Study of LGW16-03 To Identify Nerves

This is a single-arm, open-label phase I study of LGW16-03, a novel nerve-labeling fluorophore created with the goal of reducing iatrogenic injury to nerves during medical procedures. This study will be conducted in two parts. Part 1-dose escalation- will follow a 3+3 dose-escalation trial design and we will investigate the safety of LGW16-03; pharmacokinetic and fluorescence contrast data will also be collected. Escalation will be stopped if dose-limiting toxicity (DLT) is encountered. Part 2-dose expansion-will continue safety and pharmacokinetic data collection and evaluate further the fluorescence contrast to inform dose. Eligible participants will be limited to healthy patients scheduled for open-field orthopaedic surgical procedures involving exposure of a major compound nerve (i.e., a named nerve with both motor and sensory function). Participants who are determined eligible and who provide informed consent will be administered a single intravenous dose of LGW16-03 on the day of surgery (D0) approximately 60-120 minutes before anticipated induction of anesthesia. Surgical procedures will be conducted per standard of care (SOC) and LGW16-03 will not be used for surgical decision-making. Intraoperative fluorescence imaging (iFI) will begin at the time of first exposure of the target nerve and will be repeated at approximately 30 +/- 15-minute intervals until the target nerve is no longer visible, or the procedure concludes. Imaging will be performed using an FDA-approved fluorescence imaging system (Zeiss Kinevo). At each time point, images of the exposed nerve and adjacent tissues-including muscle, adipose (fat), vasculature, fascia, skin, and/or tendon-will be captured and analyzed for fluorescence signal intensity. These data will be used to calculate nerve-to-background tissue ratios (NBTR) at each time point during the surgery. These data will provide assessment of LGW16-03's ability to provide clinically meaningful intraoperative illumination of the nerve relative to surrounding tissues at the doses being investigated. Additional data will be collected in the form of surveys completed: 1) in real time by the operating surgeon performing trial operations; and 2) surgeons shown images obtained during the surgery who are then asked about the conspicuity of nerve tissue. Up to 24 patients will take part in Part 1, up to 14 patients will take part in Part 2; a maximum of 38 patients will be enrolled in the entire study. Enrollment is expected to take <18 months. Total time for this protocol is estimated to be 24 months.

Inclusion criteria

(All of the following criteria must be met by study participants to be eligible for study enrollment):

• Scheduled and medically cleared for a standard of care, open-field (not endoscopic) surgical procedure wherein a major nerve will be exposed and visible to the imaging equipment.
• Participants must be willing and able to provide informed consent for participation in the study and adhere to all study procedures.
• Intact motor and sensory function in the nerve to be imaged, as determined by physical exam performed by the operating surgeon or clinician on the study team, including:

• 5/5 motor strength in relevant muscle groups.
• Normal sensation on testing with a 5.07 Semmes-Weinstein filament or other valid testing method.
• No documented history of neuropathy of any kind.
• Age ≥ 18 years old.
• Medical clearance for surgery provided by a supervising medical provider (surgeon or primary care provider).
• Adequate renal function defined as creatinine clearance ≥ 60mL/min.
• Adequate liver function:

• Total bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN in patients with Gilbert's disease)
• ALT and AST ≤ 2.5 x ULN if no active liver involvement or ALT and AST ≤ 5 xULN with active liver involvement
• Albumin ≥3 g/dL
• Adequate hematologic and clotting function:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 8 g/dL or ≥ 5.6 mmol/L
• International Normalized Ratio (INR) ≤ 1.5 x ULN
• No growth factor support, transfusions, or albumin administration within 14 days of first dose of study treatment
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
• If of childbearing potential, must have a negative urine or serum pregnancy test and be using a medically acceptable form of contraception (e.g., hormonal birth control, intrauterine devices, double-barrier method) or abstinence.

Exclusion criteria

(Any of the following criteria would exclude a participant from study enrollment):

• Pregnant or breastfeeding persons who are not willing to stop breastfeeding. Due to the unknown safety profile of LGW16-03 in humans, and the potential for fetal or neonatal exposure through transplacental transfer or breast milk, breastfeeding is not allowed throughout the study and until at least 60 days after last dose.
• Nerve injury or dysfunction of any kind in the nerve to be imaged (e.g., diabetic neuropathy, multiple sclerosis, other neuropathy, traumatic nerve injury)
• Peripheral vascular disease requiring management a vascular surgeon.
• Prior surgery in the planned surgical region within the previous 365 days.
• Abnormal cardiac rhythm not controlled with medication, history of stroke, coronary events and/or heart failure within 1 year.
• Current evidence of renal or liver disease.
• History of fluorescein allergy.
• Direct administration of a local anesthetic agent in the region of the nerve to be imaged that could affect the motor or sensory function of the target nerve.
• Any other criteria deemed by the Principal Investigator that may prevent the participant from successfully completing the trial.