Monday, July 30, 2007 - 9:00 AM
S25

From sea bed to sick bed, discovery and development of a novel proteasome inhibitor from a marine actinomycete

R. Lam, Nereus Pharmaceuticals, Inc., San Diego, CA

NPI-0052 (salinosporamide A), a product of the obligate marine actinomycete, Salinispora tropica, is a highly potent inhibitor of the 20S proteasome.  Due to the success of velcade, the proteasome is a validated, high interest drug target.  In the preclinical studies, NPI-0052 appears superior to velcade and shows: 1) a broader and longer lasting proteasome inhibition profile; 2) efficacy against velcade, revlimid, thalomid and dexamethasome resistant tumor cells from multiple myeloma patients; 3) less cytotoxic to normal cells and 4) 7 to 10 fold higher in vivo potency.  It is currently undergoing Phase I clinical studies for the treatment of various cancers such as multiple myeloma, lymphomas and solid tumors.  NPI-0052 consists of a gamma-lactam-beta-lactone core structure which is highly unstable in the aqueous environment suh as the submerged fermentation conditions generally used in large scale production of microbial pharmaceuticals.  The seawater growth requirement of the producing organism adds an apparent complexity to the design of the commercial fermentation process.  Production of pharmaceuticals by saline fermentation has not been previously reported.  Nereus Pharmaceuticals has successfully developed a high output, scalable and efficient production of NPI-0052 in industrial-scale fermentor using saline fermentation.  The production titer and isolation yield of the saline fermentation process exceed the requirement for clinical development and meet the needs for commercial production of NPI-0052.  NPI-0052 from the saline fermentation process is used for the Phase I clinical study and is planned for subsequent clinical trials and commercial development.