New research presented at ENDO 2019 in New Orleans has reignited anticipation of a potential novel male hormonal contraceptive. After recent scientific breakthroughs, how long before men are “on the pill” or another means of hormonal contraceptive?
Unintended pregnancy is a global public health problem. The health and economic impacts on women and their children can be enormous. Unplanned children are at risk for suboptimal prenatal care, premature birth, and future health problems. In addition to coping with the stress of an unintended pregnancy, women are less likely to attain higher education and find lucrative employment, which, in turn, can negatively impact children.
Although rates worldwide have been on the decline in the last 30 years, still, around 44% of pregnancies are unplanned, with rates in developing countries tending to be higher than in developed countries. The U.S. is an exception, however, with an estimated 45% of pregnancies being unplanned. The need for contraceptive options and family planning is all too clear.
That’s where a team working jointly from the Los Angeles Biomedical Research Institute (LABiomed) in Torrance, Calif., and the University of Washington (UW) School of Medicine, in Seattle, Wash., in association with and sponsored by The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) come in. “Our lab, and all the people in this field I think I can safely say, feel that developing a male contraceptive is important because of the global problem of unplanned pregnancy, despite the fact that there are many contraceptive choices for women,” says Stephanie Page, MD, PhD, University of Washington and a co-senior investigator. “While contraceptive access remains an issue here and across the globe and needs to be addressed, we feel that providing more options for men, who currently have very limited options in terms of contraceptives, could help to make a dent in the problem of unplanned pregnancy.”
Co-senior investigator Christina Wang, MD, from LABiomed agrees wholeheartedly: “We have been pursuing this for a few years, and it’s just coming to the time when we can see real results. We noted a lot of interest from the general population that more men may be interested in male hormonal contraception and feel that there’s a need for them to participate in family planning. That’s all good.”
Oral Hormonal Contraception
Her enthusiasm is well warranted. The team is concurrently undertaking studies of three different modes of administration of five different prototype products. The biggest recent news is that their second oral modified testosterone compound has just completed a one-month safety test, an early step in the U.S. Food and Drug Administration (FDA)’s evaluation of new drugs, and a three-month trial should follow based upon their positive findings.
11-Beta-methyl-19-nortestosterone dodecylcarbonate (11-beta-MNTDC) has both androgenic and progestational activity and successfully and reversibly suppressed testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in a preclinical study of 40 healthy men. Male hormonal contraceptives use both androgen and progestin because adding the progestin suppresses sperm production more quickly, and requires less androgen than when testosterone is given alone. The actions of these two hormones, which regulate LH and FSH, are present in 11-beta-MNTDC. By shutting down the regulators of testicular function, sperm production as well as the production of testosterone is ablated. Because 11-beta-MNTDC performs like a male hormone in the body, however, the lack of testosterone is not noticeable, and libido and sexual activity were not significantly affected.
In the randomized, placebo-controlled, double-blind study, 10 men were given placebo, 14 men were given 200 mg of 11-beta-MNTDC, and 16 were given 400 mg of 11-beta-MNTDC. All participants took the capsules daily with a large breakfast to facilitate absorption and per FDA recommendations.
“Since this trial passed the safety tests, appears to be well tolerated in men, and achieved the actions that we were anticipating it to show, our next step has to be to demonstrate that it can suppress sperm production,” Wang explains. “Because we have only given 11-beta-MNTDC for 28 days, we have yet to show that the sperm count will suppress to very low levels. For a drug that works by suppressing sperm production, it will take about 90 days (three months) to demonstrate this. If the dose is adjusted right, we want to see at least 90% of men having their sperm count suppressed to a very low level to prevent pregnancy in the female partner.”
The team has conducted a six-month rodent toxicology study and is now conducting a six-month primate toxicology study, with the results to be available at the end of this year. Once these demonstrate safety, the longer trial of 11-beta-MNTDC in humans can begin.
As mentioned, 11-beta-MNTDC is not the only male hormonal contraceptive the team is working on. Like 11-beta-MNTDC, oral dimethandrolone undecanoate (DMAU) looks promising in terms of efficacy and safety and is farther along in the development cycle. “We think of them as sister compounds,” Page says. “We wanted to have multiple compounds in the pipeline, and that’s why we are developing and testing these in parallel. You never know when you’re going to encounter a hiccup during drug development. The compounds are very closely related, and we are trying to ensure that we have something that moves forward.”
Both compounds are built on a backbone of 19-nortestosterone and both have androgen and progestin actions, but there are slight chemical differences between the two, including that DMAU is a bit more androgenic. “Until we do human trials, we don’t know for certain whether those in vitro differences will translate into clinical differences,” Page says. “For example, we know that giving oral androgens is going to have some effects on cholesterol. So, it may be that one of our compounds will have less impact than the other. Or one of them has an effect that may be more beneficial than the other, or is better absorbed, or lasts longer in the blood. That’s where those slight differences could translate into something that is clinically important for a contraceptive as the project moves forward.”
So far, up to a 5-kg weight gain has been seen across studies, although some participants did not gain any weight. Researchers are not sure yet whether the weight gain is related to the compound itself or to the fact that it had to be taken with a fatty meal; however, more weight gain was seen in the groups taking the compounds than in the control groups. “We are going to work on what types of foods these compounds can be taken with down the line. It may be that we can reduce the fat content that was required for these early clinical trials,” Page says.
“While contraceptive access remains an issue here and across the globe and needs to be addressed, we feel that providing more options for men, who currently have very limited options in terms of contraceptives, could help to make a dent in the problem of unplanned pregnancy.” – Stephanie Page, MD, PhD, University of Washington, Seattle
Intramuscular Injectable Contraception
As of April 2019, trials of both oral administration and intramuscular (IM) injections of DMAU in rats and monkeys have been completed. The next step for DMAU is to see which oral dose most effectively suppresses sperm production in humans in a three-month trial. “Once that is done,” Wang says, “we can decide whether we need to have more studies to make sure that this compound is safe and tolerated when delivered orally, or can we go into a study that can prevent pregnancy in the female partner. We’re about halfway through the recruitment for this study.”
Study of IM injection of DMAU is also underway. “Because it appears to last a long time in men, progress is a bit slow,” Wang explains. “We have a safety review as we increase each of the test doses to make sure that all subjects recover before we go to the next dose in the current Phase 1 study.”
The team anticipates that both DMAU and 11-beta-MNTDC will work as long-acting reversible injectable contraception. Additionally, the absorption and bioavailability of both 11-beta-MNTDC and DMAU appears to be better after the IM injection. Oral absorption is lower. “So, as far we know, you can use much less of the drug with the IM injection,” Wang says.
Transdermal Gel Contraception
In association with the Population Council, the team also developed a transdermal gel that began testing in couples at the end of 2018. A previous test of Nestorone® (segesterone acetate) and testosterone (N/EST) showed that, for men applying the gel for six months, sperm count was suppressed to a very low concentration in about 90% of study participants. A total of 420 couples will be enrolled in the new late phase 2 trial with the primary endpoint being prevention of pregnancy.
In addition to UW and LABiomed, other testing sites will include the University of Kansas in Overland Park; the University of Edinburgh in Scotland; the University of Manchester in the U.K.; the Karolinska Institute in Stockholm, Sweden; Kenyatta National Hospital in Nairobi, Kenya; the Chilean Institute of Reproductive Medicine in Santiago; and the University of Bologna, Italy.
“Suddenly everything began developing, so that we have a study that is in late phase 2, and one going after another,” says Wang.
“We have been pursuing this for a few years, and it’s just coming to the time when we can see real results. We noted a lot of interest from the general population that more men may be interested in male hormonal contraception and feel that there’s a need for them to participate in family planning. That’s all good.” – Christina Wang, MD, LABiomed, Los Angeles, Calif.
Male hormonal contraception has been a long time coming. “Unplanned pregnancy is a big problem,” Page says, “and 50% of the population is less engaged than they could be in combating it — and that’s in part because men don’t have very many contraceptive choices.”
That could be changing very soon, however. When researchers asked men from across the globe what form of reversible birth control they would prefer, the number one response was a pill. They also know from female contraception that there is likely to be demand for longer-acting male contraceptives. “What we are trying to do is develop many methods for men,” Wang says. “Different products will be appealing to different men and to different couples, just as is the case for women. And, different products might be appealing to the same person at a different stage in his life,” echoes Page. “Just as a woman might take an oral contraceptive for a while, then switch to an IUD, for example, there’s no reason to think that men wouldn’t similarly want to change their methods or the methods they share with their partners across the lifespan.”
These eagerly awaited options for effective, reversible male contraception have something else in common: They came to be from team science.
“We all work as a team toward developing effective male contraceptives — team science is so important in accelerating development of novel solutions to health problems,” Page says. “Dr. Wang and I work very closely together, and we were honored that our DMAU paper (“Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill,” published in JCEM in February) was recognized by the Endocrine Society’s “Women in Endocrinology” organization. It’s always great to highlight how collaborative science can move things forward.”
-Horvath is a freelance writer based in Baltimore, Md. She wrote about the latest breakthroughs in obesity research in the April issue.