On-Demand Male Contraceptive Shows Promise in Preclinical Study

TDI extends congratulations to Dr. Lonny Levin and Dr. Jochen Buck and their labs on their recent Nature Communications article describing in vivo proof of concept studies for an innovative strategy to develop a rapid onset, non-hormonal, on-demand contraceptive for men (Press release with video). This remarkable achievement is an outgrowth of a multiyear, successful collaboration between their lab and TDI to translate basic biology discoveries from bench to beside.

To date, no male birth control medicines exist. Globally, as approximately half of all pregnancies are unintended, a clear unmet medical need for new, safe, and effective male contraception options exists.

The Buck / Levin labs are pioneers in soluble adenylyl cyclase (sAC) biology, isolating sAC in 1999 and generating a host of sAC-specific genetic, pharmacological, and immunological reagents to elucidate its complex biology. Interestingly, they observed that sAC knockout (KO) mice showed male-specific infertility but were otherwise healthy. In 2019, the same effect was observed in humans. Two infertile, but otherwise healthy, men were found to both have the same mutation leading to inactivation of sAC.

A successful chemical screen by the Buck / Levin labs identified a small molecule starting point useful for developing superior sAC inhibitors to replicate the biology seen in KO male mice and infertile men. To advance their hit, the Buck / Levin lab partnered with TDI. Exploiting the strengths of each team, TDI discovered the first lead molecule, TDI-10229 and then, leveraging structural biology data and computational software tools, ultimately identified a second generation sAC inhibitor, TDI-11861. It was this latter compound that was successfully deployed in the above proof-of-concept mating studies published in Nature Communications.

This research established that a single dose of TDI-11861 given to male mice successfully prevented 100% of pregnancies with no detected behavioral changes or safety issues, even in long term dosing studies. The TDI-11861 effects were reversible; one day after dosing, treated male mice were fully fertile.

Dr. Levin noted: “Among the advantages of working with TDI is that it is a collaboration. In my experience working with Pharma, I always felt like our lab was working for them; with TDI, we are afforded access to the same quality medicinal chemistry and drug discovery expertise and the TDI team worked with us.”

Overall, the now completed collaboration between the Buck / Levin lab and TDI has been highly successful: 6 prominent publications to date, plus multiple funded grant applications (circa $8M total funding via P50, R01, X01 and Male Contraceptive Initiative grants).