A SMRT new target for male contraceptives works in mice

A drug with a past life as a potential anti-cancer agent might someday have a new job as "the pill" for men, new data in mice suggest. 

In a journal article published Feb. 20 in Proceedings of the National Academy of Sciences, researchers at the Salk Institute explained how they discovered that an oral HDAC inhibitor called entinostat acts like an “off-on” switch for sperm creation that keeps male mice from reproducing without any effect on their libido. Within 60 to 90 days of stopping the pill, the mice were able to impregnate female animals again without any harm to the resulting offspring. 

Effective male contraceptives are a long time coming, senior author Ronald Evans, Ph.D., told Fierce Biotech Research in an interview. Researchers have been trying for decades to develop a noninvasive, reversible, easily accessible drug candidate that is as effective as the birth control pill is for women, with no success so far.  

“Our game-changing or transformative results are that it’s now possible to have a male equivalent of the pill that’s able to give men control as well, without having to rely on condoms,” Evans said. (Of course, this wouldn’t eliminate the need for condoms—they’re still necessary to protect against some types of sexually transmitted disease.)

Sperm production is a complex process with many components, a limiting factor in coming up with drugs to block it. Hormonal candidates, such as the drug DMAU, have mainly focused on blocking testosterone—a route that varies in effectiveness depending on the patient population and can come with side effects. A non-hormonal injectable drug called RISUG is making its way through clinical trials in India, and a version called Vasalgel is in development in the U.S. However, both of these require either an injection or an in-office procedure. 

One non-hormonal mechanism that scientists have long considered is blocking receptors for retinoic acid, a form of vitamin A that is critical to the process whereby sperm stem cells differentiate into fully functional sperm. But while this does stop sperm production in mice and rats, it comes at a cost: Retinoic acid is needed for a wide range of processes throughout the body, so inhibiting its activity systemically can lead to serious side effects, Evans explained.

“You can kind of get it to work the way you want, but it’s not specific enough to be a useful way to address the challenge of controlling spermatogenesis,” he said. Researchers have largely abandoned the effort in favor of other approaches. 

But in the new study, Evans’ lab—which was the first to clone the receptor for retinoic acid—learned that there’s another way to go about blocking its role in sperm production without systemic effects. While studying a gene regulatory factor called SMRT, one of the researchers in his lab pointed out that it was part of a complex of proteins that were involved in regulating retinoic acid receptors in sperm creation. 

“He suggested that maybe we should actually not target the retinoic acid receptor itself, but target SMRT,” Evans recalled. Not only would doing so be easier than targeting the receptor directly, but it would also be safer because the target’s systemic effects are more limited, he added. 

This led the team to see if blocking SMRT with entinostat, which Evans co-developed under his former company Syndax, would be a solution, as SMRT’s function is controlled by the same components that are interrupted by HDAC inhibitors. They gave male mice one of three different doses of the drug once a day for 60 days, then tested their ability to mate. They also tested whether taking mice off the drug would restore sperm production—and whether it would affect the health of their offspring. 

To their surprise, the approach was a success. 

“[The researcher] came back and said, ‘It really works.’ I said, ‘What do you mean it really works?’” Evans recalled. “He said, ‘It’s a total contraceptive. The mice’s libido is totally normal. And if you take it away, [their ability to reproduce] comes back.’”

None of the mice that were on the drug sired offspring during the treatment period, compared to litters of around 10 pups each from control males. Sixty days after stopping the treatment, mice in the experimental groups were able to impregnate females again to the same degree as controls. All of the pups were born healthy. 

During the treatment period, the researchers noticed that the animals’ testis size was “dose-dependently reduced” as their sperm production capacity fell. This was mostly recovered after 60 days off the drug, figures in the article showed. There were no other discernible side effects, such as weight loss that would indicate a change in testosterone levels, the researchers wrote in their paper.

“As a proof of principle, our findings indicate that chronic, oral administration of MS-275 transiently blocks male fertility without permanently affecting reproductive capacity or the genomic integrity of sperm,” they wrote.

Evans now hopes to test entinostat as a male contraceptive in larger animals and eventually in humans. The drug already has FDA breakthrough status for advanced breast cancer and has been studied in clinical trials for pancreatic cancer, brain cancer, melanoma and other cancers, so safety in humans has already been established, he said. 

Given the results, Evans’ team has no plans to look at whether other HDAC inhibitors have birth control potential as well, he said, though they might look at other medical uses for entinostat. But for now, its use as a male contraceptive “is at the top of the list,” he said. 

“That’s where we want to focus and see if there is a company that wants to actually develop this. Or do we have to start our own?” Evans, a serial biotech entrepreneur, said. “That’s kind of fun to think about.”