depot).

In 2002, Ipsen Group (formerly Beaufour Ipsen S.A.) received exclusive marketing rights for Nutropin AQ Pen outside of North America and Japan.

The Nutropin AQ Pen is manufactured by Disetronics Medical Systems (DMS) for Genentech, Inc. for exclusive use with the Nutropin AQ Pen Cartridge. The 10 mg/2 mL Nutropin AQ Pen Cartridge is manufactured by Meridian Medical Technologies.

Genentech also developed recombinant bovine growth hormone (Posilac), used in cattle, marketed by Monsanto Corp., which received FDA approval in 1993.

Biovitrum AB reports that its predecessor, Kabivitrum AB, collaborated in the research and development of Genentech’s rhGH.

Manufacture: The protein is expressed by a specific transformed strain of E. coli as a precursor fusion protein consisting of the rhGH molecule preceded by a 23 amino acid signal peptide (coding for an E. coli secretion signal sequence). The signal protein causes the protein to be secreted into the periplasm of E. coli, where the signal peptide is cleaved, and the somatropin protein is folded appropriately. Potency is assayed using WHO international standards for pituitary derived (WHO 80/505) and recombinant somatropin.

According to EMEA/European Union documents, in 1998 Genentech switched from using stock culture vials of transformed E. coli to using a designated master cell bank (MCB) stored in liquid nitrogen, with a new working cell bank created from the MCB. Either the MCB or WCB may be used for manufacture. manufacture involves: propagation of E. coli from the MCB/WCB, fermentation, harvesting, and purification. Somatropin is released from the E. coli periplasm through a series of steps involving freezing, thawing, and suspension. Somatropin is isolated and purified by standard chromatographic methods through a series of steps. Bulk solution may be stored for up to 21 days at 2-8˚C prior to filling. Filtered bulk solutions are pooled as necessary, sterilized by filtration, filled into vials, and stored at 2-8˚C. Final testing includes aggregation, proteolysis, deamidation, oxidation, post-translational modification, and lot-to-lot consistency.

As described in U.S. patent 5,795,745, assigned to Genentech, plasmid-transformed E. coli cultures are cultured in aqueous media in a steel or other fermentation vessel conventionally aerated and agitated, in aqueous media supplied with appropriate nutrients such as carbohydrate or glycerol, nitrogen sources such as ammonium sulfate, potassium sources such as potassium phosphate, trace elements, and magnesium sulfate. Upon completion of fermentation, the bacterial suspensions are centrifuged and the collected cellular solids from the broth are lysed by physical or chemical means. Cellular debris is removed and soluble growth hormone isolated and purified from the supernatant. Human growth hormone may be purified from bacterial extracts using one or more methods including: (1) polyethyleneimine fractionation; (2) gel filtration chromatography on Sephacryl S-200; (3) ion exchange chromatography on Biorex-70 resin or CM Sephadex; (4) ammonium sulphate and/or pH fractionation; and/or (5) immunoaffinity chromatography using antibody resins prepared from matrix-bound hGH IgG polyclonal or monoclonal antibodies with desorption under acid or slightly denaturing conditions. [Note, method no. 5 is not used in manufacture of Nutropin].

FDA class: Drug NDA

Approvals: Date = 19851017, first approval, NDA 20-552; orphan designation (expired 10/1992); Indication = long-term treatment of children who have growth failure due to a lack of adequate endogenous growth hormone secretion

Date = 19931117; NDA supplement; Indication = pediatric treatment of growth failure due to inadequate endogenous human growth hormone

Date = 19931117; supplement; Indication = treatment of growth retardation associated with chronic renal failure

Date = 19940308; NDA supplement; Indication = inadequate growth associated with chronic renal failure

Date = 19951108; NDA supplement; Indication = Nutropin AQ liquid formulation approved and accepted as bioequivalent to Nutropin lyophilized powder

Date = 19961230; NDA supplement; Indication = treatment of short stature associated with Turner’s syndrome

Date = 19970215; NDA supplement, orphan designation (expired 2/15/2004); Indication = for growth hormone deficiency in adults after epiphyseal closure.

Date = 19991217; NDA supplement (NDA 20-522/S-004) for Nutropin AQ, orphan designation (expires 12/17/2006); Indication = replacement of endogenous growth hormone in adults who meet specific criteria including a diagnosis of growth hormone deficiency by means of a subnormal response to a standard growth hormone stimulation test as well as the experience of adult growth hormone deficiency due to pituitary disease, tumor or trauma, or from childhood onset of the condition

Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling]:

Pediatric Patients: Nutropin [somatropin (rDNA origin) for injection] is indicated for the long-term treatment of growth failure due to a lack of adequate endogenous GH secretion.

Nutropin [somatropin (rDNA origin) for injection] is also indicated for the treatment of growth failure associated with chronic renal insufficiency up to the time of renal transplantation. Nutropin therapy should be used in conjunction with optimal management of chronic renal insufficiency.

Nutropin [somatropin (rDNA origin) for injection] is also indicated for the long-term treatment of short stature associated with Turner syndrome.

Adult Patients: Nutropin [somatropin (rDNA origin) for injection] is indicated for the replacement of endogenous GH in patients with adult GH deficiency who meet both of the following two criteria: 1. Biochemical diagnosis of adult GH deficiency by means of a subnormal response to a standard growth hormone stimulation test (peak GH <5 µg/L), and 2. Adult-onset: Patients who have adult GH deficiency either alone or with multiple hormone deficiencies (hypopituitarism) as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or Childhood-onset: Patients who were GH deficient during childhood, confirmed as an adult before replacement therapy with Nutropin is started.

Status: Genentech in April 1999 concluded a settlement with the U.S. Attorney for the Northern District of California concerning allegations that the company had illegally promoted somatropin for unapproved uses. The investigation began in 1995. The company paid a $50 million criminal fine and restitution settlement, and reported that its admitted improprieties were corrected in 1994.

On Dec. 19, 2003, Genentech submitted a supplemental NDA for Nutropin approval for the long-term treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means. ISS is defined by a height score of less than -2.25 standard deviations below the mean for normal height and associated with growth rates unlikely to permit attainment of adult height in the normal range

In Jan. 2008, Ipsen withdrew a supplemental European Union application for Nutropin AQ for long-term treatment of children with severe idiopathic short stature (ISS) not explained by growth hormone deficiency (GHD) or other medical conditions and with a predicted adult height at least 1 standard deviation score (SDS) below the target height, following the CHMP issuing a negative opinion.

Nutropin received centralized EU approval n Feb. 16, 2001.

Tech. transfer: The only patent cited by the Orange Book is 5763394,

U.S. patent 4,601,980, “Microbial expression of a gene for human growth hormone,” Goeddel, et al., July 22, 1986, and related patents assigned to Genentech Inc. describe methods for recombinant E. coli expression of hGH (particularly N-met-hGH). Related patents include 4,755,465; 5,795,745; 5,424,189; 4,898,830; and U.S. 4,658,021. The earliest patent is 4,342,832, assigned to Genentech, with priority to July 5, 1979. U.S. 4,755,465 claims Genentech’s method for manufacture of hGH for Nutropin by expression and subsequent cleavage of a pre protein for huGH containing a signal sequence. In its original New Drug Application (NDA), Genentech cited PCT/US93/07149 and the equivalent US 08/117,156 (a continuation of 07/923,401, abandoned) as exemplary patents. The filing also cited U.S. 5,096,885, “Hormone Growth Hormone Formulation.” In another section, Genentech also cited U.S. 5,096,885 with an expiration date of March 17, 2009. U.S. 4,755,465.

DataMonitor and ABN Amro report that U.S. patent protection for Nutropin and Nutropin AQ expires in 2005, and that Protropin U.S. patent protection expires in 2005 (although the source patents for these claims are not readily apparent).

Genentech settled a long-running patent dispute in Nov. 1999 with the University of California (UC) over the invention of recombinant human growth hormone, with the university alleging that Genentech had violated its patent and illegally used its property (clones). UC has received recombinant E .coli-expressed insulin patents including 4,652,525, Recombinant bacterial plasmids containing the coding sequences of insulin genes.” UC had filed patent infringement suits in federal court against Genentech in 1990 and 1997. Regarding use of its property, UC alleged that in 1979 Genentech used DNA clones obtained from a university lab (through what was described as a midnight raid by a then Genentech employee and a prior UC post-doc) to develop its rDNA hGH. Because of highly conflicting testimony from those involved, it will likely never be known which organization deserves primary credit as the source for the clone used to develop Nutropin. In June 1999, the jury was unable to reach a verdict on the infringement issue. A second trial was scheduled to begin in Jan. 2000.

Under the terms of the out-of-court settlement agreement with UC, Genentech paid the university $150 million in cash and made a contribution of $50 million toward construction of a biological sciences research building at the new Mission Bay campus of the University of California, San Francisco (UCSF). Both parties agreed that this settlement was not an admission that Genentech infringed UC’s patent or illegally used its genetic material.

In Jan. 2000, in a case brought by Bio-Technology General Corp. (BTG), later Savient Pharmaceuticals, Inc., a U.S. District court found U.S. patent 4,601,980 invalid, particularly for lack of enablement (for manufacture of hGH). This was reversed on appeal. The patent primarily concerned E. coli expression of N-methionyl-hGH, but Genentech claimed that a small amount of hGH would also be produced by intracellular cleavage of the N-met group and that the patent’s claims did not specify quantities of protein. [Note, although Bio-Technology General received FDA approval for its hGH product, Bio-Tropin, in 1995, it has been unable to market the product under an earlier patent infringement-related injunction issued by the District Court and is the target of other patent disputes. See the Bio-Tropin entry for further information].

As part of a patent dispute more fully discussed in the Norditropin entry, Novo Nodisk also challenged 4,601,980 assigned to Genentech, and Genentech countersued alleging that Novo Nordisk’s Norditropin infringes 4,601,980. As in the BTG case, this primarily involved interpretation of claim 2 concerning fusion protein expression of hGH, with the definition of hGH at issue. Novo Nordisk alleging the method of claim 2 covered only N-met-hGH, while Genentech alleged that it defined hGH in the patent to include both N-met-hGH and hGH. Novo Nordisk lost (Genentech won) in District Court, but the case was reversed on appeal, i.e., 4,601,980 does not cover Novo’s cleavable fusion process for producing hGH (Norditropin).

Novo Nordisk holds a composition-of-matter of product patent, U.S. 5,633,352, covering aspects expression of a hGH fusion protein and subsequent cleavage to hGH. On Oct. 6, 1997, Novo Nordisk filed a patent infringement lawsuit in U.S. District Court alleging that U.S. recombinant hGH marketers – Genentech, Inc., Eli Lilly & Co., Pharmacia & Upjohn Co., and Serono Laboratories, Inc. – infringe the patent. Novo Nordisk cited Nutropin as infringing its patent. Genentech lost its case on appeal against Novo Nordisk, and either dropped the suit or settled out-of-court with the other alleged infringers. 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 or Bio-Tropin, in the U.S. See the Tev-Tropin entry (#256) for further information.

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 again demanded 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 (at the beginning of this section), 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 somatotropin manufacture.

Market: Total 2006 worldwide sales reported by Roche (then majority owner of Genentech), including sales by Novartis, were CHF 494 million (~$406 million at 7/6/2007 exchange rate), up 3% from 2005 (~$395 million). The great majority of sales are by Genentech, particularly in the U.S.

Total 2009 sales of Nutropin AQ by Ipsen were $54.8 million. 2006 sales were $19.3 million. In 2009, Nutropin products(AQ and dopot) were reported to have 18% market share among somatropin products.

Total worldwide sales of Nutropin products (plus Nutropin Depot in 2004 and earlier years; see related entry) by Genentech were $371 million in 2007, $378 million in 2006, $370.5 million in 2005, $353.6 million in 2004, $321.9 million in 2003, $297.2 million in 2002, $250.2 million in 2001; $226.7 million in 2000; $221.1 million in 1999; $214.0 million in 1998; $223.6 million in 1997, $218.2 million in 1996; $219.4 million in 1995; $225.4 million in 1994; $216.8 million in 1993; $205.9 million in 1992, $185.1 million in 1991; $157.1 million in 1990; $122.7 million in 1989; $111.1 million in 1988; $85.6 million in 1987; $43.6 million in 1986; and $5.2 million in 1985.

Total U.S. Nutropin sales were $37.0.5 (98.7% of the market) in 2005, $348.8 in 2004, $ 319.5 in 2003, and $ 294.6 million in 2002. By far, the U.S. constitutes the major market for Nutropin.

The 2007 Average Wholesale Price (AWP) for Nutropin was $310.441/5 mg vials ($264.38 in 2004) with and without diluent; and $620.84/10 mg vial with and without diluent. The 2007 AWP for Nutropin AQ Pen Cartridge and vial, 2 mL, 5 mg/mL, is $620.84 (Red Book, 2007). The 2005 AWP was $278.91/5 mg vial ($264.38 in 2004); and $557.81/10 mg vial ($528.74 in 2004). The 2005 AWP for Nutropin AQ Pen Cartridge and vial, 2 mL, 5 mg/mL, was $557.81 ($528.74 in 2004).

Ongoing: In March 2005, Genentech formed a collaboration with Ipsen S.A. to develop sustained-release formulations of Nutropin.

In Dec. 2006, Altus entered into an agreement with Genentech for development, manufacture and commercialization of ALTU-238. Genentech received exclusive to North America rights with an option for global licensing. ALTU-238 is a long-acting (once-weekly subcutaneously) crystallised formulation of somatropin, with positive results reported from a Phase I trial in Oct. 2005 and from a Phase II trial in July 2006.