Researchers have found a possible way to target soluble adenylyl cyclase (sAC:ADY10), which is essential for male fertility. Using an acute-acting sAC inhibitor, an oral, on-demand, nonhormonal pill has the potential for temporary male infertility with no adverse effects.
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“If you take the sperm from a mouse, where this gene is knocked out, this sperm will never fertilize an egg,” explains Lonny Levin, PhD, professor at Weill Cornell Medicine in New York City.
The ultimate goal is to identify a sAC inhibitor that provides an on-demand contraceptive within an hour after dosing, while avoiding side effects.1
Men potentially could take the nonhormonal contraceptive pill at dinner, and their sperm would be inactive for at least a few hours, says Jochen Buck, MD, PhD, professor at Weill Cornell Medicine.
“By the next morning or day — we don’t know yet — it’s as if the pill was never there,” Levin says. “The theory is it would have no side effects.”
Their confidence in the potential of no side effects is based on the case of two Iranian farmers, who presented to an infertility clinic and were studied by investigators, Levin says. The men’s problem was described as a sAC knockout that rendered them infertile. Both men were married, middle-aged, and had no other health problems besides lacking an enzyme necessary for fertility. They had lived without this enzyme their entire lives.
“That gave us extreme confidence that people can live without this enzyme for some time,” Levin says. “It gave us even more confidence that if we have a man with an inhibitor for a few hours, there would be no problem because these two men lived without the enzyme their whole lives.”
After learning of the infertile men’s case, Levin and Buck decided an on-demand, reversible, nonhormonal male contraceptive pill was possible.
“The only thing wrong with the two men is they have increased frequency of kidney stones,” Levin says. “But they’re two people who are living without the enzyme for their whole life, so we cannot imagine that living without it for six hours would do that. As long as you didn’t take the pill every day for 30 years, I don’t see it as being a problem.”
Traditionally, there has been less attention paid to the nonhormonal male contraceptive methods. This is why the Male Contraceptive Initiative (MCI) of Durham, NC, provides seed funding for this niche, says Heather Vahdat, MPH, executive director.
“The folks working in the hormonal space are doing great work, and this was a good place for MCI to come in and put our focus,” Vahdat says.
The study, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, employs a researcher who received a postdoctoral fellowship from MCI.1
“We’ll make a number of versions of this inhibitor,” Levin says. “We’re going to see when we have the fewest side effects.”
The goal is to find a version that produces no side effects and can last as a contraceptive as long as needed, he adds.
The research is one to two years away from a Phase I clinical trial, Buck says. “We started with a first-generation compound that was not active enough. We first need a better compound.”
The Phase I trial would be designed to administer the drug and study participants’ sperm through an in vitro test. The Phase II trial would be similar, but a Phase III trial would look at the men’s real-life experience, Buck notes.
“We will need investors once we identify the compound,” Levin says.
Federal funding is necessary for the preclinical work to continue. “A chemist group can make compounds, but testing in mice is very expensive,” he says. “Without [federal grant] support, we couldn’t get to the promised land.”
If this male contraceptive approach goes through preclinical research and clinical trials to become an on-demand pill, it could become very popular among men, Levin says.
“This is purely anecdotal because we haven’t done any studies,” Levin explains. “But one thing we do, as researchers, is present to graduate students and try to attract them to work in our lab. Every male student in the room’s eyes lit up, and we got a lot of students wanting to work in the lab because they think the potential is huge.”
- Balbach M, Fushimi M, Huggins DJ, et al. Optimization of lead compounds into on-demand, nonhormonal contraceptives: Leveraging a public-private drug discovery institute collaboration. Biol Reprod 2020;103:176-182.
