Miriam E Tucker
March 19, 2018
Dose-finding and safety results of the trial in 82 healthy men were presented March 18 here ENDO 2018: The Endocrine Society Annual Meeting by Arthi Thirumalai, MBBS, acting assistant professor, University of Washington, Seattle.
"It only needs to be dosed once a day, and we didn't see any significant side effects, but it needs to be tested much longer. This is a very early phase," Study coauthor Stephanie Page, MD, PhD, professor of medicine at the university, told Medscape Medical News.
The agent, dimethandrolone undecanoate (DMAU), is a prodrug that is converted to dimethandrolone (DMA), which binds to both androgen and progesterone receptors. The long-chain fatty acid component undecanoate slows the drug's clearance, enabling the once-daily dosing.
During a press briefing, Page showed data from a multinational survey in which 60% to 80% of men indicated that they would be interested in a reversible male contraceptive if one were available, and of those, more than 30% prefer a daily pill over injected formulations.
"Many men say they would prefer a daily pill as reversible contraceptive, rather than long-acting injections or topical gels, which are also in development," she noted.
"I think the landscape has changed and the interest in male contraception is really growing," she told Medscape Medical News.
Efforts so far to develop a male contraceptive have been challenging because of the potential for hepatotoxicity and need for multiple daily dosing, she explained, adding: "[DMAU] is very different ... We hope it's a big step forward. These promising results are unprecedented in the development of a prototype male pill."
Asked to comment, Alberto Ferlin, MD, PhD, associate professor of endocrinology at the University of Brescia, Italy, and president of the Italian Society of Andrology and Sexual Medicine, said: "It's very interesting, because in one pill you have both the function of contraception but apparently no symptoms of low testosterone."
However, as did the investigators, Ferlin also cautioned that these data are short-term and very preliminary. "We should wait for a longer treatment period to see if the men develop consequences of low testosterone on lipids, glucose metabolism, and bone health."
Moreover, he noted, "Most important for contraception is the sperm count needs to go down ... If it goes down but not completely, there's still the possibility of pregnancy."
Testosterone Suppressed to 'Near-Castration' Levels
The double-blind, randomized study was conducted at two US centers.
Healthy men aged 18 to 50 years with normal reproductive function were randomized to DMAU formulated in castor oil / benzyl benzoate (100, 200, or 400 mg), powder in capsule (200 or 400 mg), or placebo in each of the formulations. All were instructed to take the drug with food.
Pharmacokinetic assessments were conducted on days 1 and 28, and safety assessments were conducted twice weekly. Of 100 patients randomized, 82 completed the study and had over 90% drug compliance. There were no dropouts because of drug-related concerns.
Serum DMA concentrations showed a dose–response effect. In all active treatment groups, serum testosterone fell to the hypogonadal range by day 4 to 7, with a median 13.4 ng/dL on day 28.
All patients who received the 400-mg powder and 12 of 13 given 400 mg of the castor oil formulation also achieved suppression of follicle-stimulating hormone and luteinizing hormone (< 1 IU/L).
That level of suppression has been associated with blockage of spermatogenesis in animals, and "would hopefully block fertility in men," although that hasn't been shown yet, Thirumalai noted.
Short-Term Safety Demonstrated
However, high-density lipoprotein cholesterol concentrations dropped by 7 to 17 mg/dL with DMAU, while low-density lipoprotein cholesterol levels didn't change. Body weight increased by 1.5 to 3.9 kg in the patients who took DMAU.
The men reported no changes in mood or sexual function on questionnaires, but 9 of the 100 reported decreased libido (8 on DMAU, 1 on placebo). Acne was reported by 5 taking DMAU and 3 on placebo.
All adverse events resolved by the end of the study, Thirumalai said.
At the press briefing, Page said that the research team has just begun a 3-month study to establish safety and sperm suppression.
She told Medscape Medical News, "We're confident, but this [current] study was too short. Ultimately, we need to do a study with couples. There's lots of work to do."
The National Institutes of Health currently holds the patent on DMAU and funded the study. Page has consulted for Clarus Therapeutics. Thirumalai and Ferlin have reported no relevant financial relationships.