The U.S. Food and Drug Administration (FDA) has approved its orphan drug asparaginase Erwinia chrysanthemi (Erwinaze? www.erwinaze.com , EUSA Pharma) for the treatment of acute lymphoblastic leukemia (ALL) in patients who have developed an allergy (hypersensitivity) to E. coli derived asparaginase and pegaspargase chemotherapy drugs used to treat ALL. The new drug will be immediately available to patients throughout the United States.

Acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes, a type of white blood cell. White blood cells help the body fight infection and are formed in the bone marrow. ALL is the most common form of childhood cancer, with approximately 2,900 patients under the age of 20 diagnosed in the USA each year [1]. It is also one of the most curable forms of cancer, with remission rates in treated children of over 95% and 75 ? 85% surviving at least five years without recurrence of leukemia [1]. Treatment involves a number of stages and drugs, and typically includes asparaginase as an essential component of current protocols.

Erwinia chrysanthemi
Asparaginase Erwinia chrysanthemi is an asparaginase enzyme that depletes the level of asparagine in the bloodstream. Asparagine is essential for cell growth, and its removal from the blood inhibits the growth of cells associated with acute lymphoblastic leukemia. Asparaginase products are derived from bacteria, and approximately 15 – 20% of patients develop hypersensitivity to modern products derived from Escherichia coli, preventing their continued treatment [2]. Erwinaze, which is produced by Erwinia chrysanthemi, is immunologically distinct from these therapies and is suitable for patients with hypersensitivity to E. coli-derived treatments. The drug was originally discovered by the UK Health Protection Agency, and the assays for the US Biologics License Application were conducted by AIBioTech, Richmond, Virginia.

Treatment options
Asparaginase Erwinia chrysanthemi is indicated as an integral part of a multi-agent regimen for the treatment of ALL patients who develop hypersensitivity to current products derived from E. coli, and is therefore the first and only approved treatment option available for patients with hypersensitivity to standard-of-care treatment with pegaspargase. Overall, an estimated 15 – 20% of ALL patients develop hypersensitivity to E. coli-derived asparaginase, representing approximately 450 – 600 children in the United States each year [2].

Erwinaze is injected directly into the muscle three times a week and works by breaking down one of the body’s protein building blocks (the amino acid, asparagine) that is present in the blood, and is necessary for the growth of all cells. Leukemia cells cannot produce this protein building block. When a patient is treated with Erwinaze the leukemia cells die. Normal human cells are able to make enough asparagine for their own needs through biosynthesis and will not be affected by treatment with Erwinaze.

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A life-saving therapy
“Treatment with asparaginase is a vital and life-saving therapy for thousands of patients, mostly children, with acute lymphoblastic leukemia each year. Unfortunately, a number of these patients develop hypersensitivity to asparaginases derived from E. coli, including pegaspargase, and are unable to complete the recommended course of treatment. The approval of the new treatment option is an important advance because it is the only treatment option that can enable these patients to continue and complete their full course of therapy,” noted Stephen E Sallan MD, Chief of Staff, Dana-Farber Cancer Institute and Professor of Pediatrics, Harvard Medical School.

Commenting on the news, Bryan Morton, President and Chief Executive Officer of EUSA Pharma, said, “The approval of Erwinaze marks a major milestone for EUSA, and represents the culmination of many years of work. Launching Erwinaze to sit alongside our existing portfolio of specialty products is also a major strategic milestone for the company, as this is the first treatment EUSA has developed internally. This achievement represents a transformation for the company, signaling our transition into a specialty development as well as commercialization organization.”

Drug approval
The safety and effectiveness of Erwinaze was evaluated in one clinical trial of 58 patients. In this trial 100% of evaluable patients achieved the asparaginase activity primary endpoint. Additional safety data was collected from the Erwinaze Master Treatment Protocol (EMTP), an expanded access program that enrolled 843 patients. Patients in both studies were unable to continue receiving pegaspargase or asparaginase derived from E. coli due to allergic reactions.

In the trial to support efficacy, the main outcome (endpoint) was the measurement of the proportion of patients with sustained asparaginase activity levels that correlate with better leukemia control and survival. All evaluable patients were shown to have maintained the pre-specified threshold for asparaginase activity at 48 or 72 hours after dosing.
Side effects associated with Erwinaze treatment include serious allergic reactions (anaphylaxis), inflammation of the pancreas (pancreatitis), high blood levels of liver enzymes (abnormal transaminases and bilirubin), blood clotting, bleeding (hemorrhage), nausea, vomiting and high blood sugar (hyperglycemia).

Prior to Erwinaze’s approval there were two asparagine specific enzyme products ? Elspar (asparaginase injection) and Oncaspar (pegaspargase) ? approved by FDA to treat patients with ALL. Both of these products are E. coli derived.

“The approval of Erwinaze underscores the FDA’s commitment to the approval of drugs for conditions with limited patient populations with unmet medical needs using novel trial endpoints,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Erwinaze has been designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the U.S.

References:
[1] US National Cancer Institute. Childhood acute lymphoblastic leukemia treatment (PDQ?).
[2] Raetz EA, Salzer WL. J Pediatr Oncol 2010:32:554-563.

For more information:
FDA: Office of Hematology and Oncology Products
FDA: Approved Drugs: Questions and Answers
NCI: Adult Acute Lymphoblastic Leukemia

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