Fundamental to the goals of surgery are functional preservation of critical nerves and minimization of post- operative patient morbidity. Unfortunately, inadvertent nerve injury during surgery continues to be a major cause of post-surgical patient morbidity due to the inability of surgeons to visualize nerves during surgery. Nerve injury is a frequent postoperative complication of minimally invasive surgeries, leading to significant patient morbidity and long-term consequences that can include chronic pain, numbness, urinary and defecatory dysfunction, sexual dysfunction, and paralysis. Inadvertent intraoperative ureteral injuries additionally contribute to the high rate of postoperative complications in this patient population. Current nerve identification strategies utilize non- quantifiable criteria such as anatomy, texture, color, and relationship to surrounding structures to distinguish nerve or ureter from non-nerve tissues. In instances of trauma, tumor invasion, or infection, nerve identification using the above criteria is especially challenging and often fails to prevent nerve damage. Using white light reflectance, which is the standard mode of illumination in operating rooms, the visual difference between small nerves and adjacent tissue can be imperceptible. There is an unmet need to improve the intraoperative visualization of nerves and ureters to preserve their function and minimize patient morbidity following surgery. There are currently no clinically approved agents that enhance nerve and ureter contrast in the same surgery. Alume Biosciences has developed a first-in-class IV-administered agent for nerve visualization. This candidate, ALM-488, is a peptide dye conjugate that binds motor, sensory, and autonomic nerves in vivo and enables nerve visualization with high nerve to non-nerve contrast with no inherent toxicity. ALM-488 fluoresces at a wavelength that is compatible for potential dual use with Near-infrared (NIR) tumor agents, and thus, is well suited to deliver on the complimentary goals of enhancing tumor tissue and nerve visualization during resections. In preclinical studies, ALM-488 labels both nerve and ureter with high selectivity, both of which can be easily visualized using existing clinically approved endoscopes. Critically, ALM-488 has recently completed clinical testing for nerve delineation in open head and neck surgeries, which demonstrated that ALM-488 is safe and has potential to significantly improve intraoperative, real time nerve identification. In this Direct to Phase II SBIR, Alume Biosciences proposes to evaluate ALM-488 for efficacy to improve nerve and ureter visualization in abdominal laparoscopic surgeries including tumor resection using FDA cleared instrumentation. They will accomplish this with a Phase 2 multi-center trial at the University of California San Diego Health and at Stanford University Medical Center to 1) define the ALM-488 dose in patients undergoing laparoscopic surgeries involving dissection of the 1) diaphragmatic hiatus (Nissen, Toupet, Heller, hiatal hernia repair) and 2) pelvic dissection for colorectal surgery (abdominal perineal resection, rectopexy, proctectomy); and 2) evaluate ALM-488 for efficacy to improve intraoperative nerve and ureter conspicuity. Alume anticipates that clinical translation of ALM-488 will be transformative for minimally invasive surgeries to prevent inadvertent injury and improve post-operative patient outcomes.
Public Health Relevance Statement: NARRATIVE There is an unmet need to improve the intraoperative visualization of nerves and ureters to preserve function and minimize patient morbidity following minimally invasive surgeries. Alume Biosciences has developed a novel peptide dye conjugate (ALM-488) that can be delivered intravenously before surgery as an agent to aid visualization of nerves during surgery. In this proposal, Alume proposes to complete a Phase 2 trial in patients undergoing minimally invasive abdominal surgery or tumor resection to establish efficacy of ALM-488 to improve intraoperative nerve and ureter visualization.
Project Terms: Abdominal; Abdomen; University Medical Centers; Academic Medical Centers; Accidents; Accounting; Anatomic Sites; Anatomic structures; Anatomy; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Burn injury; Burns; burned; California; Colorectal Surgery; Colon and Rectal Surgery; colon and rectum surgery; Color; Respiratory Diaphragm; Diaphragm; Dissection; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Dyes; Coloring Agents; Endoscopes; Exhibits; Fluorescence; Goals; Health; Hiatal Hernia; Human; Modern Man; Incidence; indexing; Infection; Intravenous infusion procedures; IV Infusion; intravenous infusion; nerve supply; innervation; instrumentation; Laparoscopes; Celioscopes; Peritoneoscopes; Light; Photoradiation; Lighting; Illumination; Methods; Morbidity - disease rate; Morbidity; Nerve; Numbness; Loss of Sensation; Operating Rooms; Patients; Pelvis; Pelvic; Pelvic Region; Peptides; Peripheral Nerves; Postoperative Complications; post-operative complications; Postoperative Period; Post-Operative; Postoperative; Rodent; Rodentia; Rodents Mammals; Safety; Time; Tissues; Body Tissues; Universities; Ureter; Schedule; chronic pain; neural injury; nerve injury; injuries; Injury; Label; improved; Procedures; Clinical; repair; repaired; Phase; Multi-center trial; Multicenter Trials; autonomic nerve; Visual; Individual; Measurement; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Intravenous; Hour; Texture; System; Location; Head and neck structure; Head and Neck; Tumor Tissue; afferent nerve; sensory nerve; gastrointestinal; Paralysed; Palsy; Plegia; paralysis; paralytic; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Sexual Dysfunction; Sex Disorders; Surgeon; Stretching; Toxic effect; Toxicities; Structure; novel; Participant; Colon Carcinoma; Colon Cancer; cancer in the colon; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Laparoscopic Surgical Procedures; Laparoscopic Surgery; laparoscopy-assisted surgery; cancer surgery; protein aminoacid sequence; peptide aminoacid sequence; peptide sequence; nerve agent; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; Molecular Interaction; Binding; Tumor Invasion; Tumor Cell Invasion; preventing; prevent; Length; Dose; Dose Limiting; Head and Neck Surgery; Motor; in vivo; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Phase I/II Trial; Phase 1/2 trial; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; urinary; Development; developmental; Colorectal Cancer; Colo-rectal Cancer; open label; open label study; preclinical study; pre-clinical study; prospective; Trauma; fluorescent imaging; fluorescence imaging; commercialization; tumor; high risk; minimally invasive; patient population; phase 2 trial; phase II trial; contrast enhanced; imaging agent; clinical candidate; clinically translatable; clinical translation; preservation; phase 3 evaluation; phase III evaluation; phase III testing; phase 3 testing; Visualization; nerve damage
