Reproductive grail: Why the male pill remains out of reach
Industry joke is that oral contraceptive for men has been five years away for the past 40 years as scientists’ efforts have failed time and again
The trouble began, as it so often does, with a bottle of Chivas Regal. In the 1950s, scientists at Sterling Drug, a now defunct pharmaceutical company, synthesised a class of chemicals that made male rats temporarily infertile. They thought they might be on to something big: the first birth control pill — for men.
After identifying several promising compounds including one known as WIN 18,446, researchers began testing them on inmates at the Oregon State Penitentiary. Within 12 weeks, the inmates’ sperm counts had plummeted. When they stopped taking the drugs, sperm production returned to normal. They experienced few side effects.
Then one of the participants drank contraband Scotch and became violently ill. Follow-up studies confirmed WIN 18,446 didn’t mix well with booze. The research was abandoned.
Time and again, efforts to produce a male contraceptive have fallen short. In October 2016, researchers reported that a hormone cocktail they’d been testing had curbed sperm production and prevented pregnancy. But they had to halt the study because men were reporting side effects such as mood changes and depression. "The joke in the field is that the male contraceptive has been five years away for the last 40 years," says John Amory, a research physician at the University of Washington School of Medicine, who has been working on the challenge for two decades.
A new form of male birth control would be a public-health triumph and could snag a significant piece of the contraceptive market, which is expected to surpass $33bn by 2023, according to research firm Global Market Insights.
In a 2002 German survey of 9,000 men in nine countries — including Brazil, France, Germany, Mexico, and the US — more than 55% of the respondents said they’d be willing to use a new form of male birth control. A later study by Johns Hopkins University estimated it could yield 44-million customers in those nine countries alone. And yet major pharmaceutical companies have mostly abandoned the chase.
Scientists have dreamed up a vast array of ideas, from the conventional — hormone gels, implants, and injections designed to temporarily suppress sperm production — to the decidedly unorthodox such as lasers beamed at testes.
Amory is trying to resurrect WIN 18,446, but turning it into a contraceptive is elusive.
A new contraceptive could give men more control over their reproductive futures, and reduce the rate of unintended pregnancies, which is about 40% worldwide.
After the US Food and Drug Administration approved the first female birth control pill, which used hormones to suppress ovulation in 1960, researchers explored taking a hormone-based approach to men. Clinical trials in ensuing decades showed dosing men with testosterone or combinations of testosterone and progestin temporarily inhibited sperm production, but that the strategy had drawbacks.
Testosterone is rapidly cleared from the body when taken orally, so a hormonal contraceptive for men would be likely to have to be delivered via injection, implant, or topical gel, rather than as a pill.
The hormones don’t work in all men, and because they don’t only affect the gonads, they can cause nasty side effects.
Some investigators seek drugs that target sperm more directly. Scientists at the University of Kansas and the University of Minnesota are studying a compound called H2-gamendazole, which prevents sperm from maturing properly, while Eppin Pharma, a small North Carolina company, is developing a drug that would stop sperm from swimming by binding to a protein on the surface of the cells. And then there’s Amory, who happened upon WIN 18,446 by accident. Sterling Drug scientists created the compound to treat parasitic infections, but when they tested it in rats, the animals became infertile.
"Then they stopped the drug, and the rats regained their fertility," he says. The results suggested the possibility of it being used as a male contraceptive. WIN’s side effects — interacting dangerously with alcohol — sounded familiar to Amory. In his clinical practice, he had occasionally prescribed Antabuse (disulfiram) to patients who struggled with alcohol addiction. The drug blocks a form of the enzyme acetaldehyde dehydrogenase (ALDH), which helps the body metabolise alcohol; drinking while taking disulfiram leads to hangover-like symptoms.
But ALDH also plays a role in converting vitamin A to retinoic acid, which is required for sperm production. Amory realised WIN 18,446 might inhibit ALDH, which would explain why it caused sperm counts to drop and why men taking it had adverse reactions to alcohol. He tested his hypothesis in rabbits. After four weeks, the retinoic acid levels in the rabbits’ testes plummeted; sperm production soon followed. "They go right down to zero. And then we stop the drug, and they come right back up."
Contraceptives have to be extraordinarily reliable. Many drugs would be considered successes if they worked half the time, but few people would use birth control that failed so frequentl
WIN seemed to hobble sperm production by disrupting the synthesis of retinoic acid. He concluded WIN represented an elegant strategy for male contraception — it just needed to be better targeted.
There are almost 20 different forms of ALDH; the liver relies primarily on ALDH2 to metabolise alcohol, while the testes use ALDH1A2 to make retinoic acid. WIN disrupted both forms of the enzyme; what they needed was a drug that blocked only ALDH1A2.
To help him tweak WIN, he turned to Alex Goldstein, a chemist. Their team tested 55,000 additional chemical compounds, identifying about 300 that inhibited ALDH1A2.
A leading contender soon emerged, with experiments suggesting it was more specific than WIN, and more potent. In 2016, they put the compound, CM-121, to the test in mice.
The results were disappointing. Within five hours of each dose, retinoic acid levels did indeed drop — then quickly returned to normal. Sperm production continued apace.
Drug development is an inherently difficult enterprise. Only 10% of the drugs that enter Phase I trials — the studies in which scientists evaluate dosing and basic safety in humans — ever make it to pharmacy shelves, and it can easily cost hundreds of millions of dollars to bring a drug to market.
Contraceptives have to be extraordinarily reliable. Many drugs would be considered successes if they worked half the time, but few people would use birth control that failed so frequently. Then there are the basic facts of reproductive biology. There’s no natural off switch for sperm production; men make sperm from puberty until death.
"Spermatogenesis is a pretty formidable foe," Amory says.
"Your body has evolved over eons to make a lot of sperm. In fact, most men make a thousand sperm every second."
With such long reproductive life spans, men could use birth control for decades longer than women typically take the pill.
Unless researchers manage to find a contraceptive with real health benefits for men, regulators will probably have a low tolerance for side effects.
"A male contraceptive solution just has to be squeaky clean," says Zahed Subhan, CEO of Eppin Pharma, the North Carolina company that is testing a drug that aims to interfere with sperm movement.
If a drug were approved and serious side effects popped up, pharmaceutical companies could face costly lawsuits.
The scale and spread of the challenges may explain why pharmaceutical companies that once had active research programmes had dropped them by about a decade ago.
Although surveys show that men are interested in male contraception, because they don’t get pregnant, they may be less motivated to take on the attendant hassles and risks.
It’s also not clear if a new male contraceptive would expand the contraceptives market or cannibalise it. Companies profiting from existing solutions might be reluctant to invest in competing products.
Scientists at universities, nonprofits, and start-ups aren’t scaring so easily. "Everybody in the male birth control area is an underdog," Goldstein says.
Amory and Goldstein’s work on WIN had been funded by the National Institutes of Health, but their grant — $1.5m over five years — ran out at the end of June, and they don’t have more money lined up yet.
Even an identical grant wouldn’t be nearly enough to develop an FDA-approved drug ready for widespread use.
Their plan is to find a better, more potent candidate, assemble evidence that it’s safe and effective, and approach pharmaceutical companies about a partnership. But that will take time.
Some entrepreneurs say the path forward requires wholly rethinking male birth control.
"What is a male contraceptive?" asks Kevin Eisenfrats, the 24-year-old cofounder and CEO of Contraline, a start-up based in Charlottesville, Virginia. "Is it a drug, or is it a medical device?"
"What we’re developing is a nonsurgical and reversible alternative to a vasectomy," Eisenfrats says.
Contraline has created a hydrogel, called Echo-V, that can be injected into the vas deferens, the thin tube that transports sperm from the testes to the urethra. Upon injection, the gel solidifies, blocking the flow of sperm but allowing other fluid to pass through. Ideally, he says, when a man is ready to have children, a doctor would dissolve the gel.
Contraline, which was launched in March 2015, hasn’t had trouble attracting investors, raising $700,000 in a preliminary seed round in 2016, followed in 2017 by a second seed round of $2.3m led by Peter Thiel’s Founders Fund.
British researchers are working on a clean-sheets pill that would stop men from ejaculating during orgasm.
A German company has devised an implantable valve that would let men turn the flow of sperm on and off with the flick of an actual switch.
And a Chinese team has piloted an approach that involves injecting gold nanoparticles into the testes and heating them with an infrared laser.
Contraline’s research team is racing to be one of the first to market with a viable solution.
Eisenfrats says he plans to begin a preclinical trial in large animals in 2018, begin human trials in 2019, and earn FDA approval in 2021.