In 2015, about 130,000 men elected to undergo radical prostatectomies (RPs). Even with nerve-sparing, incontinence and/or impotence can occur in up to 75% of cases. In our SBIR Phase I grant, we showed in vivo Proof-of-Concept of ?Nervelight,? a peripheral nerve imaging agent comprised of a Near InfraRed (NIR) dye, Dyomics 800, attached to recombinant human Nerve Growth Factor. Nervelight may spare nerves at risk in other cancer surgeries, i.e. lymph node dissection for breast cancer, or oncological parotidectomies. Hypothesis. Our scientific hypothesis is that a single dose of peripherally administered Nervelight will localize bilaterally to cavernous nerves at risk in RPs. Our commercial hypothesis is that we can translate this data into a commercial medical imaging agent to aid nerve-sparing by showing that a single dose of Nervelight: (1) can be visually detected in target nerves; (2) is safe in a GLP single dose acute toxicity study; and (3) can be produced to cGMP supporting an Investigational New Drug (IND). We will test these hypotheses in these Aims:
Aim 1. 1. We will confirm effectiveness by showing bilateral localization in cavernous nerves in adult, male nave rats after a single central injection in three pilot studies (n=90) to identify preferred injection site, route of administration (sub-cutaneous or intra-muscular), and dose. Immediately after euthanization, using the Fluobeam, we will collect a single image of neurovascular bundle from inside the incision. Using the approach established in our SBIR Phase I, we will dissect left side target nerves to assess duration of effect in large tissue samples. From right side target nerves we will confirm visual observations from Fluobeam that Nervelight has localized to target nerves by comparing two sets of contiguous sections, one set stained with nerve markers (neuronal nuclear antigen, NeuN; PGP 9.5), and the other set cryo-preserved for NIR imaging.
Aim 1. 2. Using best site, route and dose from Aim 1.1, we will determine dose in nave male adult rats (n=240) at two dose cohorts, low from Aim 1.1 and high (10X low) over eight timepoints (n=6 per timepoint group, both dose cohorts). We will analyze within- and between-group variances to statistical significance by quantifying pixels in target nerves, and will assess fluorescence in a whole body distribution study.
Aim 2. We will assess safety per Guidance, with best route from Aim 1.1 and intravenous (IV) route, in a GLP study of acute, single dose toxicity to statistical significance in rat (n=240) and dog (n=50).
Aim 3. We will complete a Chemistry, Manufacturing and Controls (CMC) Plan by developing protocols, and bioanalytics for liquid formulation GMP product into hand-filled vials for use in commercial syringes. Project Milestone. Upon funding, we will request a pre-IND meeting to review our nonclinical plan. Our Project Milestone is to complete all nonclinical work to support and open an IND for a pivotal Phase 1 safety study (n=20). We have the regulatory, clinical, and scientific team to conduct Phase III studies for commercialization.
In surgical resections for cancer, a key goal is to avoid inadvertent damage to nerves. With funding support for an SBIR Phase I grant, we showed Proof-of-Concept of a peripheral nerve imaging agent comprised of a Near InfraRed Dye attached to a naturally occurring protein, Nerve Growth Factor ? ?Nervelight.? Preliminary results suggest that a surgeon could observe Nervelight intra-operatively so that s/he could avoid damaging nerves during radical prostatectomies (RPs), thus minimizing incontinence and/or impotence. We propose to adapt Nervelight as an imaging agent to be used intra-operatively in RPs by: (1) showing effectiveness in a non-GLP study, by determining best dose, route (sub-cutaneous or intra-muscular), dose, and duration of effect after injecting Nervelight peripherally, to be absorbed by cavernous nerves at risk in retropubic RPs; (2) conducting a GLP single dose, acute toxicity study per FDA Guidance; and (3) developing manufacturing methods in a Chemistry Manufacturing and Controls (CMC) plan to produce cGMP study article. After requesting a preliminary Investigational New Drug (pre-IND) meeting, our Project Milestone is to open an IND for an unblinded safety study of Nervelight in men undergoing radical prostatectomies (n=20).