New Contraceptives for Men

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New Contraceptives for Men

• SWEET SeminarDecember 2007

Kirsten Thompson, DirectorMale Contraception
CoalitionKirsten_at_MaleContraceptives.orgwww.IMCCo
altion.org
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What well 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

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What is a contraceptive?

• Is contraception inherently inconvenient?
• What doesnt a contraceptive do?

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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

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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?

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Do men want new options?

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

Source CDC (2006) Health, United States
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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.
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What do women think?

• Only 2-3 wouldnt 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) Mens Role in Preventing
Pregnancy.
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Which male contraceptives are closest to market?

• Three methods are in clinical trials
• RISUG
• The Intra Vas Device (IVD)
• Male hormonal contraceptives
• Two interesting pre-clinical leads
• Adjudin
• RAR antagonist

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Vas-based methods
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RISUG What is it?

• A polymer gel injected into the vasa deferentia
• Partially blocks the lumen and disrupts passing
  sperm
• Now in Phase III clinical trials in India

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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.
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RISUG Side effects

• 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.
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RISUG How is it reversed?

• 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.
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The IVD What is it?

• 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

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IVD How effective 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

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IVD Side effects

• 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.
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IVD How is it reversed?

• 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.
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Hormonal methods

• Mens and womens 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

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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

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MHCs Formulations

• T-only formulations are more effective for Asian
  men

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MHCs Formulations

• T progestin formulations effective for all

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MHCs How effective are they?

• Varies by formulation and population
• Two important trials
• WHOs monthly im depot TU 97.7 effective in
  Chinese men
• Monash Medical Centers 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)562568. Turner
(2003) JCEM 88(10)46594667.
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MHCs Non-responders

• 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.
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MHCs Side effects

• 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

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MHCs How are they reversed?

• 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 141220.
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Interesting leads - Adjudin

• 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.
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Interesting leads RAR antagonist

• 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

Source Wolgemuth (2007) Future of Male
Contraception abstract.
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In summary

• Men women are ready for better options
• Promising products in the pipeline
• Investment in contraceptive technologies should
  remain part of the reproductive health agenda

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For more information

• Explanations of emerging male contraceptives
  MaleContraceptives.org
• Research community forumIMCCoalition.org