Contraceptive Development Program

Product development is challenging and has a low success rate with drugs for disease conditions. Once a candidate is identified, about 10% pass pre-clinical testing to enter clinical testing; only 12% of those products complete Phase III and FDA submission. Contraceptives are used by healthy people for long durations; thus, long-term safety is critical. The CDP has a pipeline of products in clinical evaluation, including hormonal or non-hormonal options for women, and novel hormonal methods for men. In 2024, clinical trials were conducted for safety and contraceptive evaluation of new drugs or devices in the CDP pipeline. Results from completed trials were analyzed to prepare manuscripts for the publication of findings and to provide clinical study reports to the FDA to support advancing promising products to the next stage of development. New methods for women include: (1) a novel vaginal ring that can be used for three months; (2) a long-acting injectable that inhibits ovulation for three months; (3) a novel copper IUD that provides contraceptive effectiveness for at least three years; (4) a method that protects against HIV infection as well as pregnancy; and (5) a non-hormonal vaginal shield. For male contraception, clinical evaluation of a novel transdermal hormonal male contraceptive method used by couples seeking to prevent pregnancy was completed in 2024. The trial was conducted at nine US sites and eight international sites in Europe, Africa, and South America. Data analysis is under way. Each product in development in the CDP fills an unmet need or provides greater safety to vulnerable populations at risk of unintended pregnancy.

Dr. Blithe and CDP collaborators are developing new methods for men and women to address unmet needs for safe, effective, reversible contraception. The research aligns with the 2020 NICHD Strategic Plan Scientific Theme 2: Promoting Gynecologic, Andrologic, and Reproductive Health.

Increasing contraceptive options for women

In the USA, 45% of pregnancies are unintended. One-third of reproductive age women are obese, with increased incidence of diabetes, hypertension, and risk of venous thromboembolism (VTE) for which some hormonal methods may be contraindicated; yet women with these conditions face higher risks in pregnancy and need effective contraception.

1) Contraceptive vaginal rings (CVR): Nestorone®/17β Estradiol CVR is being developed in collaboration with the Population Council. The ring has been evaluated for effectiveness over one year of use. Nestorone® is a potent progestin that blocks follicular development; 17-β estradiol supports bone health without increasing VTE risk. High effectiveness and acceptability support further development of the product.

2) Multipurpose prevention technologies (MPTs) protect against pregnancy and infection from pathogens: a Dapivirine/Levonorgestrel (LNG) Vaginal Ring may provide protection against both HIV infection and pregnancy. In collaboration with the Population Council, the product is being evaluated to assess inhibition of ovulation as well as safety and acceptability. The Woman’s Condom pivotal trial demonstrated acceptability and effectiveness of a novel female condom to prevent pregnancy and transmission of infection. A final report will be prepared to allow consideration of approval by the FDA.

3) Long-acting reversible contraceptives (LARCs) are effective, highly acceptable methods. The Copper IUD is a safe option for women with health risks or conditions that increase risks associated with unintended pregnancy. Increased bleeding and cramping associated with the currently marketed Copper IUD may deter use in nulliparous women, especially adolescents. In collaboration with the Gates Foundation and FHI-360, the CDP evaluated a Mini-Copper IUD in nulliparous women to determine effectiveness, bleeding characteristics, and pain.

4) Progestin-only injectable contraception: Levonorgestrel Butanoate (LB) is a novel injectable progestin that does not increase the risk of VTE. Injections of long-acting LB improve compliance and efficacy compared with progestin-only pills. A study is under way to optimize LB dose, route of injection and duration of ovulation inhibition.

5) Novel non-hormonal cervical barrier device for contraception: Ovaprene is a non-hormonal barrier device that is worn from the end of menses until the beginning of the next menses to protect cervical penetration of sperm after vaginal intercourse. Under a CRADA with Dare Bioscience, Ovaprene is being evaluated in the CCTN female method network for contraceptive efficacy, safety and acceptability.

Development of contraceptive methods for men

For male contraception, the only reversible method is condoms, which have high failure rates and low acceptability. Hormonal approaches to male contraception use a similar endocrine feedback regulatory loop that female methods use. In normal physiology, high testosterone (T) synthesized in testes supports spermatogenesis; lower T levels in serum maintain other androgen-dependent functions and normal sexual function. Reversible contraception is achieved with administration of exogenous progestins to suppress secretion of pituitary gonadotropins responsible for high T production in testes that is needed to support sperm production. Inhibiting testicular T synthesis stops sperm production. T replacement is administered to maintain the lower androgen levels needed in serum for T–dependent functions.

1) Nestorone®/Testosterone (Nes/T) Gel is a highly promising product for male contraception. Dr. Blithe and CDP colleagues, in collaboration with the Population Council, conducted studies with the CCTN team to determine the most effective dose of Nestorone® (a potent progestin) that caused gonadotropin suppression, inhibiting endogenous testicular T production needed to support sperm production. The team combined Nestorone® (Nes) with T in a single gel formulation delivered in a metered pump. The combined Nes/T Gel was evaluated to demonstrate that daily application inhibited testicular T synthesis, stopping sperm production while maintaining normal serum T levels to support sexual function. The novel Nes/T Gel was evaluated in couples who wish to use a novel male contraceptive product to prevent pregnancy. When couples complete a one-year efficacy period, the male partner stops using the product and enters a recovery phase to demonstrate return to normal fertility levels of sperm production. This Phase IIb trial was completed in 2024. Data analysis is under way to assess pregnancy prevention as well as safety, reversibility, and acceptability of the method. Clinical sites included nine CCTN sites in the USA, two sites in the UK, two sites in Chile, and one site in each of Sweden, Italy, Kenya, and Zimbabwe.

2) Novel progestogenic androgens for male contraception: Dimethandrolone (DMA) and 11βMethyl Nortestosterone (MNT) are novel agents with androgenic and progestin activities, suppressing gonadotropins while maintaining androgen-dependent functions. The CDP is evaluating two pro-drugs (DMA-Undecanoate and MNT-Dodecylcarbonate) in early clinical trials of safety and dose-finding. Additional novel progestogenic androgens are in development.