Insulin glulisine [rDNA origin] - Apidra; [LysB3, GluB29] insulin; insulin (human), 3B-L-lysine, 29B-L-glutamic acid-, recombinant
Status: approved; marketed
Organizations involved:
Sanofi Aventis Pharma Deutschland GmbH – Manuf.; R&D; Tech.
Sanofi Aventis Pharmaceuticals, Inc. – USA mark.
Sanofi Aventis S.A. – Intl. mark.; Parent
Hoechst Marion Roussel Deutschland GmbH – R&D; Tech.; Former
General Hospital Corp. (The) – Tech.
Novo Nordisk – Patent dispute.
Cross ref.: See the Insulin Products entry (#630).
Description: Insulin glulisine or Apidra is a formulation of a recombinant human insulin mutein (mutant or modified sequence) expressed in Escherichia coli K-12 (E. coli) cells with two amino acid substitutions, providing a more rapid onset and a shorter duration of action than human regular insulin (after subcutaneous injection). Insulin glulisine differs from human insulin in that the amino acid asparagine at the B30 position of the insulin B chain is replaced by lysine, and the lysine at position B29 is replaced by glutamic acid. Insulin glulisine has a molecular formula of C258-H384-N64-O78-S6, and molecular weight of 5,823 dalton (5.823 kDa).
Apidra (U-100) is packaged in 10 mL vials. Each mL contains 100 IU (3.49 mg) insulin glulisine, 3.15 mg m-cresol, 6 mg tris (tromethamine), 5 mg sodium chloride, 0.01 mg polysorbate 20 (Tween 20), and water for injection. The pH is adjusted to ~7.3 by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide.
Apidra is designed to cover mealtime blood sugar spikes in the treatment of type 1 and type 2 diabetes. Apidra is injected shortly before or soon after meals, and is intended to be used in regimens that include a longer acting insulin or basal insulin analog, e.g., Lantus (and in some countries, with oral hypoglycemic agents to control prandial glucose). In combination with Lantus (insulin glargine [rDNA origin] injection), a 24-hour long-acting (basal) insulin also made by Sanofi Aventis, Apidra provides a synergistic approach to total glucose control. Apidra is intended to be given by subcutaneous injection or by continuous subcutaneous pump infusion.
Nomenclature: Insulin glulisine, rDNA [BIO]; insulin glulisine [rDNA origin] [FDA]; insulin glulisine [USAN; INN; EU]; Apidra [TR]; insulin (human), 3B-L-lysine, 29B-L-glutamic acid- [CAS]; [3B-L-lysine, 29 B-l-glutamic acid] insulin (human) [CAS]; 207748-29-6 [CAS RN]; 207748-29-6 [CAS RN]; HMR 1964 [SY]; HMR-1964 [SY]; [LysB3, GluB29] insulin [SY]; NDC 0088-2500-33 [NDC]
Companies.: Insulin glulisine was originally developed by Hoechst Marion Roussel Deutschland GmbH (which merged into Aventis Pharma in Dec. 1999), now Sanofi Aventis Pharma Deutschland GmbH, a subsidiary of Sanofi Aventis S.A. Apridra is marketed in the U.S. by Sanofi Aventis Pharmaceuticals, Inc., and internationally by Sanofi Aventis S.A. Aventis Pharma merged into Sanofi Aventis S.A. in late 2004.
In Dec. 2005, Sanofi Aventis announced tment plans to invest EUR21 million in 2006 for expansion of its manufacturing facilities for Apidra in Frankfurt, Germany.
FDA class: Drug NDA
Approvals: Date = 20040416; original NDA (no. 021629)
Date = 20070615; NDA supplememnt; Indication = for intravenous administration in a clinical setting for glycemic control in adult patients with type 1 and type 2 diabetes
Date = 20080127; NDA supplement (NDA 21-629/S015); Indications: = improve glycemic control in children age 4-17 years with type 1 diabetes
Date = 20090226; NDA supplement; Indications: = refilled disposable pen (SoloSTAR) containing Apidra to improve glycemic control in adults and children (4 years and older) with type 1 diabetes or adults with type 2 diabetes.
Indications: [full text of "INDICATIONS AND USAGE” section of product insert/labeling, 7/1/2007]:
Apidra is indicated to improve glycemic control in adults and children with type 1 diabetes.
Status: On June 25, 2003, Aventis announced it had filed an NDA with FDA and a MAA for European approval for treatment of types 1 and 2 diabetes mellitus. FDA approved Apidra on April 16, 2004 (approval time = ~9.7 months; ~.81 years).
On Sept. 27, 2004, Aventis/Sanofi Aventis received European Union (EU)-wide approval for Apidra.
Aventis/Sanofi Aventis plans to file for FDA approval of its OptiClik reusable pen injector for administration of Apridra.
Apidra was launched in the U.S. on Feb. 28, 2006.
The June 2007 FDA approval for intravenous administration in a clinical setting provides an additional treatment option for many hospitalized diabetes patients who may benefit from intravenous insulin therapy in this setting.
In April 2008, EMEA/EU modified the approved EU indications: for Apidra to “Treatment of adults, adolescents and children, 6 years or older with diabetes mellitus, where treatment with insulin is required."
In Feb. 2009, FDA approved use of the SoloSTAR pen containing Apidra. Apidra SoloSTAR was expected to be available in pharmacies later in 2009.
Tech. transfer:
The Orange Book database reports (1/2013) patents (for the sc injectable formulation) 6,221,633, expiring June 18, 2018; 6,960,561, expiring Jan 25, 2023; 7,452,860 expiring March 22, 2022, and 7,696,162 expiring Mar 22, 2022. For the Solostar-packaged product, an additional patents reported is 7918833, expiring Sept. 23, 2027.
Exemplary U.S. patents include 6,221,633 (cited in the product insert), “Insulin derivatives having a rapid onset of action,” assigned to Aventis Pharma Deutschland GmbH (a subsidiary of Sanofi Aventis S.A.), expiring on Jun 18, 2018, with claims for rapid-acting insulin analogs, including insulin glulusine. This patent refers to manufacture of these recombinant insulins using E. coli fermentation methods described in U.S. 5,227,293, “Fusion proteins, their preparation and use,” co-assigned to the General Hospital Corp. (Boston, MA) and Hoechst AG, now Sanofi Aventis S.A. This patent describes E. coli expression of insoluble fusion proteins having a ballast and a proinsulin analog portion, with the ballast portion cleaved enzymatically, providing soluble protein. The fusion protein provides protection against host cell-endogenous proteases and facilitates separation/purification. For insulin (analog) manufacture, the ballast constituent and the insulin C-chain can be removed enzymatically simultaneously, yielding a derivative of the mature insulin which can be transformed into insulin without side reactions involving much loss.
EP 1926749 B1, "CLEAVAGE OF PRECURSORS OF INSULINS BY A VARIANT OF TRYPSIN," assigned to Sanofi, expires in 2026.
EP 1926749
On Sept. 2, 2005, Novo Nordisk filed a patent infringement lawsuit against Sanofi-Aventis claiming that the OptiClik pen system used with Apridra infringes a Novo Nordisk U.S. Patent. The OptiClik pen system is sanofi-aventis’s only FDA-approved insulin delivery device and is used with all its U.S. insulin products (Apidra and Lantus). The OptiClik device, which is produced for Sanofi Aventis by Ypsomed Holding AG Switzerland). Apparently, Sanofi-Aventis won this case or it was otherwise settled or abandoned.
Trials: A 12-week Phase III study compared Apridra and NovoLog (insulin aspart) from Novo Nordisk administered by continuous subcutaneous infusion (infusion pump) in type 1 diabetes patients. Both insulin analogs had comparable pharmacokinetics. A 26-week controlled randomized open-label study compared Apridra and regular human insulin injected subcutaneously in patients with type 2 diabetes also using insulin NPH. A mean residence time of 105 minutes was reported after 0.3 unit/kg subcutaneous doses in healthy subjects.
The Oct. 2008 approval of Apidra for pediatric use was based upon FDA review of a 26-week, phase III, open-label, active control study of Apidra in comparison with insulin lispro, in 572 children and adolescents (4 years and older) with type 1 diabetes..
Medical: Apridra is equipotent to human insulin, i.e., one unit of Apridra has the same glucose-lowering effect as one unit of regular human insulin. After subcutaneous administration, it has a more rapid onset and shorter duration of action. Apridra should be given within 15 minutes before a meal or within 20 minutes after starting a meal. The dosage should be individualized. Apridra is normally be used in regimens that include a longer-acting or basal insulin analog, e.g., Lantus (insulin glargine) also from Sanofi Aventis. In type 2 patients, insulin glulisine may be used without a longer-acting insulin when given in combination with a sulfonylurea.
Apridra is particularly useful for diabetics who experience spikes in blood sugar levels that occur immediately after eating. Apidra restricts postprandial glucose fluctuations in comparison to human insulin, when injected immediately before food intake. Another benefit of Apridra (and other rapid acting insulin analogs, e.g, insulin lispro) is a reduction in severe hypoglycemic events, which is especially valuable for use in younger patients.
Apidra is administered by subcutaneous injection or by continuous subcutaneous pump infusion. Apidra is absorbed faster than normal insulin after subcutaneous injection. Subcutaneous bioavailability of insulin glulisine is ~70%, with peak insulin levels at ~50 minutes after subcutaneous injection (abdominal). Absorption is more rapid after abdominal subcutaneous injection, compared to the femoral or deltoid routes.
Apidra complements Lantus (insulin glargine), a 24-hour basal insulin also from Sanofi Aventis. Apidra in combination with Lantus provides a synergistic approach to total glucose control (i.e., these may well be the only insulin control agents the patient needs).
Market: Apidra was launched in the U.S. in Feb. 2006.
The 2007 Average Wholesale Price (AWP) is $163.04/5 300 U vials, and $81.05/10 mL vial (Red Book, 2007).
Aventis (Sanofi Aventis) has projected peak worldwide sales of 400 million Euros. The author’s rough/crude guess for total 2006 sales is on the order of $300 million. Apridra competes primarily against Lilly’s Humalog and Novo Nordisk’s Novolog.
Companies involvement:
Full monograph
198 Insulin glulisine, rDNA
Nomenclature:
Insulin glulisine, rDNA [BIO]
Apidra [TR]
insulin glulisine [USAN; INN]
[3B-B-lysine, 29 B-L-glutamic acid]insulin (human)
[CAS]
insulin (human), 3B-L-lysine,29B-L-glutamic acid-
[CAS]
207748-29-6 [CAS RN]
HMR 1964 [SY]
HMR-1964 [SY]
[LysB3, GluB29] insulin [SY]
NDC 0088-2500-33 [NDC]
molecular weight (kDa) = 5.8 [51 a.a. polypeptide]
FDA Class: Drug NDA
Year of approval (FDA) = 2004
Date of 1st FDA approval = 20040416
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2023, based on 6,960,561; 2027 based on 7,918,833 for the Solostar injector; 2022, based on 7,452,860 and 7,696,162; 2026, based on 7,981,635, a process patent |
U.S. Patent Expiration Year: | 2022 |
U.S. Biosimilars Data Exclusivity Expiration: | 2016 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2011 |
U.S. Biosimilars Launchability Year: | 2023 |
U.S. Biobetters Launchability Year: | 2023 |
Biosimilars/biobetters-related EU Patents: | 2026, based on EP 1926749, a seemingly essential process patent |
EU Patent Expiration Year: | 2026 |
EU Biosimilars Data Exclusivity Expiration: | 2014 |
EU Biosimilars Orphan Exclusivity Expiration: | 2014 |
EU Biosimilars Launchability Year: | 2026 |
EU Biobetters Launchability Year: | 2026 |
Index Terms:
biopharmaceutical products
hormones
insulin, recombinant human
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
cresol, meta-
hydrochloric acid (HCl)
polysorbate 20 (Tween 20)
sodium chloride
sodium hydroxide
Sterile Water for Injection
tris (tromethamine)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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