Optimizing Radiosynthetic Yield of [18F]FTT For Wide-Spread Distribution

优化 [18F]FTT 的放射合成产量以实现广泛分布

• 批准号: 10821733
• 负责人: Hsiaoju Sharon Lee
• 金额: $ 104.39万
• 依托单位: TREVARX BIOMEDICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10821733
• 关键词: Binding; Biological Assay; Breast; Cancer Patient; Clinical Trials; Cyclic GMP; Databases; Development; Drug Formulations; Drug Stability; Ensure; Formulation; Foundations; Gene Mutation; Genes; Genomics; Image; Industry; Label; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Marketing; Measures; Methods; Modeling; Monitor; Multi-Institutional Clinical Trial; Multicenter Trials; Ovarian; Patient imaging; Pennsylvania; Performance; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Poly(ADP-ribose) Polymerase Inhibitor; Polymerase; Positron-Emission Tomography; Preparation; Procedures; Process; Production; Prostate; Proteins; Radiolabeled; Radiopharmaceuticals; Reagent; Recommendation; Sampling; Site; Small Business Technology Transfer Research; Specific qualifier value; Standardization; Technology Transfer; Testing; Tissues; Tracer; Translating; Universities; Writing; analog; clinical center; clinical translation; commercialization; companion diagnostics; design; efficacy trial; imaging biomarker; improved; in vivo; inhibitor; inhibitor therapy; innovation; malignant breast neoplasm; novel; performance site; phase 2 study; phase II trial; phase III trial; pre-Investigational New Drug meeting; precision oncology; predictive marker; protein expression; quantitative imaging; radiotracer; repaired; response; success; supply chain; targeted treatment; timeline; tumor; uptake

ABSTRACT: Poly (ADP-ribose) polymerase inhibitors (PARPi’s) have emerged as important therapeutic agents targeting a broadening class of gene mutations approved for treatment of breast, ovarian, prostate, and other cancers. Genomic assays of BRCA-related genes and tumor homologous repair deficiency are used as companion diagnostics for PARPi therapy but have imperfect predictive efficacy for PARPi response. Trevarx Biomedical Inc.’s (Trevarx) product, [18F]Fluorthanatrace ([18F]FTT), a PET-radiolabeled analog of the PARPi, rucaparib, provides quantitative images of regional PARP expression and drug engagement for all approved PARPi’s. It can thus serve as a PARPi companion diagnostic to identify those most likely to respond to PARPi therapy, and importantly, those unlikely to respond. Over 175 patients imaged in single center clinical trials support the accuracy of [18F]FTT tumor uptake as an in-vivo measure of regional PARPi drug binding, and as an effective imaging-based biomarker of PARP-1 protein levels. A pre-IND meeting with FDA suggested that approval would require: (1) a Phase 3 tissue correlating [18F]FTT uptake and PARP-1 protein expression in tumor samples and (2) multi-center Phase 2 studies of [18F]FTT’s accuracy in predicting PARPi response. A 3-center Phase 2 trial PET-tissue comparison study has been initiated as a pilot for the larger Phase 3 trial, and striking new single- center Phase 2 results on [18F]FTT predictive accuracy strongly support Phase 2 multi-center trials under development. The focus of this proposal is to establish wide-spread radiopharmaceutical supply to support the expanded multi-center trials needed for approval and subsequent clinical translation. With a 3 year competitive lead, [18F]FTT is projected to enter a Phase 3 tracer-tissue trial and multi-center Phase 2 predictive efficacy trials to support an NDA in 2025. The steps described in this project will reduce the extended timeline for FDA approval that has been observed with previous PET radiotracers. Building on the success of our Phase I STTR project (1R41CA2612590-01), this STTR Phase II proposal by Trevarx and Penn will minimize this timeline by establishing methods for unifying radiosynthesis, maximizing product consistency and production yield, and generating a database to manage a larger supply chain for [18F]FTT. We aim to establish a new paradigm for rapid commercialization of PET radiopharmaceuticals by providing a “best practice” template by combining efforts in academic centers and commercial radiopharmaceutical supplier prior to Phase 3 to efficiently bring a novel PET radiotracer to market. Our STTR Phase II proposal establishes a roadmap to move from a single center academic trial to Phase 3 multi-center trials to efficient cGMP commercial production upon NDA approval. In this revised application, we provide more details on [18F]FTT production ( i.e., synthesis kit development and product formulation) and our strategy for the combined academic/commercial rollout of our radiotracer to prepare for the Phase 3 multi-center clinical trial recommended by the FDA in our Pre-IND meeting.

摘要： 聚（ADP-核糖）聚合酶抑制剂（PARPi）已经成为靶向肿瘤的重要治疗剂。 扩大了被批准用于治疗乳腺癌、卵巢癌、前列腺癌和其他癌症的基因突变类别。 BRCA相关基因和肿瘤同源修复缺陷的基因组检测被用作伴侣 诊断PARPi治疗，但对PARPi反应的预测功效不完善。Trevarx生物医学 公司的s（Trevarx）产品，[18 F]Fluorthanatrace（[18 F]FTT），PARPi的PET放射性标记类似物，rucaparib， 提供了所有批准的PARPi的局部PARP表达和药物结合的定量图像。它 因此可以作为PARPi伴随诊断，以识别最有可能对PARPi治疗有反应的患者， 重要的是，那些不太可能回应的人。在单中心临床试验中成像的超过175名患者支持 [18F]FTT肿瘤摄取作为局部PARPi药物结合的体内测量的准确性，以及作为有效的 PARP-1蛋白水平基于成像的生物标志物。与FDA的IND前会议表明，批准将 需要：（1）肿瘤样本中与[18 F]FTT摄取和PARP-1蛋白表达相关的3期组织， (2)[18F]FTT预测PARPi应答准确性的多中心II期研究。一项3中心II期试验 PET-组织比较研究已经启动，作为更大的3期试验的试点， 中心II期[18F]FTT预测准确性结果强烈支持II期多中心试验， 发展该提案的重点是建立广泛的放射性药物供应，以支持 扩大多中心试验需要批准和随后的临床翻译。 凭借3年的竞争优势，[18 F]FTT预计将进入III期示踪剂-组织试验和多中心阶段 2项预测性疗效试验，以支持2025年的NDA。本项目中描述的步骤将减少扩展的 FDA批准的时间轴与之前的PET放射性示踪剂相同。在成功的基础上， 我们的第一阶段STTR项目（1 R41 CA 2612590 -01），Trevarx和Penn的STTR第二阶段提案将最大限度地减少 这一时间轴通过建立统一的放射合成方法，最大限度地提高产品的一致性和生产 产量，并生成一个数据库来管理[18F]FTT的更大供应链。我们的目标是建立一个新的 通过提供“最佳实践”模板， 在第三阶段之前，结合学术中心和商业放射性药物供应商的努力， 有效地将新型PET放射性示踪剂推向市场。我们的STTR第二阶段提案建立了一个路线图， 从单中心学术试验到3期多中心试验，再到高效的cGMP商业化生产， NDA批准。在这个修订后的应用程序中，我们提供了更多关于[18 F]FTT生产的细节（即，合成试剂盒 开发和产品配方）和我们的战略，为结合学术/商业推出我们的 放射性示踪剂，为FDA在我们的Pre-IND会议上推荐的3期多中心临床试验做准备。