Development of Superactive Analogs of FSH for Human Infertility

开发治疗人类不孕症的 FSH 超级活性类似物

• 批准号: 8195728
• 负责人: Bruce Dale Weintraub
• 金额: $ 97.21万
• 依托单位: TROPHOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-13 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195728
• 关键词: Adverse effects; Affect; Affinity; American; Assisted Reproductive Technology; Beds; Binding; Biological Assay; Bioreactors; Carbohydrates; Cattle; Cell Line; Chinese Hamster Ovary Cell; Clinical Trials; Couples; Development; Doctor of Philosophy; Dose; Drug Kinetics; Embryo; Embryo Transfer; Engineering; Family suidae; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Funding; Generations; Genetic; Glycoproteins; Grant; Guidelines; High Pressure Liquid Chromatography; Hormones; Human; Human Cell Line; Human Development; Human Follicle Stimulating Hormone; Immunoassay; In Vitro; Infertility; Injection of therapeutic agent; Instruction; Investigational New Drug Application; Licensing; Macaca mulatta; Marketing; Metabolic; Methods; Modeling; Monkeys; National Institute of Child Health and Human Development; Newborn Infant; Oocytes; Oryctolagus cuniculus; Ovarian; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Preparation; Production; Program Development; Property; Rattus; Recombinant Follicle Stimulating Hormone; Recombinants; Regimen; Research; Research Personnel; Rodent; Rodent Model; Screening procedure; Small Business Innovation Research Grant; Specificity; Superovulation; Technology; Technology Transfer; Therapeutic; TimeLine; Toxicology; United States National Institutes of Health; Weight; Woman; Work; absorption; analog; attenuation; base; blastocyst; cell bank; commercialization; comparative efficacy; good laboratory practice; hormone analog; immunogenicity; improved; in vivo; manufacturing facility; meetings; nonhuman primate; novel; older patient; pre-clinical; preimplantation; programs; pup; receptor binding; receptor expression; reproductive; response; scale up; urinary

DESCRIPTION (provided by applicant): Infertility affects about 10% of American couples, and there is a very large and rapidly growing market for therapeutics in this field, particularly the primary hormone responsible for ovarian oocyte development, human (h) follicle-stimulating hormone (FSH). Although available urinary and recombinant hFSH products have been quite successful, there is currently an unmet therapeutic need for improved FSH analogs for all infertile women and particularly for older patients and those relatively unresponsive to current therapies. We have previously described the first superactive analogs of glycoprotein hormones that considerably increase receptor binding affinity as well as both in vitro and in vivo biopotency and maximal efficacy. During our successfully completed phase 2 SBIR study we have achieved or exceeded all the aims including screening additional FSH analog candidates and identifying the optimal FSH analog TR 4401 for clinical trials, using multiple in vitro and in vivo rodent bioassay models including the classic ovarian weight response as well as those of oocytes, blastocysts and newborn pups resulting from embryo transfer. In all these rodent models 4401 greatly outperformed all currently available recombinant FSH preparations both in potency and efficacy related to both quantitative endpoints as well as qualitative endpoints related to oocyte or embryo quality. In addition we have shown such superior efficacy of TR4401 to standard FSH in human cell lines with reduced FSH receptor expression representing two models of human infertility, in two bovine models of infertility and in Rhesus monkeys using methods emulating human assisted reproductive technology. We have also shown that one injection of TR4401 in cows could produce comparable superovulation to the standard 8-injection regimen of porcine FSH with no attenuation of response after repeated administration. These nonhuman primate and bovine studies showed no evidence of ovarian hyperstimulation by TR4401 at neither a presumably maximal dose, nor any evidence of immunogenicity, the only two side effects of concern to FDA for this minimally modified, and thus presumably safe, FSH analog. Using an HPLC-validated immunoassay we have discovered superior pharmacokinetic properties of TR4401 in comparison to standard FSH both in rodents and monkeys, apparently the result of delayed absorption. We have also achieved development of a stable Chinese Hamster Ovary (CHO) cell line producing high levels of the final TR4401 analog; optimization of large scale bioreactor production methods; development of novel, high capacity purification methods suitable for commercial scale-up; rigorous quantification and characterization of purified analogs by multiple physicochemical methods including carbohydrate analysis. In the current application, following specific directives from FDA obtained in our highly successful Pre-IND Meeting with them, we propose all steps, including specific timelines indicated on a detailed Gantt chart, required by FDA for further commercial development of this novel FSH analog. These include establishment and characterization of a master and working CHO cell bank; manufacturing of two additional large batches of TR4401 (>200 mg each): the first under GLP and the second under GMP compliant conditions; performance all FDA-required efficacy, specificity, stability, metabolic, pharmacokinetic, pharmacodynamic and analytic studies; performance of all FDA-required toxicology studies including two-generation reproductive toxicology assessment in rats and rabbits; and submission of IND to initiate clinical trials. We have licensed TR4401 to the worldwide leading veterinary superovulation company, Bioniche, Inc. for veterinary use, with a possible option to also co-develop the analog for human use. PUBLIC HEALTH RELEVANCE: Infertility affects about 10% of American couples, and there is a very large and rapidly growing market for therapeutics in this field, particularly the primary hormone responsible for ovarian oocyte development, human (h) follicle-stimulating hormone (FSH). Although available urinary and recombinant hFSH products have been quite successful, there is currently an unmet therapeutic need for improved FSH analogs for all infertile women and particularly for older patients and those relatively unresponsive to current therapies. We have shown in previous phase one and phase two SBIR grant studies that our novel FSH superagonist, TR4401, engineered to increase binding affinity to the FSH receptor, shows greatly increased potency and efficacy compared to currently available FSH products, in multiple quantitative and qualitative oocyte endpoints in rodents, monkeys, and bovines, with no apparent side effects. We now propose to commercialize this novel FSH analog by following all the specific FDA guidelines given to us in a pre-IND meeting in order to submit an IND to that agency to initiate clinical trials.

描述（由申请人提供）：不育症影响约10％的美国夫妇，并且在该领域有一个非常大的疗法市场，尤其是负责卵巢卵母细胞发育的主要激素，人类（H）卵泡刺激激素（FSH）。尽管可用的尿液和重组HFSH产品非常成功，但目前，对于所有不育女性，尤其是老年患者以及那些对当前疗法的相对反应迟钝的人，目前尚无治疗需要改善FSH类似物。我们先前已经描述了糖蛋白激素的第一个超活性类似物，这些类似物大大增加了受体结合亲和力，以及体外和体内生物生物性和最大功效。在我们成功完成的第2阶段SBIR研究中，我们实现了或超过所有目标，包括筛选其他FSH模拟候选物，并使用多个体外和体内啮齿动物生物测定模型来确定最佳的FSH Analog TR 4401进行临床试验，包括经典的卵巢重量响应，以及来自Oocystes的经典卵巢响应以及胚胎的转移，并从中出生的新生和新生。在所有这些啮齿动物模型中，4401在效力和疗效方面都大大优于所有目前可用的重组FSH制剂，这与定量端点以及与卵母细胞或胚胎质量相关的定性终点相关。此外，我们在人类细胞系中显示了TR4401与标准FSH的高功效，其FSH受体表达降低，代表了两个人类不育症模型，在两个不育的牛模型和恒河猴中使用人类辅助生殖技术的方法。我们还表明，奶牛中的一种TR4401注射可以与猪FSH的标准8注射方案产生可比的超排卵，而重复给药后没有反应的衰减。这些非人类的灵长类动物和牛的研究表明，在可能最大剂量的情况下，TR4401的卵巢过度刺激没有证据，也没有任何免疫原性的证据，这是FDA关注的唯一两个副作用，因此对这种微中的修饰，因此可能是安全的，因此可能是安全的。使用HPLC验证的免疫测定，我们发现了与啮齿动物和猴子中的标准FSH相比，TR4401的出色药代动力学特性显然是吸收延迟的结果。我们还达到了稳定的中国仓鼠卵巢（CHO）细胞系的发展，该细胞系产生了最终的TR4401类似物的高水平。优化大规模生物反应器生产方法；开发适合商业规模的新型高容量纯化方法；通过包括碳水化合物分析在内的多种物理化学方法对纯化的类似物进行严格的定量和表征。在当前的应用程序中，按照我们与FDA的特定指令在我们与他们非常成功的预定会议中获得的特定指令，我们提出了所有步骤，包括FDA在详细的GANTT图表上指示的特定时间表，这是FDA所要求的，用于进一步的这款新型FSH类似物的商业开发。这些包括建立和表征大师和工作的CHO Cell Bank；制造另外两批TR4401（每个> 200 mg）：第一个下GLP，第二个在符合GMP的条件下；绩效所有FDA所需的疗效，特异性，稳定性，代谢，药代动力学，药效和分析研究；所有FDA频繁的毒理学研究的表现，包括大鼠和兔子的两代生殖毒理学评估；并提交IND启动临床试验。我们已将TR4401许可到全球领先的兽医超级排放公司Bioniche，Inc。供兽医使用，并可能选择可以共同开发用于人类使用的模拟。 公共卫生相关性：不育会影响约10％的美国夫妇，并且在该领域有一个非常大的且迅速增长的治疗市场，尤其是负责卵巢卵母细胞开发的主要激素，人类（H）卵泡刺激激素（FSH）。尽管可用的尿液和重组HFSH产品非常成功，但目前，对于所有不育女性，尤其是老年患者以及那些对当前疗法的相对反应迟钝的人，目前尚无治疗需要改善FSH类似物。我们已经在上一阶段和第二阶段SBIR赠款研究中表明，我们的新型FSH超级机芯TR4401工程设计旨在增加与FSH受体的结合亲和力，与当前可用的FSH产品相比，具有多种定量和定性的卵母细胞端点的持久性FSH和效率大大提高了效能和效率，这些产品中的啮齿动物，猴子，猴子和牛奶中的牛油蛋白和牛奶中均不受任何效果。现在，我们建议通过遵循预先召开会议中给我们的所有特定FDA准则，以便向该机构提交该机构启动临床试验的所有特定的FDA指南，以使我们的所有特定FDA指南进行商业化。