A birth control pill for men is finally within reach
A male birth control pill may be in sight.
A team of researchers based at the University of Minnesota Twin Cities made a stunning announcement on Wednesday at the spring meeting of the American Chemical Society.
Medicinal chemist and study leader Gunda I. Georg said in a press conference on Wednesday that "the efficacy [of the drug] was about 99 percent" in tests with mice. That puts this contraceptive for men on par with similar drugs for women, which were first approved by the FDA in 1960.
Researchers targeted a form of vitamin A, not testosterone
Prior attempts at creating a birth control drug for men have targeted the male sex hormone testosterone, but those efforts were stymied by side effects like depression and increased risk of cardiovascular disease.
So instead of looking at testosterone, the researchers behind this new study tried something else. “It has been known for a very long time that depriving male mice of vitamin A [causes them to] become infertile,” Georg says.
That was the clue that led the researchers to the compound YCT529.
But finding that compound was no easy task, since the body uses vitamin A in its different forms for all kinds of essential tasks, like building white blood cells and reconstructing bone.
Previous research led the researchers to focus on a specific form of vitamin A that’s essential to the growth and development of cells and embryos, called retinoic acid.
It turns out humans have three types of retinoic acid receptors (RARs). Researchers had already found a compound that blocks all three, but Georg and her team wanted to figure out if they could narrow their focus (and limit the risk of side effects) by targeting only the receptors that are actually responsible for fertility.
Genetically modified mice, computer simulations, and luminescent cells
The researchers did that through “knockout” studies that use genetically modified mice with typical genetic profiles — except for having a specific gene turned off. They bred mice with each of the three forms of receptor — RAR-α, RAR-β, and RAR-γ — knocked out and discovered that individuals without RAR-α were infertile.
Importantly, mice without RAR-α seemed healthy otherwise, which is a big advantage of knockout studies, George says. Researchers want to see “the desired effect [and that] the mice are also viable and healthy.”
With RAR-α in their sights, the researchers started looking for a compound that would block that receptor without interfering with RAR-β or RAR-γ.
The researchers didn’t go around testing every molecule they could get their hands on. They created a list of likely candidates by using computers to triage compounds and find out which ones could “be predicted to [bind] with RAR-α” based on structural differences across the three types of receptors.
“[W]e use competition modeling before making a compound to see whether it binds to RAR-α and whether it can also bind to [RAR-β and RAR-γ],” Georg says.
With that information in hand, they moved on to testing the likely molecules in living cells. They created genetic lines of cells that made it easy to determine if a compound was inhibiting the activity of the receptors.
“We put a luminescence-producing gene” into each of three modified cell lines, according to Md Abdullah al Noman. When a receptor in one of those cells started binding to a retinoic acid molecule, the cell would start to glow.
Conversely, “if our compound inhibits the binding of retinoic acid, that will [also] inhibit the production of luminescence,” al Noman says.
“We want a compound that can only bind [to] and slow activity in the [RAR-α] producing cell, not in the beta and gamma producing cells,” he says.
And that’s exactly what they found in YCT529.
An old-fashioned mating study confirmed their results
The researchers finished this phase of their research with a mating study. “Male mice were given the drug every day, and they were together with female mice,” Georg says.
The researchers’ job was a lot less complicated at this phase of the research: All they needed to measure was the number of babies born. At first, there was no change, “but after we gave this drug for several weeks, the pregnancies went down,” Georg says. “The efficacy was about 99 percent.”
That puts YCT529 right on par with "the" pill. And, after two weeks off of the drug, the mice were producing normal sperm and having babies again. To Georg, these results are “very, very promising.”
Clinical trials could start by the end of 2022
Of course, this research is nowhere close to finished.
“These are mice… not humans,” explains Georg. Conducting trials in humans is a completely different challenge — and a far more expensive one — than laboratory experiments. The researchers have licensed the compound to a startup that’s currently in the process of applying for permission from the FDA to start human tests.
If that process goes well, Georg says clinical trials should start by the end of this year. Incredibly, Georg says the drug could make it to market within five years. "Usually, it takes a lot longer, but if everything works out well, perhaps we can be faster.”
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