New Contraceptives for Men

SWEET SeminarDecember 2007

Kirsten Thompson, DirectorMale Contraception CoalitionKirsten@MaleContraceptives.org

www.IMCCoaltion.org

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

What is a contraceptive?

• Is contraception inherently inconvenient?• What doesn’t a contraceptive do?

The big picture

• Worldwide, fertility is declining

• 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

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?”

Do men want new options?

Over 40% of US couples rely on the currently available male contraceptives

Source: CDC (2006) Health, United States

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.

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.

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?

Vas-based methods

•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?

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-lastingThe 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.

• 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

• 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?

• 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?

• 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?

• 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

• 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?

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

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

T-only formulations are more effective for Asian men

MHCs – Formulations

T + progestin formulations effective for all

MHCs – Formulations

• 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?

• Central mystery of MHCsSome 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”

• 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

• 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?

• 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

• 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.

• 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

• Explanations of emerging male contraceptives MaleContraceptives.org

• Research community forumIMCCoalition.org

For more information