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

摘要： 此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，[68Ga]P16-093，专门针对前列腺特异性 前列腺癌患者的膜抗原(PSMA)检测前列腺癌是导致癌症的第二大原因 美国男性死于癌症。市场上没有市场上可用的68Ga PSMA抑制剂， 这阻止了这种临床上有用的诊断药物的广泛使用。的优势 使用放射性标记的PSMA抑制剂靶向PSMA是100x-1000x倍增表达水平的组合 前列腺癌上皮中PSMA与NM亲和常数的结合结果 在~gt；50的摄取比率，而其他建议用于PCA的放射性示踪剂显示更低的摄取比率 5阶，能够检测到小得多的病变。 我们的[68Ga]P16-093试剂使用了专利的螯合剂-连接剂-药效团组合，并已进行了 临床前评估情况良好。Five Eleven Pharma正在IND下自筹资金进行两期I期临床试验 #133222使用[68Ga]P16-093.确定癌症患者的人体剂量学和药动学。 这些试验的初步数据显示，良好的安全性概况，有利的剂量测定和积累 [68Ga]P16-093在PSMA表达的组织和前列腺癌病变中的表达。在这一早期发展阶段， FDA建议对药物化学进行进一步调查，以支持更长期的研究 制定[68Ga]P16-093并最终提交保密协议。 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，考虑到FDA针对身份的评论， 最终药物产品中异构体的定量和稳定性。成功完成Fast Track阶段后 将具有充分的数据来充分表征药物物质[68Ga]P16-093的异构体含量， 包括同分异构体含量如何影响其生物活性。 在Fast Track SBIR的第二阶段，我们提出了一项IIa阶段的临床研究，重点是PSMA成像 初次治疗后出现生化复发(BCR)且血清PSA升高的PCa患者。这个 IIa期临床试验的终点是在以下情况下检测BCR患者管理护理的20%变化 使用[68Ga]P16-093成像信息与基于护理成像标准的治疗方案的比较 独自一人。这一试点疗效数据将帮助Five Eleven Pharma设计IIb/III阶段研究，在咨询后 与FDA合作，将导致启用NDA的临床协议。

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.