Summary of “Game-Changer” Male Contraceptive – Experimental Drug Stops Sperm in Their Tracks and Prevents Pregnancies:
Weill Cornell Medicine investigators have developed an experimental contraceptive drug candidate that temporarily stops sperm movement and prevents pregnancies in preclinical models, potentially opening the door for an on-demand male contraceptive. The drug works by inhibiting the protein soluble adenylyl cyclase and has been successfully tested in mice, with results showing that sperm motility is halted for up to two and a half hours. To move forward, the team is now repeating the experiment in a different preclinical model and preparing for human clinical trials.
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Experimental Contraceptive Drug Candidate Developed by Weill Cornell Medicine Investigators
An experimental contraceptive drug candidate developed by Weill Cornell Medicine investigators temporarily stops sperm in their tracks and prevents pregnancies in preclinical models. The study, published in the journal Nature Communications on February 14, demonstrates that an on-demand male contraceptive is possible.
The discovery could be a “game-changer” for contraception, according to the study’s co-senior authors Dr. Jochen Buck and Dr. Lonny Levin, who are professors of pharmacology at Weill Cornell Medicine.
Sperm Motility Halted by sAC Inhibitor
This video shows the motility of human sperm in the absence (left, vehicle control) or presence (right, sAC inhibitor) of the experimental male contraceptive drug candidate. Credit: Dr. Melanie Balbach
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 a 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 Prevents Pregnancy in Preclinical Models
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.
Medicinal Chemistry and Collaboration with TDI
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 The 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.
Next Steps for the Team
“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.”
Reference: “On-demand male contraception via acute inhibition of soluble adenylyl cyclase” by Melanie Balbach, Thomas Rossetti, Jacob Ferreira, Lubna Ghanem, Carla Ritagliati, Robert W. Myers, David J. Huggins, Clemens Steegborn, Ileana C. Miranda, Peter T. Meinke, Jochen Buck and Lonny R. Levin, 14 February 2023, Nature Communications.
DOI: 10.1038/s41467-023-36119-6
