Male contraceptive shows promise

In preclinical models, an investigational contraceptive medication created by Weill Cornell Medicine researchers temporarily inhibits sperm and prevents pregnancies. The study, which was published in Nature Communications on February 14, reveals the feasibility of on-demand male contraception.

According to the study's co-senior authors, Weill Cornell Medicine professors of pharmacology Dr. Jochen Buck and Dr. Lonny Levin, the discovery could be a "game-changer" for contraception.

Drs. Buck and Levin noted that condoms, which have existed for about 2000 years, and vasectomies have been men's only options to date. Research on male oral contraceptives has stalled, partly because potential contraceptives for men must clear a much higher bar for safety and side effects, Dr. Levin said. Because men don't bear the risks associated with carrying a pregnancy, he explained, the field assumes men will have a low tolerance for potential contraceptive side effects.

Drs. Buck and Levin did not initially set out to find a male contraceptive. They were friends and colleagues with complementary skill sets. But when Dr. Levin challenged Dr. Buck to isolate an important cellular signaling protein called soluble adenylyl cyclase (sAC) that had long eluded biochemists, Dr. Buck couldn't resist. It took him two years. Drs. Buck and Levin then shifted their research focus to studying sAC and eventually merged their laboratories.

The team discovered that mice genetically engineered to lack sAC are infertile. Then in 2018, Dr. Melanie Balbach, a postdoctoral associate in their lab, made an exciting discovery while working on sAC inhibitors as a possible treatment for an eye condition. She found that mice that were given a drug that inactivates sAC produce sperm that cannot propel themselves forward. The team was reassured that sAC inhibition might be a safe contraceptive option by another team's report that men who lacked the gene encoding sAC were infertile but otherwise healthy.

The new Nature Communications study demonstrates that a single dose of an sAC inhibitor called TDI-11861 immobilizes mice sperm for up to two and half hours and that the effects persist in the female reproductive tract after mating. After three hours, some sperm begin regaining motility; by 24 hours, nearly all sperm have recovered normal movement.

TDI-11861-treated male mice paired with female mice exhibited normal mating behavior but did not impregnate females despite 52 different mating attempts. Male mice treated with an inactive control substance, by contrast, impregnated almost one-third of their mates.

"Our inhibitor works within 30 minutes to an hour," Dr. Balbach said. "Every other experimental hormonal or nonhormonal male contraceptive takes weeks to bring sperm count down or render them unable to fertilize eggs."

Additionally, Dr. Balbach noted that it takes weeks to reverse the effects of other hormonal and nonhormonal male contraceptives in development. She said that since sAC inhibitors wear off within hours, and men would take it only when, and as often, as needed, they could allow men to make day-to-day decisions about their fertility.

Drs. Balbach and Levin noted that it took substantial medicinal chemistry work to develop TDI-11861, and this was accomplished in partnership with the Tri-Institutional Therapeutics Discovery Institute (TDI). The TDI works with investigators from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and Rockefeller University to expedite early-stage drug discovery.

"This highly productive collaboration between TDI and the Buck/Levin lab clearly illustrates the power of partnering pharma-trained drug discovery scientists with academic innovators," said Dr. Peter Meinke, Sanders Director of the TDI.

The Buck/Levin lab's collaboration with TDI was fostered and nurtured by Weill Cornell Medicine Enterprise Innovation, the office that accelerates the translation and commercialization of technologies arising from research conducted by Weill Cornell faculty and trainees. In addition, Enterprise Innovation is leading the out-licensing of this discovery to their start-up company.

"The team is already working on making sAC inhibitors better suited for use in humans," Dr. Levin said. Drs. Buck and Levin launched Sacyl Pharmaceuticals with colleague Dr. Gregory Kopf, who serves as the company's Chief Scientific Officer.

The next step for the team is repeating their experiments in a different preclinical model. These experiments would lay the groundwork for human clinical trials that would test the effect of sAC inhibition on sperm motility in healthy human males, Dr. Buck said.

If the drug development and clinical trials are successful, Dr. Levin said he hopes to walk into a pharmacy one day and hear a man request "the male pill."