ESTYBON® (rigosertib, ON 01910.Na)

ESTYBON (rigosertib) is a novel multikinase inhibitor, with selective cytotoxic effects on tumor cells without impact on normal cells. Key direct molecular targets of ESTYBON in cancer cells include the &alpha and &beta isoforms of PI 3-kinases. A significant effect of ESTYBON in cancer cells is the induction of multiple centrosomes during cell division, resulting in a multi-polar spindle and total disorganization of the mitotic apparatus, a phenomenon called chromosomal catastrophe. There is also evidence that ESTYBON modulates the ERK/MAPK (growth) and AKT/PKB (survival) pathways, promoting apoptosis in cancer cells. This activity is also evident in cancer cells harboring various anti-apoptotic and drug-resistance mutations.

Given the unique mechanism of action on tumor cell survival pathways, ESTYBON has the potential to be active against a wide variety of cancers. In fact, monotherapy with ESTYBON demonstrated activity in hematologic malignancies as well as in solid tumors. When combined with other anti-cancer agents, activity has been demonstrated in many intractable cancers including pancreatic cancer and platinum-refractory ovarian cancer. Ongoing Phase I and Phase II trials in advanced, heavily pre-treated cancer patients have demonstrated a desirable safety profile, with a lack of serious toxicities that are commonly associated with standard chemotherapy (neutropenia and neurotoxicity) or other kinase inhibitors (skin rash, severe diarrhea). Early clinical results from ESTYBON combination studies with either oxaliplatin or gemcitabine indicate rapid response in pancreatic, breast, colon, ovarian, and lymphoma patients, suggesting multiple indications for solid tumors.

The lead indication, based on mechanistic rationale and proof of concept, is myelodysplastic syndromes (MDS) for which there are considerable unmet needs. MDS comprises a range of diverse bone marrow stem cell disorders characterized by ineffective hematopoiesis, cytopenias, and predisposition to developing leukemia. Only two agents are currently approved for treating all forms of MDS. Since both agents act through the same hypomethylation mechanism, once patients fail one of these treatments, they are left with no other approved anti-cancer drug treatment. The current outlook for MDS patients who have relapsed or are refractory is very poor, with a median survival of approximately four months.

Based upon promising Phase II studies with ESTYBON in patients with MDS, Onconova has initiated a randomized, registration enabling, Phase III trial in which its efficacy is compared to best supportive care. MDS patients (with excess blasts) who do not tolerate or have relapsed after treatment with currently approved MDS treatments are being enrolled. This study of ESTYBON in MDS is named ONTIME (ON 01910.Na Trial In Myelodysplastic SyndromE) and will include patients from more than 60 centers worldwide. ONTIME has the potential to be a groundbreaking study, as it will leverage the earlier clinical work performed in a group of MDS patients with a specific karyotype, Trisomy 8 (three copies of a chromosome 8). In these patients the molecular pathogenesis of the disease is associated with the overexpression of cyclin D1. In initial studies involving Trisomy 8 patients, ESTYBON treatment rapidly decreased cellular cyclin D1 levels and blast (cancerous cells) count in the bone marrow. The ONTIME trial is supported by a major research award from the Leukemia and Lymphoma Society®.

In clinical studies of patients with solid tumors treated with ESTYBON, promising results have been noted in several types of cancer, including pancreatic cancer. These Phase I/II trials have led to a Phase II/III multi-center, randomized, controlled trial (ONTRAC, ON 01910.Na TRial in Patients with Advanced Pancreatic Cancer) which will compare the efficacy and safety of ESTYBON combined with gemcitabine to that of gemcitabine alone in previously untreated patients.

The studies summarized above have utilized an intravenous administration of ESTYBON. Oral administration studies of ESTYBON have progressed beyond proof-of-concept studies in cancer patients with hematologic malignancies or solid tumors. Oral administration has demonstrated clinical activity and in dose escalation studies appears to be well tolerated by patients.

Onconova and SymBio Pharmaceuticals Limited have agreed to collaborate on the development and commercialization of ESTYBON (rigosertib) in Japan and Korea.

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. The ESTYBON pivotal MDS trial will be conducted by Onconova in the U.S. and Europe, with patient enrollment in the U.S. beginning 4Q 2010. A summary of completed and ongoing clinical studies is presented below.