The Endocrine Society's 97th Annual Meeting & Expo:
Nonhormonal Male Contraception: Epididymal Protease Inhibitor (Eppin)
Targets for nonhormonal male contraception, the pharmacologic pipeline for such targets, and the development of Epididymal Protease Inhibitor (Eppin) were the topics of a talk given by Michael G. O’Rand, PhD, Cofounder, President, and Chief Scientific Officer of Eppin Pharma, Inc, Chapel Hill, NC. Dr. O’Rand spoke on March 5, 2015, at The Endocrine Society Annual Meeting in San Diego, CA.
Need for a Male Contraceptive Agent
“In the US 3.1 million unintended pregnancies occur annually due to inconsistent or non-use of contraception. The contraceptive market consists of short-term methods such as condoms and oral contraception, long-term methods, including implants and intrauterine devices, and permanent methods such as tubal ligations and vasectomies,” explained Dr. O’Rand.
“Despite significant research into male contraceptives, innovation has been limited, the only male contraceptive options being the condom and vasectomy,” he said. “Surgical vasectomy entails ligation (severing) of the vas deferens. In the US, 13.3% of married men have had a vasectomy, 57% between age 40 and 49 years. The major limiting factor for vasectomy is high cost, which means vasectomy is not generally an option for young men. Condom sales, on the other hand, are $430-600 million. Though significantly more cost-effective and a spontaneous solution compared to vasectomy, 18% of condoms (per couple over 1 year of use) fail, and only 8% of contraceptive users choose barrier methods.”
Valuable Option for Women As Well
The average US woman wants to have two children, a goal requiring over 30 years of contraception. Women’s satisfaction rate with contraception is less than 60% for every method except tubal ligation. Hormonal birth control products are not an option for many women, partly because of a plethora of potential side effects. Of the approximately 62 million women of reproductive age (15-44 years) in the US, 70% (43 million) are sexually active and do not wish to become pregnant. Without contraception, high rates of women are vulnerable to pregnancy.
These issues indicate an unmet need for improved birth control options for women, the primary consumers of contraceptive products. Though Eppin Pharma’s product is not initially intended for female use, the product can clearly benefit women in committed relationships. It is also suitable for couples who decide not to have children, but who, nevertheless, do not wish to pursue permanent contraception. This new alternative makes Eppin Pharma’s product a significant option for committed couples.
Target Sites of Nonsurgical, Nonhormonal Male Contraception
Target sites are:
- The testis (spermatogenesis-specific stages and Sertoli/support cells)
- The epididymis (principle and basal cells)
- Spermatozoa (testicular, epididymal, and ejaculate)
Strategy for Developing a Male Contraceptive Agent
The strategy for developing a male contraceptive agent involves four focuses:
- To determine whether the essential function can be blocked
- To find an assay to measure efficacy
- To characterize the molecular basis of the target
- To determine the mechanism of action
Agents in the Male Contraceptive Pipeline
- Eppin, inhibits motility
- Lonidamine, disrupts Sertoli cell-spermatid
- Indenopyridine, disrupts spermatogenesis
- Bid-dichloroacetyldiamine, inhibits conversion of vitamin A to retinoic acid
- BMS-189453, causes spermatid misalignment to inhibit sperm release
- JQ1, binds acetylated histone 4 associated with meiotic and post-meiotic chromosomes
- ATPase inhibitor, affects sperm motility and hyperactivation
- Ion channel blocker, inhibits CatSper/Hv1
The human EPPIN gene codes for EPPIN protein, which is a protease inhibitor.
The goal in developing eppin as a contraceptive target was to identify a small organic compound that would bind to the EPPIN protein and mimic the effect of semenogelin or anti-EPPIN antibodies.
Physiological Role of Eppin
Eppin provides strong microbicidal activity and protection from protease activity, thereby modulating prostate-specific antigen activity. Eppin also binds to semenogelin, the protein in semen. Eppin, with bound semenogelin, inhibits sperm motility until semenogelin is removed for capacitation and motility in the female reproductive tract.
Binding of anti-EPPIN antibodies or semenogelin to eppin’s semenogelin binding site results in:
1. A rapid decrease in sperm intracellular pH (<1 minute)
2. A decrease in sperm intracellular calcium levels
3. The cessation of sperm motility
Eppin has been studied in male macaques, and immunization resulted in antibodies that caused effective and reversible contraception, as well as a reduction in sperm motility and loss of semen coagulum. Blocking EPPIN in human sperm results in a loss of EPPIN-semenogelin binding and sperm motility.
Eppin Drug Discovery Pathway
Eppin drug development has involved two phases, which began in 2010: assay development and compound profiling/data analysis. The compound was optimized in 2012 and 2013, and 2014 saw pharmacokinetic/toxicology testing in rats and oral bioavailability studies. In 2015, we plan to continue with nonhuman primate testing of the drug’s bioavailability and effects on sperm motility.
Optimizing the compound involved characterizing eppin’s semenogelin 1 binding site and determining the compound’s in vivo activity, which was binding to the EPPIN protein and mimicking semenogelin 1 to stop sperm motility.
This action was proposed to occur in the epididymis and continue in the vagina.
March 18, 2015