Data Show Encouraging Results for a Potential New Front-Line Treatment
Approach in AML
CAMBRIDGE, Mass., June 2 /PRNewswire-FirstCall/ -- Genzyme Corp. (Nasdaq: GENZ) reported preliminary data today from a fully-enrolled pivotal, phase 2 study examining the safety and effectiveness of Clolar(R) (clofarabine) as a single agent in previously untreated, older adult patients with acute myelogenous leukemia (AML) who are unlikely to benefit from conventional "7+3" anthracycline plus cytarabine-based induction chemotherapy.
Results from the CLASSIC-II clinical trial show that patients with unfavorable prognostic factors who received single agent clofarabine exhibited a 45 percent overall remission rate based on investigator assessment, with manageable treatment-related side effects. Importantly, the 30 day all-cause mortality, one of the secondary endpoints in this study, was only 9.6 percent, which compares favorably to existing treatment options. Data from the study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
"The therapeutic outcomes for older AML patients have not improved in the past thirty years," stated Mark J. Enyedy, president of Genzyme Oncology, a business unit of Genzyme Corporation. "These data highlight the potential of clofarabine to become an innovative and much needed treatment option for these patients. We look forward to submitting a supplemental new drug application in the United States later this year to expand the current product label into front-line therapy for adult AML and to make a similar filing in Europe around this same time."
As reported at ASCO, investigator-assessed response data show a 45 percent overall remission rate among patients treated with single agent clofarabine, with 40 percent of patients achieving a complete remission to therapy and 5 percent attaining a complete remission with incomplete platelet recovery. Overall remission in this study is defined as a patient achieving either complete remission or complete remission with incomplete platelet recovery. Secondary endpoints include duration of remission, disease free survival, overall survival, safety and thirty-day mortality. The CLASSIC II study data are based on clinical responses from 115 patients at 20 sites in the U.S.
Data also show overall remission rates of 50 percent among patients with prior blood disorders; 43 percent in patients with adverse cytogenetics; 40 percent in patients 70 years of age and older; and 38 percent in patients with an ECOG performance status of 2. Remission rates in patients with up to three pre-defined risk factors required for study enrollment also exceeded 40 percent.
The study also demonstrated that the toxicity profile of clofarabine was predictable and manageable. Drug-related adverse events occurring in more than 15 percent of patients included nausea, febrile neutropenia, vomiting, diarrhea and rash; most were grade 1 or 2. As expected, Grade 4 neutropenia and thrombocytopenia occurred in a majority of patients. Only five of 115 patients discontinued treatment due to an adverse event or toxicity precluding further therapy. The study has completed enrollment and patients are being followed for remission duration, disease-free survival and overall survival. An independent panel of hematologists and hematopathologists are confirming the investigators' assessment of responses.
"In addition to the excellent overall safety and efficacy findings we are observing with single agent clofarabine, we also see impressive responses in older patients with poor prognostic cytogenetic abnormalities when treated with the drug," stated Harry P. Erba, MD, Ph.D., University of Michigan, one of the co-principal investigators for this study. "This study helps to define a new approach to treatment for patients unlikely to benefit from conventional 7+3 induction chemotherapy and provides support for the importance of assessing cytogenetics prior to induction treatment."
"The positive results seen in this study provide a compelling case for a novel, effective, therapeutic option for older adult patients with AML who have multiple unfavorable prognostic factors," added Hagop Kantarjian, M.D. MD Anderson Cancer Center and the other co-principal investigator for the CLASSIC II study. "In our published research from MD Anderson, older AML patients with one to three unfavorable prognostic factors are at risk of lower complete remission rates and higher 60-day mortality. We look forward to analyzing the final independently-assessed study results, particularly the remission duration data, for this very difficult-to-treat population."
In addition to presentation at ASCO, a podium appearance of the preliminary CLASSIC-II data also will be delivered by Dr. Erba at the upcoming European Hematology Association meeting in Copenhagen, Denmark on Sunday, June 15.
Patients in the CLASSIC-II study must have previously untreated AML, be 60 years or older and be unlikely to benefit from conventional induction chemotherapy based on the presence of at least one of the following adverse prognostic factors: age greater than or equal to 70, pre-existing hematological disorder such as myelodysplastic syndrome (MDS), poor health performance, or intermediate or unfavorable cytogenetics. Patients also had to be previously untreated and unlikely to benefit from conventional induction chemotherapy (7+3 anthracycline plus cytarabine) based on the presence of at least one of these poor prognostic factors at baseline.
Patients received an induction cycle of intravenous clofarabine administered as 30mg/m2 per day for five consecutive days then, based on their response, received up to five additional cycles of treatment at a dose of 20 mg/m2 per day for five consecutive days.
Significant Unmet Medical Need
The CLASSIC II study is designed to address a high unmet medical need among older AML patients who currently have limited treatment options. According to the American Cancer Society, each year approximately 6,500 people over the age of 60 are diagnosed with AML in the U.S. The median survival for those receiving therapy can vary from one to thirteen months, and the five-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 unfavorable (adverse) cytogenetics and pre-existing blood disorders such as MDS that result in lower response rates and worse treatment outcomes to conventional induction chemotherapy compared with younger patients. In addition, conventional induction chemotherapy is poorly tolerated in older patients with unfavorable risk factors, and early induction mortality usually ranges from 10-30 percent but can exceed 30 percent in older patients with a poor performance status.
This study builds on promising results from two prior studies of single agent clofarabine in previously untreated older patients with AML deemed unfit for chemotherapy, based mostly on poor performance status and presence of co-morbid illnesses. These studies were conducted by Alan Burnett, M.D., of Cardiff University in the United Kingdom and presented at earlier American Society of Hematology meetings.
Clolar Clinical Development
A separate, phase 3 pivotal study (CLASSIC I) of clofarabine in relapsed adult AML patients aged 55 and older and previously treated with at least one, but not more than two, prior induction regimens is underway. This randomized, double-blind, placebo-controlled study will compare the combination of clofarabine and cytarabine (Ara-C) to cytarabine alone.
A second phase 3 study of clofarabine sponsored by the Eastern Cooperative Oncology Group is expected to begin enrolling patients next year. This study will compare single agent clofarabine to conventional induction chemotherapy in untreated AML patients age 60 and older who are considered suitable for conventional induction chemotherapy.
Clolar is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory ALL after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.
Genzyme also is actively exploring additional therapeutic indications for Clolar, including in MDS.
Genzyme Hosts Investor Call Tomorrow Morning
Genzyme will host an investor call tomorrow morning, Tuesday, June 3 at 10 a.m. EST. The preliminary data from the CLASSIC-II pivotal study will be reviewed and there will be opportunity for investors to ask questions of Genzyme.
To participate in the call, please dial 1-888-982-7287 in the U.S. or 1-210-234-0251 outside of the U.S. The participant passcode is "Genzyme."
A replay of this call will be available by dialing 1-800-695-3397. This call will also be available live on the investor events section of http://www.genzyme.com. Replays of the call will be available until 10:59 p.m. on June 10, 2008.
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, and organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome.
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. Cardiac disorders, including tachycardia, pericardial effusion, and left ventricular systolic dysfunction, have been noted in up to 35% of pediatric patients treated with Clolar. However, the presence of these disorders in patients prior to Clolar administration and/or previous therapy or concurrent illness in patients receiving Clolar makes the etiology of these disorders unclear.
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 http://www.CLOLAR.com.
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 diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as immune disease, cardiovascular disease, and other areas of unmet medical need.
This press release contains forward-looking statements, including statements regarding the potential administration, dosing and therapeutic benefit of Clolar in various cancer indications; the expected results of the data generated from the Clolar clinical trials; and the requirements and plans for regulatory filings and approvals for Clolar in additional indications. These risks and uncertainties include, among others, the timing of discussions with the FDA regarding clinical studies and approval of Clolar in additional indications; the timing and content of decisions by the FDA related to clinical trials and approval of Clolar in additional indications; the actual efficacy and safety of Clolar for the indications in which it is being tested; 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 March 31, 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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