Asparaginase - Elspar; L-asparaginase; L-asparagine aminohydrolase
Status: approved; marketed; being withdrawn from the market,with manufacturing halted in 2012
Organizations involved:
Merck & Co., Inc. – Former
Lundbeck A/S - Manuf.; R&D; Tech.; World mark.; Former
Ovation Pharmaceuticals, Inc. – Former
Lilly, Eli & Co. – R&D; Tech.; Former
Cross ref: See the Asparaginase Products entry and the other Asparaginase product entries.
Description: Asparaginase or Elspar is a lyophilized (freeze-dried) formulation of L-asparaginase type EC-2 enzyme obtained from fermentation of Escherichia coli (E. coli). Activity is expressed in terms of International Units (I.U.) according to the recommendation of the International Union of Biochemistry. The specific activity of Elspar is at least 225 I.U. per milligram of protein.
Purified E. coli L-asparaginase (not specifically that is Elspar) has been reported to have a molecular weight of 133-141 kDa and is composed of 4 subunits, each with an active site; has specific activity of between 300-400 µmol of substrate/minute/mg of protein; has an isolectric point between pH 4.6-5.5; with Km of about 1 x 10-5. Elspar contains no antimicrobial preservatives (and is meant for 1-time use).
Each 10 mL vial contains 10,000 I.U. of L-asparaginase and 80 mg of mannitol for intravenous or intramuscular injection after reconstitution. The product is stored at 2-8°C (36-46°F; refrigerated) and is labeled with the expiration date.
Nomenclature: Asparaginase, E. coli/Merck [BIO]; Elspar [TR]; asparaginase [FDA USAN]; Colaspase [BAN]; L-asparaginase [CAS JAN]; 9015-68-3 [CAS RN]; asparagine amino-hy-drolase [SY]; crisantaspase [SY]; NSC 109229 [SY NCI]; asparaginase, L- (E. coli) [SY]; ASP [SY]; L-asparagine aminohydrolase [SY]; E.C. 3.5.1.1 [EC]; NDC 67386-411-51 [NDC]; NDC 0006-4612-00 [NDC former]
Companies.: Elspar was developed and is manufactured by Merck & Co., Inc.; CBER/FDA est. no. 0002, at facilities in Riverside, PA. It was marketed in the U.S. by Merck, and internationally by Merck affiliates until the mid- or late-2005, when Ovation Pharmaceuticals (now Lundbeck) assumed marketing of Elspar from Merck (after it experienced difficulties with FDA; see the Status section below). Merck may have for short time continued as the manufacturer of L-asparaginase and Elspar, supplying these to Ovation. However, Lundbeck in 2012, as it withdrew the product from the market (see below), reported transfer of manufacture to a CMO.
In Oct. 2011, Lundbeck AS acquired Ovation.
In Sept. 2012, Lundbeck informed physicians in a letter that beginning in Dec. 2012, it would stop supplying Elspar because it has been unable to get a steady supply of the API. The company had used a contractor to make Elspar. When Lundbeck fully acquired the product in 2006, the company had to update underlying process technology and analytical methods to meet new guidelines for biologics. However, "Authorities in some markets outside the U.S. have been reluctant to accept many of these improvements, due to evolving and often tighter controls linked to biologics." Even with all of its investments, the company had difficulty getting a guaranteed supply of the API, and to continue doing that would have required additional process and specification changes that might not be approved by regulators.
Manufacture: Merck’s manufacture of asparaginase included E. coli fermentation, alkali lysis, multiple ion-exchange adsorptions, ammonium sulfate precipitation, multiple dialysis-concentration steps, and ethanol crystallization (as reported in U.S. patent 4,729,957 concerning Erwinia-derived enzyme).
FDA class: Biologic PLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19780110; first approval, PLA [now converted to BLA 101063]
Date = 20020801; BLA supplement; Indication = added a Geriatric Use subsection in the Precautions section of the package insert
Date = 20040629; BLA supplement; Indication = inclusion of an Immunogenicity subsection in the Adverse Reactions section of the product insert
Date = 20060721; BLA supplement (granted to Ovation); Indication = revision of Adverse Reactions section of the product insert to include pancreatitis, cerebral vascular events, hepatic failure, depletion of plasma levels of Proteins C, S and antithrombin III, and seizures
Date = 20070330; BLA supplement (granted to Ovation); Indication = revision of product insert and labeling to be in compliance with new content and format requirements, and including clinical data from Clinical Oncology Group (COG) studies
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling; 5/8/2007]:
Elspar is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).
Status: Original approval was granted on Jan. 10, 1978. However, as is all too common, CDER, FDA (Drugs@FDA.gov) now reports original approval as Jan. 2, 1994. Most likely, this is a supplemental approval date that has been swapped in and is now promulgated as the official original approval date, because that is the earliest or best date available to FDA (which has corrupted and not bothered to correct its legacy/pre-1980s biologics approvals data, and for many older biologics now simply passes off the best or earliest dates available as the official approval dates).
In Feb. 2005, FDA conducted an inspection of Merck’s Cherokee plant in Riverside, PA, and had serious concerns about the manufacturing of L-asparaginase and Elspar. FDA citedMerck for the lack of approval for changes in the production process†that could have a substantially adverse effect on the product. The letter stated, “Specifically, you failed to notify FDA upon establishing a new working cell culture from a pro-existing working cell culture. Your records referenced that each new lyophilization series is sequentially prepared from the previous lyophilization series. There has been no evaluation or comparability study to support this practice.” Merck responded, but the FDA found Merck’s answers deficient and issued a warning letter on July 22, 2005. It is unclear as to the resolution of this issue. However, by or at the end of 2005, Merck had transferred marketing of Elspar to Ovation Pharmaceuticals, Inc.
No EU centralized approval granted - country-by-country in Europe.
Tech. transfer: Merck licensed asparaginase crystallization technology, involving the use of magnesium, from Eli Lilly & Co. Related U.S. patent(s) were not located (apparently, not patented and/or prior to coverage of the databases used), and would now be long-expired (from Dr. Baer, one of the Lilly researchers).
Medical: A significant portion of patients, up to 78%, treated with Elspar develop dose-limiting hypersensitivity (allergic reactions) to the E. coli-derived protein. PEG-Asparaginase (Oncaspar; see entry below) and Erwinase/Erwinaze are available for use by patients with significant Elspar hypersensitivity.
Market: The 2010 Average Wholesale Price (AWP) was $70.42/vial, with a Direct Price (Manufacturer’s discount price) of $52.73. The 2007 AWP was $63.28/vial, with a Direct Price of $52.73.
Companies involvement:
Full monograph
609 Asparaginase, E. coli/Ovation
Nomenclature:
Asparaginase, E. coli/Ovation [BIO]
Elspar [TR]
Asparaginase [FDA USAN]
Colaspase [BAN]
L-Asparaginase [CAS JAN]
9015-68-3 [CAS RN]
ASP [SY]
Asparaginase, L- (E. coli) [SY]
Asparagine aminohydrolase [SY]
Crisantaspase [SY]
L-asparagine aminohydrolase [SY]
NSC 109229 [SY NCI]
E.C. 3.5.1.1 [EC]
NDC 0006-4612-00 [NDC Former]
NDC 67386-411-51 [NDC]
molecular weight (kDa) = 133
FDA Class: Biologic PLA
Year of approval (FDA) = 1978
Date of 1st FDA approval = 19780110
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
enzymes
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
alginate, propylene glycol
aminohydrolase
ammonia
ammonium sulfate
asparagine
ethanol
mannitol
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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