Development of ALM-488 for nerve and ureter visualization during abdominal surgery

开发用于腹部手术期间神经和输尿管可视化的 ALM-488

基本信息

批准号：
10699258
负责人：
Brett J. Berman
金额：
$ 93.72万
依托单位：
ALUME BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-08 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699258
关键词：
Abdomen Academic Medical Centers Accidents Accounting Anatomy Binding Biological Sciences Burn injury California Clinical Colon Carcinoma Color Colorectal Cancer Colorectal Surgery Development Dissection Dose Dose Limiting Dyes Endoscopes Excision Exhibits Fluorescence Functional disorder Goals Head and Neck Surgery Head and neck structure Health Hiatal Hernia Hour Human Incidence Individual Infection Injury Intravenous Intravenous infusion procedures Label Laparoscopes Laparoscopic Surgical Procedures Length Light Lighting Location Malignant neoplasm of ovary Measurement Methods Monitor Morbidity - disease rate Motor Multicenter Trials Nerve Numbness Operating Rooms Operative Surgical Procedures Paralysed Participant Patient-Focused Outcomes Patients Pelvis Peptides Peripheral Nerves Pharmaceutical Preparations Phase Phase I/II Trial Postoperative Complications Postoperative Period Procedures Respiratory Diaphragm Rodent Safety Schedule Sexual Dysfunction Small Business Innovation Research Grant Stretching Structure Surgeon System Texture Time Tissues Toxic effect Trauma Tumor Cell Invasion Tumor Tissue Universities Ureter Visual Visualization afferent nerve autonomic nerve cancer surgery chronic pain clinical candidate clinical translation commercialization contrast enhanced fluorescence imaging gastrointestinal high risk imaging agent improved in vivo indexing instrumentation minimally invasive nerve agent nerve damage nerve injury nerve supply novel open label patient population phase 3 testing phase II trial preclinical study preservation prevent prospective protein aminoacid sequence repaired research clinical testing tumor urinary

项目摘要

PROJECT SUMMARY 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.

项目摘要手术目标的基础是临界神经的功能保存和最小化。手术患者发病率。不幸的是，手术期间无意的神经损伤仍然是主要原因手术后患者的发病率是由于外科医生在手术过程中可视化神经而导致的。神经损伤是微创手术的常见术后并发症，导致患者的发病率明显以及可能包括慢性疼痛，麻木，尿和缺乏障碍的长期后果，性功能障碍和瘫痪。无意内术中输尿管损伤也有助于高该患者人群的术后并发症发生率。当前的神经识别策略利用非可量化标准，例如解剖学，质地，颜色和与周围结构的关系，以区分来自非神经组织的神经或输尿管。在创伤，肿瘤侵袭或感染的情况下，神经识别使用上述标准特别具有挑战性，并且通常无法防止神经损伤。使用白光反射率，这是手术室中照明的标准模式，小小之间的视觉差异神经和邻近组织是不可察觉的。有未满足的需要改善术中的神经和输尿管的可视化以保持其功能并最大程度地减少手术后患者的发病率。目前尚无临床认可的药物在同一手术中增强神经和输尿管对比度。 Alum Biosciences已开发出一种一类静脉注射剂，用于神经可视化。这个候选人， ALM-488是一种肽染料结合物，在体内结合运动，感觉和自主神经，并使神经启用具有高神经的可视化对形成鲜明对比，没有固有的毒性。 ALM-488荧光在波长处这是与近红外（NIR）肿瘤剂的潜在双重用途兼容的，因此非常适合提供关于在切除过程中增强肿瘤组织和神经可视化的免费目标。在临床前研究，ALM-488标记具有高选择性的神经和输尿管，这两者都可以轻松地使用现有的临床认可的内窥镜。至关重要的是，ALM-488最近完成了神经的临床测试张开的头部和颈部手术中的描述，证明ALM-488是安全的，并且有可能显着改善术中，实时神经识别。在直接到II期SBIR中，Alume Biosciences建议评估ALM-488的功效，以改善腹部的神经和输尿管可视化腹腔镜手术包括使用FDA清除仪器切除肿瘤。他们会做到这一点在加利福尼亚大学圣地亚哥卫生大学和斯坦福大学进行2期多中心试验医疗中心至1）在接受腹腔镜手术的患者中定义ALM-488剂量 1）diaphragmatic hiatus（Nissen，Toupet，Heller，裂孔疝修复）和2）结直肠骨的骨盆解剖手术（腹部会阴切除，直肠切除术）； 2）评估ALM-488以提高功效术中神经和输尿管显着性。 Alum预计ALM-488的临床翻译将是最小侵入性手术的变革性，以防止无意间损伤并改善术后患者结果。