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

• 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
• 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

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 手术目标的基础是关键神经的功能保留和最大限度地减少术后并发症。 手术患者发病率。不幸的是，手术过程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期间无法观察神经，导致术后患者发病率增加。神经损伤 是微创手术常见的术后并发症，导致患者严重发病 以及长期后果，包括慢性疼痛、麻木、排尿和排便功能障碍， 性功能障碍和瘫痪意外的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。目前的神经识别策略利用非神经元识别技术。 可量化的标准，如解剖结构，纹理，颜色和与周围结构的关系，以区分 从非神经组织中分离神经或输尿管。在创伤、肿瘤侵袭或感染的情况下，神经识别 使用上述标准尤其具有挑战性，并且通常不能防止神经损伤。使用白色光 反射率，这是手术室照明的标准模式，视觉差异小 神经和邻近组织是不可察觉的。有一个未满足的需求，以改善术中 神经和输尿管的可视化，以保护其功能，并最大限度地减少手术后患者的发病率。 目前还没有临床批准的药物可以在同一手术中增强神经和输尿管的对比度。 生物科学公司已经开发出一种一流的静脉注射剂，用于神经可视化。这位候选人 ALM-488是一种肽染料缀合物，其在体内结合运动神经、感觉神经和自主神经，并使神经传导性神经传导。 具有高神经与非神经对比度的可视化，无固有毒性。ALM-488发出波长为 其与近红外（NIR）肿瘤剂的潜在双重用途相容，因此非常适合于递送 在切除过程中增强肿瘤组织和神经可视化的互补目标。在临床前 在一些研究中，ALM-488以高选择性标记神经和输尿管，这两者都可以使用 现有临床批准的内窥镜。至关重要的是，ALM-488最近完成了神经 在开放性头颈外科手术中的描绘，这表明ALM-488是安全的，并有潜力 显著提高了术中真实的时间神经识别。在此直接进入第二阶段SBIR， Biosciences建议评估ALM-488改善腹部手术中神经和输尿管可视化的功效 腹腔镜手术，包括使用FDA批准的器械进行肿瘤切除。他们会做到的 在加州圣地亚哥健康大学和斯坦福大学进行了2期多中心试验 医疗中心1）定义接受涉及夹层的腹腔镜手术的患者中的ALM-488剂量 1）食管裂孔（Nissen、Toupet、Heller、食管裂孔疝修补术）和2）用于结直肠的盆腔剥离术 手术（腹部会阴切除术、直肠固定术、直肠切除术）;以及2）评估ALM-488的功效以改善 术中神经和输尿管清晰度。Alzheimer预计，ALM-488的临床翻译将是可行的。 微创手术的变革，以防止意外伤害并改善术后患者 结果。