Genzyme Corporation announced that its supplemental New Drug Application for Clolar (clofarabine) will be discussed Tuesday, September 1 at a public meeting of the FDA's Oncologic Drugs Advisory Committee in Silver Spring, Maryland. The panel is expected to consider the clinical trial results Genzyme submitted to support the approval and labelling of Clolar to treat older adult patients with acute myeloid leukaemia (AML), the most common type of acute leukaemia in adults.

Clolar is currently approved for paediatric acute lymphoblastic leukaemia (ALL) patients who have relapsed or have refractory disease after at least two prior regimens.

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

Genzyme's supplemental NDA seeks approval for Clolar's use as a single agent in previously untreated adults aged 60 or older with AML who have at least one unfavourable prognostic risk factor. Many older AML patients with unfavourable prognostic factors currently have poor treatment outcomes using currently available therapies for initial induction therapy. Clinical studies to optimize therapeutic approaches with existing agents have not resulted in improved outcomes in older adults with AML during the last three decades. The last induction therapy for newly diagnosed AML patients was approved in 1990. If approved, Clolar would fulfil an unmet need for this difficult to treat patient population, a Genzyme release said.

"Most AML patients who are 60 years or older and have unfavourable prognostic factors do not receive conventional induction therapy because of the lower response rates and high treatment-related mortality," said Mark Enyedy, president of Genzyme Oncology and Multiple Sclerosis. "The clofarabine data in this patient population demonstrate durable complete remissions with low treatment-related mortality and suggest that Clolar could provide an important new therapeutic option for these patients."

Genzyme has submitted the results of its multi-centre CLASSIC II pivotal study to support its label expansion filing. This single-arm Phase 2 study, which was based on the recommendations of a panel of AML experts, analyzed 112 adult AML patients aged 60 years and older with one or more unfavourable prognostic factors, including age 70 years or older, an antecedent haematologic disorder (AHD), poor performance status, or intermediate or unfavourable cytogenetics. As reported in peer-reviewed literature, these risk factors predict poor outcomes in older patients with conventional induction therapy.

The CLASSIC II study data exceeded the protocol-defined criterion for the trial's primary end point: overall remission (OR). Patients receiving Clolar had a 45.5 per cent OR rate, including a 37.5 per cent complete remission rate (CR) and an eight percent complete remission rate with incomplete platelet recovery (CRp). Remission rates appeared consistent regardless of the type or number of unfavourable risk factors. The OR rate was 48 per cent for patients (N=25) with one pre-defined risk factor, 51 per cent for patients (N=45) with two risk factors, and 38 per cent for patients (N=40) with three risk factors. Most patients who responded to treatment achieved remission after one cycle.

The study also found that Clolar remissions were durable. Durable complete remission has been accepted as an established surrogate for clinical benefit in patients with acute leukaemias. The median duration of remission in overall responders (CR+CRp) was estimated as 51.6 weeks (12 months). The durability of remissions appeared similar regardless of age, AHD, poor cytogenetic profile, or number of unfavourable prognostic factors. The estimated median overall survival for all patients was 40.7 weeks (9 months), for responding patients was 59.1 weeks (14 months), and for patients who achieved CR was 65.3 weeks (15 months).

"Clolar demonstrates durable remissions and an acceptable safety profile in this older patient population," said Harry P. Erba, M.D, Ph.D., University of Michigan, one of the co-principal investigators of the Classic II study. "These older patients with unfavorable risk factors are unlikely to benefit from currently available therapy and I am hopeful that Clolar will be approved in this new indication."

The safety profile of Clolar was generally predictable and manageable. The all-cause induction 30-day mortality was 9.8 per cent and was consistent regardless of the presence or number of unfavourable prognostic factors. The safety findings were consistent with those for the approved Clolar paediatric ALL indication. The most commonly occurring adverse reactions included nausea, vomiting, diarrhoea, febrile neutropenia, rash, headache, fever, fatigue, hypokalemia, pneumonia, anorexia, pruritus, increased liver transaminases, neutropenia, thrombocytopenia, mucosal inflammation.

The American Cancer Society estimates that approximately 12,810 people will be diagnosed with AML in the United States in 2009. About 70 percent of these patients will die from the disease, and almost all will be adults. The median age of a patient with AML is about 67 years. As an acute disease, AML progresses rapidly and is typically fatal within weeks or months if left untreated.

The Prescription Drug User Fee Act action date for Clolar in the adult AML indication has been extended to December 2009. The extension is based on a determination by the FDA that additional long-term follow-up data sets, submitted as a supplement to the original application, represents a major amendment and requires additional review time. The additional long-term data sets support, and are consistent with, findings previously observed in the CLASSIC II trial.

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 11,000 employees in locations spanning the globe and 2008 revenues of $4.6 billion.