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.
Public Health Relevance Statement: Public Health Relevance: This research proposal is relevant to public health because it will develop a new male non- hormonal contraceptive that will enhance family planning throughout the world and give men and women additional contraceptive choices. Currently men are limited in their options for contraception to condoms and vasectomy. Therefore a non-hormonal male contraceptive will fill an unmet need in contraception. The proposal is designed to develop a drug for male contraception that targets EPPIN. The proposal will provide: 1) the mechanism of action of the drug and 2) preclinical testing for semen availability.
Project Terms: Address; Aftercare; Antibodies; Area; base; Binding (Molecular Function); Calcium; cell motility; Cells; Complex; condoms; Contraceptive Agents; Contraceptive methods; contraceptive target; cost; cost effective; Data; design; Development; dosage; Drug effect disorder; Drug Targeting; Ejaculation; Epididymis; Failure (biologic function); Family Planning; Future; Goals; Hematology; Hormonal; hormonal contraception; Human; In Vitro; innovation; Lead; Ligation; Liquid substance; male; Male Condoms; Male Contraceptions; Male Contraceptive Agents; Male Contraceptive Devices; Marketing; men; Methods; Modeling; Monkeys; nonhuman primate; novel therapeutics; Operative Surgical Procedures; Oral Contraceptives; Oregon; Organ; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; pre-clinical; Preclinical Testing; Preparation; Prevalence; Primates; Procedures; Proteins; public health medicine (field); public health relevance; Publishing; Research; Research Proposals; Rodent; Sales; screening; Seminal fluid; Serine Protease; Sex Behavior; Small Business Technology Transfer Research; Solutions; sperm cell; Sperm Motility; Spermatogenesis; Surface; Testing; Testis; Therapeutic; Therapeutic Agents; Time; Toxicology; unintended pregnancy; United States; Vas deferens structure; Vasectomy; Woman; young man
