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Medical News & Perspectives
September 14, 2017

Work Progresses on Male Contraceptives, but Hurdles Remain

JAMA. Published online September 14, 2017. doi:10.1001/jama.2017.10302

The first female contraceptive pill came on the market more than a half-century ago, but don’t expect to see sales of a male counterpart any time soon. For now, birth control options under men’s control remain limited to withdrawal or condoms, both of which have relatively high failure rates due to imperfect use, or vasectomy—highly effective but considered irreversible.

It’s easy to assume that the dearth of male contraceptives stems from men's long-time dominance in research laboratories and pharmaceutical company boardrooms. After all, the men in positions of power probably preferred to leave the responsibility for birth control up to women, who had more at stake with an unwanted pregnancy.

But the explanation is more complex than that. True, pharmaceutical companies don’t appear to be interested in developing male contraceptives, but economics seems to be the main factor.

Reluctant Drug Makers

Attracting large pharmaceutical companies’ interest has been difficult for a number of reasons. Drug makers don’t regard contraceptives as potential blockbusters, like Pfizer’s cholesterol-lowering atorvastatin, which racked up more than $100 billion in sales in less than 15 years after its 1997 debut. Pfizer manufactures such female contraceptives as Alesse and Lo/Ovral, but “male contraceptives are not one of our strategic areas for research and development,” a Pfizer spokesman told JAMA.

“I think the reason pharma is out of the development business right now for male methods is they see the regulatory risks as too high…from a financial standpoint,” said Stephanie Page, MD, PhD, a section head in the division of metabolism, endocrinology, and nutrition at the University of Washington School of Medicine.

A male method would have to be at least as effective in preventing pregnancy as birth control pills (which are about 91% effective with typical use), said Gregory Kopf, PhD, director of research and development for contraceptive technology innovations at FHI360, formerly Family Health International, a nonprofit headquartered in Durham, North Carolina.

Given that women’s birth control methods are highly effective and many are available as inexpensive generics, it’s unlikely a drug company could charge enough for a male contraceptive to cover the entire expense of research and development, although consumers might be willing to pay a premium for the first available male contraceptive, Kopf said.

Liability is also a concern with contraceptives, said endocrinologist Christina Wang, MD, professor of medicine and assistant dean in clinical and translational sciences at the David Geffen School of Medicine at UCLA, who is working on a transdermal hormonal contraceptive for men. “You are not treating a disease. You are dealing with healthy men and women.” So while patients with cancer are willing to tolerate chemotherapy drugs’ adverse events for the possibility of a cure, the safety bar is much higher for contraceptive drugs.

Public-Private Partnerships

The National Institutes of Health, nongovernmental organizations such as the Population Council, and private foundations are funding research into male contraceptives, but they alone can’t take on the larger, phase 3 clinical trials required by the US Food and Drug Administration (FDA).

However, if the NIH or foundations could lay the groundwork by funding phase 1, phase 2a, and even phase 2b trials, manufacturers might feel confident enough in a male contraceptive to pay for the larger, more expensive phase 3 trials, said Daniel Johnston, PhD, chief of the Contraceptive Research Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “Our current paradigm reduces the risk for an industry partner.”

The NICHD spends $20 million to $24 million a year on contraceptive research, fairly evenly divided between male and female methods, Johnston said. But the NIH is not in the business of ushering products through the FDA and then marketing them if they’re approved.

“Anything we develop, we have to get somebody to take it. There has to be a partnership at the other end of this,” said Johnston, who previously worked with Kopf at Wyeth.

The NICHD is looking to form public-private partnerships through a mechanism called a cooperative research and development agreement (CRADA). The National Institute of Allergy and Infectious Diseases has used CRADAs to bring vaccines to market, Johnston said. The NICHD entered into a CRADA with HRA Pharma, a French company, to develop the progestin ulipristal acetate as an emergency contraceptive called ella.

Johnston said he doesn’t expect a major pharmaceutical company to be interested in partnering with NICHD on a male contraceptive. “I think everybody likes to think it will be Pfizer, it will be GSK” or another large company that has been active in the women’s health space, he explained. The problem, though, is they don’t have divisions of male health—few companies do—so they don’t have a sales force ready to market a male contraceptive.

“I remain very concerned over who our commercial partners will be,” Johnston said.

Going Hormonal

Research is furthest along on hormonal contraceptives, but they might be harder to sell to drug companies as well as to men than other types of male birth control, Kopf said.

When he worked as assistant vice president and then vice president of women’s health discovery at Wyeth, “[I]t was agreed across the board: We are not going to touch that,” Kopf said. Pfizer acquired Wyeth in 2009.

The first large-scale, multicountry phase 2 trial of an injectable hormonal contraceptive, a combination regimen of progestogen and testosterone shown to suppress sperm production, was terminated early because of concerns about adverse events, the most common of which were acne, changes in weight, increased libido, and mood disorders. Even so, only 1 of the trial’s 2 independent safety committees recommended stopping the injections earlier than planned, the researchers reported in October 2016. The study lasted long enough to demonstrate that the contraceptive was reversible and highly effective in preventing pregnancy.

Page thinks the adverse effects have been overblown. “The side effects in all the male hormonal contraceptive studies to date essentially have not been particularly severe,” she said. “In general, in the small studies that have been done, there hasn’t been a huge alarm bell for safety.”

Wang and Page have worked on a contraceptive gel that men would rub into their shoulders daily, taking care not to transfer it to others with whom they might come in contact. The gel contains testosterone and nesterone, a potent progestin. In a clinical trial, the combination administered as a gel effectively suppressed sperm production in 89% of men who received it, according to findings reported in 2012.

The next step, of course, is to see whether the testosterone-nesterone gel actually prevents pregnancy, which is not the same thing as demonstrating that it suppresses sperm production. The NICHD-funded trial expects to begin enrolling next spring a total of about 400 couples in 3 US cities and Chile, Kenya, Sweden, and Italy, Wang said. When the man’s sperm count drops to 1 million/mL of seminal fluid, he and his partner will stop using a back-up contraceptive.

The researchers will follow up with the couples to see how well the gel prevents them from conceiving. “Pregnancy in the female will be the end point,” Wang said. “This is a big leap for us.”

With the support of NICHD, Page and Wang are also developing an androgen called dimethandrolone undecanoate (DMAU) as both a male birth control pill and longer-acting injectable. Given orally to male rabbits, DMAU suppressed sperm production enough to induce infertility, and fertility returned after treatment stopped, researchers reported in 2011.

A 28-day safety study of a DMAU pill in healthy men has been completed but not yet published, Page said. “I can tell you we were very pleased” with the safety profile and how well DMAU suppressed sperm production, she said.

Nonhormonal Approaches

A 2003 article spurred scientists to think about more targeted approaches to male contraception that would have fewer adverse effects than hormonal contraceptives, Johnston said.

The authors estimated that roughly 4% of the male genome, expressed largely or only in the testes, was devoted to producing sperm. Their study was conducted in mice, but other research has shown that murine and human genes involved in sperm production are remarkably similar.

“What that means is there are an awful lot of specific targets for a male contraceptive.” Johnson said. In other words, targeting a gene involved in one step of the process of sperm production might lead to an effective birth control method for men that, because of its specificity, would be relatively free of adverse effects.

Much of his time at Wyeth a decade ago was spent trying to develop a targeted, nonhormonal male contraceptive, but research into this approach lags behind that of hormonal contraceptives, Johnston said. One obstacle is the difficulty in crossing the blood-testes barrier, he said.

One nonhormonal male contraceptive is expected to begin enrolling men in a clinical trial next year, although it is a device, not a drug. The company Revolution Contraceptives, a subsidiary of the nonprofit Parsemus Foundation in the San Francisco Bay area, is developing what is called reversible inhibition of sperm under guidance (RISUG; marketed as Vasalgel), which Parsemus Executive Director Linda Brent, PhD, likens to a reversible vasectomy.

The device is composed of a high-molecular-weight polymer powder dissolved in a biocompatible solvent. It is injected into the vasa deferentia and remains in a soft gel-like state that allows water-soluble molecules to pass but not sperm. When men decide they no longer want to avoid pregnancy, they’d receive a second injection—sodium bicarbonate, the active ingredient in baking soda—to dissolve the polymer.

In a study published last year, researchers showed that the polymer provided effective contraception in rabbits, and one published in February showed the same in rhesus monkeys. A study of 7 rabbits published in March showed not only that the device was an effective contraceptive but that it was reversible after 14 months.

Parsemus expects to launch the first clinical trial in 2018, Brent said. “Our first goal is just to make sure that it works as a contraceptive. We feel very confident that it’s going to do well.”

If You Build It, Will They Come?

Whether men will clamor for an effective contraceptive that they can control remains to be seen, although, Brent said, more than 50 000 people have signed up for email updates about the polymer contraceptive. While Parsemus doesn’t know how those people break down by sex, the company has figured out that two-thirds of the product’s more than 21 000 Facebook followers are men, she said.

“We’ve actually been a little bit surprised at the great number of men interested in Vasalgel,” Brent said. “They want to have reproductive control.”

For now, a quarter of contraceptive use worldwide involves men, according to a recent report. But the options under men’s control leave much room for improvement, the authors wrote.

“Condoms are generally available but lack certain desirable qualities and are not popular for long-term use,” they wrote. That’s been the case for decades, though. Why are men now pressing for equality when it comes to contraception? “What is different now compared to 50 years ago is it’s very easy to determine paternity,” Kopf said.

Even men in established relationships want to be able to time fatherhood so that it fits in with their work and education plans, said Aaron Hamlin, MPH, executive director of the Male Contraception Initiative, which the Parsemus Foundation established in 2014.

“Whether you’re a man or a woman, you like to be in control of your own fertility,” Hamlin said.

It’s not clear who would prescribe a male contraceptive, Wang said, speculating that primary care physicians would be a likely choice.

Johnston noted that men tend not to see urologists until they’re older, when they’re more likely to discuss erectile dysfunction drugs than contraception.

Many questions remain. “How are you going to sell this? How are you going to put this on the market?” he said. “If you do it well, you can make a market, and if you do it poorly, you can destroy a market.”

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