Male contraceptives have been a topic of interest for many years, and a new on-demand contraceptive could provide more options for men who want to take an active role in family planning. However, it’s important to note that preclinical studies are just the first step in the drug development process. While the results are promising, further testing is needed to determine if the drug is safe and effective for humans.
In preclinical models, an experimental contraceptive drug developed by Weill Cornell Medicine researchers temporarily stops sperm and prevents pregnancies. The study, published in Nature Communications, demonstrates the feasibility of an on-demand male contraceptive.
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 been around for about 2000 years, and vasectomies have been the only options for men up to this point. Male oral contraceptive research has stalled, in part because potential contraceptives for men must meet a much higher standard for safety and side effects, according to Dr. Levin. He explained that because men do not bear the risks associated with pregnancy, the field assumes men will have a low tolerance for potential contraceptive side effects.
This highly productive collaboration between TDI and the Buck/Levin lab exemplifies the power of collaborating pharma-trained drug discovery scientists with academic innovators.
Dr. Peter Meinke
Drs. Buck and Levin did not set out to discover a male contraceptive. They were colleagues and friends with complementary skill sets. But when Dr. Levin challenged Dr. Buck to isolate soluble adenylyl cyclase (sAC), an important cellular signaling protein that had long eluded biochemists, Dr. Buck couldn’t say no. He needed two years. Drs. Buck and Levin then shifted their research focus to studying sAC, and their laboratories eventually merged.
The researchers discovered that mice genetically engineered to be deficient in sAC are infertile. Dr. Melanie Balbach, a postdoctoral associate in their lab, then made an exciting discovery in 2018 while researching sAC inhibitors as a potential treatment for an eye condition. She discovered that mice given a drug that inhibits sAC produce sperm that cannot move forward. Another team’s report that men who lacked the gene encoding sAC were infertile but otherwise healthy reassured the team that sAC inhibition could be a safe contraceptive option.
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.
Male mice treated with TDI-11861 exhibited normal mating behavior but did not impregnate females despite 52 mating attempts. Male mice exposed to an inactive control substance, on the other hand, impregnated nearly one-third of their mates.
“Our inhibitor works in 30 minutes to an hour,” said Dr. Balbach. “Every other experimental hormonal or nonhormonal male contraceptive takes weeks to reduce sperm count or render sperm infertile.”
Dr. Balbach also mentioned that it takes weeks to reverse the effects of other hormonal and nonhormonal male contraceptives in development. She claimed that because sAC inhibitors wear off in hours and men would only take them as needed, they could allow men to make day-to-day decisions about their fertility.
Drs. Balbach and Levin noted that developing TDI-11861 required extensive medicinal chemistry work, which was accomplished in collaboration with the Tri-Institutional Therapeutics Discovery Institute (TDI). To accelerate early-stage drug discovery, the TDI collaborates with researchers from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and Rockefeller University.
“This highly productive collaboration between TDI and the Buck/Levin lab exemplifies the power of collaborating pharma-trained drug discovery scientists with academic innovators,” said Dr. Peter Meinke, Sanders Director of the TDI.
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, facilitated and nurtured the Buck/Levin lab’s collaboration with TDI. Furthermore, Enterprise Innovation is in charge of licensing this discovery to their start-up company.
“The team is already working on improving sAC inhibitors for human use,” Dr. Levin said. Sacyl Pharmaceuticals was founded by Drs. Buck and Levin, along with colleague Dr. Gregory Kopf, who serves as the company’s Chief Scientific Officer.
The team’s next step is to replicate their experiments in a different preclinical model. These studies would lay the groundwork for human clinical trials testing the effect of sAC inhibition on sperm motility in healthy human males, according to Dr. Buck. Dr. Levin said he hopes to walk into a pharmacy one day and hear a man ask for “the male pill” if the drug development and clinical trials are successful.
