The U.S. Food and Drug Administration’s (FDA) Office of Orphan Products Development has granted orphan drug designation for VAL-083 for the treatment of glioma, including glioblastoma multiforme (GBM), the most common and aggressive form of brain cancer.

Of the estimated 17,000 primary brain tumors diagnosed in the United States each year, approximately 60% are gliomas. Attention was drawn to this form of brain cancer when Senator Ted Kennedy was diagnosed with glioblastoma and ultimately died from it.

Newly diagnosed patients suffering from GBM are initially treated through invasive brain surgery, although disease progression following surgical resection is nearly 100%. Temozolomide (Temodar?, Schering Corp/Merck & Co) in combination with radiation is the front-line therapy for GBM following surgery. Approximately 60% of GBM patients treated with temozolomide experience tumor progression within one year. Bevacizumab (Avastin?, Genentech) has been approved for the treatment of GBM in patients failing temozolomide. According to the Avastin? label, approximately 20% of patients failing temozolomide respond to bevacizumab therapy. Approximately 48% of patients who are diagnosed with GBM will fail both front-line therapy and bevacizumab.

New threatment options
VAL-083, novel N7 alkylating agent being developed by Del Mar Pharmaceuticals, represents a “first in class” small-molecule chemotherapeutic, which has been assessed in multiple NCI-sponsored clinical studies. Published pre-clinical and clinical data suggest that VAL-083 may be active against a range of tumor types, including GBM. The companyis sponsoring a phase I/II open-label, single arm dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of VAL-083 in patients with histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (GBM), now recurrent.

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The study is being conducted under the direction of Howard Burris M.D.at the Sarah Cannon Research Institute in Nashville, Tennessee. Patients with prior low-grade glioma or anaplastic glioma are eligible, if histologic assessment demonstrates transformation to GBM. Patients must have been previously treated for GBM with surgery and/or radiation, if appropriate, and must have failed both bevacizumaband temozolomide, unless either or both are contra-indicated. Response to therapy and disease progression will be evaluated by MRI prior to each treatment cycle. An initial phase of the study, currently being enrolled, involves dose escalation cohorts until a maximum tolerated dose (MTD) is established in the context of modern care. Once the modernized dosing regimen has been established, additional patients will be enrolled at the MTD (or other selected optimum dosing regimen).

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Results from thes studiesis anticipated later this year. Data fromthe trialswill be presented on April 1, 2012 at the American Association for Cancer Research (AACR) Annual Meeting (being held March 31 – April 4, 2012 in Chicago, USA) is expected to show that VAL-083 surpasses temozolomide activity and inhibits cancer stem cells providing a new potential treatment option for glioblastoma multiforme

Mechanism of action
Based on published research, the mechanism of action (MOA)of VAL-083 is understood to be a bi-functional alkylating agent; however, the functional groups associated with alkylating events has been shown to differ from other alkylating agents used in the treatment of GBM.

Standard treatment
Temozolomide in combination with radiation is a standard front-line therapy for the treatment of newly diagnosed GBM. however, the majority of patients fail to respond to treatment with Temozolomide. Published research suggests that the activity of a naturally occurring DNA repair enzyme called O6-methylguanine-DNA methyltransferase (MGMT) may be responsible for resistance to temozolomide and other alkylating agents used in the treatment of GBM.

“These pre-clinical data from human brain tumor cell lines distinguishes VAL-083 from standard-of-care by demonstrating that the unique mechanism and anti-tumor activity of VAL-083 is independent of MGMT-related drug resistance,” said Jeffrey Bacha, President & CEO of DelMar Pharma. “We believe that this work, which is ongoing, illustrates the promise of VAL-083 in refractory GBM and may allow physicians to eventually tailor therapy for those less likely to respond to the current front-line standard-of-care.”

Orphan drug
VAL-083 orphan drug designation will help further development of the drug. ?This orphan drug designation along with encouraging research results represents another important step in advancing this important new therapy to patients suffering from GBM, stated Jeffrey Bacha DelMar Pharma?s President & CEO. ?The FDA?s decision to grant orphan drug designation underscores the urgency of the need for new treatments for this life threatening cancer. We look forward to working cooperatively with the agency to advance this potentially important new therapy through the clinical trial and regulatory approval process.?

The Orphan Drug Designation is granted by the FDA Office of Orphan Products Development to promote the development of new therapies for rare diseases and disorders affecting fewer than 200,000 individuals in the United States. Among the benefits of orphan designation in the United States are seven years of market exclusivity following FDA approval, waiver or partial payment of application fees, and tax credits for clinical testing expenses conducted after orphan designation is received.

For more information:
Clinicat trial: Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma.ClinicalTrials.gov Identifier: NCT01478178

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