Contraceptive testing for semen availability in male monkeys

 描述(申请人提供)：2011年全球避孕药具市场价值为160亿美元，预计2013-2018年的年复合增长率为5.9%，2018年将达到233亿美元的估计价值。这一市场的一个重要的高影响驱动因素是意外怀孕的流行。在美国，每年有310万人因不一致或没有使用避孕措施而意外怀孕。尽管在男性避孕药领域进行了大量研究，但创新一直受到严重限制。目前，男性在避孕、避孕套和输精管结扎术方面的选择有限。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质Eppin的非荷尔蒙男性避孕药。我们设想，我们的治疗将以口服方式进行，并在性行为前相对较短的时间内按需服用。与荷尔蒙避孕药不同，荷尔蒙避孕药会抑制精子发生，而其他非荷尔蒙药物会阻断细胞内的特定途径，而服用我们的药物后，它会出现在附睾液中，并与精子表面的Eppin结合。靶标Eppin只存在于男性中，存在于睾丸和附睾的精子上，从而减少了非特异性结合的担忧。在射精过程中，精原蛋白(SEMG1)与Eppin结合，抑制射精精子的前进运动。随后，SEMG1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小的有机分子，它模仿精胶蛋白或抗Eppin结合Eppin的效果(即该化合物结合Eppin，从而抑制精子运动)。这项STTR1期提案的具体目标是在初步数据的基础上，测试一种针对Eppin的男性避孕药物。特定目标#1将描述先导化合物(TZ4_121)的作用机制，并根据目标#2所需合成额外数量的先导化合物。我们预计该化合物通过抑制精子内部钙和pH的增加来抑制人类精子的活动，与SEMG1/抗Eppin抗体的已建立的作用机制相同。具体目标#2将收集和评估治疗后雄性猴子精液中先导化合物的可用性数据。这一目标将决定静脉注射。在精液中提供足够的药物浓度以抑制人类精子运动所需的剂量。只有灵长类动物才有精胶蛋白(SEMG1)和Eppin，它们作为精子表面的复合体发挥作用，抑制精子的活力。AIM#2将作为俄勒冈州国家灵长类研究中心的分包合同执行。这项STTRI期研究将展示作用机制和“原则证明”，即我们的先导化合物在非人类灵长类动物的精液中可用，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第二阶段进行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.