The Tennessee-based biopharmaceutical company, who presented research findings at the American Association of Pharmaceutical Scientists (AAPS) conference in San Diego last week, has developed a once-daily oral male contraceptive pill that is reversible. There is much R&D in the area of male contraceptives at a time when condoms, vasectomy and abstinence are the only methods currently available to men to prevent pregnancy. A lot of hope has been pinned on testosterone or some other hormonal contraceptive with the aim of developing it in a pill form. But testosterone has so far proved unsuccessful in being formulated as an oral dosage form and can only be administered through a patch or injection. GTx' male contraceptive, on the other hand, has promising potential for the 21st Century man, according to GTx preclinical R&D vice president James Dalton.
"People are using hormonal agents for contraception but it hasn't been possible with an oral agent before. If you can do it orally, why wouldn't you?" Dalton told in-PharmaTechnologist.com. The secret of GTx' oral formulation was the development of a selective androgen receptor modulator (SARM), which had the ability to suppress sperm production. SARMs are new synthetic non-steroidal molecules which have the ability to mimic steroids by acting on receptors but without the unwanted side effects. But unlike steroids, SARMs can easily be formulated into an oral form, which, Dalton said, would increase convenience for the users.
GTx' male contraceptive candidate C-31 works by suppressing luteinising hormone, which in turn, suppresses testosterone production. A lack of testosterone stops the production of sperm. Dalton and Ohio State University graduate student Amanda Jones treated animals for three months with the oral formulation and found that sperm production was halted. When taken off the medication, the researchers found the animals' fertility returned after 100 days. "With women and birth control you want to stop fertility and know you can still have children [when you stop taking the birth control]. It's the same for men," Dalton said. The pill would take up to three months to take effect "just because sperm are in the testes that have to be depleted and that can take up to two to three months at least".
It would take the same amount of time for fertility to return, Dalton said. Because of the length of time needed for effects to take place, there probably would not be a problem if the man missed taking a pill one day, Dalton said. "Men are probably safer [than women] in that regard of missing a pill because it takes so long to start generating sperm again." The question is would men take a contraceptive pill?
According to Dalton, the literature suggests men in their 20s and 30s would consider using a contraceptive so there was a potential market there. The problem was convincing pharmaceutical companies to develop the drug, he said. Despite that, GTx entered into a more than $500m collaboration with Merck earlier this month to develop SARMs. Under the agreement, the two companies would combine their respective SARM research programmes and would include the development of GTx' lead SARM candidate, Ostarine, which is currently in Phase II trials for treatment of muscle loss in patients with cancer, and the research, development and commercialisation of future SARM molecules. Other non-hormonal candidates that have been investigated as male contraceptives include: the plant-derived compound gossypol, but there are questions about its reversibility; the Chinese herbal medicine Tripterygium wilfordii, which is used in the treatment of autoimmune diseases and has the known side effect of infertility but has other undesirable side effects; Nifedipine, a high blood pressure medication thought to have a contraceptive effect in some men which works by blocking the calcium channels in sperm membranes; Miglustat, approved under the brand name Zavesca in both the US and the EU for treatment of Gaucher Disease, interferes with sperm development and is reversible; a protein called CatSper that sperm need in order to beat their tails to move, but no drug has been developed to target the protein yet; sperm enzyme inhibitors; chloroform extract of Carica papaya seeds; oleanolic acid, a plant-derived substance found in cloves; and immunocontraceptives, which direct the immune system against cells in the reproductive system.
C-31 as an oral male contraceptive is still about five years away from Phase I clinical trials.