crisantaspase - Erwinaze; Erwinase; L-asparaginase; L-asparagine aminohydrolase
Status: marketed internationally; BLA approved in Nov. 2011
Organizations involved:
Centre for Applied Microbiology Research – Manuf.; R&D; Tech.
OPi, Ltd. – R&D; Tech.; World mark.
EUSA Pharma Inc. – Parent
Jazz Pharmaceuticals Inc. – Parent
Ipsen Ltd. – Former
Ipsen S.A. – Parent; Former
Porton International plc – Former
Cross ref: See the entries above for Asparaginase Products and the other Asparaginase products marketed in the U.S. See also entry above for Kidrolase, another bacterial-derived asparaginase, also marketed by OPi.
Description: L-Asparaginase or Erwinase (with the name Erwinaze in the U.S. after its approval) is a lyophilized (freeze-dried) formulation of L-asparaginase obtained from (Erwinia chrysanthemi, a Gram negative rod bacterium and coliform in the family enterobacteriacea. Erwinia chrysanthemi L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The molecular weight of E. chrysanthemi L-asparaginase is 133 kDa +/- .5 kDa, essentially the same as E. coli L-asparaginase. The activity of Erwinase is expressed in terms of International Units. Each vial contains 10,000 International Units of asparaginase Erwinia chryanthemi. Erwinase/ Erwinaze is supplied as a sterile, lyophilized, white powder in vials.
Erwinase has long been marketed in Europe and many other countries worldwide, but the product was only recently approved in the U.S. L-asparaginase from Erwinia chrysanthemi, is immunologically distinct from and is suitable for patients with hypersensitivity to E. coli-derived asparaginase products.
Excipients reported for Erwinase are sodium chloride and dextrose monohydrate. Erwinase has a shelf-life of three years. Excipients reported for Erwinaze (upon U.S. approval) are glucose monohydrate (5.0 mg) sodium chloride (0.5 mg).
Nomenclature: Asparaginase/Erwinia [BIO]; Erwinase [TR U.S.]; Erwinase [TR; former in U.S.]; crisantaspase [INN]; asparaginase [SY]; L-asparaginase [SY]; L-asparagine aminohydrolase [SY]; Erwinia L-asparaginase [SY]; E.C. 3.5.1.1 [EC]; NDC 57902-249-01 [NDC]
Note, FDA did not adopt crisantaspase, the INN, as the U.S. established (official, compendial) name. No USAN has been assigned to this product, and no applications are known to be pending (as of Dec. 2012).
Companies.: Erwinase was originally developed and is manufactured by the Centre for Applied Microbiology Research (CAMR; Porton Down, UK), Microbiological Research Authority [formerly the Public Health Laboratory Service (PHLS)], Health Protection Agency (HPA), United Kingdom. CAMR has dedicated a 750 L biorector to manufacture of Erwinia L-asparaginase.
From 1994 through fall 2005, Erwinase was marketed internationally by Ipsen Ltd., a subsidiary of Ipsen S.A. Before that, it was marketed by the Speywood Pharmaceuticals subsidiary of Porton International plc, which was acquired by Ipsen in 1994. CAMR manufacturing facilities were upgraded in 2005. [Note, as is increasingly common, FDA attributes the sponsor, EUSA Pharma, as the manufacturer].
Since late 2005, OPi, Ltd. has exclusively marketed Erwinase worldwide. EUSA Pharma Inc. acquired OPi in March 2007. Ohara Pharmaceutical Co. Ltd. has licensed Japanese marketing rights from EUSA.
In May 2008, EUSA Pharma completed acquisition of Cytogen for $22.6 million. In July 2012, Jazz Pharmaceuticals acquired EUSA Pharma
FDA class: Biologic BLA
Approvals: Date = 20111108, full BLA
Status: Erwinase was formerly a Group or Class C cancer drug in the U.S., a class of drugs otherwise unavailable in the U.S. but purchased and distributed as needed to individual patients by the National Cancer Institute (NCI), NIH. Group C is comparable to a treatment IND program and was administered by the NCI under an agreement with the FDA.
In Nov. 2006, OPi received filed an IND with FDA enabling U.S. patients with acute lymphoblastic leukemia (ALL) and hypersensitivity to current U.S.-approved L-asparaginase to have facilitated access to Erwinase through various cooperative protocols already in place in the U.S. OPi reported, “The FDA has expressed its strong interest in having Erwinase approved and available to patients as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with ALL and hypersensitivity to currently approved L-asparaginase preparations.”
The enzyme, renamed Erwinaze for the U.S. market, received full BLA approval on Nov. 9, 2011, with orphan designation. The application had received priority review. EUSA Pharma had completed the rolling submission of its BLA on Nov. 1, 2010, after receiving Fast Track designation. The time from submission to approval was 12.6 months, with the PDUFA date not met; and the BLA going through just 1 approval cycle.
No EU centralized approval granted - country-by-country in Europe.
Tech. transfer: U.S. patent 5,310,670, assigned to the U.K. Public Health Laboratory Service (CAMR), describes aspects of L-asparaginase manufacture from Erwinia chry-santhemi. U.S. 4,729,957, assigned to the National Institutes of Health (NIH) describes production scale manufacture of L-asparaginase from E. chrysanthemi, apparently an attempt by NIH to develop an alternative source for purchase of L-asparaginase.
Trials: The safety and effectiveness of Erwinaze was evaluated in one clinical trial of 58 patients. Additional safety data was collected from the Erwinaze Master Treatment Protocol (EMTP), an expanded access program that enrolled 843 patients. Patients in both studies were unable to continue receiving pegaspargase or asparaginase derived from E. coli due to allergic reactions. Side effects associated with
Erwinaze treatment included serious allergic
reactions (anaphylaxis), inflammation of the
pancreas (pancreatitis), high blood levels
of liver enzymes (abnormal transaminases
and bilirubin), blood clotting, bleeding
(hemorrhage), nausea, vomiting and high
blood sugar (hyperglycemia).
In its trial to support efficacy, the main endpoint was the measurement of the proportion of patients with sustained asparaginase activity levels that correlate with better leukemia control and survival. All evaluable patients were shown to have maintained the pre-specified threshold for asparaginase activity at 48 or 72 hours after dosing.
Medical: Erwinase/Erwinaze is used to treat patients with acute lymphoblastic leukemia (ALL), who have developed an allergy (hypersensitivity) to the E. coli-derived asparaginase and pegaspargase products used to treat ALL. Erwinaze is injected directly into the muscle three times a week. The plasma half-life of E. coli L-asparaginase is 7-13 hours.
Market: The market for Erwinase is rather small. OPi reported total 2006 sales of $23 million, with this from both Kidrolase and Erwinase.
Prior to Erwinaze’s approval there were two asparagine specific enzyme products in the U.S. – Elspar (asparaginase injection) and Oncaspar (pegaspargase) – to treat patients with ALL. Both of these products are E. coli derived.
Companies involvement:
Full monograph
610 Asparaginase/Erwinia
Nomenclature:
Asparaginase/Erwinia [BIO]
Erwinaze [TR US]
Erwinase [TR]
asparaginase Erwinia chrysanthemi [FDA]
crisantaspase [INN USAN]
asparaginase [SY]
Erwinia L-asparaginase [SY]
L-Asparaginase [SY]
L-asparagine aminohydrolase [SY]
E.C. 3.5.1.1 [EC]
NDC 57902-249-01 [NDC]
molecular weight (kDa) = 133
FDA Class: Drug NDA
Year of approval (FDA) = 2011
Date of 1st FDA approval = 20111109
(in format YYYYMMDD)
Index Terms:
bacterial culture <!-- bacterialculture -->
biopharmaceutical products
enzymes
CTH
Erwinia chrysanthemi
Erwinia chrysanthemi
dextrose
lyophilized (freeze-dried)
sodium chloride
Factor XIII
orphan status
PrefGel
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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