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

摘要： 本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）显像剂，[68 Ga]P16-093，特异性靶向前列腺特异性 膜抗原（PSMA）在前列腺癌患者中的作用。前列腺癌是前列腺癌的第二大病因。 美国男性死于癌症市场上没有市售的68 Ga PSMA抑制剂， 这阻碍了这类临床有用的诊断药物的广泛使用。的优点 使用放射性标记的PSMA抑制剂靶向PSMA是100 x-1000 x倍表达水平的 PSMA对前列腺癌上皮细胞的作用，其与nM亲和常数组合导致 在摄取率>50，而其他放射性示踪剂提出的PCa表现出低得多的摄取率， 5级，能够检测更小的病变。 我们的[68 Ga]P16-093试剂利用专有的螯合剂-接头-药效团组合， 在临床前评估中。Five Eleven Pharma正在IND下自筹资金进行两项I期临床试验 #133222使用[68 Ga]P16-093测定癌症患者的人体剂量学和药代动力学。 来自这些试验的初步数据显示了良好的安全性、有利的剂量测定和累积。 PSMA表达组织和前列腺癌病变中的[68 Ga]P16-093。在这个早期发展阶段， FDA建议对原料药化学进行进一步调查，以支持更长期的研究。 开发[68 Ga]P16-093并最终提交NDA。 快速通道提案的第1阶段研究旨在验证[68 Ga]P16-的制造工艺。 093通过有针对性的“压力”测试，考虑到FDA关于身份的评论， 最终制剂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[68 Ga]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Fast Track 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患者在初次治疗后出现生化复发（BCR）-血清PSA升高。的 IIa期临床试验的终点是检测BCR患者的管理治疗发生20%的变化， 比较使用[68 Ga]P16-093成像信息的治疗计划与基于标准护理成像的治疗计划 一个人这些试验性疗效数据将帮助Five Eleven Pharma设计IIb/III期研究， 与FDA合作，将导致NDA启用临床协议。

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.