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

使用不可见的近红外(NIR)荧光灯的图像引导手术将继续存在。多重 Stryker、奥林巴斯、美敦力和直觉外科公司的商业成像系统现在可用于 人体外科手术。然而，只有创新的近红外荧光团才能解决主要的临床问题。 库拉德尔发明了一种新的近红外荧光发光体家族，被称为“两性离子”，或者更准确地说， 几何平衡，电中性，多离子聚亚甲基吲哚菁类。两性离子近红外荧光团， 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 100%的肾脏清除和排出尿液。 在静脉注射低剂量(≤2.5 mg)后1-10分钟内，输尿管变得高度近红外 长达3.6小时的荧光，从而使外科医生能够在所有腹盆腔中避开它们 癌症手术。事实上，在大多数情况下，ZW800-1消除了手术解剖、识别和隔离的需要 可节省20分钟以上的手术时间，减少麻醉时间，降低手术风险 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的实验中心视为高价值资产 治疗(NEXT)计划，并被接受进入首例人类肠道。两种毒性，以及 遗传毒性和致突变性都非常低。库拉德尔使用了直接到第二阶段的SBIR拨款(NCI 5R44-CA-210820-02)，以扩大cGMP生产，鉴定杂质，并优化无菌填充整理，而 欧洲的合作者在人类志愿者身上进行了一期试验，在患者身上进行了二期试验 接受腹盆癌切除手术。公布了第一阶段和第二阶段试验的结果 以下是例外，并验证了我们的假设，即ZW800-1是一种理想的输尿管成像造影剂。 FLARE®、奥林巴斯®和达芬奇®近红外荧光单次低剂量输尿管成像数小时 成像系统，如果需要，可以为较长的病例重复使用。 ZW800-1现在准备完成剩余的市场审批步骤，我们预计 在腹盆癌手术中被广泛采用。我们应用程序的创新方面包括cGMP 合成和无菌填充-整理策略，不需要辅料或其他添加剂，但最终结果 具有5年稳定性的药物产品，以及只需≈800万美元即可获得保密协议的商业化计划 然而，提交的结果是一种毛利率为93%的商业产品，年市场规模超过1亿美元。我们的 竞争地位也异常强劲，因为ZW800-1在美国、欧洲、 日本和澳大利亚，以及独特的药代动力学，没有其他竞争对手的近红外荧光团可以与之匹敌。 我们的长期目标是一劳永逸地解决癌症手术中输尿管标测的问题。

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.