Contraceptive testing for semen availability in male monkeys

 描述（由申请人提供）：2011年全球避孕药市场价值为160亿美元，预计2013年至2018年将以5.9%的复合年增长率增长，2018年估计价值将达到233亿美元。这个市场的一个重要的高影响力驱动因素是意外怀孕的普遍性。在美国，每年有310万例意外怀孕是由于不一致或不使用避孕措施造成的。尽管在男性避孕药具领域进行了大量研究，但创新受到严重限制。目前，男子的避孕选择仅限于避孕套和输精管结扎术。男性和女性希望获得更好的短期避孕选择。EPPIN PHARMA正在开发一种针对人类精子表面蛋白EPPIN的非激素男性避孕药。我们设想，我们的治疗将口服，并采取按需在性活动前相对较短的时间。与抑制精子发生的激素避孕药和其他阻断细胞内特定途径的非激素药物不同，在给予我们的药物后，它将存在于附睾液中并与精子表面的EPPIN结合。靶向EPPIN仅存在于雄性中;在睾丸和附睾中的精子上，从而减少非特异性结合问题。在射精过程中，精液凝固蛋白（SEMG 1）与EPPIN结合，抑制射精精子的前向运动。随后SEMG 1被丝氨酸蛋白酶PSA水解，产生向前运动的精子。Eppin Pharma的先导化合物是一种有机小分子，可模拟精液凝固蛋白或抗EPPIN结合EPPIN的作用（即该化合物结合EPPIN，从而抑制精子活力）。该STTR 1期提案的具体目标旨在建立在初步数据的基础上，并测试一种针对EPPIN的男性避孕药物。具体目标1将表征先导化合物（TZ4_121）的作用机制，并根据目标2的需要合成额外量的先导化合物。我们预期该化合物通过抑制精子内部钙和pH值的增加来抑制人精子活力，这与SEMG 1/抗EPPIN抗体的既定作用机制相同。具体目标#2将收集并评估给药后雄性猴中先导化合物的精液可用性数据。这一目的将确定在精液中提供足够的药物浓度以抑制人类精子活力所需的静脉注射剂量。只有灵长类动物才有精液凝固蛋白（SEMG 1）和EPPIN，它们作为精子表面的复合物发挥作用，抑制活力。目标2将作为与俄勒冈州国家灵长类动物研究中心合作的一个项目进行。这项STTR I期研究将证明作用机制和“原理证明”，即我们的先导化合物可用于非人类灵长类动物的精液，使这种避孕方法在男性中可行。获得非人灵长类动物数据将导致在STTR II期开展ADME和DMPK研究，解决更具体的问题（例如耐受性、器官功能和血液学参数），为IND做准备。

 DESCRIPTION (provided by applicant): The global contraceptives market was valued at $16.0 billion in 2011 and is expected to grow at a CAGR of 5.9% from 2013 to 2018, to reach an estimated value of $23.3 billion in 2018. An important high impact driver of this market is the prevalence of unintended pregnancies. In the US there are 3.1 million unintended pregnancies annually through inconsistent or non-use of contraception. Despite significant research in the area of male contraceptives, innovation has been severely limited. Currently men are limited in their options for contraception to condoms and vasectomy. Men and women want access to better short term contraceptive choices. EPPIN PHARMA is developing a non-hormonal male contraceptive that targets the protein EPPIN on the surface of human sperm. We envision that our therapeutic will be administered orally and be taken on- demand a relatively short time before sexual activity. Unlike hormonal contraception which inhibits spermatogenesis and other non-hormonal agents that block specific pathways inside a cell, following administration of our drug it will be present in epididymal fluid and bind to EPPIN on the surface of sperm. The target EPPIN is only present in the male; on sperm in the testis and epididymis, thereby reducing non-specific binding concerns. During ejaculation semenogelin (SEMG1) binds to EPPIN, inhibiting the progressive motility of ejaculate spermatozoa. Subsequently SEMG1 is hydrolyzed by the serine protease PSA, resulting in forwardly motile spermatozoa. Eppin Pharma's lead compound is a small organic molecule that mimics the effect of semenogelin or anti-EPPIN binding EPPIN (i.e. the compound binds EPPIN and thereby inhibits sperm motility). The Specific Aims of this STTR Phase 1 proposal are designed to build on preliminary data and test a drug for male contraception that targets EPPIN. Specific aim #1 will characterize the mechanism of action of the lead compound (TZ4_121) and synthesize additional amounts of our lead compound as needed for aim #2. We expect the compound to inhibit human sperm motility by inhibiting increases in sperm internal calcium and pH, identical to the established mechanism of action of SEMG1/anti-EPPIN antibodies. Specific aim #2 will collect and assess data of semen availability of the lead compound in the male monkey after treatment. This aim will determine the i.v. dosage needed to provide sufficient drug concentration in the semen to inhibit human sperm motility. Only primates have semenogelin (SEMG1) and EPPIN, which function as a complex on the sperm surface to inhibit motility. Aim #2 will be carried out as a subcontract with the Oregon National Primate Research Center. This STTR phase I study will demonstrate mechanism of action and a "proof of principle" that our lead compound is available in semen of non-human primates, making this method of contraception feasible in men. Obtaining non-human primate data will lead to ADME and DMPK studies in STTR phase II, addressing more specific issues (e.g. toleration, organ function, and hematology parameters) in preparation for an IND.