Commercialization of a proprietary Ga-68 PSMA-targeted drug for PET imaging in recurrent prostate cancer

用于复发性前列腺癌 PET 成像的专有 Ga-68 PSMA 靶向药物的商业化

• 批准号: 9896923
• 负责人: David Alexoff
• 金额: $ 85.31万
• 依托单位: FIVE ELEVEN PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896923
• 关键词: Address; Adoption; Affinity; Animals; Area; Behavior; Biochemical; Biological; Biological Assay; Cancer Patient; Capromab Pendetide; Caring; Cause of Death; Cells; Chelating Agents; Chemicals; Chemistry; Cities; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Communities; Consult; Data; Detection; Development; Devices; Diagnostic; Dose; Drug Kinetics; Drug Targeting; Epithelium; Europe; Evaluation; Exhibits; FOLH1 gene; Formularies; Formulation; Funding; Generations; Goals; High Pressure Liquid Chromatography; Hour; Human; Image; Investigation; Isomerism; Label; Lead; Legal patent; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medical; Metastatic Prostate Cancer; Methods; Morphology; Patients; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Philadelphia; Positron-Emission Tomography; Probability; Process; Production; Property; Prostate Adenocarcinoma; Protocols documentation; Published Comment; Radioisotopes; Radiolabeled; Recurrence; Recurrent disease; Safety; Science; Screening for Prostate Cancer; Site; Small Business Innovation Research Grant; Stress; Stress Tests; Testing; Therapeutic; Time; Tissues; Universities; base; bone imaging; cancer imaging; clinical care; clinically significant; commercialization; contrast imaging; design; dosimetry; drug sensitivity; experience; experimental study; human data; imaging agent; improved outcome; inhibitor/antagonist; interest; manufacturing process; meetings; men; molecular imaging; novel; off-patent; overexpression; pharmacophore; phase 1 study; phase 2 study; pre-clinical; preclinical evaluation; prevent; prospective; radiochemical; radiotracer; repository; research clinical testing; secondary outcome; serum PSA; specific biomarkers; standard of care; targeted agent; targeted imaging; tool; treatment planning; uptake

Abstract: The objective of this Fast Track proposal is to support the development and commercialization of a proprietary positron emission tomography (PET) imaging agent, [68Ga]P16-093, that specifically targets prostate specific membrane antigen (PSMA) in patients with prostate cancer. Prostate cancer is the second leading cause of death from cancer in U.S. men. There are no commercially available 68Ga PSMA inhibitors on the market, which is preventing the widespread use of this clinically useful class of diagnostic drugs. The advantage of targeting PSMA using radiolabeled PSMA inhibitors is the combination of 100x–1000x fold expression levels of PSMA on the epithelium of prostate adenocarcinomas, which in combination with nM affinity constants results in uptake ratios of >50 whereas other radiotracers proposed for PCa exhibit much lower uptake ratios of the order of 5, enabling detection of much smaller lesions. Our [68Ga]P16-093 agent utilizes a proprietary chelator-linker-pharmacophore combination and has performed well in pre-clinical evaluation. Five Eleven Pharma is self-funding two Phase I clinical trials under IND #133222 to determine human dosimetry and pharmacokinetics in cancer patients using [68Ga]P16-093. Preliminary data from these trials has shown a good safety profile, favorable dosimetry and accumulation of [68Ga]P16-093 in PSMA-expressing tissue and prostate cancer lesions. During this early phase development, the FDA has suggested further investigations into the drug substance chemistry to support the longer term development of [68Ga]P16-093 and eventual NDA filing. The Phase 1 study of the Fast Track proposal is designed to validate the manufacturing process of [68Ga]P16- 093 through targeted “stress” testing, taking into account comments by the FDA addressing the identity, quantitation and stability of isomers in the final drug product. After successful completion of Fast Track Phase I, will have sufficient data to fully characterize the isomer content of the drug substance [68Ga]P16-093, including how isomer content may impact its biological activity. In Phase 2 of the Fast Track SBIR we proposes a Phase IIa clinical study that will focus on PSMA imaging in PCa patients presenting with biochemical recurrence (BCR) – rising serum PSA after primary treatment. The endpoint of the Phase IIa clinical trial is to detect a 20% change in management care in BCR patients when comparing treatment plans using [68Ga]P16-093 imaging information those based on standard of care imaging alone. This pilot efficacy data will help Five Eleven Pharma to design Phase IIb/III studies that, after consulting with the FDA, will lead to NDA-enabling clinical protocols.

抽象的： 该快速通道提案的目标是支持专有技术的开发和商业化 正电子发射断层扫描 (PET) 成像剂 [68Ga]P16-093，专门针对前列腺特异性 前列腺癌患者的膜抗原（PSMA）。前列腺癌是第二大原因 美国男性死于癌症的人数。 There are no commercially available 68Ga PSMA inhibitors on the market, 这阻碍了这类临床上有用的诊断药物的广泛使用。优点 使用放射性标记的 PSMA 抑制剂靶向 PSMA 是 100 倍至 1000 倍表达水平的组合 前列腺腺癌上皮上的 PSMA 与 nM 亲和常数相结合 的摄取率 >50，而其他针对 PCa 的放射性示踪剂的摄取率要低得多 5 的数量级，能够检测到更小的病变。 我们的 [68Ga]P16-093 试剂采用专有的螯合剂-连接剂-药效基团组合，并表现出 临床前评估良好。 5-11 Pharma 正在自筹资金进行 IND 下的两项 I 期临床试验 #133222 使用 [68Ga]P16-093 确定癌症患者的人体剂量测定和药代动力学。 这些试验的初步数据显示出良好的安全性、有利的剂量测定和积累 PSMA表达组织和前列腺癌病变中的[68Ga]P16-093。在这个早期开发阶段， FDA 建议对原料药化学进行进一步调查，以支持长期目标 [68Ga]P16-093 的开发和最终的 NDA 备案。 快速通道提案的第一阶段研究旨在验证 [68Ga]P16- 的制造工艺 093 通过有针对性的“压力”测试，考虑 FDA 关于身份的评论， 最终药品中异构体的定量和稳定性。成功完成快速通道阶段后 I，将有足够的数据来充分表征原料药[68Ga]P16-093的异构体含量， 包括异构体含量如何影响其生物活性。 在快速通道 SBIR 的第 2 阶段，我们提出了一项 IIa 期临床研究，该研究将重点关注 PSMA 成像 PCa 患者出现生化复发 (BCR)——初次治疗后血清 PSA 升高。这 IIa 期临床试验的终点是检测 BCR 患者的管理护理发生 20% 的变化 使用 [68Ga]P16-093 成像信息比较基于护理成像标准的治疗计划 独自的。该试点疗效数据将帮助 5-11 Pharma 设计 IIb/III 期研究，在咨询后 与 FDA 合作，将导致 NDA 支持的临床方案。