Human Insulin Injection (recombinant DNA origin) - Regular, Human Insulin Injection (recombinant DNA origin) or Novolin R; Lente, Human Insulin Zinc Suspension (recombinant DNA origin) or Novolin L; NPH, Human Insulin Isophane Suspension (recombinant DNA origin) or Novolin N; Buffered Regular Human Insulin Injection (rDNA origin) or Velosulin BR; Actraphane; Protaphane
Status - approved; marketed
Organizations involved:
Novo Nordisk A/S – Manuf.; R&D; Tech.; Parent
Novo Nordisk Pharm., Inc. – Manuf.; USA mark.
Torrent Pharmaceuticals – Manuf.
Washington Research Foundation (WRF) – Tech.
University of Washington – Tech.
Genentech, Inc. – Tech.; Patent dispute
Cetus Corp. – Tech.; Former
Chiron Corp. – Tech.; Former
Hoffmann-La Roche Ltd. – Tech.
City of Hope National Medical Center – R&D; Tech.; Patent dispute.
Cross ref.: See the Insulin Products entry (#630).
Description: Human Insulin Injection (recombinant DNA origin) or Novolin formulations contain recombinant human insulin protein expressed by a transformed Saccharomyces cerevisiae (yeast) cell line. This yeast expressed insulin has the same primary amino acid sequence and properties, including therapeutic activity, as human insulins obtained from other sources, including E. coli bacterial expressed insulin. Novolin insulin is manufactured in various formulations to provide a range of onset and duration characteristics. See the Insulin Products entry for further information about these different types of insulin formulations.
Novolin (referring to the insulin component and/or the family of Novolin products) recombinant insulin formulations are available in vials and in cartridges of varying doses for use in NovoPen insulin delivery systems. Novolin formulations contain 1,000 units of insulin in 10 mL (100 units/mL; U-100). Novolin Regular, NPH and 70/30 premix formulations are available in vials, disposable insulin pens, and cartridges. In Jan. 2003, Novo Nordisk launched NovoPen Junior, an insulin delivery system for children and adults with half-unit dosing increments. Novolin L (Lente; insulin zinc suspension) is available in vials. Velosulin Buffered Regular (Velosulin BR) is regular Novolin specially buffered for use in insulin delivery pumps. Different types of syringes and needles are often used with different insulins, and patients may also custom mix insulin products in vials for their own use.
Novolin R (amorphous human insulin), like other regular insulins, has a short duration of action, starting about 1/2 hour after injection, maximal effects between 2-5 hours, and ending about 8 hours after injection. Novolin L or Lente is a suspension of about 70% insulin zinc crystals and 30% Novolin R. Novolin L has an intermediate duration of action, starting at about 2.5 hours after injection, maximal between 7-15 hours, and ending about 22 hours after injection. Novolin N is a suspension of NPH (insulin zinc protamine complex) or isophane insulin. Novolin N has an intermediate duration of action, starting about 1.5 hours after injection, maximal at 4-12 hours, and lasting up to 24 hours after injection. Novolin 70/30 is a suspension mixture of 70% Novolin N and 30% Novolin R. Novolin 70/30 has an intermediate duration of action, starting about 1/2 hour after injection, maximal between 2-12 hours, and lasting up to 24 hours after injection. Velosulin BR is specially formulated for use in external insulin infusion pumps and with U-100 syringes. Many of these formulations with recombinant insulin replaced earlier comparable formulations containing semi-synthetic human insulin (porcine insulin converted to human insulin).
Nomenclature: Insulin, rDNA/Novo [BIO]; Novolin R [TR]; Novolin L [TR]; Novolin Lente [TR in U.S.]; Velosulin BR [TR]; Novolin N [TR]; Novolin 70/30 [TR]; Actarapid [TR in Europe]; Actraphane [TR for isophane insulin in Europe]; Protaphane [TR for protamine insulin in Europe]; ReliOn [TR assigned to Wal-Mart]; Regular, Human Insulin Injection (recombinant DNA origin) [FDA]; Lente, Human Insulin Zinc Suspension (recombinant DNA origin) [FDA]; Buffered Regular Human Insulin Injection (rDNA origin) [FDA]; 70% NPH, Lente, Human Insulin Zinc Suspension and 30% Regular, Human Insulin Injection (recombinant DNA origin) [FDA]; NPH, Human Insulin Isophane Suspension (recombinant DNA origin) [FDA]; Insulin Human [USAN INN BAN for uncomplexed insulin]; 9004-10-8 [CAS RN]; 11061-68-0 [CAS RN]; Human Insulin (Neutral Protamine Hagedorn) [SY]; Human Insulin (NPH) [SY]
Companies.: Novolin products were developed and are manufactured and marketed worldwide by Novo Nordisk A/S and affiliates. Novo Nordisk is doubling the capacity of its Chartres, France, insulin manufacturing facility, with completion expected in 2006. Insulin products may also be manufactured by Novo Nordisk Pharmaceuticals Industries, Inc. (Clayton, NC), and/or at parent company facilities in Denmark. In Oct. 2004, Novo Nordisk announced a $100 million expansion of these insulin manufacturing facilities. The first phase, to be completed in 2006, will double capacity. The second phase of the expansion will include two new FlexPen assembly and packaging lines.
In Aug. 2007, Millipore Corp. expanded its existing agreement with Novo Nordisk (from its acquisition of Celliance from Serologicals), regarding insulin manufacture and marketing (for cell culture use). Millipore received exclusive worldwide rights to market and sell Novo Nordisk ecombinant human insulin, branded as Incelligent SG and Incelligent AF, for cell culture applications. These products are manufactured in separate facilities from those used by Lilly for manufacture of human pharmaceutical insulin.
In 2008, Novo Nordisk announced that it would invest ~$400 million to establish a new insulin facility in Tianjin, China, due to come online in 2012..
In Nov. 2009, Novo Nordisk opened a a new 3,000 sq. m insulin manufacturing facility in Kadi, India, with a capacity of 26 million vials/year in partnership with Torrent Pharmaceuticals. Novo Nordisk was then also constructing manufacturing facilities in China.
In Nov. 2009, Novo Nordisk closed down its insulin manufacturing plant in Kalundborg, Denmark; and also reported increasing its insulin production capacity, up to capacity of 26 million vials/year, in India with the commissioning of a new manufacturing facility operated by Torrent Pharmaceuticals, the sole Indian producer of insulin products for Novo Nordisk since 1992.
In Oct. 2010, Novo Nordisk reported it was investing $73 million in the expansion of its manufacturing facility in Clayton, NC, for increased production of “a new generation of disposable insulin pens” delivered as “autodosers” to provide people with diabetes “a more convenient way to manage their health and engage in a healthy lifestyle,”
FDA class: Drug NDA OTC
Approvals: Date = not available; NDA; first approval; apparently for (semi)synthetic Novolin R; Indication = management of type 1 diabetes (diabetes mellitus)
Date = 19860000; NDA supplement; approved as over-the-counter (OTC) drug); Indication = first approval for Velosulin BR (for insulin pump)
Date = 19910625; NDA supplement; Indication = approval of recombinant Novolin R
Date = 19910625; NDA supplement; Indication = approval of recombinant Novolin L
Date = 19910701; NDA supplement; Indication = approval of recombinant Novolin N
Date = 19990720; NDA supplement; Indication = approval of buffered Regular Human Insulin Injection (rDNA origin) or Velosulin BR formulated for use in insulin infusion pumps and with U-100 insulin syringes
Date = 20020411; NDA supplement; Indication = packaging in NovoPen Junior
Date = 20100625; NDA supplement; Indication = provide NovoPen Junior carton labels listing Denmark as the manufacturing site for NovoPen Junior [The NovoPen Junior was approved on April 11, 2002 . Approval did not include carton labels].
Date = 20120227; NDA supplement; Indication = “Prior Approval” supplemental new drug application provides for conversion of the Package Insert (PI) to comply with the Physician Labeling Rule and associated labeling changes to the Patient Package Insert (PPI) and Instructions for Use (IFU)
Indications: [Note, as over-the-counter (OTC) or non-prescription drugs, Novolin formulations do not have a traditional product insert/labeling; according to the Novo Nordisk medical information department]
Status: Novolin Lente (Novolin L) was phased out (discontinued) in fall 2003. The availability of new longer-acting insulin analogs, e.g., Lantus (see related entry), had resulted in less use of traditional Lente formulations.
Novo Nordisk received European Union approval in fall 2006 for NovoMix 30, the first premixed insulin suitable for once-daily initiation and subsequent intensification of treatment, if needed. NovoMix 30 contains both rapid-acting insulin aspart (30% NovoLog) and intermediate-acting regular insulin (70%) in one dose, providing a dual-release formula. NovoMix 30 may be a good treatment choice for patients who prefer convenient, effective once or twice-daily insulin therapy.
Novo Nordisk formerly marketed Novotard recombinant regular insulin in the European Union. This was approved on Oct. 7, 2002, and the approval voluntarily withdrawn on Nov. 16. 2006.
Novolin did not receive centralized EU approval, with European approvals country-by-country.
Tech. transfer: Recombinant insulin U.S. patents assigned to Novo Industri A/S, now Novo Nordisk, include 4,916,212, “DNA-sequence encoding biosynthetic insulin precursors and process for preparing the insulin precursors and human insulin,” April 10, 1990. This concerns recombinant yeast-expressed single chain insulin precursors, particularly B(1-29)-A(1-21), with a short selectively cleavable amino acid sequence at the N-terminal of the B-chain precursor protecting the molecule from enzymatic degradation, with a bridging chain connecting the carboxyl terminus of the B(1-29)-chain with the amino terminus of the A(1-21)-chain, expressed in high yields, and with correctly positioned disulfide bridges. The protecting amino acid sequence is cleaved by yeast dipeptidase enzymes, whether added or present in the cultured yeast.
The FDA’s Orange Book Database reports that exclusivity for Velosulin BR expired July 19, 2002; and that for Novolin R, Velosulin BR and Novolin R, Novolin L, Novolin N, and Novolin 70/30, “There are no unexpired patents for this product in the Orange Book Database,” i.e., that relevant U.S. patents have expired. DataMonitor and ABN Ambro report that U.S. patent protection for Novolin expires in 2005.
Chiron Corp. has reported that it has received manufacturing-related patent licensing royalties on sales of insulin by Novo, with royalties stopping 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., now Chiron Corp., issued Dec. 23, 1986. Other patents that likely licensed from Chiron include U.S. patent 4,914,026, “Alpha factor leader sequence directed secretion of insulin,” assigned to Chiron Corp., issued April 3, 1990, describing methods and compositions for efficient yeast production of insulin polypeptides. The proinsulin gene is joined to secretion and processing signals for expression and secretion in yeast. cDNA constructs are provided for insertion into plasmid vectors to provide for expression, processing and secretion of “pre”-proinsulin. This provides a polypeptide having the identical sequence to the naturally occurring human insulin at greatly enhanced yields, and subsequent preparative operations and purification are simplified. The invention is exemplified by the same cell line, PYinsl (also described in U.S. 5,015,575).
U.S. patent 5,015,575, “Hybrid DNA synthesis of insulin,” assigned to Chiron Corp., issued May 14, 1991, a continuation of 4,914,026, further describes methods and compositions for the recombinant production of “pre”-proinsulin in yeast host cells and secretion of processed “pre”-proinsulin into the nutrient medium. The “pre”-proinsulin refers to a gene encoding for human proinsulin in a reading frame with a leader sequence and processing signals efficiently recognized by the yeast host, with the “pre” portion providing the secretion and processing signals associated with the yeast host (not the human sequences naturally present for processing the native prepropeptide to proinsulin). The cDNA gene for proinsulin is used with the regulatory, leader and processing signals, and transcriptional terminator of yeast alpha-factor. The human proinsulin cDNA is restricted with EcoRI to provide a fragment (EcoRI-EcoRI) having a complete coding sequence for proinsulin, as well as flanking sequences. The DNA constructs are produced by joining these DNA sequences from diverse sources, providing a construct stably replicated in a yeast host and an efficient high level production of processed “pre”-proinsulin into the nutrient medium, where it may be isolated in high yield. The yeast cell line AB103(PYinsl), also referred to as pyinsl, was deposited as ATCC acc. no. 20670 on April 6, 1983. Note, this method shares some similarities with the prb method used by Lilly for manufacture of insulin from E. coli expression of preproinsulin (see the entry above for Lilly’s Humulin insulin products).
Yeast expression system technology used for manufacture was developed by the University of Washington and Genentech, and has been nonexclusively licensed to Novo Nordisk by the Washington Research Foundation (WRF), the licensing agent for this family of yeast expression patents. The patents, particularly the more recent ones, broadly claim processes and materials for expression of proteins in yeast. Patents include U.S. 5,854,018 and 5,856,123, which are continuations of 5,618,676(issued April 8, 1997), concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. . All three U.S. patents will expire in 2014. The new patents are broader, and claim processes and materials for expression of proteins in recombinant yeast systems generally.
In 1998, Genentech settled a U.S. patent dispute with Novo Nordisk relating to recombinant insulin (and human growth hormone). Genentech had accused Novo Nordisk of infringing insulin-related patents. Novo Nordisk received a worldwide license under Genentech’s patents relating to insulin, and Genentech received certain payments. As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech is appealing 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 involvement in recombinant insulin development. Genentech is appealing to the California State Supreme Court.
Novo Nordisk has nonexclusively licensed recombinant manufacturing technology from Hoffmann-La Roche Ltd., with these patents reported to start expiring in 2003.
Market: In July 2009, Novo Nordisk reported, "FlexPen is the world’s most widely used prefilled insulin pen, trusted daily by more than three million people worldwide... Compared to other insulin delivery devices that have to be manually loaded with insulin cartridges, prefilled pens are ready to use, eliminating the step of loading insulin cartridge into the delivery device."
Novo Nordisk does not break out sales of its insulin products. Total insulin product sales by the company in 2006 were $2.653 billion. Total worldwide sales of Novolin products were about $1.3 billion in 1999. With Novo Nordisk the leading marketer of insulins worldwide, presumably, current sales of Novolin products are over $1 billion (blockbuster status), but with increasing competition, the author’s rough/crude guess for 2007 sales is ≥$1.5 billion.
The 2007 over-the-counter (OTC) Average Wholesale Price (AWP) for Novolin N 100 U/mL 10 mL vials is $39.60; for Novolin 70/30 Penfil 70 U/mL 3 mL is $125.42 for five; for Novolin 70/30 Innolet (prefilled) is $84.30 for five 3-mL vials; for Novolin R Penfill 100 U/mL 3 mL vials is $125.42 for five; for Novolin 70/30 100 U total/mL 10 mL is $39.60 (2007 Red Book). For comparison, the 2005 AWPs for Novolin N 100 U/mL 10 mL vials were $32.03; for Novolin 70/30 Penfil 70 U/mL 3 mL, $101.44 for five; for Novolin 70/30 Innolet (prefilled), $68.19 for five 3-mL vials; for Novolin R Penfill 100 U/mL 3 mL vials, $101.44 for five; for Novolin 70/30 100 U total/mL 10 mL, $32.03 (2005 Red Book).
Novo Nordisk repackages Novolin as ReliOn for by Wal-Mar in the U.S. .
During May 2004, among the major insulins in the U.S. market (Humalog, Humulin, Novolin, Novolog, and Lantus), 61,081 prescriptions were filled for Novolin (12.3% market share). About 5% of U.S. type 1 diabetes patients use an insulin pump (e.g., with Velosulin BR).
Companies involvement:
Full monograph
193 Insulin, rDNA/Novo
Nomenclature:
Insulin, rDNA/Novo [BIO]
Novolin R [TR in U.S.]
Actraphane [TR for isophane insulin in Europe]
Novolin L [TR in U.S.]
Novolin Lente [TR in U.S.]
Protaphane [TR for protamine insulin in Europe]
Velosulin BR [TR for buffered solution]
Novolin N [TR in U.S.]
Novolin 70/30 [TR in U.S. for 70%/30% mixture of Novolin N and Novolin L]
Actarapid [TR in Europe]
Regular, Human Insulin Injection (recombinant DNA origin) [FDA]
70% NPH, Lente, Human Insulin Zinc Suspension and 30% Regular, Human Insulin Injection (recombinant DNA origin) [FDA]
Buffered Regular Human Insulin Injection (rDNA origin) [FDA]
Lente, Human Insulin Zinc Suspension (recombinant DNA origin) [FDA]
NPH, Human Insulin Isophane Suspension (recombinant DNA origin) [FDA]
Insulin Human [USAN INN BAN for uncomplexed protein]
11061-68-0 [CAS RN]
9004-10-8 [CAS RN]
Human Insulin (Neutral Protamine Hagedorn) [SY for NPH]
Human Insulin (NPH) [SY]
molecular weight (kDa) = 5.8 [51 a.a. polypeptide]
FDA Class: Drug NDA
Year of approval (FDA) = 1983
Date of 1st FDA approval = 19830000
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | Orange Book reports that Novolin R, Velosulin BR and Novolin R, Novolin L, Novolin N, Velosulin B and Novolin 70/30 U.S. patents have expired.
PWC has reported 2001. DataMonitor and ABN Ambro report that U.S. patent protection for Novolin expires in 2005.
2005 is arbitrarily used as the expiration date. |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 1995 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1990 |
U.S. Biosimilars Launchability Year: | 2005 |
U.S. Biobetters Launchability Year: | 2005 |
Biosimilars/biobetters-related EU Patents: | expired; biosimilar insulin applications already have been filed; 2004 arbitrarily used as EU expiration date; No centralized EU approval, no biosimilars possible |
EU Patent Expiration Year: | 2004 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2004 |
EU Biobetters Launchability Year: | 2004 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
hormones
insulin, recombinant human
recombinant DNA
yeast source materials
AB103
ATCC 20670
PYinsl yeast cells
Saccharomyces cerevisiae (yeast)
pre-proinsulin
protamine
zinc
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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