Toxicology (IND-enabling) studies for a novel nerve imaging agent for prostate cancer

ABSTRACT Translational safety studies in novel nerve imaging agent for radical prostatectomies In this two-year proposal, we will complete IND-enabling studies for NerveLight, a nerve imaging agent. We apply single dose NerveLight interstitially (topically), intra-operatively for ~ 15 min at the beginning of radical prostatectomies, then wash the excess. There is no marketed, soluble, non-device nerve imaging agent. NerveLight is comprised of a Near InfraRed (NIR) dye that fluoresces in the 800 region, attached to recombinant human Nerve Growth Factor (rhNGF). In preliminary canine studies, we have shown that the dye can be detected in clinical systems designed to image indocyanine green (ICG). It is known that rhNGF binds selectively to tropomyosin kinase A (TrkA) high affinity receptors expressed at the distal ends of nerve tissue. When the NGF/TrkA complex is endocytosed, dye attached to rhNGF is moved to nerve cell bodies. In separate repeat doses, dye and rhNGF when given as eye drops are safe. We previously showed that NerveLight can be (i) visualized and is selective in all rat studies (n=103); (ii) of which n=46 were in radical prostatectomies; and (iii) completed non-GLP dose-range finding studies in rat to statistical significance in rat. Project Milestone. The Project Milestone is to confirm safety – exposure to NerveLight toxicity exposure in tissue - per FDA Guidance in two species, rat and dog - in GLP, nonclinical IND-enabling studies. Hypothesis, Specific Aims. We hypothesize that safety will be confirmed in GLP toxicology and in vitro safety pharmacology studies in rat and dog. We will test that hypothesis in the following Specific Aims: Specific Aim 1. In Aim 1.1, using the same imaging and surgical protocols as previously, we will conduct non- GLP, pilot, dose-range finding studies in anesthetized, male adult, non-neutered naïve dogs in an “open” procedure (acute, non-survival). In Aim 1.2, after incision, NerveLight is applied, washed, then prostate and at- risk nerve tissue are harvested, then non-GLP imaging and molecular histology are done. Success criteria for Aim 1 are to: (i) determine canine dose via absorption and visualization for the Dye-Adduct-Ratio (DAR2) variant determined in rat; and (ii) use co-localization to confirm agent is in target nerves. Specific Aim 2. In Aim 2.1, we will conduct GLP toxicology and safety pharmacology in rat and dog per established translational nonclinical design. Success criteria are that all results fall within 10% of values for hematology and biochemistry known for both species. In Aim 2.2, we use the same established histology methods as in Aim 1.2, here to GLP, to statistical significance, again using co-localization to confirm that agent is target nerves. Next steps. Prior to beginning this Project, we will have selected a not-novel imaging system in which NerveLight can be detected (no funding requested). Upon completion of an IND, we will test three Single Ascending Doses of NerveLight in a clinical Phase 1 study in men undergoing radical prostatectomies. Manzanita is expert in conjugation chemistry, analytics, rhNGF science, neurology, and regulatory affairs.