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

ZW800-1：第一个用于癌症成像的两性离子近红外荧光团

• 批准号: 10408716
• 负责人: John V Frangioni
• 金额: $ 80.8万
• 依托单位: CURADEL, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408716
• 关键词: Adhesions; Adoption; Amber; Anesthesia procedures; Australia; Award; Binding; Budgets; Clinical; Contrast Media; Cyclic GMP; Development; Dose; Drug Approval; Drug Kinetics; Education; Europe; Excipients; Excision; Exhibits; Family; Fees; Freeze Drying; Funding; Goals; Grant; Healthcare Systems; Hour; Human; Human Volunteers; Image-Guided Surgery; Injections; Intravenous; Intuition; Investigational Therapies; Investments; Japan; Label; Legal patent; Light; Methods; Minor; Morbidity - disease rate; Near-infrared optical imaging; New England; Normal tissue morphology; Operative Surgical Procedures; Organ; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I/II Trial; Phase III Clinical Trials; Positioning Attribute; Powder dose form; Problem Solving; Production; Renal clearance function; Risk; Savings; Services; Small Business Innovation Research Grant; Surgeon; System; Testing; Time; Toxic effect; Ureter; Urine; Validation; Vial device; analytical method; base; cGMP production; cancer imaging; cancer surgery; commercialization; cost; drug distribution; first-in-human; fluorophore; genotoxicity; imaging system; innovation; novel; phase I trial; phase II trial; polyion; programs; scale up; sterility testing; uptake

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.

使用不可见近红外 (NIR) 荧光灯的图像引导手术将继续存在。多种的 Stryker、Olympus、Medtronic 和 Intuitive Surgical 的商业成像系统现已上市 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 发明了一种新型近红外荧光团家族，称为“两性离子”，或更准确地说， 几何平衡、电中性、聚离子聚次甲基吲哚菁。两性离子近红外荧光团， 例如 ZW800-1，在正常组织和器官中表现出超低的非特异性结合和摄取，以及 100% 肾脏清除并排入尿液。 低剂量（≤ 2.5 mg）静脉（IV）注射后 1-10 分钟内，输尿管变得高度 NIR 荧光时间长达 3.6 小时，从而使外科医生能够在整个腹盆腔手术过程中避免它们 癌症手术。事实上，在大多数情况下，ZW800-1 无需通过手术解剖、识别和隔离 整个输尿管，节省超过 20 分钟的手术时间，减少麻醉时间，并降低风险 并发症，例如粘连。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 1.35B 美元）和高患者发病率。 由于其临床潜力，ZW800-1 被 NCI 实验实验室视为高价值资产 治疗（NExT）计划并被接受进入人体首次治疗。两种物种的毒性，以及 遗传毒性和致突变性极低。 Curadel 使用了直接进入第二阶段 SBIR 拨款（NCI 5R44-CA-210820-02），以扩大 cGMP 生产、鉴定杂质并优化无菌灌装完成，同时 欧洲的合作者对人类志愿者进行了第一阶段试验，并对患者进行了第二阶段试验 接受腹盆腔癌症切除手术。第一阶段和第二阶段试验的结果已公布 这些都是例外，验证了我们的假设，即 ZW800-1 是输尿管标测的理想造影剂。 单次低剂量可在 FLARE®、Olympus® 和 Da Vinci® NIR 荧光上进行数小时的输尿管标测 成像系统，如果需要更长的病例可以重复。 ZW800-1 现在已准备好完成我们预期的市场审批的剩余步骤 在腹盆腔癌手术中广泛采用。我们应用的创新方面包括 cGMP 合成和无菌灌装完成策略，不需要赋形剂或其他添加剂，但会产生最终结果 稳定性超过 5 年的药品，以及仅需约 800 万美元即可获得 NDA 的商业化计划 提交后，商业产品的毛利率超过 93%，年市场规模超过 1 亿美元。我们的 由于 ZW800-1 在美国、欧洲、 日本和澳大利亚，以及其他竞争性近红外荧光团无法比拟的独特药代动力学。 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。