The first product for male birth control is almost here.
In the first phase of clinical trials, two experimental male contraceptive pills – DMAU and 11β-MNTDC – appeared to effectively lower testosterone without causing unacceptable side effects.
According to the researchers, there are similar pathways for the hormonal control of reproductive function in women.
“We are building on the knowledge of many decades of contraceptive development for women as well as our success with other combination hormonal methods such as Nestorone® (a progestogen) and Testosterone gel for regulating LH secretion and sperm production in men,” lead researcher, Tamar Jacobsohn of the Contraceptive Development Program (CPD) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Dr. Diana Blithe, Program Chief of CDP, told IE in an interview.
Only two contraceptive methods for people with sperm
Ever since the birth control pill was first approved as a contraceptive in the US in 1960, the onus of birth control has largely fallen on people with female reproductive systems.
According to the Centers for Disease Control and Prevention (CDC), in 2015-2017, 64.9 percent of the 72.2 million women aged 15–49 in the United States were using contraception, with the most common method being female sterilization, oral contraceptive pills, long-acting reversible contraceptives (LARCs), and the male condom (8.7%).
Data from the 2015–2017 National Survey of Family Growth revealed that nearly all women use some form of contraception method at some point in their lifetime. Currently, the US Food and Drug Administration has approved 17 birth control methods for people with female reproductive systems and only two for people with male reproductive systems – condoms and vasectomy. Some people also practice methods such as natural family planning (or “fertility awareness”) or the pullout method, but both of these methods have a very high rate of failure.
In recent years, there have been reports of trials for hormone gels and injections for men, but these are not widely available. According to data from Global Market Insights, if a new male contraceptive method were to be approved in the next five years, the market is projected to be around $1 billion by 2024 and could grow at the rate of six percent over the next ten years,
As yet, however, there are no new birth control methods on the market for those who produce sperm.
Big Pharma and health risks pose challenges
There have been several challenges when it comes to developing a male hormonal contraceptive.
“The first includes developing a first-of-its-kind drug to be used by healthy men who do not face health risks from pregnancy,” said Blithe and Jacobsohn.
This sets the bar for safety very high. As always, with the new medication, extensive testing is required to ensure that there are no health risks, which is different from the side effects, they stressed.
Androgens are male hormones; these are naturally produced in the body and are a requirement for the normal sexual development of both males and females. In males, the predominant androgen is testosterone. In genetic males, testosterone has a number of roles, including regulating sex drive, bone mass, fat distribution, muscle mass and strength, and the production of red blood cells and sperm.
However, current formulations of oral testosterone derivatives require multiple doses per day.
There have been a number of obstacles to the development of a male oral contraceptive. One is that reliably and completely blocking the production of millions of sperm every day (in males) versus preventing the release of a single egg a month (in females) is a lot more complicated, biologically speaking. Those drugs that have been tested have often had serious side effects.
However, there has also been little interest from large pharmaceutical companies, some of whom make billions from the female contraceptive pill, and there is little funding available for clinical trials of these drugs. All of this makes the research more challenging.
However, “With more awareness of the potential market for these products, through clinical trials and acceptability trials globally, large pharmaceutical companies may become more interested in supporting the research. If that happens, through our research efforts and the efforts of male contraceptive development generally, it could help speed up the process of developing more options for men,” Blithe and Jacobsohn said.
‘The’ drugs explained
The drugs involved in the current study are Dimethandrolone (DMA) and 11β-methyl-19-nortestosterone (11β-MNT), which are progestogenic-androgens, which means they are single agents with two functions.
To elaborate, “the progestogenic function serves to lower the pituitary production of gonadotropin hormones (FSH and LH). Inhibiting LH leads to lower testosterone in the testis,” according to Blithe and Jacobsohn.
In theory, sperm production would be inhibited in the absence of adequate testosterone in the testis.
Why these specific compounds?
“The androgenic function of these molecules supports sexual function and other bodily functions that rely on adequate testosterone levels in the blood. These progestogenic androgens are being tested because they are orally bioavailable and thus can be used as a pill (research shows that men would like to use oral pills), and because both functions may be delivered with a single drug instead of two combined drugs,” Blithe and Jacobsohn explained.
Testosterone levels notably dropped below the normal range
The study included 96 healthy male participants in two Phase 1 clinical trials. As aforementioned, the usage of DMAU and 11β-MNTDC suppress testosterone. Lowering testosterone levels can lead to unpleasant side effects, but most men involved in the study were willing to continue using the drugs.
“Many of the men joining our clinical trials are extremely enthusiastic about the prospect of male contraception. They are dedicated to helping move the product forward through clinical trials,” Blithe and Jacobsohn said.
In each trial, the men were randomly assigned to receive doses of two or four oral pills, of either the active drug or the placebo, daily for 28 days. Testosterone levels in those taking the active drug notably dropped below the normal range after seven days on the active drug. And in men taking the placebo, testosterone levels stayed within the normal range.
Among the participants, 75 percent of the men who took the active drug said that they would be willing to use it in the future, in comparison with 46.4 percent of those who took the placebo.
It was also observed that men who took the four-pill daily dose (400 milligrams) had lower levels of testosterone than those taking the two-pill, 200-milligram dose.
No serious side effects were observed
“Research on non-hormonal methods is quite active, with several different mechanisms being explored,” Blithe and Jacobsohn said.
A few months ago, a team of researchers based at the University of Minnesota Twin Cities tested the compound YCT529, which focuses on receptors for a specific form of vitamin A, called retinoic acid, that’s essential to the growth and development of cells and embryos. After the drug was given to mice for several weeks, the pregnancies among the mice went down.
“No [non-hormonal medication] has successfully transitioned to clinical evaluation, but progress is being made toward that goal. It cannot be assumed that non-hormonal methods will be free of side effects, so we will have to wait for those clinical trials to begin to see if anything emerges that was not evident in pre-clinical qualifying studies,” Blithe and Jacobsohn said.
Jacobsohn and her team are working with contraceptive mechanisms to replace androgen function either with testosterone or other androgenic drugs to minimize or prevent side effects.
And in the current studies, no adverse effects or side effects were observed with either of the drugs. “Mild side effects included acne and changes in libido (both increased and decreased), headaches, and erectile dysfunction in a few individuals. All side effects were resolved by the end of the study,” they said.
Currently, amid an efficacy trial
In the Phase 1b trial of testing, the researchers are looking at the pharmacodynamics, pharmacokinetics, and safety of the drug.
After Phase 1 trials, longer and larger studies are required, the researchers pointed out. “Since the treatment is used in healthy men, the studies are sequential and escalating to ensure that safety is maintained across longer treatment in a larger number of individuals,” Blithe and Jacobsohn said.
Phase 2 trials would look at the longer periods of treatment to confirm safety “and determine if the drugs can inhibit sperm production.”
Additionally, researchers at the CDP are also amid conducting a Phase 2b (efficacy) trial for a combination Nestorone/Testosterone gel product, “which we hope will be the first groundbreaking product for male contraception, thus paving the way for other drugs to become available within the next ten years,” Blithe and Jacobsohn said.
If drugs successfully reach Phase 2b efficacy testing in couples, the trials will be lengthy, requiring a two-year commitment from couples to demonstrate suppression, efficacy, and recovery. Discussions with the FDA on what would be expected in Phase 3 will take place if the Phase 2 trials are successful.
On par with the pill for women
The researchers are hoping to create a birth control pill that can be taken once daily, like those which are available for women.
“Given that these drugs also combat the side effects of hypogonadism with their androgenic effects, further research is necessary to look at them as a possibility for androgen replacement therapy as well. Similar to the use of hormonal birth control for women for a variety of reasons other than pregnancy prevention, the same may be possible for men,” Blithe and Jacobsohn said.
Just the prospect of male contraception becoming widely available is imperative for reproductive autonomy and equality. “The development of contraceptive products for men will both increase available options for men and allow for many women to have more options for sharing the contraceptive burden,” they added.
A promising development in hormonal male contraception (HMC) is a class of bifunctional prodrugs that combine both androgenic and progestogenic activities into a single molecule. Examples of these prodrugs currently being studied are dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) (1, 2). The inactive prodrugs are cleaved to release active drug over a 24-hour timeframe, providing once-a-day dosing. As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production and circulating levels. Low testosterone levels might lead to unpleasant symptoms of hypogonadism if DMAU and 11β-MNTDC are not providing sufficient and effective androgenicity. Therefore, we examined the impact of the novel progestogenic androgens on serum testosterone levels and acceptability of varying dosages of these oral prodrugs in a secondary analysis of two Phase 1 placebo-controlled trials. Healthy male participants were randomized to take two or four oral pills of active drug or placebo per day. As DMAU and 11β-MNTDC share similar mechanisms of action and tolerability, we examined the association of dosage as well as testosterone concentrations on combined drug acceptability versus placebo. Survey respondents across the two trials (39 DMAU, 30 11β-MNTDC, 28 combined placebo group) shared similar baseline demographics. After seven days of usage, testosterone levels for those using either prodrug dropped to levels below 100 ng/dL while testosterone levels for those using the placebo (400-600 ng/dL) remained within the reference. Recipients of either DMAU or 11β-MNTDC reported greater willingness to use the active prodrug in the future (75%), compared to placebo recipients (46.4%, p=0.007). Throughout the 28-day oral pill usage, while average testosterone levels during the period of suppression (day 7 to 28) were very low, they were significantly higher in the 200 mg group than in the 400 mg group (92.7 ng/dL vs. 49.6 ng/dL, p-value <0.001). Participants using 2 pills (200 mg, n=33) versus 4 pills (400 mg, n=35) of active drug did not report a significant difference in general satisfaction, willingness to use in the future, or recommendation of the study pill to other men (p=0.85, p=0.48, p=0.60, respectively). In placebo-controlled trials, men randomized to use active, daily oral progestogenic androgen prodrugs reported greater acceptability with their respective regimens than did men who received placebo pills despite low serum testosterone levels. Oral hormonal male contraceptive pill prototypes, DMAU and 11β-MNTDC, significantly suppress serum testosterone while providing sufficient androgenicity to be acceptable to most men.