1. New Contraceptives for Men SWEET Seminar December 2007 Kirsten Thompson, Director Male Contraception Coalition Kirsten@MaleContraceptives.org www.IMCCoaltion.org Kirsten@MaleContraceptives.org www.IMCCoaltion.org

2. What we’ll cover today Why family planning remains relevant Why male contraceptives are important Evidence of a male contraceptive market 5 male contraceptives in or approaching clinical trials

3. What is a contraceptive? Is contraception inherently inconvenient? What doesn’t a contraceptive do?

4. The big picture Worldwide, fertility is decliningWorldwide Desired family size is a moving target Unmet need remains substantial Method mix is a quality indicator Dissatisfaction / discontinuation / lack of compliance with existing methods

5. Do men want new options? We get letters every day from men around the world asking: “How can I get access to these new contraceptives?”

6. Do men want new options? Over 40% of US couples rely on the currently available male contraceptives Source: CDC (2006) Health, United States

7. Surveys say “Yes” In 12 countries, the majority of men would use a new hormonal male contraceptive –50% of US men Men are motivated by desire to share family planning responsibility & have direct control over their fertility Sources: Martin (2000) Human Reproduction 15(3): 637-45. Heinemann (2005) Human Reproduction 20(2): 549-56. MCC (2007) Male Contraception Quarterly 3: 1-4.

8. What do women think? Only 2-3% wouldn’t trust their partners to use a male contraceptive Sources: Glasier (2000) Human Reproduction 15(3): 646-9. MCC (2007) Male Contraception Quarterly 3: 1-4. KFF (1997) Men’s Role in Preventing Pregnancy.

9. Three methods are in clinical trials: RISUG The Intra Vas Device (IVD) Male hormonal contraceptives Two interesting pre-clinical leads: Adjudin RAR antagonist Which male contraceptives are closest to market?

10. Vas-based methods

11. A polymer gel injected into the vasa deferentia Partially blocks the lumen and disrupts passing sperm Now in Phase III clinical trials in India RISUG – What is it?

12. RISUG – How effective is it? Extremely effective (>99%) 200+ men have been treated with RISUG 2 pregnancies: 1 due to improper delivery, 1 due to marital infidelity Long-lasting The first clinical trial volunteers received RISUG in 1992; Informal follow-up visits show they still have effective contraception today Sources: Guha (1993) Contraception 48(4): 367-75. Guha (1997) Contraception 56(4): 245-50.

13. Transient, painless scrotal swelling which resolves with no intervention within 2 weeks Prostate indicators all healthy after 8 years of RISUG use in Phase II trial volunteers Zero clinical trial attrition to date Source: Sharma (2001) Reproduction 122(3): 431-6. RISUG – Side effects

14. Reversal proven in monkeys after 1½ years of use, all had normal sperm count within 3 months of reversal Sodium bicarbonate solution Multiple injections and reversals effective in monkeys Not yet (formally) tested in men Sources: Lohiya (2000) Int J of Andrology 23(1): 36-42. Lohiya (2005) Contraception 71(3): 214-26. RISUG – How is it reversed?

15. US design in Phase I trials: dual silicone plugs inserted into the vas block sperm Chinese design has completed Phase II trials: single urethane stent filled with nylon mesh allows vasal fluid to pass but traps sperm The IVD – What is it?

16. US design awaiting completion of trial; past designs 90-100% effective Chinese design 100% effective, no pregnancies in 123 couples in 1 year Like vasectomy, effective after 3 months Sperm count required to confirm IVD – How effective is it?

17. Similar to “no scalpel vasectomy”, but less frequent and less severe 10% reported mild pain, 3% developed granulomas No spontaneous reversal, no congestive epididymitis Higher satisfaction rate than NSV Source: Song (2006) Int J Andrology 29(4): 489-95. IVD – Side effects

18. Reversal proven in primates after 7 months of use, all had normal sperm count within 1 month of reversal Another 20 minute out-patient procedure required to remove, as opposed to 3-4 hours of microsurgery for vasovasostomy Not yet tested in men Source: Zaneveld (1999) In Rajalakshmi & Griffin (eds.), Male Contraception: Present and Future, p. 293. IVD – How is it reversed?

19. Hormonal methods Men’s and women’s hormones are analogous in function LH stimulates T production in Leydig cells FSH stimulates spermatid production when T is present Blood-testis barrier regulates internal testes environment

20. MHCs – What are they? Supra-physiological dose of testosterone suppresses testicular production of T and halts spermatogenesis May include a progestin for faster, more complete suppression No orally available T; delivery via implants, depot injections, transdermal gels and patches

21. T-only formulations are more effective for Asian men MHCs – Formulations

22. T + progestin formulations effective for all MHCs – Formulations

23. Varies by formulation and population Two important trials: –WHO’s monthly im depot TU 97.7% effective in Chinese men –Monash Medical Center’s T pellets every 4 months + im DMPA every 3 months 100% effective in Australian men 3-10% “Non-responders” Sources: Gu (2003) JCEM 88(2):562–568. Turner (2003) JCEM 88(10):4659–4667. MHCs – How effective are they?

24. Central mystery of MHCs Some men keep producing sperm despite extreme suppression of FSH and LH Theories: –genetic differences in androgen regulation –phytoestrogens in the diet –INSL3 production Source: Amory (2007) J Andrology E-pub ahead of print. MHCs – “Non-responders”

25. Similar to side effects experienced by women on hormonal contraceptives Mild weight gain, increase in lean muscle mass, acne Drop in HDL cholesterol level with some androgens No prostate over-stimulation observed in studies up to 18 months MHCs – Side effects

26. Stop treatment, hormones begin rebound, spermatogenesis reinitiates Meta analysis showed all formulations reliably reversible within 3-5 months Minimum 2½ month recovery due to lag for production of mature sperm Source: Liu (2006) The Lancet 367: 1412–20. MHCs – How are they reversed?

27. Non-toxic lonidamine analog Disrupts cellular bridges between spermatids and Sertoli cells Clever targeted delivery by attaching Adjudin to a modified FSH Population Council researchers working to improve delivery method and bring down production costs Source: Mruk (2006) Nature Medicine 12(11):1323-8. Interesting leads - Adjudin

28. Retinoic acid required for sperm production 1 week of RAR antagonist treatment blocks sperm production for 3 months 100% effective, no observable side effects, fully reversible Researchers at Columbia University testing in other animal models Interesting leads – RAR antagonist Source: Wolgemuth (2007) Future of Male Contraception abstract.

29. Men & women are ready for better options Promising products in the pipeline Investment in contraceptive technologies should remain part of the reproductive health agenda In summary

30. Explanations of emerging male contraceptives MaleContraceptives.org MaleContraceptives.org Research community forum IMCCoalition.org IMCCoalition.org For more information