Phase III Trial Results Show Elitek (rasburicase) Significantly Reduced Plasma Uric Acid Levels versus Allopurinol in Adults with Hematologic Cancers at Risk for Tumor Lysis Syndrome

SAN FRANCISCO, December 06, 2008 /PRNewswire-FirstCall/ -- Sanofi-aventis today announced results of a randomized phase III study presented at the 50th Annual Meeting of the American Society of Hematology. The study in adult patients with hematological malignancies at high or potential risk for tumor lysis syndrome (TLS) demonstrated that Elitek(R) (rasburicase) significantly reduced plasma uric acid (PUA) levels compared to allopurinol alone (p=0.0012). The study also compared a sequential combination of the two agents (Elitek for three days followed by allopurinol for three days, with one day overlap) versus allopurinol alone, which showed a reduction in plasma uric acid levels for the sequential combination versus allopurinol alone (p=0.06).

Tumor lysis syndrome is a potentially life-threatening metabolic complication that can result either spontaneously or following treatment of certain types of rapid-growing cancers, particularly leukemia or lymphoma. The syndrome develops when a particularly large volume of cells associated with fast growing tumors are destroyed, releasing cellular by-products into the blood system such as uric acid, faster than can be eliminated. Elevated levels of plasma uric acid can cause hyperuricemia, a serious condition that can lead to renal failure if not controlled.

The primary objective of the multi-center, open-label, randomized, parallel group comparative study was to compare the adequacy of control of PUA concentration and the safety profile in three treatment arms. Among the three treatment arms, plasma uric acid response rate (defined as normalization or maintenance of PUA levels less than or equal to 7.5mg/dl at days 3-7) was 87% of patients treated with Elitek compared to 66% receiving allopurinol alone (p=0.001) and 78% with Elitek/allopurinol (p=0.06). Among patients at high risk for tumor lysis syndrome, the PUA response rate was 89% with Elitek vs. 68% with allopurinol and 79% with the Elitek/allopurinol combination (p=0.0012). The PUA response rate among patients with baseline hyperuricemia defined as plasma uric acid >7.5mg/dL was 90% with Elitek versus 53% with allopurinol and 77% with Elitek/allopurinol (p=0.0151). The time to control, or normalize, PUA in hyperuricemic patients was 4.1 hours among patients treated with Elitek (n=18 [95% CI=4.0 to 4.5]), 4.1 hours with the Elitek/allopurinol combination (n=12 [95% CI=3.9 to 4.5) and 27.0 hours in the allopurinol alone arm (n=17 [95% CI=4.0 to 49.0]).

"In this investigational study, Elitek controlled plasma uric acid in a larger percentage of patients and in a shorter period of time than allopurinol, the current U.S. standard treatment in adults," said principal investigator Dr. Jorge Cortes, Professor of Medicine and Deputy Chair, Department of Leukemia at The , MD Anderson Cancer Center, in Houston, Texas.

In both Elitek groups, there was a 2% incidence of Grade 3/4 related events and <5% hypersensitivity or immuno-allergic reactions, 1% of which were Grade 3 or higher. The most common serious adverse reactions regardless of the relationship to the study drug were neutropenic sepsis (5.4% / 1.1% / 3.3%), neutropenic infection (5.4% / 4.3% / 8.8%), and febrile neutropenia (4.3% / 3.3% / 5.5%), pulmonary hemorrhage (1.1% / 3.3% / 0%), and respiratory failure (2.2% / 3.3% / 1.1%) in the Elitek, Elitek/allopurinol and allopurinol arms, respectively. Elitek treatment-related events were considered rarely serious, and less than or equal to 1% led to discontinuation of treatment. Investigators reported that there were no major differences in safety or tolerability between the three treatment arms, and that most adverse events were related to chemotherapy and/or the underlying disease.

These study results will form the basis for a supplemental new drug application submission to the U.S. Food and Drug Administration.

Patients received Elitek at a dosage of 0.20 mg/kg/day for five days (n=92), Elitek at the same dosage for three days plus allopurinol (300 mg/day) starting on the third day and continuing for another two days (n=92), or allopurinol (300 mg/day) for five days (n=91). Secondary objectives of the study were to evaluate among the three treatment arms the AUC (area under the curve) of plasma uric acid from baseline through 48 hours after the last planned anti-hyperuricemic treatment, the time to plasma uric acid control, safety (including immunogenicity) and pharmacokinetics.

Patients eligible to enter the study were at least 18 years old with Eastern Cooperative Oncology Group (ECOG) performance 0-3, a life expectancy of greater than three months and at either high or potential risk for TLS: High risk for TLS was defined as hyperuricemia from the cancer at baseline (plasma uric acid >7.5 mg/dL), very aggressive lymphoma/leukemia as defined by the Revised European-American Lymphoma (REAL) criteria, acute myeloid leukemia (AML), chronic myeloid leukemia (CML) in blast crisis, or high grade myelodysplastic syndrome (MDS) with >10% bone marrow involvement. Potential risk for TLS was defined as diagnosis of aggressive lymphoma/leukemia based on REAL classification plus one or more of the following criteria: LDH>2xULN (IU/I), Stage III-IV disease or Stage I-III disease with at least one lymph node/tumor >5 cm.

Visit www.elitek.com for more information about Elitek(R).

Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone. Sanofi-aventis is listed in Paris and in New York .

    Contact: Noelle Boyd, sanofi-aventis U.S., (908) 981-6489

CONTACT: Noelle Boyd, sanofi-aventis U.S., +1-908-981-6489

Web site: http://www.sanofi-aventis.us/

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Posted: December 2008

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