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

项目总结 外科手术的基本目标是保留关键神经的功能和最大限度地减少术后并发症 手术病人发病率。不幸的是，手术中无意的神经损伤仍然是一个主要原因。 由于外科医生在手术过程中不能观察到神经，手术后病人的发病率。神经损伤 是微创手术中常见的术后并发症，导致患者发病率显著升高。 以及长期后果，包括慢性疼痛、麻木、排尿和排便功能障碍， 性功能障碍和瘫痪。术中不慎的输尿管损伤也是导致高 这一患者群体的术后并发症发生率。目前的神经识别策略使用非 可量化的标准，如解剖、纹理、颜色和与周围结构的关系，以区分 神经或输尿管来自非神经组织。在创伤、肿瘤侵袭或感染的情况下，神经识别 使用上述标准尤其具有挑战性，而且往往无法预防神经损伤。使用白光 反射率，这是手术室的标准照明模式，视觉上的差别很小 神经和邻近组织可能是不可察觉的。还有一个尚未得到满足的需要，那就是改善术中 可视化的神经和输尿管，以保留其功能和减少术后患者的发病率。 目前还没有临床批准的药物在同一手术中增强神经和输尿管对比。 阿鲁姆生物科学公司已经开发出一种用于神经可视化的一流的IV给药制剂。这位候选人， ALM-488是一种多肽染料结合物，可在体内结合运动神经、感觉神经和自主神经，使神经 具有高度神经与非神经对比的可视化，无固有毒性。ALM-488的波长荧光 它与近红外(NIR)肿瘤药物的潜在双重用途相兼容，因此非常适合于输送 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。在临床前阶段 研究表明，ALM-488标记神经和输尿管具有很高的选择性，两者都可以很容易地使用 现有的经临床批准的内窥镜。至关重要的是，ALM-488最近完成了对神经的临床测试 在头颈部开放手术中的应用，表明ALM-488是安全的，并具有潜在的 显著提高了术中实时神经识别能力。在此直接到第二阶段SBIR，Alume 生物科学公司建议评估ALM-488在改善腹部神经和输尿管可视化方面的有效性 使用FDA批准的器械进行包括肿瘤切除在内的腹腔镜手术。他们会做到这一点的 在加州大学圣地亚哥分校和斯坦福大学进行了一项2期多中心试验 医疗中心将1)确定接受涉及夹层的腹腔镜手术患者的ALM-488剂量 1)隔裂孔(Nissen、Touet、Heller、裂孔疝修补术)和2)盆腔分离术治疗结直肠癌 手术(腹会阴切除、直肠固定术、直肠切除术)；以及2)评估ALM-488的疗效以改进 术中神经输尿管显影。Alume预计ALM-488的临床翻译将是 变革微创手术以防止意外伤害和改善术后患者 结果。

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.