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Rasburicase Approved for the Management of Plasma Uric Acid Levels in Adults with Leukememia

Bridgewater, NJ – October 16, 2009 – Sanofi-aventis U.S. announced that the U.S. Food and Drug Administration (FDA) has granted marketing approval for rasburicase (Elitek) to be used 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.

Today’s FDA approval was based on pivotal Phase 3 trial results which demonstrated that Elitek significantly reduced PUA levels when compared to the current standard of care (oral allopurinol) in adults with hematologic cancers at risk for the potentially life-threatening complication of TLS. Patients considered at high risk for TLS either had an elevated level of PUA (hyperuricemia) due to a malignancy, or were diagnosed with a very aggressive hematologic malignancy (leukemia or lymphoma).

“The approval of Elitek in adult patients with cancer now provides physicians with an important new option for managing elevated plasma uric acid which could result in tumor lysis syndrome, a potentially life-threatening complication that can develop from anti-cancer therapy,” said principal investigator Dr. Jorge Cortes, Professor of Medicine and Deputy Chair, Department of Leukemia at The University of Texas, M.D. Anderson Cancer Center, in Houston, Texas.

Clinical TLS was defined by changes in at least two or more laboratory parameters, namely hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia, along with at least one of the following clinical events occurring within 7 days of treatment: renal failure/injury, need for dialysis, and/or serum creatinine increase greater than 1.5 x ULN, arrhythmia or seizure (according to the Cairo-Bishop criteria).

“We are very proud that Elitek – which has already been shown to bring significant treatment benefits to pediatric patients at risk of developing this complication – has now been approved by the U.S. Food and Drug Administration to help adult patients as well,” said Dr. Paul Chew, Senior Vice President, U.S. Chief Science Officer/Chief Medical Officer of sanofi-aventis U.S. “This approval is also an example of sanofi-aventis’ commitment to further exploring our existing compounds and the potential benefit they bring to patients with serious diseases, such as in the areas of oncology and hematology.”

Study Background
The primary objective of the multi-center, open-label, randomized, parallel group comparative study was to compare the safety and the effectiveness of three treatments (intravenous Elitek (rasburicase) alone daily for 5 days, intravenous Elitek daily for day 1 to day 3 followed by oral allopurinol daily for day 3 to day 5, and oral allopurinol alone daily for 5 days) in achieving uric acid response rate. The daily dose of Elitek was 0.20 mg/kg, while that of allopurinol was 300 mg. The PUA response rate was defined as the proportion of patients with PUA levels less than or equal to 7.5 mg/dL from day 3 to day 7 after initiation of treatment.

Results showed that among patients treated with Elitek alone or followed by oral allopurinol, uric acid levels were less than or equal to 2.0 mg/dL in 96% of patients (at 4 hours of the day 1 dose). There were no patients in either Elitek group with documented failure to control uric acid. In patients treated with Elitek alone (n=92), the PUA response rate was 87%, which was higher than that seen with patients treated with oral allopurinol alone (n=91) at 66% (p=0.0009), a statistically significant difference, or those treated with the Elitek/oral allopurinol combination (n=92) at 78%. The Elitek versus Elitek/oral allopurinol combination difference in PUA response rate was not statistically significant.

Antihyperuricemic treatment was extended beyond five days in 4.4% of patients treated with oral allopurinol alone and 6.5% of patients treated with the Elitek/oral allopurinol combination, versus 0% of patients receiving Elitek alone. Clinical TLS occurred in 3% of Elitek-treated patients, 3% of Elitek/oral allopurinol-treated patients, and 4% of oral allopurinol-treated patients.

Hypersensitivity reactions occurred in 4.3% of patients treated with Elitek alone and 1.1% of patients treated with the Elitek/oral allopurinol combination. Hypersensitivity reactions included arthralgia, injection site irritation, peripheral edema, and rash. The most common Grade 3/4 related adverse reactions regardless of relationship to study drug were sepsis (5.4%/6.5%/4.4%), hypophosphatemia (4.3%/6.5%/6.6%), anxiety (3.3%/0%/0%), abdominal pain (3.3%/4.3%/2.2%), hyperbilirubinemia (3.3%/2.2%/4.4%) and increased alanine aminotransferase (3.3%/4.3%/2.2%) in the Elitek, Elitek/oral allopurinol and oral allopurinol arms, respectively. Of note, all patients were receiving anti-cancer chemotherapy and/or biologic anti-cancer agents for their primary disease. The following serious adverse reactions occurred with a difference in incidence of greater than or equal to 2% in patients receiving Elitek compared to patients receiving oral allopurinol: pulmonary hemorrhage, respiratory failure, supraventricular arrhythmias, ischemic coronary artery disorders, and abdominal and gastrointestinal infections.

Based on the results of the above study, Elitek is now indicated at a daily dose of 0.20 mg/kg intravenously for up to 5 days for the initial management of plasma uric acid levels in adults with leukemia, lymphoma and solid tumors receiving anti-cancer therapy expected to result in tumor lysis syndrome and subsequent elevation of plasma uric acid.

About Elitek
A recombinant urate oxidase enzyme, Elitek is the first recombinant uricolytic agent approved in the U.S. to maintain PUA levels in patients receiving anti-cancer therapy. Elitek rapidly catabolizes circulating uric acid into allantoin, a highly soluble by-product that is easily excreted by the kidneys. Elitek reduces circulating uric acid levels as soon as 4 hours after the first dose. Elitek was initially approved by the U.S. FDA in 2002 to manage PUA levels in pediatric patients receiving anti-cancer treatment and at risk for TLS. Visit www.elitekinfo.com for more information about Elitek.

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