Status - approved; marketed

Organizations involved:

Novo Nordisk A/S – Manuf.; R&D; Tech.; Intl. mark.

Bedford Laboratories – USA mark.

Ben Venue Laboratories – Parent

Boehringer Ingelheim Pharma KG – Parent

Cetus Corp. – Tech.; Former

Chiron Corp. – Tech.; Former

Hoffmann-La Roche Ltd. – Tech.

Washington Research Foundation (WRF) – Tech.

University of Washington – Tech.

Genentech, Inc. – Tech.

Paladin Labs Inc. – Canada mark.

Cross ref.: See the Glucagon Products entry. See also Glucagon from Eli Lilly.

Description: Glucagon (rDNA origin) for Injection or GlucaGen is a lyophilized (freeze-dried) formulation of recombinant non-glycosylated human glucagon (presumably, as hydrochloride or HCl salt) expressed by Saccharomyces cerevisiae (yeast), used for both therapeutic and diagnostic indications:.

Glucagon is packaged in kits containing a vial of sterile glucagon powder and a disposable syringe containing sterile diluent for reconstitution and administration. The vial contains 1 mg (1 unit) of glucagon and 49 mg of lactose. Hydrochloric acid may be added during manufacture to adjust the pH of the product. The diluent syringe holds Water for Injection, USP; 12 mg/ml of glycerin; and hydrochloric acid (HCl). The product is stored at room temperature, 20-25°C (68-77°F).

The GlucaGen HypoKit for treatment of severe hypoglycemic reactions that may occur in individuals who have insulin-dependent diabetes was launched in July 2005. The HypoKit is fully portable and can be used wherever it is needed, in any setting. The kit consists of a syringe prefilled with sterile water for mixing and a 1 mg (1 unit) vial of GlucaGen powder. The hard-shell, bright orange case provides product protection, does not require refrigeration, and is easily identifiable in an emergency. GlucaGen HypoKit is safe for use in children.

Nomenclature: Glucagon, rDNA/Novo [BIO]; GlucaGen [TR]; Glucagon, recombinant for injection [FDA]; Glucagon [CAS USAN INN BAN JAN]; Glucagon USP [USP]; 16941-32-5 [CAS RN]; 9007-92-5 [CAS RN]; NDC 55390-004-1

Companies.: GlucaGen is manufactured by Novo Nordisk A/S at facilities in Copenhagen, Denmark (and/or Clayton, NC). U.S. marketing was assumed in 1999 by Bedford Laboratories, a division of Ben Venue Laboratories, Inc., a member of the Boehringer Ingelheim family of companies. GlucGen is marketed internationally by Novo Nordisk and affiliates, e.g., Paladin Labs Inc. has marketing rights in Canada.

Manufacture: A host yeast cell line was transformed with a plasmid containing the sequence for the yeast truncated mating factor alpha1 leader sequence joined with a synthetic gene encoding the 29 amino acids of glucagon. manufacture involves aerobic fed-batch fermentation of the transformed cell line with a continuous contolled dosage of glucose. The fermentation broth (supernatant) is treated with alkali to dissolve precipitated glucagon, since glucagon ans a low solubility at the pH level used during fermentation. Glucagon is purified from the supernatant by a series of chromatographic and precipitation steps. Glucagon with over 98% puritiy is lyophilized and vials filled and packaged. No animal-derived products are used in the manufacture of GlucaGen.

FDA class: Drug NDA 505(b)(2)

Approvals: Date = 19980622; NDA 20-918

Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling, received 12/13/2000]:

For the treatment of hypoglycemia: GlucaGen is used to treat hypoglycemic (low blood sugar) reactions which may occur in patients with diabetes treated with insulin. Because GlucaGen depletes glycogen stores, the patient should be give supplemental carbohydrates as soon as he/she awakens and is able to swallow, especially children or adolescents. Medical evaluation is recommended for all patients who experience severe hypoglycemia.

For use as a diagnostic aid: GlucaGen is indicated for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract. Glucagon is as effective for this examination as are anticholinergic drugs. However, the addition of the anticholinergic agent may result in increased side effects.

Status: The NDA was filed on Sept. 18, 1997, received priority review, and was approved on June 22, 1998 (approval time = ~.75 year).

FDA approval of GlucaGen was based primarily on studies showing bioequivalence to animal-derived glucagon and a small safety study in healthy volunteers, along with references to the scientific and medical literature, i.e., no traditional, large, Phase III efficacy studies were performed. In this respect, GlucaGen has been cited as essentially a generic (follow-on protein, biogeneric, biosimilar, biocomparable, etc.) drug approval. Sandoz/Novartis pointed this out in June 2004 in response to critics of its pending application for 505(b)(2) generic drug (follow-on protein) approval of, Omnitrope, its recombinant somatropin (human growth hormone; see #255).

The first market launches for GlucaGen were in mid-1993 for diagnostic indications: in Switzerland, The Netherlands, and Denmark. GlucaGen is currently marketed in 25 or more countries worldwide by Novo and its affiliates. It is also approved in some of these countries for treatment of insulin-induced hypoglycemia (low blood sugar). Paladin Labs Inc. filed for approval in Canada in July 2004.

GlucaGen received approval under 505(b)(2) regulations, allowing approval based on comparability with other previously-approved drug(s), and without the need for large-scale Phase III trials to prove safety and efficacy. In many respects, this might now be considered a generic biopharmaceutical (biogeneric, biosimilar, biocomparable, follow-on protein) approval.

In “The FDA’s assessment of follow-on protein products: a historical perspective,” Nature Reviews Drug Discovery (published online April 13, 2007), FDA reported on and rationalized its prior approvals of biogeneric/follow-on products. FDA noted, “The FDA has approved two recombinant follow-on versions of glucagon. The approvals were based on data that bridged the recombinant versions to the clinical data supporting the determination of safety and effectiveness for the natural-source products; they were also based on the extensive clinical experience with those natural-source products. Data included structural characterization of the recombinant product, which demonstrated an amino-acid sequence identical to human and bovine pancreatic glucagons; pharmacokinetic and pharmacodynamic data, which demonstrated similarity to the natural-source products; immunogenicity and safety data, which showed no increase in antibody titres; and a safety profile comparable with the natural-source products.”

No centralized EU approval granted. European approvals are country-by-country.

Tech. transfer: Based on the time GlucaGen spent in FDA regulatory review (under 35 USC §156), the expiration date of U.S. patent 4,826,763, “Process for preparing glucagon or fragments or derivatives thereof in yeast,” concerning recombinant yeast-expressed glucagon (1-29), assigned to Novo Nordisk, was extended by 1,421 days (3.9 years) to March 23, 2010. This patent includes description of the preferred synthetic oligonucleotide sequence transferred into yeast plasmid CPOT (ATCC No. 39685), resulting in the pMT612 yeast expression plasmid. S. cerevisiae strain MT615 transformed with plasmid pMT612 was deposited with the Deutche Sammlung von Mikroorganismen (DSM) as DSM 3184.

There are no entries for this product listed in the FDA Orange Book Database.

EP0189998, "A process for preparing glucagon or derivatives thereof in a transformed yeast strain," and EP0760677, "A PHARMACEUTICAL PREPARATION COMPRISING GLUCAGON," both assigned to Novo Nordisk, expired in 2006.

Chiron Corp. reports that it has received manufacturing-related patent licensing royalties on sales of GlucaGen, and that royalties stopped in late 2003 with the expiration of relevant patents. This appears to involve U.S. 4,631,257, “Stable high copy number plasmids,” assigned to Cetus Corp., later Chiron Corp., issued Dec. 23, 1986.

Novo Nordisk has nonexclusively licensed recombinant manufacturing technology from Hoffmann-La Roche Ltd., with these patents reported to start expiring in 2003.

Yeast expression technology was developed by the Univ. of Washington and Genentech, and was nonexclusively licensed to Novo Nordisk by the Washington Research Foundation (WRF; acting as patent agent for the university and Genentech). Related patents include U.S. 5,618,676 (issued April 8, 1997) and continuations, 5,854,018 and 5,856,123, concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. All three U.S. patents expire in 2014. The newer patents are broader, as they claim processes and materials for expression of proteins in recombinant yeast systems generally. WRF is the exclusive licensing agent for this family of yeast expression patents. The issued patents, particularly the more recently issued patents, broadly claim processes and materials for expression of proteins in yeast.

Market: In Sept. 2009, Novo Nordisk reported that Glucagen is the market leader glucagon product in Europe.

The 2007 Average Wholesale Price (AWP) for the Emergency Kit is $91.95 from Novo Nordisk (Red Book, 2007); and the AWP for the Diagnostic Kit (a generic from Bedford) is $84.00. For comparison, the 2005 Average Wholesale Price (AWP) for the Emergency Kit was $713.88 for 10 ($71.39 each), and the AWP for the Diagnostic Kit was $71.39 (Red Book, 2005).