Development of A Non-Hormonal Male Oral Contraceptive

Eppin Pharma Inc. of Chapel Hill, North Carolina, is developing an effective, short term, and fully reversible oral contraceptive for use by men. EppinPharma is currently optimizing the development of lead contraceptive compounds in preparation for an IND filing with the FDA.

Overview
EppinPharma’s lead male contraceptive candidate is a small organic compound that binds to EPPIN (SPINLW1; epididymal protease inhibitor), a protein on the surface of human sperm, resulting in the loss of sperm motility. Preclinical studies conducted by the O’Rand Laboratory at the University of North Carolina, Chapel Hill, USA, and reported in Science (O’Rand et al., 2004 [7]) demonstrated compelling “proof of principle” that EPPIN is a key target for male contraception.

EPPIN PHARMA INC is developing a non-hormonal male contraceptive drug that targets EPPIN offering the potential for effective, safe and reversible contraception. Importantly, Eppin Pharma’s contraceptive candidates exert their activity via a direct pharmacological action that inhibits sperm motility. The molecular target for these compounds is highly specific and therefore, drugs with contraceptive potential can be expected to affect a minimum number of body systems. Such a non-hormonal option for male contraception is preferable to hormonal treatments because the types of hormones that make men infertile have more severe side effects than those used in the female pill.

EPPIN (SPINLW1; epididymal protease inhibitor) coats the surface of human testicular, epididymal and ejaculate spermatozoa in an EPPIN protein complex (EPC) containing lactotransferrin and clusterin [1,2]. During ejaculation semenogelin (SEMG1) binds to EPPIN in the complex [1,3] inhibiting the progressive motility of ejaculate spermatozoa. Subsequently SEMG1 is hydrolyzed by the serine protease PSA (prostate specific antigen) [4] and EPPIN modulates PSA hydrolysis of SEMG1 on the sperm surface, resulting in forwardly motile spermatozoa [5,6]. Based on research published in Science in 2004 [7] demonstrating the “proof of principle” that anti-EPPIN antibodies, binding EPPIN on the sperm surface, resulted in the complete and reversible contraception of male monkeys immunized with EPPIN, we are currently optimizing a small organic lead molecule for the development of a sperm contraceptive.

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Immunocontraception is not considered a viable option for a marketable product for efficacy, safety, and economic reasons, therefore Eppin Pharma has developed a series of small organic compounds that will mimic the effect of anti-EPPIN binding to EPPIN (i.e. compounds that bind EPPIN and thereby inhibit sperm motility). The development of a non-hormonal male contraceptive 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. In recent surveys the satisfaction rate for women on contraception is less than 60% for every method except tubal ligation and men want access to better contraceptives [8,9,10]. Therefore, a non-hormonal male contraceptive will fill an unmet need in contraception. We envision that our product will comprise a small organic compound that inhibits sperm motility by fitting into the EPPIN-SEMG1 binding site on the surface of spermatozoa. Further we envision that the drug will be administered orally and be taken on-demand a relatively short time before sexual activity and ejaculation.

Our contraceptive drug candidates inhibit sperm motility by binding to EPPIN on the sperm surface. Their binding to EPPIN causes a rapid (~1 minute) decrease in intracellular pH, which is followed by a loss of intracellular calcium that is necessary for sperm motility [11].

Once our contraceptive drug is present in the body, it will be distributed to various body fluids and tissues. The target EPPIN is only present in the male and only present in testis and epididymal tissues thereby reducing non-specific binding concerns. Following administration of the drug it will be present in epididymal fluid and bind to EPPIN on the surface of sperm, which are stored there prior to ejaculation. Any additional sperm stored in the vas would also have the drug bound to them. Prior to ejaculation EPPIN will have coated all of the stored sperm. Upon ejaculation, sperm will move through the vas; seminal fluid, containing the protein semenogelin (SEMG1) and prostatic fluid will be added to the ejaculate. SEMG1 is the natural binding partner for EPPIN and could compete with our drug for binding to EPPIN in the semen; however, SEMG1 bound to EPPIN inhibits sperm motility, making any competition moot. During the first thirty minutes after ejaculation, the ejaculate clot is hydrolyzed by an enzyme in the prostatic fluid (PSA) and SEMG1 is removed from the sperm. Our drug would still be present in the semen, binding EPPIN and continuing to inhibit sperm motility. Because the sperm have been treated before ejaculation, while stored in the epididymis, they should be non-motile in the semen, depending upon the timing of drug administration.

References Cited

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  2. Richardson RT, Sivashanmugam P, Hall SH, Hamil KG, Moore PA, Ruben SM, French FS, O’Rand MG. 2001. Cloning and sequencing of human Eppin: A novel family of protease inhibitors expressed in the epididymis and testis. Gene 270: 93-102 18.
  3. O’Rand MG, Widgren EE, Wang Z, Richardson RT. 2006. Eppin: an effective target for male contraception. Molecular and Cellular Endocrinology 250: 157-162. PMID 16423450 17.
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  7. O’Rand MG, Widgren EE, Sivashanmugam P, Richardson RT, Hall SH, French FS, VandeVoort CA, Ramachandra SG, Ramesh V, Rao AJ. 2004. Reversible Immunocontraception in Male Monkeys Immunized with Eppin. Science 306: 1189-1190
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