ZW800-1: The 1st Zwitterionic NIR Fluorophore for Cancer Imaging & Ureter Mapping

使用不可见近红外（NIR）荧光的图像引导手术将继续存在。多 来自斯特赖克、奥林巴斯、美敦力和Intuitive Surgical的商业成像系统现在可用于 人体手术然而，只有创新的近红外荧光团才能解决主要的临床问题。 Curadel发明了一种新的近红外荧光团家族，称为"两性离子"，或者更准确地说， 几何平衡的、电中性的、多离子聚甲川吲哚菁。两性离子NIR荧光团， 如ZW800 - 1，在正常组织和器官中表现出超低非特异性结合和摄取，以及 100%肾脏清除率和尿液消除率。 在低剂量（≤ 2.5 mg）静脉（IV）注射后1 - 10 min内，输尿管变得高度NIR 荧光长达3.6小时，从而为外科医生提供了在所有腹盆手术期间避免它们的能力。 癌症手术事实上，在大多数情况下，ZW 800 - 1消除了手术解剖、识别和分离的需要 输尿管，节省20分钟以上的手术时间，减少麻醉时间，并降低 并发症，如粘连。目前，输尿管损伤在癌症手术中相当常见，并导致 巨大的成本（仅在美国每年就有13.5亿美元）和高患者发病率。 由于其临床潜力，ZW800 - 1被NCI的实验室视为高价值资产。 治疗（NExT）计划，并被接受到第一次在人类道。两种毒性，以及 遗传毒性和致突变性非常低。Curadel使用了直接到第二阶段SBIR赠款（NCI 5R44-CA-210820 - 02），以扩大cGMP生产规模，鉴定杂质，并优化无菌灌装-成品， 欧洲的合作者对人类志愿者进行了1期试验，对患者进行了2期试验 接受腹盆手术切除肿瘤1期和2期试验的结果显示 这证实了ZW 800 - 1是一种理想输尿管造影剂的假设。 单次低剂量可在FLARE®、Olympus®和Da芬奇® NIR荧光上进行长达数小时的输尿管标测 成像系统，并可以重复，如果需要更长的情况下。 ZW800 - 1现在准备完成剩余的市场批准步骤，我们预计 广泛应用于腹盆癌手术。我们应用的创新方面包括cGMP 不需要赋形剂或其他添加剂的合成和无菌灌装-成品策略， 具有> 5年稳定性的药物产品，以及仅需1.8亿美元即可进入NDA的商业化计划 提交的结果是商业产品的毛利率超过93%，年市场超过1亿美元。我们 由于ZW 800 - 1在美国、欧洲 日本和澳大利亚，和独特的药代动力学，没有其他竞争的近红外荧光团可以匹配。 我们的长期目标是一劳永逸地解决癌症手术中的输尿管标测问题。

Image-guided surgery using invisible near-infrared (NIR) fluorescent light is here to stay. Multiple commercial imaging systems from Stryker, Olympus, Medtronic, and Intuitive Surgical are now available for human surgery. However, only innovative NIR fluorophores will solve major clinical problems. Curadel has invented a novel family of NIR fluorophores termed “zwitterionic,” or more precisely, geometrically-balanced, electrically-neutral, polyionic polymethine indocyanines. Zwitterionic NIR fluorophores, such as ZW800-1, exhibit ultralow non-specific binding and uptake in normal tissues and organs, as well as 100% renal clearance and elimination into urine. Within 1-10 min after a low (≤ 2.5 mg) dose intravenous (IV) injection, the ureters become highly NIR fluorescent for up to 3.6 h, thus providing surgeons with the ability to avoid them during all abdominopelvic cancer surgeries. In fact, in most cases ZW800-1 eliminates the need to surgically dissect, identify, and isolate the ureters altogether, saving over 20 min of OR time, reducing anesthesia time, and reducing the risk of complications, such as adhesions. Currently, ureter damage is quite common in cancer surgery and leads to enormous cost ($1.35B annually in the USA alone) and high patient morbidity. Because of its clinical potential, ZW800-1 was deemed a high value asset by the NCI’s Experimental Therapeutics (NExT) Program and was accepted into the first-in-human tract. Two-species toxicity, as well as genotoxicity and mutagenicity, were extraordinarily low. Curadel used a Direct-to-Phase II SBIR grant (NCI 5R44-CA-210820-02) to scale-up cGMP production, qualify impurities, and optimize aseptic fill-finish, while collaborators in Europe performed a Phase 1 trial on human volunteers and a Phase 2 trial on patients undergoing abdominopelvic surgery for cancer resection. The results of the Phase 1 and 2 trials presented herein are exceptional and validate our hypothesis that ZW800-1 is an ideal contrast agent for ureter mapping. A single low dose permitted ureter mapping for hours on FLARE®, Olympus®, and Da Vinci® NIR fluorescence imaging systems, and could be repeated if needed for longer cases. ZW800-1 is now poised to complete the remaining steps of market approval where we anticipate widespread adoption in abdominopelvic cancer surgery. Innovative aspects of our application include a cGMP synthesis and aseptic fill-finish strategy that does not require excipients or other additives yet results in a final drug product with > 5 years of stability, and a commercialization plan that requires only ≈ $8M to get to NDA submission yet results in a commercial product with >93% gross margin and a $100M+ annual market. Our competitive position is also unusually strong because of issued patent claims for ZW800-1 in USA, Europe, Japan, and Australia, and unique pharmacokinetics that no other competing NIR fluorophore can match. Our long-term goal is to solve the problem of ureter mapping during cancer surgery once and for all.