Researchers have released positive results from a Phase II study of Nestorone/testosterone (NES/T) transdermal gel, the first male contraception method to progress to Phase II clinical trials. Investigators are expected to publish more results from the Phase IIb study in the fall and then move to Phase III trials.1,2
Investigators found that men were interested and engaged in using the gel contraceptive method and wanted to continue using it even after the trial ended.1
When scientists began formulating the transdermal gel two decades ago, they designed it for female contraception using only Nestorone, which was developed by the Population Council.
It quickly was clear that the gel also could be used as a male contraceptive. Since men need testosterone, the male contraceptive gel needed to replace the testosterone suppressed by Nestorone with synthetic testosterone.
The same progestin molecule can block the testicle and secretion of testosterone in men, says Régine Sitruk-Ware, MD, a distinguished scientist with the Population Council and a former adjunct professor in the labs at Rockefeller University in New York.
Men need testosterone for their libido, muscles, hair, and male characteristics.
“So, we associate progestin with androgen, and that’s the principle of male hormonal contraceptive,” she adds. “We started with a gel and used Nestorone and testosterone gel separately for the first study; it actually blocked the gonadotropins and sperm production profoundly.”
The National Institutes of Health began to collaborate with the Population Council a couple of decades ago on the contraceptive gel and has been very interested in a male contraception option, she says.
“We did those finding studies, using several doses, until we found the lowest effective dose, and it was the proper dose — 8 milligrams of Nestorone and 62 milligrams of testosterone,” Sitruk-Ware explains. “We made a compound gel.”
Only 10% of the hormones are absorbed in the bloodstream. Researchers quickly learned that the absorbed amount of testosterone was too low to replace what some men needed.
“We wanted to replace it exactly — not above — not lower, so we adjusted the formulation, and now it’s 74 mg of testosterone per 5 grams of gel,” she says.
This dose appeared to replace their testosterone and resulted in normal function, she adds.
By 2018, the research had progressed to clinical trials and was ready for a Phase II trial. Researchers had more than 400 participants. Those results were shared at the Fourth International Congress on Male Contraception, organized by the International Consortium for Male Contraception and the Population Council on June 6, 2024, at Rockefeller University.1
“This year, we are publishing results of our Phase IIB study,” Sitruk-Ware says. “Phase III will be after we submit the results of this report; we hope to be published before the end of the year.”
Researchers have submitted a full report and data to the Food and Drug Administration (FDA). They will discuss with the FDA how many couples (likely 1,200) they will need to include in the Phase III trial.
“We will look for partners to get the funding because Phase III is very expensive, and we would need approximately 35 centers to reach all these people,” she explains. “Enrollment should be as quick as possible if we want to finish the program in a reasonable time.”
Contraception funding is always a problem, and the lack of funding is why the Population Council did not develop a new female contraceptive gel with Nestorone, Sitruk-Ware notes.
“We were approved for the female contraception Annovera, a birth control ring, which was approved by the FDA in 2018 for females. We also had this gel associated with Nestorone, and we conducted the first study in women,” she explains. “It worked well at blocking ovulation, but we didn’t find any funders interested in funding a program for the gel.”
The gel product was put on hold until they learned that men also were interested in a hormonal contraceptive gel.
Because of strong male interest in contraception — especially since the U.S. Supreme Court overturned Roe v. Wade — enrollment may not be a problem for the Phase III trial, she notes.
Funding male contraception has been a decades-long problem for researchers. “For a long time, pharmaceutical companies didn’t fund male contraception because they didn’t think there was a market, that men would be interested,” she says.
“Then they saw the interest in men post-Dobbs, so it was proof there would be a market; we’ve seen many companies interested in us, and we’re hoping to get a partner in the months to come,” she adds.
The gel product proved to be popular with men since clinical trials began. “From the moment we announced the study at each site, they had fliers, and their phone rang all the time. It was a big demand,” Sitruk-Ware says.
Many people who express interest will not qualify for enrollment, including men with certain conditions, including active hypertension.
“We also have to be very careful to not enroll people with severe depression or a history of severe depression that is not corrected by treatment because the modification of hormones may trigger mood changes,” she says.
Participants also have to have a normal sperm count. When they call to show interest in participating in the trial, they are screened over the phone and then asked to come into the center for tests.
Once enrolled, men apply the clear gel to their shoulders after they have showered. To prevent anyone else from having contact with the gel, they wear a shirt. The gel is applied daily, usually in the morning or at night before bed. The men are told to apply it after having sex so their partners will not get some of the hormone on their skin. “They have freedom to adjust it to their way of life,” Sitruk-Ware says.
It takes daily use of the gel for 12 weeks to fully suppress sperm. After 12 weeks, a couple can rely entirely on the male contraceptive to prevent pregnancy. But it has to be applied every day, or sperm production could return.
When men stop using the gel, their sperm production returns to normal levels in about 12 weeks.
If all goes as planned, the first male hormonal contraceptive could be on the market in the next decade, Sitruk-Ware says.
“I’m very optimistic. I think we could speed up the program, but we need the money, and it depends on whether we have a partner like a large company or investor to help us conduct Phase III trials,” she says.
REFERENCES
- Sitruk-Ware R. Reversible male contraception: New technologies and perspectives. Rome Congress 2024. Presented on May 13, 2024.
- Spotlight: One year and counting: Male birth control study reaches milestone. National Institute of Child Health and Human Development. Aug. 2, 2022. https://www.nichd.nih.gov/newsroom/news/080222-NEST
Researchers have released positive results from a Phase II study of Nestorone/testosterone (NES/T) transdermal gel, the first male contraception method to progress to Phase II clinical trials.
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