[2002]-[ONT-093]-[oral P-gp inhibitor][Ontogen]
Oncology
ONT-093: Reversing Multidrug Resistance (MDR) During Chemotherapy Illustration courtesy of
The Biotech Journal
Approximately 50% of cancer patients receive chemotherapy, and as many as 75% of these patients experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. This phenomenon, termed multidrug resistance (MDR), is the most common cause of chemotherapy failure. It is well established that the majority of tumors develop MDR through over-expression of the drug efflux pump P-glycoprotein (P-gp). Inhibition of P-gp is acknowledged as a viable means of reversing MDR; however, existing P-gp inhibitors so far have demonstrated limited clinical success due to limitations in potency and specificity.
Ontogen is currently conducting Phase I clinical studies to evaluate the reversal of MDR using ONT-093, a highly potent and specific and oral P-gp inhibitor. ONT-093 was designed with unique structural, biological and metabolic properties that enable it to prevent the emergence of resistance at the onset of chemotherapy and to reverse resistance that develops during the course of cancer treatment.
Pre-clinical studies demonstrated that ONT-093 is a successful inhibitor of P-gp in vitro and reverses MDR in human tumors in animal models. Four ONT-093 clinical trials have established the safety of ONT-093 in healthy volunteers and an additional Phase I study of ONT-093, initiated in May 2001, is evaluating the tolerability and pharmacokinetics of ONT-093 combined with intravenous Taxol® (paclitaxel) in cancer patients. Ontogen has filed an IND in Canada, and a U.S. IND filing is pending.
ONT-093: Improving Oral Bioavailability of Established Chemotherapeutic Agents
Ontogen also is evaluating ONT-093 in Phase I clinical testing to enhance the oral bioavailability of drugs that are P-gp substrates requiring either high dosage forms or intravenous administration. P-gp also has been implicated in the poor oral absorption of a significant number of important therapeutic agents, and ONT-093 as an adjuvant agent could significantly enhance the utility of cancer drugs such as Taxol and Taxotere® (docetaxel).
Additional Oncology Compounds
Ontogen has utilized its proprietary discovery and development technologies to identify modulators of validated cancer targets, including:
Met, an important signaling receptor for tumor angiogenesis, tumor cell proliferation and migration;
IGF-1 receptor tyrosine kinase, a key effector in breast and prostate cancer, as well as psoriasis;
SHP-2 tyrosine phosphatase, an enzyme critical to the growth of EGF-dependent tumors; and,
Focal adhesion kinase (FAK), a suppressor of cell apoptosis in various tumor types.
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