Genzyme Seeks U.S. Approval for Clolar® to Treat Adult AML



CAMBRIDGE, Mass.--(BUSINESS WIRE)--Genzyme Corporation (Nasdaq: GENZ) announced today that it has filed a supplemental New Drug Application with the U.S. Food and Drug Administration for the use of Clolar® (clofarabine) to treat adult patients with acute myeloid leukemia (AML). The company has requested priority review of its application and, if granted, Clolar could be approved for this indication in the first half of 2009.

Clolar is currently approved in the United States and Europe for the treatment of acute lymphoblastic leukemia (ALL) in relapsed and refractory pediatric patients one to 21 years old who have received at least two prior treatments, and it is now a standard of care in this setting. Genzyme is developing clofarabine globally for the treatment of adult AML, earlier-line pediatric ALL, and myelodysplastic syndromes (MDS), broader indications that the company estimates could drive peak annual sales of the product to approximately $600 million.

“Clolar has an important role in the treatment of pediatric leukemia and has great potential to help a broader set of patients with hematological disorders,” said Beth Trehu, M.D., vice president and general manager for Clofarabine. “We are committed to fulfilling the potential of this product by expanding its indications and securing approvals globally.”

Supplemental NDA filing

AML is a cancer characterized by the rapid proliferation of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. The condition is the most common acute leukemia affecting adults.

Genzyme’s supplemental NDA seeks approval for Clolar’s use as a single agent in previously untreated adults aged 60 years or older with AML who have at least one unfavorable prognostic factor. Many older AML patients with unfavorable prognostic indicators currently have poor outcomes using available induction chemotherapy. Clolar, if approved, would fulfill an unmet need for this difficult to treat patient population. Approximately 30 percent of older adult patients with AML receive any form of chemotherapy.

According to the American Cancer Society, in 2008 approximately 13,290 people will be diagnosed with acute myeloid leukemia (AML) in the United States, and most AML patients will be adults. The median age of a patient with AML is about 67 years.

The median survival for those patients receiving the current available induction chemotherapy—which is associated with high mortality—can vary from 1 to 13 months, and the 5-year survival rate over the past three decades remains at less than 10 to 15 percent. Older AML patients often have disease features such as an adverse cytogenetics profile or pre-existing blood disorders such as MDS that result in lower response rates and worse treatment outcomes compared to younger patients treated with conventional combination chemotherapy. In addition, current therapies are poorly tolerated in older patients with unfavorable risk factors, such as advanced age and poor performance status.

Genzyme will use the results of the CLASSIC II study to support its label expansion filing. This large Phase 2 clinical trial demonstrated that patients with at least one pre-specified unfavorable prognostic factor who received single agent Clolar achieved a 45 percent overall remission rate, including a 40 percent complete remission rate and a 5 percent complete remission rate with incomplete platelet recovery. These data were presented in June at the American Society of Clinical Oncology meeting. Updated data will be presented in December at the American Society of Hematology (ASH) meeting in San Francisco.

Importantly, the 30 day all-cause mortality, one of the study’s secondary endpoints, was 9.6 percent, which compares favorably to conventional induction chemotherapy, known as the “7 + 3” regimen, where the 30 day induction mortality ranges from 10-30 percent up to 50-80 percent with increasing age and worsening performance status.

These patients had manageable treatment-related side effects. The most commonly occurring adverse reactions included nausea, febrile neutropenia, vomiting, diarrhea, rash, increased alanine aminotransferase, increased aspartate aminotransferase, fatigue, pneumonia, fever, headache, neutropenia, anorexia, mucosal inflammation, pruritus, and thrombocytopenia.

“The therapeutic outcomes for older AML patients have not improved in the past 30 years,” said Michael Vasconcelles, M.D., group vice president, Oncology Clinical Research. “These data highlight the potential of clofarabine to become an innovative and much needed treatment option for this group.”

Updated CLASSIC II trial data from the independent response review panel, including disease free survival, will be presented next month in an oral presentation at the ASH annual meeting by Harry P. Erba, M.D., Ph.D., of the University of Michigan, a co-principal study investigator along with Hagop Kantarjian, M.D., of the University of Texas M.D. Anderson Cancer Center.

Product Expansion

Genzyme is working to expand clofarabine’s availability worldwide. In Europe, where Clolar is sold under the trade name Evoltra® and where the incidence of adult AML is similar to that of the U.S., Genzyme anticipates filing for an expanded label in adult AML in 2009. Genzyme’s European filing will include the CLASSIC II study as well as longer-term follow-up data. Genzyme is seeking approval for pediatric ALL and will seek approval for Clolar in adult AML in multiple countries throughout the world where the company has built an infrastructure base in the Hematology market through other products such as Thymoglobulin.

Clolar is also being evaluated in Phase 3 clinical trials to test its single agent efficacy and safety as a front-line therapy in adult AML, as well as in combination therapy for newly diagnosed and relapsed patients. Three Phase 2 study abstracts (#964,1936, and 2964) with Clolar in relapsed/refractory AML patients will be presented at ASH.

Genzyme is also pursuing indications for MDS, a group of conditions caused by abnormal blood-forming cells of the bone marrow. About 30 percent of MDS cases progress into acute myeloid leukemia. MDS incidence ranges from 12,000 to 20,000 cases per year in the U.S. and Europe. About 80 to 90 percent of MDS patients are older than 60 years of age. Genzyme is currently conducting MDS trials with an oral formulation of clofarabine to confirm the optimal dose and schedule, and is supporting other MDS cancer trials. An oral presentation (#222) of the MDS study results will be given at ASH.

In the pediatric setting, there are several ongoing studies exploring the usage of Clolar as combination therapy in relapsed/refractory ALL patients and in earlier lines of therapy. In the United States, the average incidence of ALL in pediatric patients is roughly 3,000 cases per year, and in the EU it is nearly 2,000. An abstract (#2925) on a Phase 1 and 2 trial using Clolar in combination in patients with relapsed/refractory acute leukemia will be presented at ASH.

About Clolar

Clolar has Orphan Drug designation for adult and pediatric ALL, and seven years of market exclusivity in the United States for relapsed/refractory pediatric ALL. The FDA also granted six months of extended market exclusivity to Clolar under the Best Pharmaceuticals for Children Act.

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis.

Administration of Clolar results in a rapid reduction of peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome, or organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

The most common side effects seen after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection.

Liver and kidney function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and Clolar is excreted primarily through the kidneys. Concomitant use of medications known to induce hepatic toxicity should be avoided.

Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breast feeding while receiving treatment with Clolar.

For more information about Clolar, please call 1-800-RX CLOLAR or visit www.CLOLAR.com.

About Genzyme

One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 10,000 employees in locations spanning the globe and 2007 revenues of $3.8 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honor awarded by the President of the United States for technological innovation.

With many established products and services helping patients in nearly 90 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.

This press release contains forward-looking statements regarding Genzyme’s future business plans and strategies, including statements regarding: the potential for receipt of U.S. marketing approval for Clolar for treatment of adult AML in the first half of 2009; Genzyme’s assessment of the sales potential for Clolar in AML and MDS; plans to expand the approved indications for Clolar and secure global approvals for the product; plans to file for an expanded label in adult AML in the EU in 2009 and the expected timing for receipt of approval; and planned presentations of several Clolar trials at the upcoming ASH meeting. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially. These risks and uncertainties include, among others: the timing and outcome of discussions with the FDA and EMEA regarding approval of Clolar in adult AML; the actual safety and efficacy of Clolar for the indications in which it is being tested, including MDS; Genzyme’s ability to secure global approvals for adult AML and MDS; and the risks and uncertainties described in reports filed by Genzyme with the U.S. Securities and Exchange Commission, including without limitation the factors discussed under the caption "Risk Factors" in Genzyme's Quarterly Report on Form 10-Q for the quarter ended September 30, 2008. We caution investors not to place undue reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and we undertake no obligation to update or revise the statements.

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