ON 013105 Anti-Cancer Agent

Cyclin D Modulator for Lymphoma and Solid Tumors:
Phase I Clinical Stage

ON 013105, a new chemical entity in Phase I clinical development, is a potent anti-cancer drug that targets cyclin D1 over-expression. It exhibits striking and selective effects on cell cycle progression in tumor cells, driving them into apoptosis following mitotic arrest. Over-expression of cyclin D1 is causally related to the genesis and maintenance of a variety of hematological malignancies (particularly lymphomas) and certain cases of solid tumors, including breast cancer.

MECHANISM OF ACTION

Treatment with ON 013105 drives cancer cells into apoptosis following mitotic arrest. In contrast, normal cells are not arrested in mitosis, as shown by fluorescence-activated cell sorting (FACS) analyses.

Selective Mitotic Arrest in ON 013105-Treated Cancer Cells

ON 013105 exhibits low nanomolar potency against many human cancer cell lines, including drug-resistant cells. Protein immunoblotting (Western blots) demonstrates reduction of cyclin D1 and apoptosis in ON 013105-treated mantle cell lymphoma (MCL) cells.

In vivo, human MCL tumor xenografts in mice are inhibited by ON 013105 in a dose-responsive manner. In addition, several combination regimens have been tested with ON 013105 and additive or synergistic anti-tumor activity has been observed.

CLINICAL STUDIES

The initial Phase I dose-escalation study of ON 013105 is underway, testing a once-weekly regimen in patients with relapsed/refractory lymphoma, at the Moffitt Cancer Center, Tampa, FL. Other trials employing various schedules and entry criteria are being planned.

THERAPEUTIC OPPORTUNITIES

Initial therapeutic indications for clinical exploration of ON 013105 are MCL (U.S. annual incidence 3,500), other non-Hodgkin B-cell lymphomas (U.S. incidence 66,000), and chronic lymphocytic leukemia (U.S. incidence 15,000). To our knowledge, ON 013105 is a first-in-man therapy targeting cyclin D1 over-expression.

MCL provides a unique opportunity for rapid "proof of principle" of this anti-tumor mechanism:

• MCL is a serious unmet medical need; bone marrow transplantation is rarely successful;
• Chemotherapy and biological agents have limited efficacy and patients rapidly relapse;
• Cyclin D1 over-expression is a hallmark of this disease and provides a molecular biomarker;
• In MCL patients, higher levels of cyclin D1 correlate with more aggressive proliferation of the malignant cells and overall poor prognosis.

In addition to hematologic indications, cyclin D1 over-expression has been implicated in a number of solid tumors, including certain types of breast (U.S. incidence 185,000), lung (U.S. incidence 215,000), and bladder (U.S. incidence 68,000) cancers.. Genetic evidence indicates that in mammary tissues devoid of cyclin D, tumor induction by two key pathways is completely blocked, suggesting a therapeutic rationale for cyclin D modulation in breast cancer. Hence, ON 013105 offers the potential to treat a broad array of cancers.