ZYBRESTAT™ (combretastatin / CA4P parenteral) - ONCOLOGY
(Click here for OPTHALMOLOGY)

ZYBRESTAT (combretastatin-A4 phosphate / CA4P) is OXiGENE's lead vascular disrupting agent (VDA) product candidate, which is currently being evaluated in multiple clinical trials as a treatment for various solid tumors.

ZYBRESTAT acts via a well-validated therapeutic mechanism: depriving tumors of blood supply necessary for growth and survival. The drug exerts its anti-tumor effects by selectively affecting and disabling tumor vasculature, thereby acutely inducing: reduction in tumor blood-flow, oxygen starvation of the tumor, and build-up of tumor metabolic by-products--all of which cause cancer cells within the central core of the tumor to die.

ZYBRESTAT is poised to become a first-in-class VDA product. In July 2007, OXiGENE initiated a 180-patient pivotal registration study with ZYBRESTAT for the treatment of anaplastic thyroid cancer, a highly lethal and aggressive malignancy for which there is currently no treatment, under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). The FDA has granted ZYBRESTAT “Fast-Track” status as a potential therapy for serious and life-threatening diseases, and ZYBRESTAT has also received “Orphan Drug” designations, which confer market exclusivity and tax benefits, in the U.S. and European Union.

To date, ZYBRESTAT has shown promising results in mulitple clinical studies:

-- In an open-label, Phase II study of ZYBRESTAT (monotherapy) in patients with advanced, relapsed anaplastic thyroid cancer, median survival time and one-year survival rate exceeded published survival statistics reported in the clinical literature for similar patient cohorts.

-- ZYBRESTAT has shown clinical activity against anaplastic thyroid cancer (complete response, partial response and stable disease) as well as other tumor types, including ovarian cancer.

-- In five Phase I studies ZYBRESTAT has shown significant and consistent ability to cause reductions in tumor blood-flow.

ZYBRESTAT has broad potential therapeutic utility across a wide range of different solid tumor types, and can potentially be combined with mainstay oncology treatment modalities: chemotherapy, radiation therapy and newer, "molecularly-targeted therapies," such as tumor angiogenesis inhibitors. Preclinical studies have demonstrated that ZYBRESTAT has synergistic or additive effects when incorporated in various combination regimens with all of these treatment modalities. There is a strong scientific rationale for combining ZYBRESTAT and tumor angiogenesis inhibiting drugs, and ZYBRESTAT is the first VDA to be tested in humans in combination with a tumor-angiogenesis-inhibiting drug (bevacizumab / AVASTIN®).

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ZYBRESTAT (topical)  - OPHTHALMOLOGY

Similar to the situation in cancer, blood-supply deprivation with anigogenesis-inhibiting drugs has been validated as an effective therapeutic approach for patients with the wet form of age-related macular degeneration (ARMD)--the leading cause of blindness in adults over age-50--as well as other ophthalmological diseases and conditions in which abnormal blood-vessel growth plays a key role in disease pathophysiology. Although several angiogenesis-inhibiting drugs have recently been approved for the treatment of wet ARMD, they must be injected on a regular basis directly into the eye (intravitreal injection) and can cause side-effects.

OXiGENE believes that a patient-friendly, topical formulation of ZYBRESTAT (e.g., eye-drop) is feasible and would have significant advantages for patients with ARMD and other eye diseases when administered either as a monotherapy or in combination with current intravitreally-injected products.

OXiGENE has demonstrated successful human proof-of-concept with ZYBRESTAT, administered intravenously, in patients with myopic macular degeneration, a form of macular degeneration. Based on these results, the company is advancing development of a topical formulation of ZYBRESTAT as a treatment for age-related macular degeneration and potentially other ophthalmological diseases in which abnormal neovascularization plays a role in disease pathophysiology. Based on the results of preclinical biodistribution studies, OXiGENE believes that it is feasible to deliver ZYBRESTAT topically, in a drop or other formulation, to the eye and achieve drug levels in the back of the eye, (where, in the case of ARMD, abnormal, disease-associated vessels are located) that are more than sufficient to cause therapeutic effects.

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OXi4503

OXi4503 (combretastatin A1 di-phosphate / CA1P) is a unique and highly potent, dual-mechanism vascular disrupting agent (VDA). Like its structural analog, ZYBRESTAT, OXi4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. In addition, however, preclinical data demonstrates that OXi4503 is metabolized by oxidative enzymes (e.g., tyrosinase and peroxidases), which are elevated in many solid tumors and tumor infiltrates, to an orthoquinone chemical species that has direct cytotoxic effects on tumor cells. Preclinical studies have demonstrated that OXi4503 has (i) single-agent activity against a range of xenograft tumor models; and (ii) synergistic or additive effects when incorporated in various combination regimens with chemotherapy, molecularly-targeted therapies (including tumor-angiogenesis inhibitors), and radiation therapy.

OXi4503 is currently being evaluated as a monotherapy in a Phase I dose-escalation study in patients with advanced solid tumors.

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Vascular Disrupting Technology

Vascular disruption represents a new approach to a validated therapeutic strategy: depriving tumors (and, in the case of eye disease, pathologic neovascular lesions) of blood supply.

In solid solid tumors, vascular disrupting agents (VDA's), such as ZYBRESTAT and OXi4503, rapidly disrupt the vasculature within the tumor, reduce blood-flow, and deprive the tumor of oxygen and nutrients, resulting in tumor cell death. This disruption of the newly formed blood vessels contrasts with the action of anti-angiogenic therapies, which are designed to prevent new blood vessel formation. The following table contrasts and compares OXiGENE's VDAs with anti-angiogenic agents:

OXiGENE believes its VDA product candidates may offer advantages over current anti-angiogenic drugs, including superior efficacy and reduced side-effects.

In addition, there is a strong scientific rationale for combining VDA and anti-angiogenesis therapies. OXiGENE and its scientific collaborators have published preclinical research results showing that the combination of OXiGENE VDAs and certain anti-angiogenic drugs (i.e., monoclonal antibodies targeting vascular endothelial growth factor, or VEGF) have synergistic anti-tumor effects. Building upon these results, OXiGENE has undertaken the first-ever human clinical trial of a VDA (ZYBRESTAT) in combination with an anti-angiogenic agent (bevacizumab / AVASTIN.)

Additional Benefits of Vascular Disrupting Agents:

• This method of treatment is designed to target newly formed abnormal blood vessels, rather than the established blood vessels found in healthy tissue, resulting in fewer side effects in the oncology setting than conventional disease treatments such as radiation and chemotherapy.
  
  
• VDAs are designed to address the complete spectrum of solid tumors, whereas other approaches, which directly target tumor cells, require the development of different drugs for different types of solid tumors.
  
  
• VDAs are designed to target endothelial cells associated with new blood vessel formation, so drug resistant mutations are unlikely to occur.
  
  
• Damaging one or two blood vessels can cause thousands of tumor cells to die.
  
  
• The ability of VDAs to selectively target newly formed or abnormal blood vessels makes them well-suited for certain ocular diseases, such as age-related macular degeneration, in which the formation of new, abnormal blood vessels in the eye plays a key role in disease.

For a demonstration of how ZYBRESTAT works, please click here.

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