Estybon™ New Mechanism Targeted Drug for Cancer

Targets Mitotic and PI-3 Kinase Pathways:
Phase II Clinical Stage

Estybon™ (ON 01910.Na) is a patented small molecule anti-cancer agent. Phase I and Phase II clinical trials in advanced, heavily pre-treated cancer patients have demonstrated a desirable safety profile, with a remarkable lack of toxicities that are commonly associated with standard chemotherapy (neutropenia and neurotoxicity) or other kinase inhibitors (skin rash, severe diarrhea). The lead indication, based on mechanistic rationale and proof of concept studies, is myelodysplastic syndromes (MDS). Additional hematologic and solid tumor indications are being developed, both as single agent and in combination therapy. An oral formulation of Estybon™ is entering the clinic, initially for MDS patients. U.S. Patent #7,598,232 covering this novel drug and its applications issued in October 2009 and international patents have been filed. Composition of matter patent coverage extends to at least 2025.

Clinical experience has shown that single agent Estybon™ is active in both solid tumors and hematological cancers. MDS trials have revealed a high rate in inducing onset of bone marrow response and improving cytopenias in advanced MDS patients. This high level of activity combined with low hematological toxicity and good tolerability of Estybon™ in treatment-refractory MDS patients, may provide an option for patients who have no effective treatments available. In September 2009, the U.S. FDA granted orphan-drug designation of ON 01910.Na for treatment of MDS. A multi-center pivotal clinical study in MDS patients is being supported by a major research award from The Leukemia and Lymphoma Society®.

In 2008, results of the first-in-man study of Estybon™ in advanced cancer patients were published in Journal of Clinical Oncology. Initial promising results in MDS patients were presented at the ASH annual meeting.

MECHANISM OF ACTION

Estybon™ has a multi-targeted mechanism of action resulting in a selective mitotic block and cell death in cancer cells. In particular, the polo-like kinase (PLK) pathway is affected, causing polynumeric centrosomes and dysregulation of mitosis. At the molecular level, Estybon™ inhibits the PI-3 Kinase, ERK (growth) and AKT (pro-survival) pathways. Estybon™ is effective in killing cancer cells with various anti-apoptotic and drug-resistance mutations.

CLINICAL TRIALS

Results from combination trials with either oxaliplatin or gemcitabine indicate rapid response in breast, colon, ovarian, and lymphoma patients, suggesting multiple approval pathways for solid tumor indications. A summary of clinical studies is presented below. In addition, a multi-center pivotal trial with MDS patients is beginning in 2010.