In preclinical models, a Weill Cornell Medicine-developed investigational contraceptive medication candidate momentarily halts sperm in their tracks and prevents pregnancies. The study, published in Nature Communications on February 14, indicates the feasibility of a male contraception that may be administered on demand.
According to the co-senior authors of the study, professors of pharmacology at Weill Cornell Medicine Drs. Jochen Buck and Lonny Levin, the discovery could be a “game-changer” for contraception. As per the news release, condoms, which have been around for around 2,000 years, and vasectomies have been the only options for males to date, according to Drs. Buck and Levin. Dr.
Levin explained that research on oral contraceptives for men has stopped in part because prospective contraceptives for men must clear a much higher bar in terms of safety and negative effects. Because men do not incur the dangers of carrying a pregnancy, he continued, the science expects males will have a low tolerance for potential contraceptive side effects.
The initial objective of Drs. Buck and Levin were not to discover a male contraceptive. They were friends and coworkers who had comparable skill sets. Dr. Buck, however, could not resist Dr. Levin’s challenge to isolate soluble adenylyl cyclase (sAC), an essential physiological signaling protein that had eluded biochemists for a long time. Two years passed by. Drs. Buck and Levin subsequently united their laboratory and moved their research focus to the study of sAC.
The group found that mice genetically modified to lack sAC are sterile. Dr. Melanie Balbach, a postdoctoral fellow in their group, made an intriguing discovery in 2018 while researching on sAC inhibitors as a potential treatment for an eye ailment.
She discovered that animals given a medication that inhibits sAC make sperm that cannot drive themselves forward. Men who lacked the gene encoding sAC were infertile but otherwise healthy, which satisfied the investigators that sAC inhibition could be a safe contraceptive approach.
New research published in Nature Communications demonstrates that a single dose of the sAC inhibitor TDI-11861 immobilizes mouse sperm for up to 2.5 hours and that the effects continue in the female reproductive system after mating. After three hours, some sperm begin to regain motility, and after twenty-four hours, nearly all sperm have regained normal movement.
Male mice treated with TDI-11861 exhibited normal mating activity when matched with female mice; however, despite 52 mating attempts, none of the females became pregnant. In contrast, roughly one-third of the mates of male mice treated with an inactive placebo became pregnant.
Dr. Balbach stated, “Our inhibitor is effective within 30 to 60 minutes.” Every other experimental hormonal or nonhormonal male contraception requires weeks to reduce sperm count or render sperm infertile.
Dr. Balbach also emphasized that it takes weeks to undo the effects of various hormonal and nonhormonal male contraceptives during development. She stated that because sAC inhibitors wear off within hours and men would only take them when necessary, they would enable men to make daily decisions regarding their fertility.
Drs. Balbach and Levin observed that the development of TDI-11861 required extensive medicinal chemistry study, which was carried out in collaboration with the Tri-Institutional Therapeutics Discovery Institute (TDI). The TDI collaborates with Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and The Rockefeller University to accelerate early-stage drug discovery.
“This extremely productive relationship between TDI and the Buck/Levin lab exemplifies the power of pairing pharma-trained drug discovery experts with academia innovators,” stated Dr. Peter Meinke, Sanders Director of TDI.
The Buck/Levin lab’s collaboration with TDI was encouraged and nourished by Weill Cornell Medicine Enterprise Innovation, the office that accelerates the translation and commercialization of technologies resulting from Weill Cornell faculty and trainee research. Moreover, Enterprise Innovation is overseeing the licensing of this finding to their startup company.
Dr. Levin stated that the team is already trying to improve the suitability of sAC inhibitors for human use. Drs. Buck and Levin founded Sacyl Pharmaceuticals alongside Dr. Gregory Kopf, the company’s chief scientific officer.
The following step for the group is to repeat their findings in a different preclinical model. According to Dr. Buck, these experiments would establish the framework for human clinical trials that would examine the effect of sAC inhibition on sperm motility in healthy human males. If the drug development and clinical testing are successful, Dr. Levin wants to one day enter a drugstore and hear a man ask for “the male pill.”
