Image-guided surgery using invisible near-infrared (NIR) light is in the midst of a renaissance. Multiple commercial imaging systems, including Curadel's state-of-the-art FLARE system, are available for pre- clinical, veterinary, and human surgery. However, the ultimate success of the field will depend on innovative NIR fluorophores that solve important clinical problems. Curadel has invented a novel family of NIR fluorophores termed ?zwitterionic.? More precisely, they are geometrically balanced, electrically-neutral, polyionic polymethine indocyanines. Zwitterionic NIR fluorophores exhibit extremely low non-specific binding and uptake in normal tissues and organs after a single intravenous injection, yet have extremely high extinction coefficient, quantum yield, and signal strength. Because of these properties, zwitterionic NIR fluorophores create the highest possible signal-to-background ratio (SBR). There are two immediate clinical uses for zwitterionic NIR fluorophores that make them so attractive commercially. First, they can be conjugated in one chemical step, through either N-hydroxysuccinimide (NHS) esters, tetrafluorophenyl (TFP) esters, or maleimide to any cancer-targeted small molecule, peptidomimetic, antibody, protein, or nanoparticle thus creating a targeted NIR fluorescent contrast agent for cancer surgery. Second, when injected in their simplest carboxylic acid form, zwitterionic NIR fluorophores exhibit 100% renal clearance and elimination into urine. This causes the ureters to become NIR fluorescent for several hours after a single intravenous injection, thus providing surgeons with the ability to avoid the ureters during cancer surgeries of the abdomen and pelvis. Ureter damage, while uncommon, leads to extraordinarily high cost and patient morbidity. Because of its clinical potential, ZW800-1 was deemed a high value asset by the NCI's Experimental Therapeutics (NExT) Program and was accepted into the first-in-human tract. In consultation with the FDA, the NExT Program paid for a complete two-species toxicology package, a genotoxicity package, and mutagenicity package, all of which were negative (see Appendix). Because of ZW800-1, and Curadel's drug portfolio of over 315 unique chemical entities, the most important companies in the field of surgery have visited us, and most are interested in investment and/or distribution. The message we have received, though, is consistent ? investment will only come after first-in-human clinical trials of ZW800-1 are completed. In this direct-to-Phase 2 (D2P2) SBIR application, our approach to solve our current dilemma is systematic. cGMP manufacturing of ZW800-1 under ISO-7, aseptic fill-finish including lyophilization under ISO 5/4.8, then a Phase 1A/1B clinical study at our major academic collaboration site, the Leiden University Medical Center (LUMC) in the Netherlands. Completion of the aims will position Curadel to execute a sizeable distribution/investment deal with a major player in the surgical space, and thus cross the ?valley of death.?
Image-guided surgery using invisible near-infrared (NIR) fluorescent light requires two things, an imaging system that ?sees? this special type of light, and drugs (called fluorophores) that light up whatever target the surgeon needs to see. Curadel has invented a new class of NIR fluorophores called ?zwitterionic,? which solve several problems that arise during cancer surgery. When combined with targeting molecules, zwitterionic NIR fluorophores create the best performing contrast agents in the field. When used alone, they highlight the ureters and help surgeons avoid damage to them. In this D2P2 SBIR application, we describe the steps necessary to perform first-in-human clinical testing of ZW800-1 and thus cross the ?valley of death? for the technology.
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