Clinical Translation of Near Infrared Nerve-Specific Fluorophores for Nerve-sparing Prostatectomy

PROJECT SUMMARY Iatrogenic nerve injury is one of the most feared complications of surgery. Nerves are critically important to the function of most tissues and nerve injury can lead to permanent disability. Surgery is performed commonly in the U.S. with approximately 40 million operations annually, incurring up to 600,000 iatrogenic nerve injuries. One procedure particularly plagued by nerve damage is radical prostatectomy (RP), where nerve damage occurs in up to 60% of patients, despite the practice of nerve sparing surgical methods for >30 years. At present there is no clinically approved technology to improve visual recognition of nerve tissue during surgery, leaving surgeons to rely largely on anatomical knowledge to locate small or buried nerves invisible to the naked eye. Fluorescence-guided surgery (FGS) is a nascent field with demonstrated efficacy in improving surgical outcomes for cancer resection and normal anatomy preservation using molecularly-targeted fluorophores and commercial FGS imaging systems. We have developed several first-in-kind, targeted, near-infrared (NIR) fluorophores that label nerve tissue with high affinity—to date the most promising is IT01-08. IT01-08 specifically labels rodent, swine and canine nerves following systemic administration and demonstrates cross reactivity in ex vivo human specimen staining. Notably, we have developed a library of IT01-08 derivatives, several of which have displayed vastly improved water solubilities and toxicity profiles in preliminary testing, increasing the no observed adverse effect level (NOAEL) doses 2-10X. Final solubility, toxicology, and pharmacology testing is required to select a lead compound from IT01-08 and its derivatives. Following lead compound selection, clinical translation of the optimal NIR nerve-specific fluorophore will enhance nerve identification during nerve-sparing RP, resulting in reduced nerve injury and improved patient outcomes. This study’s immediate milestones include – Phase I: (1) selection of a clinically viable, NIR nerve-specific fluorophore for translation, (2) relevant pharmacokinetics, dose ranging pharmacodynamics, and biodistribution quantification, and (3) preliminary toxicology analysis to guide investigational new drug (IND)-enabling studies. Phase II: (4) good laboratory practice (GLP) synthesized fluorophore and formulation product for, (5) a GLP two-species pharmacology and toxicology (pharm/tox) study facilitating, (6) a successful IND application to the FDA. Our long-term strategic plan is to develop our NIR nerve- specific fluorophores for human use to enhance the identification and preservation of nerves with broad clinical impact for all surgical subspecialties. Completion of the proposed aims will establish pre-clinical testing of these promising nerve highlighting agents towards first-in-human trials and provide a strong foundation for industry partnerships and investment for clinical translation.