Status: approved; marketed

Organizations involved:

Sanofi Aventis S.A. — R&D; Tech.; Intl. mark.; Parent

Sanofi Aventis Pharmaceuticals, Inc. – USA mark.

Sanofi-Synthelabo, Inc. — R&D; Tech.; Former

GlaxoSmithKline (GSK) – Manuf.

Washington Research Foundation (WRF) – Tech.

University of Washington – Tech.

Genentech, Inc. – Tech.

Cross ref.: See the entry below for Puricase, a pegylated rasburicase product.

Description: Rasburicase (Elitek) is a lyophilized (freeze-dried) formulation of recombinant urate oxidase (uricase; urate oxygen oxidoreductase; EC 1.7.3.3) enzyme expressed by transformed Saccharomyces cerevisiae (yeast). The cDNA coding for rasburicase was cloned from a strain of the fungus Aspergillus flavus.

Urate oxidase catalyzes the enzymatic oxidation of uric acid into allantoin, an inactive and soluble metabolite. Urate oxidase is a tetramer enzyme composed of four identical units with a molecular weight of 34,152 Dalton (34.15 kDa), with an empirical formula of C1523H2383N417O462S7. Each monomer unit, formed from a single polypeptide chain containing 301 amino acids, is acetylated at the N-terminal end and does not have intra- or inter-disulfide bridges.

Elitek is used for the prevention and management of malignancy treatment-associated hyperuricemia or excess levels of uric acid (associated with tumor lysis syndrome). Pediatric and other patients receiving chemotherapy for hematological cancers may develop acute tumor lysis syndrome (TLS), involving excess purines and uric acid levels in the blood resulting from the lysis of tumors. TLS may be most acute after starting chemotherapy. Acute hyperuricemia can result in acute renal failure.

Elitek is supplied in a 3 mL glass vial containing 1.5 mg lyophilized rasburicase powder, 10.6 mg mannitol, 15.9 mg L-alanine, and between 12.6 and 14.3 mg of dibasic sodium phosphate. A 2 ml vial of solvent composed of 1.0 mL sterile Water for Injection, USP, and 1.0 mg Poloxamer 188 (a block copolymer of ethylene oxide and of propylene oxide) is provided for reconstitution. Elitek and diluent should be stored at 2-8˚C (refrigerated). The dating period for rasburicase is 36 months from the date of manufacture when stored at 2-8°C. The date of manufacture is the date of final sterile filtration of the formulated drug product. Elitek is exempt from lot release requuirements.

Nomenclature: urate oxidase, rDNA [BIO]; Elitek [TR]; rasburicase [FDA USAN]; re-Uox [SY]; Uox [SY]; uric acid oxidase, recombinant [SY]; urate oxygen oxidoreductase [SY]; SR29142 [SY]; Fasturtec [TR in Europe]; E.C. 1.7.3.3 [Enzyme Comm.]; NDC 0024-5150-10 and NDC 0024-5151-75 [NDC]

Biological.: Urate oxidase catalyzes the enzymatic oxidation of uric acid to allantoin, an inactive and soluble metabolite. This enzyme exists in most primates, birds, most insects, and a few reptiles. Uric acid is the end product of purine catabolism in higher primates and humans, and can accumulate to toxic levels (hyperuricemia). Purines, e.g., adenine and guanine, result from the catabolism of nucleic acids. Purines are first broken down to hypoxanthine; and xanthine oxidase converts hypoxanthine to xanthine, and xanthine to uric acid, which is then is removed from the blood by the kidneys and excreted in the urine. Allantoin, which results from urate oxidase action on uric acid, is 5–10 times more soluble than uric acid and is more readily eliminated in the urine via the kidneys than uric acid.

Humans lack uricase and do not produce allantonin. This is the result of a mutation that introduces a premature termination codon in the coding sequence of the human uricase gene. Purine catabolism in humans terminates with the production of uric acid which is relatively insoluble (the solubility index in distilled water is 13.2 mg/dl) making humans susceptible to a pathological condition known as hyperuricemia. Renal handling of uric acid is complex and requires glomerular filtration, reabsorption of filtered urate, tubular secretion, and postsecretory reabsorption.

Biological.: Urate oxidase was first purified in 1968 from cultures of the fungus Aspergillus flavus. Enzyme derived from fermentation of A. flavus has been marketed as Uricozyme by Sanofi-Synthelabo in France since 1975 and in Italy since 1984. A U.S. clinical trial with Uricozyme was reported in 1997. However, Uricozyme’s complex manufacturing process and other factors have limited the product’s availability and approvals in additional countries. Urate oxidase from culture of A. flavus is difficult to obtain in high purity and yields. A. flavus is also liable to produce highly toxic aflatoxins, which can be difficult to separate off. Uricozyme has a specific urate oxidase activity of about 8 U/mg. Urate oxidase was first reported as cloned by Sanofi in E. coli, A. flavus and S. cerevisiae in 1992 (e.g., see Leplatois P., et al., Gene,122, 139-145).

Companies.: Urate oxidase was originally developed by Sanofi-Synthelabo, Inc. (subsidiary of Sanofi-Synthelabo S.A., Sanofi Aventis S.A.), CBER/FDA est. no. 1294.Elitek is manufactured by GlaxoSmithKline (GSK) at facilities in 76960 Notre-Dame de Bondeville, France. Sanofi Aventis Pharmaceuticals, Inc. markets Elitek in the U.S., and its parent, Sanofi Aventis S.A., markets it internationally.

Manufacture: Rasburicase is manufactured using convention recombinant yeast culture/fermentation methods.

FDA class: Biologic BLA

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 20020712; BLA (BL 103946/0); orphan designation (granted 10/11/2000, expired 7/12/2009)

Date = 20091009; supplemental BLA; Indication = for the initial management of plasma uric acid (PUA) levels in adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis syndrome (TLS) and subsequent elevations of plasma uric acid

Indications: [excerpt from the "Indications and Usage” section of the product insert/labeling]:

Elitek is a recombinant urate-oxidase indicated for initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.

Limitation of use: Elitek is indicated only for a single course of treatment Status: With its FDA approval, Elitek was exempted from CBER/FDA lot release inspection requirements.

European Union approval was granted in March 2001 for use in patients with hematologic malignant disease with bulky syndrome and high risk of tumor lysis syndrome at chemotherapy initiation..

Elitek is now marketed throughout Europe and the U.S., and it is being made available in Australia, Asia and Latin America.

Tech. transfer: Patents assigned to Sanofi covering aspects of rasburicase include U.S. 5,541,098, "Urate oxidase activity protein, recombinant gene coding therefor, expression vector, micro-organisms and transformed cells,"expiring Jul 30, 2013, concerning recombinant forms of urate oxidase; and 5,811,096. "Stable liquid composition containing urate oxidase and lyophilized composition for its preparation," expiring May 10, 2016, concerning stable aqueous formulations, including the use of Poloxamer 188. These patents are assigned to Sanofi.

EP0408461, "Protein with urate oxidase activity, recombinant gene coding therefor, expression vector, micro-organisms and transformed cells," expired in 2010. EP0742013, "Stable liquid composition containing urate oxidase and lyophilized composition for its preparation," expires in 2016.

Yeast expression technology developed by the Univ. of Washington and Genentech was nonexclusively licensed from the Washington Research Foundation (WRF; acting as patent agent for the university and Genentech). Related patents include U.S. 5,618,676 and continuations, 5,854,018 and 5,856,123, concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. All three U.S. patents expire in 2014. The newer patents are broader, as they claim processes and materials for expression of proteins in recombinant yeast systems generally. WRF is the exclusive licensing agent for this family of yeast expression patents. The issued patents, particularly the more recently issued patents, broadly claim processes and materials for expression of proteins in yeast.

Medical: Elitek is administered an infusion immediately prior to and during the initiation of chemotherapy for hematological malignancies. Administration leads to a rapid decline in uric acid levels, which may protect against renal failure. It is generally well tolerated, with the commonest side effects including fever, nausea, vomiting and rash. Rasburicase is significantly more expensive than allopurinol. However, cost savings may result from a decreased incidence of renal impairment requiring dialysis. It may be particularly useful in patients with high grade tumours with a high proliferation index who are at risk of significant tumour lysis syndrome.

Elitek is indicated only for a single course of treatment.

Elitek is used for prophylaxis and treatment of acute hyperuricemia associated with initial chemotherapy for hematological malignancies, e.g., lymphoid leukemia (B and T cell), non-Hodgkin’s lymphoma (including Burkitt’s lymphoma) and acute myelogenous leukemia (AML). The rapid increase of uric acid plasma levels is a major consequence of tumor lysis syndrome (TLS). This frequently occurs with hematological malignancies in children with chemosensitive tumors at the initiation of chemotherapy. The major risk from TLS is acute renal failure caused by precipitation of uric acid crystals in the kidneys. This is severe and sometimes life-threatenin, and generally requires treatment with kidney dialysis. Early administration of Elitek rapidly converts poorly soluble uric acid into highly soluble allantoin, which is readily excreted by the kidneys, preventing accumulation of excess uric acid.

The recommended dose and schedule of Elitek is 0.15 or 0.20 mg/kg as a single daily infusion over 30 minutes for 5 days. The 18 hour in vivo half-life of rasburicase necessitates daily infusion. After reconstitution with supplied diluent, it is further diluted with 50 mL sterile normal saline solution. Chemotherapy may be initiated 4 to 24 hours after the first dose of Elitek. Rasburicase has a rapid onset of action, resulting in decreases in uric acid plasma levels within two to four hours. This enables rapid initiation of chemotherapy and avoids or reduces chemotherapy delays. Overall elimination half-life is 18 hours.

Elitek treatment allows chemotherapy to be delivered without delays and prevents hyperuricemia-related complications, including renal compromise. The main side effect of Elitek is the potential for a hypersensitivity reaction. This occurred in about 5% of Uricozyme recipients, but occurs at a much lower rate in Elitek recipients.

Disease: Hyperuricemia is defined as occurring when the serum level of uric acid is above 8 mg/dl. Hyperuricemia can result in the formation of uric acid crystals in the serum, which can precipitate in joints, skin and kidneys. This can result in inflammation of the joints (gout), renal failure, metabolic acidosis, and hyperkalemia. Overproduction of uric acid can have a variety of origins, including congenital metabolic defects, Lesch-Nyhan syndrome, excess ingestion of purine or proteins, and treatments with uricosuric drugs. Hyperuricemia is also found in patients that have had heart or kidney transplants and are being treated with immunosupressive agents. Hyperuricemia can lead to the loss of kidney function in these patients and can produce significant morbidity and mortality.

Hyperuricemia is also found in patients with malignant diseases. Chemotherapy and radiation therapy of cancer patients can induce a life-threatening condition known as tumor lysis syndrome. Hematologic malignancies, such as leukemias and lymphomas, are responsible for most cases of tumor lysis syndrome (TLS), characterized by the rapid development of hyperuricemia, hyperkalemia, hyperphosphatemia, and acute renal failure. Acute renal failure is the result of the intrarenal precipitation of uric acid. Tumor lysis syndrome is often triggered by cell death induced by chemotherapy or radiotherapy, resulting in the release of intracellular substances. However, occasionally cancer patients with a heavy tumor burden may exhibit hyperuricemia and other features of tumor lysis syndrome even in the absence of radiotherapy or chemotherapy because of the high turnover of malignant cells with subsequent catabolism of released purines into uric acid.

Uricase has been shown to be an effective treatment for hyperuricemia and tumor lysis syndrome. Treatment with uricase converts uric acid into the highly soluble allantoin. Uricase, if adequately filtered into the urine, may even dissolve already precipitated uric acid crystals and improve renal function. Uricase has a number of advantages in the treatment of hyperuricemia and nephrolithiasis including the speed of the hypouricemic effect (reduction of hyperuricemia of the order of 50% in less than 24 h) and better protection of the kidney against lithiasis compared with other drugs such as allopurinol.

Therapy for the prevention and treatment of the acute renal failure associated with tumor lysis syndrome is a considerable challenge and is currently unsatisfactory for a number of reasons. Methods of treating hyperuricemia include hydration, urinary alkalinization, osmotic diuresis and allopurinol therapy. However, the difficulty in the treatment of hyperuricemia lies in the potential for aggravating other consequences of tumor lysis syndrome. For example, alkalinization of urine to increase uric acid solubility facilitates precipitation of calcium phosphate.

Allopurinol (4-hydroxypurinol), an analog of xanthine, has long been the standard treatment for hyperuricemia and also for the prevention of tumor lysis syndrome. Allopurinol is converted to oxypurinol, which then binds to and inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine and xanthine to uric acid. As a result, uric acid production is inhibited, and xanthine and hypoxanthine concentrations increase. However, allopurinol does not remove uric acid that is already present and deposited intrarenally as crystals. As a result, it is often several days (sometimes 10-14 days) from the initial treatment with allopurinol before a significant decrease in uric acid in serum can be observed. While the solubilities of xanthine and hypoxanthine are only slightly greater than that of uric acid, the purines are catabolized to xanthine, hypoxanthine, and uric acid during allopurinol treatment, rather than mostly to uric acid. The result is that the urinary concentration of uric acid decreases below its solubility and further formation of uric acid crytstals is prevented. However, during excessive catabolism of purines, allopurinol therapy may lead to intrarenal precipitation of hypoxanthine and xanthine, with further aggravation of acute renal failure. This situation has been well documented in clinical practice. Allopurinol therapy is also associated with significant toxicity and can cause death. Its severe toxic effects include cutaneous hypersensitivity reactions, leukopenia, and hepatomegaly. Although allopurinol can block the formation of uric acid, it does little to solubilize the uric acid which is already present.

The risk posed by uric acid accumulation is particularly significant when treating certain pediatric cancers, whose prognosis is often favorable. Fasturtec/Elitek has therefore been studied in children with cancer.

Market: Sanofi-Sythelabo, upon FDA approval, projected that “Worldwide sales of Fasturtec/Elitek should reach EUR 100 million in 2005.” The author’s rough guess (with no substantive information to work from) for total 2006 sales is in the range of $100 million.

The 2007 Average Wholesale Price (AWP) is $1,502.68 for 3 1.5 mg vials; and $2,504.47/75 mg vial (Red Book, 2007).

Competition: Uricozyme, containing uricase obtained from culture of Aspergillus flavus fungi, was previously manufactured and marketed by Sanofi-Synthelabo, now Sanofi Aventis. Elitek has replaced this product in all countries, except perhaps for France and Italy where the medical literature still discusses it as being available. Because of the foreign nature of the Aspergillus enzyme, therapy is often limited to a single dose due to the risk of hypersensitivity reactions in about 4.5% of patients. Recombinant A. flavus-based uricase (Elitek) is associated with a lower incidence of hypersensitivity reactions than the non-recombinant product. Besides potential immunogenicity and toxicity, a factor preventing general application of naturally-derived uricase in hyperuricemia is the complicated manufacturing process of the enzyme involving fermentation, extraction, and purification, as well as the standardization of enzyme activity. Aspergillus flavus, used for Elitek manufacture, is not easy to work with because of its physiology and genetics, making it difficult to obtain strains that can produce substantial amounts of the enzyme. A. flavus can also produce aflatoxins, which can be difficult to remove during the purification process. The purified uricase must be checked to ensure that it is free from these toxins