The drug product candidate which we have advanced the furthest is Cintredekin Besudotox, a tumor-targeting toxin being developed as a treatment for glioblastoma multiforme, or GBM, a deadly form of brain cancer.

Glioblastoma multiformes (GBM) is the most common type of malignant primary brain tumor in adults. They are very aggressive, having tentacles that spread and mix with normal brain tissue, damaging the adjacent tissue as they grow uncontrollably in the brain. Treatment success has not significantly changed over the last 20 years, with most patients living less than one year after diagnosis despite aggressive surgery, radiation and chemotherapy.

Radiation therapy has been the most effective adjuvant therapy for these tumors, but the inherent resistance to radiation therapy and the risk of damaging the adjacent normal brain tissue limits its overall efficacy. GBM is intrinsically resistant to most chemotherapy and very few drugs cross the natural barrier present in the blood vessels of the brain (blood-brain barrier) which means that even drugs that work in the laboratory and in animals cannot reach the tumor cells within the brain. This unfortunate combination has resulted in only two FDA approved chemotherapy for this type of tumor with two forms of delivery, by vein or by local biodegradable wafers. The impact of these approved therapies increases survival in patients with this deadly tumor by only a few weeks.

Cintredekin Besudotox delivered by convection-enhanced delivery (direct micro infusion into the brain), on the other hand, is designed to molecularly target the tumor cells while sparing the healthy brain tissue. This form of regional and molecular targeting may represent one of the first scientifically sound treatment regimens, providing hope for overcoming one of the greatest hurdles in brain tumor therapy. The very problem that prevented drugs from entering the brain may now be used to keep the drug in the brain.

Cintredekin Besudotox is a recombinant protein consisting of a single molecule composed of two parts: a tumor-targeting molecule and a cytotoxic agent. The targeting component consists of interleukin 13(IL-13), an immune regulatory cytokine. Malignant glioma cells, as compared to normal brain cells, express IL-13 receptors at a higher density. The cytotoxic agent is a potent bacterially derived toxin called PE38. Cintredekin Besudotox is designed to detect and bind IL-13 receptors on the surface of malignant glioma cells and selectively deliver PE38 to destroy tumor cells. Cintredekin Besudotox is administered by a technique known as convection-enhanced delivery, or CED, in which the drug is delivered through catheters inserted in brain tissue surrounding the tumor (peritumoral administration) or into the tumor (intratumoral administration) following surgical resection of the tumor. CED is designed to infuse Cintredekin Besudotox directly to the tumor site and adjacent brain tissue with the goal of killing resident tumor cells and preventing recurrence of tumor cell growth. We hope to show that this method of delivery minimizes both damage to the surrounding cell and toxicity from systemic drug exposure.

We have exclusively licensed Cintredekin Besudotox from the NIH and the FDA, and have been developing this drug product candidate under a Cooperative Research and Development Agreement, or CRADA, with the FDA Center for Biologics Evaluation and Research, or CBER. Cintredekin Besudotox has received orphan drug designation in the US and Europe and FDA has designated it for the fast track drug development program. In addition, Cintredekin Besudotox has been selected to participate in the FDA's Continuous Marketing Application, CMA, Pilot 2 program. We also hold a non-exclusive license to utilize a patented process owned by the U.S. government relating to convection enhanced delivery, or CED, for use with drugs, including Cintredekin Besudotox, in the treatment of gliomas.

In early 2007, NeoPharm completed its Phase III clinical trial for Cintredekin Besudotox. Upon review of the trial results with us in March 2007, the FDA concluded that an additional Phase III confirmatory trial would be required prior to acceptance of a potential BLA filing by NeoPharm. In June 2008, NeoPharm signed a letter of intent with a clinical research organization (CRO) with regard to the CRO's engagement to oversee a planned confirmatory Phase III trial for Cintredekin Besudotox. This initial Phase III confirmatory trial was to have the primary objective of overall survival, with a secondary objective of progression-free survival for patients with recurrent GBM against the standard of care.  Subsequently, NeoPharm received notification from the Directorate General of Health Services - Office of Drugs Controller General (India) ("DCGI") that it will not at this time grant regulatory approval for NeoPharm to conduct its planned confirmatory IL-13 Phase III trial.  In its previous correspondence, the DCGI requested concurrent enrollment of patients in the trial in the USA. 

In the fourth quarter of 2008, NeoPharm signed a Cooperative Research and Development Agreement ("CRADA") with the National Institute of Neurological Diseases and Stroke ("NINDS"), a part of the National Institutes of Health ("NIH"), for research on a therapeutic agent for untreatable brain diseases in humans.  Under the terms of the CRADA, NINDS will deliver IL-13 in conjunction with a surrogate marker via NINDS' patented methodology of Convection Enhanced Delivery ("CED"), which was previously licensed to NeoPharm.  NeoPharm will provide its proprietary drug and technical resources to study its effects in various brain cancers in humans.  NINDS Institutional Review Board ("IRB") has approved the protocol and NeoPharm has granted NINDS authorization to cross-reference its prior IL-13 IND for the treatment of GBM.