Urokinase for Injection - Kinlytic; Abbocath-T; Abbokinase; Abbokinase Open-Cath
Status: approved in U.S., but not currently marketed
Organizations involved:
Microbix Biosystems Inc. – R&D; Tech.; Manuf.; Former
Zydus Cadilla Healthcare Ltd. - Manuf.; R&D; Tech.; World mark
ImaRx Therapeutics, Inc. – Former
Abbott Labs. – Manuf.; R&D; Tech.; Former
Hospira – Former
Angiogen, LLC – R&D
Cross ref: See the entries for Urokinase/Microbix (ThromboClear; #627), a biogeneric version of Abbokinase which is replacing this product; and the Fibrinolytic and Thrombolytic Enzymes entry (#613).
Description: Abbokinase is a lyophilized (freeze-dried) formulation of the low molecular weight form of dimeric (two-chain) human urokinase enzyme obtained from culture of neonatal human kidney cells. Urokinase activates (converts) human plasminogen to the active fibrinolytic/thrombolytic enzyme plasmin. Plasmin degrades fibrin, the primary structural component of blood clots, as well as fibrinogen, and other plasma proteins. Endogenous or native human urokinase is produced by the kidney and can be found in the urine. There are two forms of human urokinase differing in molecular weight and having similar clinical effects. Abbokinase contains primarily the low molecular weight form of the enzyme, consisting of an A chain of 2,000 Daltons (2 kDa) linked by a sulfhydryl bond to a B chain of 30,400 daltons (30.4 kDa).
Abbokinase is supplied as a sterile white powder in vials containing 250,000 International Units (IU) of urokinase activity for intravenous or intracoro-nary infusion only. After reconstitution with 5 mL of Sterile Water for Injection, USP, each mL of Abbokinase contains 50,000 IU of urokinase activity. Each vial also contains mannitol (25 mg/vial), Albumin (Human) (250 mg/vial) as a stabilizer, and sodium chloride (50 mg/vial). The pH is adjusted with sodium hydroxide and/or hydrochloric acid prior to lyophilization. Abbokinase contains no preservatives. The product is stored at 2-8˚C (refrigerated). Following reconstitution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, each mL contains 50,000 IU of urokinase activity, 0.5% mannitol, 5% Albumin (Human), and 1% sodium chloride. Thin translucent filaments may occur in reconstituted vials, but do not indicate any decrease in potency, and no clinical problems have been associated with filaments.
Abbokinase Open-Cath (no longer marketed; reformulated and replaced by Abbocath-T as trade name) is a formulation of urokinase for catheter clearance (removal of blood clots in catheters). It was supplied in single dose Univial packages of 1 mL. Each mL of reconstituted Abbokinase Open-Cath/ Abbocath-T contains 5,000 IU of urokinase activity, 5 mg gelatin (bovine source), 15 mg mannitol, 1.7 mg sodium chloride, and 4.6 mg monobasic sodium phosphate anhydrous.
Note, Serono, Inc. received FDA approval for Urokinase for Injection (Breokinase), but voluntarily withdrew its NDA in October 2000, prior to launching the product in the U.S.
Nomenclature: Urokinase/ImaRx [BIO]; Urokinase [FDA USAN INN BAN JAN]; Abbokinase for Injection [TR]; Abbocath-T [TR]; Abbokinase Open-Cath [TR; former]; kinase (enzyme-activating), uro- [CAS]; NDC 0074-6109-05; NDC 0074-6111-01; NDC 0074-6145-01 [NDC)
Note, with its Sept. 2008 acquisition by Microbix, Abbokinase was renamed Kinlytic. This same name will be used for the comparable product to be manufactured by Microbix]
Biological.: Urokinase can be isolated from human urine or fetal kidney cell culture. Urokinase was first licensed for use in France in 1972. Urokinase directly activates the transformation of plasminogen to plasmin without requiring a cofactor. Its half-life in the blood is 2 minutes. Unlike streptokinase, urokinase is not immunogenic, does not induce antibodies, and is better tolerated than streptokinase.
Companies.: Abbokinase was originally and for a long time manufactured by Abbott Labs., CBER/FDA lic. no. 0043. Host neonatal kidney cells used for cell culture were supplied by BioWhittaker, Inc., now Cambrex Bio Science Walkersville, Inc., a subsidiary of Cambrex Bio Science, Inc., which was was acquired by and merged into Lonza in mid-2006. The product was originally marketed internationally by Abbott Labs. (when available and released by FDA).
Abbokinase Open-Cath is no longer manufactured or marketed, at least in the U.S., and has been renamed or replaced by Abbocath-T, which is marketed in the U.S. by Hospira, a subsidiary of Abbott.
In April 2006, ImaRx Therapeutics, Inc., acquired full markteing rights, manufactuing rights and technology, including cell lines, and existing stocks of Abbokinase from Abbott, and began selling Abbokinase for treatment of acute massive pulmonary embolism in Oct. 2006. At the time, the existing stocks of urokinase were expected to last four years.
In Jan. 2008, ImaRx signed a letter of intent to transfer the manufacturing process and NDA to Microbix Biosystems to provide new source for urokinase. Microbix had the right to develop urokinase for certain new indications: in catheter clearance and prophylaxis of serious catheter related complications such as blood stream infections and venous thrombi. Microbix’ also expected to investigate the potential in oncology and ophthalmology. With a new manufacturer of urokinase, ImaRx expected to be able to expand sales to additional vascular physicians and acute care institutions and to explore clinical development of urokinase for additional vascular indications: (other than those to be pursued by Microbix), such as stroke, peripheral arterial occlusion, deep vein thrombosis and myocardial infarction. . ImaRx was to retain and continue to sell its existing drug inventory (from Abbott) and retained exclusive rights to sell the drug for the currently approved indication. ImaRx intends to transfer the manufacturing process and NDA to Microbix and begin purchasing the drug from Microbix as its existing inventory became depleted in ~2 years (towards end of 2009). Thus, Microbix’s own development of ThromboClear (see entry below), a biogeneric version of urokinase, ceased. Microbix planned to spin off its urokinase assets to a new subsidiary, Klarogen Biotherapeutics, which would purchase these assets for $17 million.
In April 2008, ImaRx completed its acquisition of Abbokinase from Abbott Labs.
In Sept. 2008, Microbix acquired all urokinase assets from ImaRx for $2.5 million. These assets include the ImaRx remaining Abbokinase inventory, the NDA for Abbokinase (now rebranded as Kinlytic), key raw materials for urokinase manufacture, and the its sales and marketing infrastructure. The acquired inventory had been pending FDA product inventory release since receipt of a May 2008 approvable letter by ImaRx. Upon receiving FDA release of the Urokinase inventory, a further $ 2.5 million bonus
would be paid to ImaRx. The acquired inventory at the time had a retail value of more than $35 million. Microbix intended to sell its inventory of Abbokinase (renamed Kinlytic) before marketing its Kinlytic it manufactures itself. Microbix’ manufacturing facility in Toronto, Canada (see the entry for Urokinase, former/Microbix), has capacity to produce up to $100 million in sales.
By 2012, Microbix had apparently not yet scaled-up manufacture and obtained approvals for Kinlytic.
In Aug. 2012, Microbix licensed to Zydus Cadila all its rights and expertise relating to KINLYTIC. Zydus Cadila become responsible for all further investments, including regulatory, product development, manufacturing and marketing. Zydus Cadila will be transferring manufacturing to its own biologics facility, which permits Microbix to avoid major manufacturing scale-up and validation costs. Microbix will receive significant royalties on all sales of KINLYTIC, plus a multi-million dollar milestone payment upon Zydus Cadila's achievement of $100 million in annual sales. The Zydus Cadila partnership provides the financial and human resources to supplement Microbix' know how and return KINLYTIC (urokinase) to the market.
Manufacture: The lower molecular weight form of human urokinase is isolated and purified from cultured human neonatal kidney cells, and are not obtained from fetal tissue. The primary human neonatal kidney (HNK) cells are obtained by BioWhittaker from kidneys harvested from newborns having died of natural causes. A single vial of Abboki-nase contains urokinase produced using cultured cells derived from one or two donors. Overlapping safeguards in the production process include screening of donors and testing of the cells, controls for proper harvesting, storage, and proper handling of materials used in all stages of manufacturing. Kidney donations are obtained exclusively in the U.S. from neonates (birth to 28 days) for whom death has not been attributed to infectious causes and having exhibited no evidence of an infectious disease (including from examination of the maternal and neonatal donor medical records). The maternal and neonatal donor screening process also identifies specific risk factors for known infectious diseases, and includes testing of sera for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV-1, HIV-2, HTLV-I, HTLV-II, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Donors with sera testing positive or associated with other risk factors are excluded.
Purified lower molecular weight urokinase is subjected to heat (pasteurization) treatment (60˚C for 10 hours) for viral inactivation, and lyophilized (freeze-dried) at -35˚C for over 2 hours. The heat inactivation process substantially inactivates HIV and hepatitis C virus (HCV), but has variable effects on other viruses and infectious agents. The pH is adjusted with sodium hydroxide and/or hydrochloric acid prior to lyophilization. The manufacturing process has been validated in laboratory studies to inactivate and/or remove a diverse panel of spiked model enveloped and non-enveloped viruses. During the manufacturing process, cells are tested at multiple stages for the presence of viruses using in vitro and in vivo tests capable of detecting a wide range of viruses. Cells are also screened for human papillomavirus (HPV) using a DNA detection-based test, and for reovirus using a polymerase chain reaction (PCR)-based test. See the Status section for further manufacturing-related information.
FDA class: Drug NDA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19780116; original approval, NDA (BN761021-0); Indication = for the lysis of acute massive pulmonary emboli and emboli accompanied by unstable hemodynamics (i.e., failure to maintain blood pressure without supportive means)
Date = unknown; Indication = for treatment of coronary artery thrombosis to lyse acute thrombi obstructing coronary arteries, associated with transmural myocardial infarction
Date = 19940000 (est. by former product manager), granted to Abbokinase OpenCath; Indication = the restoration of patency to intravenous catheters, including central venous catheters, obstructed by clotted blood or fibrin
Date = 20021010, supplemental NDA for Abbokinase; Indication = included kidney cell procurement and manufacturing improvements; revised lot release protocol; removal of coronary artery thrombosis and catheter clearance indications: (i.e., Abbokinase Open-Cath no longer approved); reapproval for treatment of adults for the lysis of acute massive pulmonary emboli
Indications: [Full text of "INDICATIONS AND USAGE” section of the product insert/labeling]:
Abbokinase is indicated in adults:
• For the lysis of acute massive pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments.
• For the lysis of pulmonary emboli accompanied by unstable hemodynamics, i.e., failure to maintain blood pressure without supportive measures.
The diagnosis should be confirmed by objective means, such as pulmonary angiography or non-invasive procedures such as lung scanning.
Status: Urokinase is regulated as a drug, not biologic, and was approved under section 505 regulations. This means that generic biopharmaceutical (biogeneric; biosimilar; biocomparable; follow-on) versions of urokinase could, theoretically, be approved under abbreviated 505(b)(2) regulations.
On Jan. 25, 1998, after finding violations of Current Good Manufacturing Practices (cGMP) by Abbott, FDA issued a letter recommending that Abbokinase be reserved for only those situations where substitutes are not available. On July 16, 1999, FDA informed Abbott of additional concerns related to manufacturing deficiencies for Abbokinase, and distribution of the product was halted. FDA concerns included lack of validation of the viral inactivation process and other deficiencies in the manufacturing processes, the testing of the product, and the screening and testing of the donors of kidney cells. During an in process control study, Abbott had detected reovirus in three lots of cell culture harvest material prior to the purification and viral inactivation processes. Also, source kidney cells were obtained from populations considered by FDA to be at high risk for a variety of infectious diseases, including tropical diseases and; FDA considered donor screening and testing to be inadequate and not consistently or reliably performed. For example, the screening did not include the questioning of the mothers to determine infectious disease status or specific risk factors for infectious diseases, and donors were not tested for hepatitis C virus (HCV) infection. Abbott now tests for HCV in source kidney cells.
With its Oct. 2002 (re)approval, including improved donor selection, facilities, and manufacturing processes, Abbokinase was schedule for relaunch. However, it was no longer approved for catheter clearance or cardiac thrombosis indications:.
In June 2001, a U.S. District Court ruled in Microbix Biosystems, Inc vs. BioWhittaker, Inc. that Abbott and Bio-Whittaker had violated the Sherman Act (antitrust violation) in refusing to provide human neonatal kidney (HNK) cells to Microbix Biosystems Inc., which is developing a generic version of urokinase (ThromboClear). This reaffirmed a lower court’s ruling and injunction requiring sale of HNK cells by Bio-Whittaker to Microbix (which did not occur, due to FDA halt of manufacture, and Microbix failed to secure its own manufacturing facilities and lost its development partner). Abbott had entered into an exclusive supply agreement with BioWhittaker after learning about the Microbix’s plans for competing product development. No awards or punishments were specified, since the evidence concerning damages was considered “speculative,” with neither of the companies then manufacturing the product, and due to the other factors affecting Microbix’s difficulties in developing its product. See the ThromboClear entry below for further information.
Abbokinase Open-Cath was not reintroduced after manufacture and marketing of Abbokinase restarted in fall 2002. Abbott had planned to reintroduce the same or similar product under the trade name Abbocath-T. In first-half 2004, this and many other hospital supply products were transferred to Hospira (Lake Forest, IL), a company spun-off from Abbott. Hospira subsequently decided not to (re)launch the product. However, Abbokinase Open-Cath was still reported in the 2005 Red Book (of pharmaceutical prices), indicating remaining stocks still within their dating period were being marketed in the U.S
Abbokinase, with its 2002 (re)approval for the treatment of pulmonary embolism (but loss of coronary emboli and catheter clearance indications:), subsequently reentered the U.S. market, but was only marketed by Abbott for this indication. Abbokinase has been relaunched in European and other international markets.
The 2007 Red Book (of reported U.S. list prices for pharmaceuticals) only contains an entry for Abbocath-T, indicating this this catheter clearance product has been reintroduced in the U.S. market. Abbokinase in vials is no longer reported, indicating it is no longer marketed in the U.S. Current CDER/FDA databases only list the original and the 2002 (re)approval solely for the pulmonary embolism indication; and nothing relevant was retrieved in a search of news sources. The source for (re)approval of Abbocath-T/Abbokinase Open-Cath approval in the U.S. is unknown. Abbocath-T catherters are currently (7/2007) marketed in the U.S. by Hospira, a subsidiary of Abbott. Abbocath-T have been approved as a medical device, with its approval simply not in FDA public databases (which are of generally low quality).
In May 2007, ImaRx received an “approvable letter” from FDA, with release of product for sales then halted. FDA requested additional product characterization data to allow a dating extension. In Jan. 2008, ImaRx received authorization for lot release, and resumed distribution of Abbokinase. This was the first lot to be released with extended expiration dating.
Tech. transfer: Neither Abbokinase nore Kinlytic has no entries in the Orange Book database.
Trials: ImaRx is conducting (in 2008) an immunogenicity trial with Abbokinase to evaluate patients’ immune response to the product. With the Sept. 2008 full acquistion of Abbokinase by Microbix, the company planned to address FDA concerns and obtain release of previously manufactured Abbokinase.
Medical: Abbokinase treatment should be instituted as soon as possible after onset of pulmonary embolism using a constant infusion pump. A loading dose of 2,000 IU/lb (4,400 IU/kg) is generally given as Abbokinase in 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, followed by continuous infusion of 2,000 IU/lb/hr (4,400 IU/kg/hr) at a rate of 15 mL/hour for 12 hours.
Urokinase Open-Cath was formerly widely used for catheter clearance, but has now been replaced by use of Cathflo Activase (#269) for this indication and, eventually, ThromboClear (see entry below).
Disease: Pulmonary embolism or lung blood clots affect an estimated 500,000 patients in the U.S. annually.
Market: In Aug. 2012, with the acquisition by Zydus Cadilla, the market for Kinlytic was projected at $400 million/year.
In the U.S., Abbokinase had been a relatively low cost, commodity product (compared to some newer plasminogen activator products). It was also reported that the product (going back to Abbokinas) "has been administered to over 4 million patients since it was first approved in the U.S. in 1978."
In Jan. 2008, ImaRx reported, “Urokinase has been administered to over four million patients and has a more than 20-year history of delivering safe and predictable results;” and “It is estimated that approximately 700 acute care hospitals in the U.S. currently include urokinase on their pharmacy formularies.”
Microbix estimates that the market opportunity for Urokinase is at least U.S. $500 million annually for indications: including pulmonary embolism and catheter management, with growth in oncology and ophthalmology potentially larger than these indications:.
The 2007 AWP for Abbocath-T (only some of many options available, mostly different needle widths, lengths and lot sizes) is $147.60 for 100 prefilled syringes with varying guage needles (unchanged since 2004).
The 2005 Average Wholesale Price (AWP) for Abbokinase was $538.42/vial, with a Direct Cost (Manufacturer’s discount price) of $453.41 (Red Book, 2005).
Abbokinase in vials in not listed in the 2007 Red Book, indicating it is no longer marketed in the U.S., i.e., that only Abbokinase Open-Cath is available in the U.S.
Abbokinase worldwide sales has been projected by various analysts (and Microbix, see ThomboClear entry below) to reach $360 million by 2005. The market for Abbokinase was forecast to reach $360 million by 2005 according to a May 16, 2002 report published by J.P. Morgan (perhaps, the source for others citing this figure).
However, sales have likely fallen in recent years as newer recombinant thrombolytics, notably Activase, have matured, had their prices reduced and largely replaced nonrecombinant products.
Sales for 2007 were over $10 million. U.S. sales (when approved for broader indications:) in 1998 were $270 million and $150 million in 1995. Abbokinase was used by an ~4 million patients from 1978 to 1998.
ThromboClear (see entry below), if approved for pulmonary emboli, will provide direct competition for Abbokinase. Even though Abbokinase is probably the least expensive plasminogen activator/clot buster, Genpharm is expected to market it below the cost of Abbokinase.
Competition: Abbokinase (and streptokinase) has largely been replaced in recent years in the U.S. (and other highly developed countries) by other thrombolytic agents, such as the recombinant tissue plasminogen activators, e.g., Activase, TNKase, and Retavase. See also the Fibrinolytic and Thrombolytic Enzymes entry (#613). Abbokinase Open-Cath has been replaced in the U.S. (and likely other highly developed countries) by Cathflo Activase.
In many lesser-developed countries, urokinase is the leading plasminogen activator treatment, because it is the least expensive. Worldwide, Abbokinase “has been the primary treatment in the clinical management of coronary artery thrombosis for the last 20 years” (according to Microbix). Angikinase (urokinase) is manufactured and marketed in Egypt by SEDICO.
R&D: In April 2006, Microbix formed a collaboration with Angiogen, LLC (Chicago, IL) for the development of urokinase for prostate, colon and other cancer therapy. Presumably, this collaboration is continuing, now using Abbokinase to be manufactured by Microbix. With this agreement, Microbix began concentrating on developing ThromboClear (and now, presumably, Abbokinase) for these new indications:, rather than as a fully biogeneric product (see entry below). Both Angiogen and Microbix believe their new proprietary cancer treatment will greatly improve the standard of care in solid tumor therapy. Angiogen is providing its patented technology which uses urokinase in a cocktail with an approved small chemical drug that acts as a free sulfhydryl donor. Once inside the body, this Angiostatic Cocktail generates the anti-cancer agent Angiostatin 4.5 (AS4.5), which destroys specific blood vessels, removing the blood supply that nourishes the tumor. Microbix will supply the urokinase for the combination product. Positive Phase I trial results were reported in June 2006.
Companies involvement:
Full monograph
626 Urokinase/ImaRx
Nomenclature:
Urokinase/ImaRx [BIO]
Kinlytic [TR US]
Abbocath-T [TR]
Abbokinase [TR former]
Abbokinase Open-Cath [TR former]
Urokinase [FDA USAN INN BAN JAN]
Urokinase For Injection [FDA]
kinase (enzyme-activating), uro- [CAS]
NDC 0074-6109-05; NDC 0074-6111-01; NDC 0074-6145-01 [NDC]
FDA Class: Drug NDA
Year of approval (FDA) = 1978
Date of 1st FDA approval = 19780116
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | long expired; 1990 arbitrarily used as expiration date; not marketed in the U.S. (making biosimilars impossible) |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 1990 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1985 |
U.S. Biosimilars Launchability Year: | |
U.S. Biobetters Launchability Year: | 1990 |
Biosimilars/biobetters-related EU Patents: | long expired; 1990 arbitrarily used as expiration date |
EU Patent Expiration Year: | 1990 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | 1990 |
Index Terms:
biopharmaceutical products
Biorex-70 resin
bovine materials used<!-- bovinesource -->
enzymes
enzymes, fibrinolytic/thrombolytic
human materials used<!-- humansource -->
cells, human
human kidney cells, neonatal
kidney cells, human neonatal
mammalian cell culture
Albumin (Human)
fibrin
fibrinogen
gelatin (bovine source)
heat treatment (pasteurization)
hydrochloric acid (HCl)
lyophilized (freeze-dried)
mannitol
plasmin
plasminogen
sodium chloride
sodium hydroxide
sodium phosphate, monobasic
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
BHK-21 (C-13)
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US US777
EM999 Not Available/Not Marketed in EU
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