Transcript New Contraceptives for Men - Johns Hopkins Bloomberg

New Contraceptives for Men
SWEET Seminar
December 2007
Kirsten Thompson, Director
Male Contraception Coalition
[email protected]
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.
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
Vas-based methods
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
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.
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.
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.
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
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
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.
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.
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
MHCs – Formulations
T-only formulations are more effective for Asian men
MHCs – Formulations
T + progestin formulations effective for all
MHCs – How effective are they?
• 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 – “Non-responders”
• 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 – 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
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: 1412–20.
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.
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.
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
For more information
• Explanations of
emerging male
contraceptives
MaleContraceptives.org
• Research
community
forum
IMCCoalition.org