Locus Pharmaceuticals, Inc., a world leader in computational drug design, has submitted an Investigational New Drug (IND) application to the FDA to begin a phase I human clinical study of the company's lead compound, LP-261, an orally administered small molecule for the treatment of cancer.
LP-261 was developed by Locus using its proprietary computational drug design technologies. It is predicted to interact with tubulin at a unique binding site. In tumour cells, LP-261 induces growth arrest at the G2/M phase resulting in programmed cell death (apoptosis). Approved tubulin targeting agents, such as the taxanes, are a highly effective class of cancer-killing agents, and such cytotoxics represent one of the largest markets in the pharmaceutical industry. The clinical limitations to these approved agents include iv delivery and multi-drug resistance.
The phase I clinical study is designed to evaluate the safety and pharmacokinetic profile of LP-261 in patients with advanced metastatic tumours or blood cancers, as well as refractory cancer that has progressed despite previous chemotherapy. LP-261 has been shown preclinically to have 100 per cent oral bioavailability in several animal species. Tumour response and blood levels of LP-261 will be assessed, and biomarkers of tubulin function, tumour cell division, and angiogenesis will be monitored.
LP-261 has been shown to be effective in cancer cells that are resistant to taxol, vinblastine and Gleevec. LP-261 does not appear to be a substrate for MDR pumps that pump out drugs from the tumour cell. In preclinical studies, LP-261 demonstrates broad anti-tumour and anti-angiogenic activity both in vitro and in vivo, including tumour regression in solid tumour xenograft models (e.g., non-small cell lung cancer and colon). It is anticipated that the dual effects on cell growth and proliferation could allow broad application of LP-261, including its use in combination therapy.
"All of the approved tubulin drugs target either the taxane or vinca sites, are parenterally administered and are natural products which can present manufacturing or toxicity issues," said H. Joseph Reiser, Ph.D., Chairman and CEO of Locus. "We believe that LP-261, as an oral, synthetic compound targeting the colchicine site, could have a very exciting profile across various solid and blood-borne cancer types."
Consistent with its transition to a clinical stage company, Locus also announced that Howard A. Ball, Ph.D. was appointed Senior Director of Preclinical Development, a newly created position. Most recently, Dr. Ball was Director, Research-Clinical Interface at Epigenesis where he oversaw the asthma and COPD therapeutics programs. Prior to that, he was Clinical Pharmacologist in Oncology with Novartis and was involved in the development of Gleevec, the VEGF inhibitor, PTK787, and MMP inhibitors.