ON 013105 Anti-Cancer Agent

Cyclin D Modulator: Targeting Lymphoma

ON 013105 is a new chemical entity, currently in Phase I clinical development, which targets cyclin D1 overexpression. It exhibits selective effects on cell cycle progression in malignant tumor cells driving them into apoptosis following mitotic arrest, whereas, normal healthy cells are not arrested in mitosis by ON 013105.

ON 013105 exhibits cytotoxicity at nanomolar concentrations against a wide spectrum of human cancer cell lines including those which have shown drug-resistant abilities. Immunochemical analysis demonstrates a reduction of cyclin D1 and increased apoptosis in both cell culture and animal tumor models of ON 013105-treated mantle cell lymphoma (MCL). Human MCL tumor xenografts are inhibited by ON 013105 in a dose-responsive manner. In addition, several combination therapy regimens with ON 013105 have demonstrated additive or synergistic anti-tumor activity.

Initial therapeutic indications for clinical exploration of ON 013105 are MCL, other non-Hodgkin B-cell lymphomas, and chronic lymphocytic leukemia. Onconova has identified MCL as providing a unique "proof of principle" opportunity for this anti-tumor mechanism:

• MCL is a serious unmet medical need; bone marrow transplantation is rarely successful
• In MCL patients, higher levels of cyclin D1 correlate with aggressive proliferation of malignant cells and overall poor prognosis
• Chemotherapy and biological agents have limited efficacy and patients rapidly relapse

Cyclin D1 overexpression has been implicated in numerous solid tumors as well, including certain types of breast, lung, and bladder cancers. Genetic evidence indicates that in mammary tissues devoid of cyclin D1, tumor induction by two key pathways is completely blocked, supporting the therapeutic rationale for cyclin D modulation by ON 013105 in 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.

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.