Novel drug for male contraception shows early signs of efficacy in Promega-sponsored study in mice

A novel, non-hormonal reversible contraceptive for men appears to be effective in mice, based on the results of a study sponsored by biological analysis company Promega. 

Reporting May 23 in Science, researchers from Baylor College of Medicine and Lawrence Berkeley National Laboratory described how they developed a small molecule inhibitor called CDD-2807 that reduced fertility in male mice without any signs of toxicity. When the mice were taken off the drug, their fertility returned. 

Synthetic derivatives of testosterone called dimethandrolone undecanoate (DMAU) and 11b-MNTDC are being tested as reversible male contraceptives in clinical trials but there are concerns about side effects, many of which overlap with those linked to birth control for women. On the preclinical side, researchers have looked at repurposing a cancer drug and targeting the retinoic acid receptor among other strategies, though none aside from the synthetic testosterone have made it to humans yet. 

The Baylor team’s drug represents an entirely new strategy. The scientists pulled from nature’s playbook by hunting for compounds that inhibit serine/threonine kinase 33 (STK33), an enzyme that when mutated causes male sterility in both humans and mice. A screen of a multibillion-compound DNA-encoded drug library gave them a handful of potential contenders, which they used to design CDD-2807. 

To see if the drug would work, the researchers tested it in male mice, following two different protocols to do so. In the first, they injected six mice intraperitoneally with a control solution and six with CDD-2807 twice daily at 15 mg/kg for 21 days, then placed them with fertile female mice.

A month later, nearly all the mice in the control group sired at least seven offspring per female on average. While four of the six mice in the CDD-2807 group also had offspring, the litters were much smaller—less than one pup per female. By the second month, all the mice in the control group sired large litters but none of the treated mice did. 

In the second protocol, the mice in the experimental group were given CDD-2807 once a day, but at 50 mg/kg. All the mice in the control group had pups—again, at least seven on average per female—while one mouse in the experimental group produced a single pup. No pups were born to any of the treated mice in the second month. 

The researchers studied the drug’s reversibility by stopping it and then placing some of the mice in each group with new mates. For the mice in the first protocol, the one with the lower dose given twice daily, all of the mice in the experimental group had pups within the first month, with litter sizes on par with controls. Treated mice in the second protocol ultimately sired large litters too, but took about two months to do so. 

None of the treated mice lost weight or died during the study, a sign that the treatment was safe. The size of their testis didn’t change either, a side effect that has been seen with other male contraceptive drugs that have been studied in mice. “These findings provide substantial support that targeted nonhormonal approaches can be effective in the development of a male contraceptive pill,” the researchers wrote in the abstract of their article.

While the results point toward efficacy, only human studies will show whether it’s a viable candidate for male contraception, as graduate student Jarrett Holdaway and Gunda Georg, Ph.D., both of the University of Minneapolis College of Pharmacy and unaffiliated with the research, pointed out in a commentary that ran in Science along with the article. The drug will also need to be taken by mouth, not injected, to be commercially viable.

“A successful male contraceptive pill needs to be orally bioavailable, which has been a challenge for several drug candidates,” Holdaway and Georg wrote. “Additionally, a male contraceptive pill … must navigate substantial safety hurdles before being considered for approval.” That includes long-term safety as well, they added. 

The researchers plan to continue studying CDD-2807 as a therapeutic target and to come up with other versions of the drug that they’ll test in primates, the press release said.