Status - approved; marketed

Organizations involved:

Lilly, Eli & Co. – R&D; World mark.; Parent

Lilly France S.A. – Manuf.

Hoffmann-La Roche Inc. – Tech.

Novo Nordisk Pharm., Inc. – Patent dispute

Genentech Inc. – Patent dispute

Cross ref.: See Somatotropin (hGH) Products entry and other somatropin product entries.

Description: Somatropin, rDNA Origin, for Injection or Humatrope is a lyophilized (freeze-dried) formulation of recombinant human growth hormone (hGH) protein expressed by Escherichia coli (E. coli). The hGH has 191 amino acid residues, a molecular weight of about 22,125 Daltons (22.125 kDa), and molecular formula of C990-H1528-N262-O300-S7. The amino acid sequence, activity, and other properties are identical to that of human growth hormone of pituitary origin and other rDNA E. coli hGH products (other than somatrem).

The reported units of hGH per vial of Humatrope have changed from approximately 13 IU to 15 IU. This did not represent a change in product purity or the quantity of somatropin per vial. Rather, the change in units was a result of harmonizing the defined specific activity of the reference standard used with the current international WHO (World Health Organization) reference standard. The specific activity of the International Standard for somatropin is now defined as 3 International Units per mg of protein (previously designated as approximately 2.67 IU/mg). Humatrope is now labeled based on a specific activity of 3 IU/mg. This change in reference standard activity did not affect the recommended weekly dosage of 0.18 mg of somatropin per kg of body weight for pediatric patients. However, due to the reference standard change, the weekly units administered are measured as 0.54 IU/kg of body weight (previously ~0.48 IU/kg of body weight).

Humatrope is packaged in vials for reconstitution for either subcutaneous or intramuscular injection, and in prefilled cartridges for use only with Lilly’s HumatroPen subcutaneous injection device. Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles), 25 mg mannitol, 5 mg glycine and 1.13 mg dibasic sodium phosphate. Phosphoric acid and/or sodium hydroxide may have been added to adjust the pH. Each vial is supplied in a combination package with an accompanying 5 mL vial of Water for Injection containing 0.3% metacresol as a preservative and 1.7% glycerin.

The HumatroPen provides an easy-to-use method for hGH dosing. Once reconstituted, dissolved somatropin in the cartridges can be used for 28 days when refrigerated, so few cartridge changes are required. The patient simply turns a dose knob to select the required dose. The cartridges contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin, along with, respectively: mannitol 18 mg, 36 mg, or 72 mg; glycine 6 mg, 12 mg, or 24 mg; and dibasic sodium phosphate 1.36 mg, 2.72 mg, or 5.43 mg. Each cartridge is supplied in a combination package with a syringe containing ~3 mL of solution for reconstitution. The diluent contains Water for Injection; 0.3% metacresol as a preservative; and 1.7%, 0.29%, or 0.29% glycerin in the 6 mg, 12 mg, and 24 mg cartridges respectively.

Nomenclature: Somatropin, rDNA/Lilly [BIO]; Humatrope [TR]; HumatroPen [TR for pen injector]; Somatropin (rDNA origin) [FDA]; Somatropin (rDNA origin) For Injection Vials [FDA]; Somatropin (rDNA origin) For Injection Cartridges For Use With The Humatropen Injection Device [FDA]; somatropin [USAN INN]; 12629-01-5 [CAS RN]; growth hormone (human) [SY]; human growth hormone, recombinant [SY]; hGH [SY]; LY137998 [SY]; Crescormon [SY]; somatomammotropin [SY]; rhGH [SY]; Umatrope [TR in France]; NDC 0002-7335-16; NDC 0002-8089-01; NDC 0002-8090-01; NDC 0002-8091-01 [NDC]

Companies.: Humatrope is marketed in the U.S. by Eli Lilly & Co. (Indianapolis, IN), and internationally by Lilly affiliates. Humatrope is reported to be manufactured by Lilly France S.A. (Fegersheim, France); and since 1985 at Lilly facilities in Speke, U.K. Lilly reported in May 2003 that it was investing $72 million to increase production capacity at this plant.

Manufacture: The hGH is expressed by a specific transformed strain of E. coli as a precursor consisting of the rhGH molecule with an N-methionyl (met) residue (N-met-hGH), resulting from the E. coli transcription start signal sequence. This precursor is directed to the plasma membrane of the cell, the N-terminal methionyl is removed, properly folded protein is secreted into the periplasm, and subjected to multiple purification steps.

FDA class: Drug NDA

Approvals: Date = 19870308, NDA, first approval; orphan designation (expired 3/1994); Indication = for the long-term treatment of children who have growth failure due to inadequate secretion of normal endogenous growth hormone

Date = 19961230; NDA supplement; orphan designation (granted 05/08/1990; expired 12/30/2003); Indication = treatment of short stature associated with Turner syndrome

Date = 19990000 (est.); NDA supplement; Indication = new cartridge-based pen injector device

Date = 20030725; NDA supplement (19-640/S-033); Indication = for the long-term treatment of idiopathic short stature, also called non-growth hormone-deficient short stature (i.e., use in healthy children of short stature who are not hormone-deficient or have other medical reasons for their height)

Date = 20090112; NDA supplement; Indication = approval of three reusable, mechanical pen-injectors (HumatroPen 6, HumatroPen 12 and HumatroPen 24) for self-administration of human growth hormone, using the currently approved Humatrope 3 mL cartridges (6 mg, 12 mg, and 24 mg). The supplement also provided for a hidden needle cover to provide the option to inject with the needle hidden from view.

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

Pediatric Patients--Humatrope is indicated for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone.

Humatrope is indicated for the treatment of short stature associated with Turner syndrome in patients whose epiphyses are not closed.

Adult Patients – Humatrope is indicated for replacement of endogenous somatotropin in adults with somatotropin deficiency syndrome who meet both of the following two criteria: 1. Adult Onset: Patients who have somatotropin deficiency syndrome, 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 growth hormone-deficient during childhood who have somatotropin deficiency syndrome confirmed as an adult before replacement therapy with Humatrope is started; and 2. Biochemical diagnosis of somatotropin deficiency syndrome, by means of a negative response to a standard growth hormone stimulation test.

Status: The July 2003 approval of Humatrope for nongrowth hormone deficient short stature applies to the shortest 1.2% of children in the U.S. For a 10-year-old boy, this would be the equivalent of 4 feet 1 inch tall; and corresponds to adults who would naturally grow no more than 5 feet 3 inches tall for men, 4 feet 11 inches tall for women. This and other approvals of hGH products for use in a broader population than just hGH-deficient children have been controversial. Many view such use of a potentially dangerous hormone as purely a cosmetic use, rather than medical necessity, and view these approvals as supporting and/or encouraging further expanded off-label (unapproved) use to increase the height of children not otherwise meeting approved indication qualifications.

Humatrope has not received centralized EU approval, with European approvals country-by-country.

Tech. transfer: Relevant U.S. patents expired (Orange Book).

Exemplary U.S. patents include 3,853,833 (now expired). Hoffmann-La Roche Inc. receives/received certain royalties from Lilly related to licensing of an unspecified U.S. patent. DataMonitor and ABN Amro reported that U.S. patent protection for Humatrope expired in 2003 (although, this may not be the case, as indicated by the infringement suit described below).

Novo Nordisk holds a composition-of-matter patent, U.S. 5,633,352, May 27, 1997, covering aspects expression of a hGH fusion protein and subsequent cleavage to hGH. On Oct. 6, 1997, Novo Nordisk filed a patent infringement suit in the U.S. District Court for the District of New Jersey alleging that other recombinant hGH manufacturers – Genentech, Inc., Eli Lilly & Co., Pharmacia & Upjohn Co. (now Pfizer) and Serono Laboratories, Inc. – each infringe this patent. Novo Nordisk also asserted two other hGH-related patents against Lilly/Humatrope. Lilly’s involvement in this suit may not yet been resolved, while several companies, perhaps including Lilly, have settled out-of-court. 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.

Market: Total 2009 sales were $449 million, $468 million in 2008; and $416 million in 2007. Total 2006 sales of Humatrope were ~$397 million, down 4% from 2005 ($413 million); $414.4 in 2005, $430 million in 2004, and $371 million in 2003. Analysts estimated total 1997 sales at about $260 million.

In 2009, Humatrope was reported to have 24% market worldwide among somatropin products (with the total market about $2.75-$3.0 billion).

The 2007 Average Wholesale Price (AWP) was $357.60/6 mg cartridge; $715.00/12 mg cartridge, $1,430.40/24 mg cartridge; $298.00/5 mg vial, with a Direct Price (discount price) of $234.28; and $1,788.10/six 5 mg vials, with a Direct Price of $1,405.70. The 2005 AWPs were $267.75/5 mg vial ($253.80 in 2004), $1,608.50 for six ($1,522.79 in 2004); $321.30/6 mg cartridge/pen ($304.55 in 2004); $642.60/12 mg cartridge/pen ($609.12 in 2004); and $1,285.20/24 mg cartridge/pen ($1,218.24 in 2004).

Ongoing: Alkermes Inc. concluded an agreement with Lilly in Feb. 2000 for the development and licensing of inhaled formulations of hGH using Alkermes’ AIR pulmonary delivery technology. In June 2003, positive results were reported from a Phase I trial.

Lilly collaborated with Emisphere Technologies, Inc. for development of oral recombinant hGH using its eligen technology using synthetic compounds as carriers. Results from early trials were positive. However, in Aug. 2003, this collaboration was terminated with Lilly returning all rights to Emisphere.