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Clinical Targets - Non-Hodgkin's Lymphoma/Solid Tumors/Autoimmune Disease

PPI 2458

We are focusing our research and development efforts on PPI-2458, a novel, proprietary oral compound targeted at the inhibition of the enzyme methionine aminopeptidase type 2, or MetAP-2. PPI-2458 is based on the fumagillin class of compounds. This class of compounds has been shown to prevent the formation of new blood vessels (known as angiogenesis) as well as abnormal cell growth; both events are known contributors to the growth of aberrant tissues in diseases such as cancer and rheumatoid arthritis. Clinical development with previous fumagillin derivatives has been limited by their pharmacokinetic and toxicity profiles. In preclinical studies to date, PPI-2458 has demonstrated the potent activity of this class of compounds, while displaying an improved pharmacokinetic and toxicity profile. The improved pharmacokinetic profile enables oral administration of PPI-2458, which we believe represents an additional improvement over its predecessors. We believe that, due to its antiproliferative and antiangiogenic activity, PPI-2458 has the potential to address broad therapeutic areas, and we are currently in the process of establishing a plan for additional clinical studies for this compound. In light of the anticipated development costs associated with the PPI-2458 clinical program, we anticipate seeking a partner for this program as clinical development advances.

PPI-2458 for Cancer Indications

In preclinical studies conducted independently by us and the National Cancer Institute, or NCI, in both cellular and animal models, PPI-2458 demonstrated significant anti-tumor activity against several varied cancer cell lines. The NCI has presented its data on the anti-angiogenic activity of PPI-2458 and its preclinical efficacy in a variety of xenograft animal models of human cancer, which indicates that the activity of PPI-2458 compares favorably to that of TNP-470, another compound of this class that was previously studied by TAP Pharmaceutical Products Inc. To evaluate the activity of PPI-2458 on a molecular level, we have developed a proprietary pharmacodynamic assay to assess the level of inhibition achieved by PPI-2458 of its target enzyme, MetAP-2. Preclinical research has demonstrated that inhibition of MetAP-2 by PPI-2458 directly correlates with biological anti-cancer activity in cell lines and tumors grown in animal models. During 2005, we presented preclinical data demonstrating that due to its potent inhibition of MetAP-2, PPI-2458 has potential for use as a new therapy for non-Hodgkin’s lymphoma, or NHL. MetAP-2 is highly expressed in human germinal center B cells and some of the neoplastic counterparts of these cells, which are NHL subtypes, such as diffuse large B cell lymphoma and follicular lymphoma. PPI-2458 has been shown to reduce the formation of germinal centers in lymphoid tissues in animal models, to have direct anti-proliferative activity on several NHL cell lines in vivo and to inhibit the growth of NHL tumor xenografts in a preclinical animal model. Other studies have demonstrated that PPI-2458 significantly inhibited the growth of certain tumors in a dose-dependent manner, and that the degree of growth inhibition was correlated to the level of MetAP-2 inhibition achieved by PPI-2458. Additionally, in preclinical animal models, the activity of PPI-2458 is synergistic with several chemotherapeutic agents that are routinely used in combination in NHL patients. There is also published evidence that MetAP-2 is highly expressed in some other human cancer cell lines and, accordingly, we believe that PPI-2458 may have much broader therapeutic application in oncology and that these results provide the scientific rationale for clinical investigation of PPI-2458 in cancer patients.

During the fourth quarter of 2003, we initiated our first clinical trial for PPI-2458 evaluating an oral formulation in non-Hodgkin's lymphoma patients who were no longer responding to other therapies. In March 2004, the FDA placed this trial on clinical hold due to a non-clinical safety concern. In June 2004, we received clearance from the FDA to resume clinical trials, and in late 2004, we opened a phase 1 clinical trial of PPI-2458 in non-Hodgkin’s lymphoma patients. During the first quarter of 2005, we expanded the enrollment criteria of this trial to include patients with solid tumors. This trial is designed to assess the safety and tolerability of orally administered PPI-2458 and to identify the maximum tolerated dose. As a secondary endpoint, the study will assess the pharmacokinetics and the pharmacodynamic activity of PPI-2458. While the clinical trial is still in its early stages, thus far oral dosing of PPI-2458 has been well tolerated and has produced substantial inhibition of molecular targeted MetAP-2 activity in most subjects evaluated.

PPI-2458 for Inflammatory and Autoimmune Indications

We continue to evaluate the therapeutic potential of PPI-2458 in inflammatory and autoimmune disorders, including rheumatoid arthritis. A hallmark of rheumatoid arthritis is the progressive destruction of articular joints and joint surfaces, characterized by the rapid, uncontrolled growth of the cells that line the joints, called synoviocytes. The synoviocytes, in turn, secrete a variety of chemicals that contribute to inflammation, tissue degradation and harmful new blood vessel formation. Previously published data from our preclinical studies demonstrate that PPI-2458 inhibits the growth of both human endothelial cells and human fibroblast-like synoviocytes derived from rheumatoid arthritis patients. Both cell types are thought to be important in the progression of joint destruction in rheumatoid arthritis patients. In addition, growth inhibition of these PPI-2458-sensitive cell types in rheumatoid arthritis has been shown in preclinical studies to be linked to MetAP-2 enzyme inhibition in a dose-dependent fashion. In a rodent model of rheumatoid arthritis, PPI-2458 in well-tolerated doses also significantly lessened joint swelling when administered therapeutically after the onset of chronic disease. Based on preclinical data we have generated, we believe that PPI-2458 could be a potential treatment with disease-modifying activity for rheumatoid arthritis and other inflammatory and autoimmune disorders.