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1
Horm onal M ale Contraception: Endocrine Concepts
Christina Wang, MDProfessor of Medicine
David Geffen School of Medicine at UCLAAssociate Director
UCLA Clinical and Translational Science InstituteHarbor-UCLA Medical Center
and Los Angeles Biomedical Research Institute
Disclosures
• National Institutes of Child Health and Human Development
• C larus Therapeutics, TesoRX, Antares
Male Hormonal Contraception• Currently available methods include
condom (high user failure rate) and vasectomy (considered irreversible)
• A variety of male contraceptive methods should be available to men to meet the needs of different cultural and ethnic backgrounds
• Focus on hormonal male contraception while a number of new leads (testicular and post-testicular) are being investigated
MALE HORMONAL METHODS Target Population
• Stable monogamous union• Spacing and delay of family• Desire of male partner to share family planning
responsibilities• Female methods unacceptable• Gender Equity
H o rm o n a l M e th o d s o f
M a le C o n tra c e p tio n :
A n d ro g e n s
A n d ro g e n s +
P ro g e s tin s
A n d ro g e n s + G n R H
A n ta g o n is t
F S H in h ib it io n -in h ib in , F S H
im m u n iz a tio n
T
WHO Studies to Assess the Contraceptive Efficacy of Hormonally Induced Azoospermia &
Oligozoospermia (Proof of Concept)
Study 1: W ill hormonally induced azoosperm ia by testosterone injections provide continuing protection as a male contraceptive? W HO 1990
Study 2: W ill hormonally induced oligozoosperm ia be efficacious as a male contraceptive? W HO 1996
U S c e n te rs s u p p o rte d b y C O N R A D
2
Contraceptive Efficacy Of Injectable Testosterone-induced Oligozoospermia
E x p o s u r e
( Y e a r s )
P r e g n a n c ie s P r e g n a n c y R a te s
p e r 1 0 0 p e r s o n
y e a r s ( C I )
Severe Oligozoo-spermia (0.1 to 3 M/ml)
49.5 4 8.1 (2.2 to 20.7)
Azoospermia 230.4 0 0.0 (0.0 to 1.6)
Both Groups 279.9 4 1.4 (0.4 to 3.7)
U S C e n te r s s u p p o r te d b y C O N R A D
W H O , 1 9 9 6
Male Hormonal Contraception
n Phase 3 multicenter study in Chinan 1045 men (age 20-45 yr)n Testosterone Undecanoate 1000 mg
loading followed by 500 mg IM every 4 weeks for 30 months
n 855 men entered efficacy, 733 completed 30 months of TU injections
Gu et al, JCEM, 2009
Male Hormonal Contraception
n 43 men failed to suppress (4.7/100 couple yr) to sperm count < 1 million/mL
n 10 men showed sperm rebound to >1 million/mL (1.3/100 couple yr)
Method failure 6/100 couple yr
n 9 pregnancies ( 6 in those who showed sperm rebound)
Contraceptive failure rate 1.1 /100 couples yr
G U e t a l , J C E M , 2 0 0 9
Male Hormonal Contraceptionn Male hormonal contraceptives are as effective as
female oral birth control pills in preventing pregnancies
n Clinical trials in male hormonal contraception have progressed to the point where it is possible to suppress sperm counts to or near zero in most men with androgens alone (Phase 3 studies in China) or in combination with progestins (WHO-CONRAD study: Testosterone Undecanoate and Norethindrone enanthate injection
Efficacy of Injectable Combined Hormonal
Contraception for Men
Suppression : 95.9/100 users
(95% CI 92.8 to 97.9) suppress
to sperm count < 1 million/ml by
24 weeks
Contraceptive Efficacy: 4
pregnancies in 266 couples,
1.57/100 users (95%CI 0.59 to
4.14). Pearl Index 2.18/100
person years (95% CI 0.82-5.80)
Maintenance: 3 men sperm
counts rebound within 3 months.
Recovery: 94.8/100users (95%
CI 91.5-97.1) by 52 weeks.
Behre et al, JCEM 2016
Androgens and Progestins for Male Contraception
Pros• Addition of a progestin increases the rate extent of spermatogenesis suppression ( L iu e t a l J C E M 2 0 0 8 )
• Combination of androgens and progestins may reduce the dose of androgen required to achieve contraceptive efficacy
Cons• Combination may have more adverse effects than
androgens alone• Combination regimens are more complex and the
optimal steroid combinations, formulations and doses have to determined.
3
Months to threshold 2.5 5 10 15 20
Proportionrecovered
(%)
0
20
40
60
80
100
3 M/mL 2.5 (2.4-2.7)10 M/mL 3.0 (2.9-3.1)20 M/mL 3.4 (3.2-3.5)Baseline 5.4 (5.1-5.8)
Median (95% CI)
n 20 M/mL 1234 308 49 11 3n Baseline 1400 600 104 17 3
n 3 M/mL 790 136 16 4 0n 10 M/mL 1054 228 26 6 2
Recovery to Different Sperm Thresholds (Kaplan-Meier Plots) L iu e t a l 2 0 0 6 Horm onal Methods of Contraception:
Future Developm ents
n New user friendly delivery systems for steroid hormones e.g. transdermal and long acting injectable
n Modified androgens with progesterone receptor binding activity
Phase III
Discovery projects
D e v e lo p m e n t p ro je c ts
Products resulting from NICHD supported research- could be a useful adjunct to
hormonal contraceptive methods.•SpermCheck– Vasectomy •Fertility
• N E S /T G e l - P h a s e II
s p e rm a to g e n e s is in h ib it io n
c o m p le te d- P h a s e IIb
c o n tra c e p tiv e e ff ic a c y s tu d y (
2018)
• D M A U ( S A R M )
o r a l- Single dose
com pleted.─Repeat dose (28 day)
gonadotropin suppression─3-6 m onths sperm atogenesis
suppression (2018)
Horm
onal
Male
Early Development(Pre-clinical)
LaunchedP h a s e I -
f irs t- in -m a n
P h a s e II –s a fe ty &
e ff ic a c y
• 11 β M N T D C
(S A R M ) o ra l 9 2 0 1 7 )
• D M A U S A R M -
IM in je c tio n (2 0 1 7 )
Male Hormonal Method Research & Development
DiscoveryP h a s e I –
re p e a t d o s e
New Androgen/Progestin Screening & Development
• Acyline (GnRH antagonist)
CCTN
Nestorone + Testosterone Gels Study Rationale
• To develop a provider independent, user friendly male contraceptive
• Gels applied to skin delivered relatively stable levels of both Testosterone (T) and Nestorone (NES)
• NES has no estrogenic, androgenic and little glucocorticoid activity but is a very potent progestin
• Pilot study with NES + T gels showed significant and effective suppression of spermatogenesis (Mahabadi et al J Clin Endocrinol Metab 2009)
NES + T Gels Phase 2 Study Design3 groups: T gel 10 g/day + Nes 0 mg/day
T gel 10 g/day + Nes 8 mg/dayT gel 10 g/day +Nes 12 mg/day
S c re e n
4 w k s
F S H /L H /N e s
R e c o v e ry
1 2 w k s
N e s /F S H /L H a t
2 4 , 4 8 , 7 2 h , 1 a n d 2 w e e k s
S e m e n a n a ly s e s
F S H /L H /N E S /T /S H B G
Tre a tm e n t
2 4 w k s
Sperm Concentration (million/mL) In Efficacy Eligible subjects (Median, 25 and 75 percentile)
0 8 16 24 32 40 48 56
Sper
m C
once
ntra
tion
(mill
ion/
ml 4
th ro
ot tr
ansf
orm
ed)
0
1
16
81
256
+ Nes 0mgT+Nes 8mgT+Nes 12mgLower Limit
Pre Treatment Recovery
12 12 6 2 1
I la n i e t a l, J C E M 2 0 1 2
4
Percent M en W ith Sperm ConcentrationsSuppressed to 0, ≤ 1, ≤ 3, > 3 m illion/m l
Week0 4 8 12 16 20 24 28 32 36 40
% S
ubje
cts
0
20
40
60
80
100
Azoospermic<=1 million/ml<=3 million/ml>3 million/ml
Treatment Recovery
Week0 4 8 12 16 20 24 28 32 36 40
% S
ubje
cts
0
20
40
60
80
100Treatment Recovery
Week0 4 8 12 16 20 24 28 32 36 40
% S
ubje
cts
0
20
40
60
80
100Treatment Recovery
T + N e s 0 m g
T + N e s 8 m g T + N e s 1 2 m g
I la n i e t a l, J C E M 2 0 1 2
Nestorone + Testosterone Gel Study
• No serious adverse event• No skin irritability at application site
• Acne in 21% and weight gain in 7% of men
• Changes in mood and sexual function were sim ilar in the testosterone versus the testosterone +nestorone groups
Transdermal Nestorone and Testosterone: Issue
• Possible transfer of both horm ones from men to another persona on close skin contact
• Must wear protective clothing or shower before close contact w ith women or children
• We studied the transference of both hormones from men to women upon skin contact under direct version
Male
Hours0 4 8 12 16 20 24
Test
oste
rone
(ng/
dl)
200
400
600
800
1000
BaselineTshirtShowerNo Intervention
Visits 2-7
Female
Hours0 4 8 12 16 20 24 28 32 36 40 44 48
T(ng
/dl)
0
20
40
60
80
100
120
BaselineT ShirtShowerNo Intervention
Follow Up
F/U Unsch
Visits 2-7 Female C Avg
BaseL
ineTsh
irt
Shower
NoInterve
ntion
T Ca
vg (n
g/dl
)
0
20
40
60
80
100
Male C avg
BaseL
ineTsh
irt
Shower
NoInterve
ntion
T C
Avg
(ng/
dL)
0
200
400
600
800
1000
A v e ra g e S e ru m T (n g / d l) L e v e ls a fte r T/ N E S G e l A p p lic a t io n w ith m a le w e a r in g a T s h ir t ,
a fte r a S h o w e r a n d N o In te r v e n t io n
Male
Hours0 4 8 12 16 20 24
Nest
oron
e(pg
/ml)
0
200
400
600
800
TshirtShowerNo Intervention
Visits 3-7 Male C Avg
Tshirt
Shower
NoInterve
ntion
Nes
toro
ne C
Avg
(pg/
ml)
0
50
100
150
200
250
300
350
Female
Hours0 4 8 12 16 20 24 28 32 36 40 44 48
Nes
toro
ne(p
g/m
l)
LLOQ
15
20
25
30
35
40
T ShirtShowerNo Intervention
Visits 3-7
Female C Avg
Tshirt
Shower
NoInterve
ntion
Nes
toro
ne C
Avg
(p
g/m
l)
LLOQ
15
20
25
30
35
40
A v e ra g e S e ru m N e sto ro n e (p g / m l) L e v e ls a fte r T/ N E S G e l A p p lic a t io n w ith m a le w e a r in g a
T s h ir t , a fte r a S h o w e r a n d N o In te r v e n t io n Testosterone and Nestorone Contraceptive Efficacy Study
• Contraceptive Efficacy Study with combined testosterone and Nestorone gel
• 4 months suppression phase and 12 months efficacy with 350 couples to assess pregnancy in partner
• Assessment of adherence to treatment • Safety and tolerability and acceptability• 9 centers in 4 continents, supported by
NICHD to start in 2n d quarter 2018
5
Clinical Evaluation of Nestorone® (NES) and Testosterone (T) Combination Gel for
Male Contraception (Phase 2b)
Prim ary Endpoint
• Twelve-month (365 days) cumulativecontraceptive efficacy (during the efficacy portionof the study)
• Kaplan-Meier methods to estimate the twelve-month cumulative pregnancy probability (and 95%CI) in the typical use population.
Clinical Evaluation of Nestorone® (NES) and Testosterone (T) Combination Gel for
Male Contraception (Phase 2b)
S c re e n in g
S u p p re s s io n R e c o v e ryE ffic a c y4 1 6 w k s 5 2 w e e k s 2 4 w e e k s
P a r a m e te r s to b e a s s e s s e d a t e n r o l lm e n t a n d th e n :
M a le : W e e k ly p h o n e c a l ls o r te x t m e s s a g e
M o n th ly v is i t s fo r s e m e n a n a ly s e s , N E S a n d o th e r h o r m o n e le v e lsS a fe ty la b s e v e r y 3 m o n th s
P H Q 9 , P s y c h o s e x u a l q u e s t io n n a ir e a n d IP S S e v e r y 3 m o n th s
M a le a c c e p ta b i l i t y q u e s t io n n a ir e e v e r y 6 m o n th sC o n t r a c e p t iv e u s e , s e x u a l a c t iv i t y e v e r y m o n th
F e m a le : E v e r y 3 m o n th s , o p t io n to a t te n d m o r e f r e q u e n t ly
M o n th ly c a l ls in b e tw e e n v is i t sB le e d in g a n d c o i ta l d ia r y
F e m a le a c c e p ta b i l i t y q u e s t io n n a ir e e v e r y 3 m o n th s
P r e g n a n c y te s t a t s c r e e n in g , e n te r in g s u p p r e s s io n a n d e ff ic a c y ,
Androgens with progestational activities:• D im ethandrolone Undecanoate
• 11- Beta m ethyl 19-Nortestosterone 17-β dodecylcarbonate
DMAU and DMAConversion of DMAU to DMA
• DMA has enhanced androgen receptor binding activity compared to testosterone (Cook et al, 2005) and has same binding activity to progesterone activity
• DMA is not aromatized and 5 alpha reduction is not necessary for its activity (Attardi et al, 2008)
• D M A is m ore po ten t than tes tos te rone , thus D M A U a t a low dose m ay have the sam e e fficacy as tes tos te rone
• D M A has bo th and rogen ic and p roges ta tiona l ac tiv ity, then D M A m ay be used as a s ing le agen t fo r m a le ho rm ona l con tracep tion
DMAU for male contraception, a new option for contraception?
Tolerability and Safety of DMAUPhase 1 study• Three formulations, • Single dose• Dose ranging from 100 to 800 mg dose• No serious adverse events (AE)• Acne in participants possibly related to DMAU,
other AEs not related to study medications• No clinically significant changes in blood counts,
clinical chemistry and EKGs including QCT interval
6
Serum DMAU and DMA levels after DMAU Oral Administration in Different Formulations – fasting or
after food
B
A
SEDDS
0 4 8 12 16 20 24
Powder
0 4 8 12 16 20 24
DMAU
(ng/
ml)
1
10
100
1000
5000
200400Placebo
Castor Oil
Hour0 4 8 12 16 20 24
DMAU (ng/ml) Fasting
Powder
0 4 8 12 16 20 24
Castor Oil
Hour0 4 8 12 16 20 24
SEDDS
0 4 8 12 16 20 24
DMAU (ng/ml) with Food
SEDDS
0 4 8 12 16 20 24
Powder
0 4 8 12 16 20 24
DM
A (n
g/m
l)
0.512
510
50100
200400Placebo
Castor Oil
Hour0 4 8 12 16 20 24
DMA (ng/ml) Fasting
Powder
0 4 8 12 16 20 24
Castor Oil
Hour0 4 8 12 16 20 24
SEDDS
0 4 8 12 16 20 24
DMA (ng/ml) with Food
S u ra m p u d i e t a l, 2 0 1 5
A y o u b / P a g e e t a l, 2 0 1 6
Suppression of Serum LH over 24 h after a Single Oral Dose of DMAU
A y o u b / P a g e e t a l , 2 0 1 6
LH Cavg (u/l)
DMAU (mg)
020
040
0 020
040
0 020
040
0 020
040
0
LH
(u
/l)
0
1
2
3
4
5
Powder CastorOil SEDDS ALL
LH Cmin (u/l)
020
040
0 020
040
0 020
040
0 020
040
0
Powder CastorOil SEDDS ALL
0.0028
0.0007
<0.0001
<0.0001
A y o u b / P a g e e t a l , 2 0 1 6
Suppression of Serum T over 24 h after a Single Oral Dose of DMAU
T cavg (ng/dl)
DMAU (mg)
0200
400 0
200
400 0
200
400 0
200
400
T (
ng
/dl)
0
100
200
300
400
500
600
700Powder CastorOil SEDDS ALL
T cmin (ng/dl)
0200
400 0
200
400 0
200
400 0
200
400
Powder CastorOil SEDDS ALL
<0.0001
<0.0001
0.0327
0.0005
<0.0001
Next Steps for DMAU• Completed 28 days repeat dose study for
safety and tolerability, pharmacokinetics and suppression of gonadotropins
• Prelim inary data showed marked suppression of LH, FSH and T
Serum DMA after 28 days oral dosing of DMAU
Followup
Day
D30
D31
D49-
56D7
0-76
Day 3-26
Day
D2 D4 D7 D10
D14
D17
D21
D24
DMA (ng/ml) Mean +/- SEMDay 1
Hour0 4 8 12 16 20 24
DM
A(ng
/ml)
05
101520253035404550
Day 28
Hour0 4 8 12 16 20 24
Placebo C100 C200 P200 P400 C400
DMA C Average
Placeb
o
Castor10
0
Castor20
0
Powder200
Powder400
Castor40
0
DMA
Cavg
(ng/
ml)
0
2
4
6
8
10
12
Day 1Day 28
DMA C Max
Placeb
o
Castor10
0
Castor20
0
Powder200
Powder400
Castor40
0
DMA
Cmax
(ng/
ml)
0
10
20
30
40
50
60
Suppression of Serum LH after 28 days dosing of oral DMAU
Followup
DayD49-
56
D70-
76
Day 3-26
Day
D4 D7 D10
D14
D17
D21
D24
LH (mIU/ml) Mean +/- SEMDay 1
Hour0 4 8 12 16 20 24
LH(m
IU/m
l)
0
1
2
3
4
5
6
7Day 28
Hour0 4 8 12 16 20 24
Placebo C100 C200 P200 P400 C400
LH C Average
Placeb
o
Castor10
0
Castor20
0
Powder200
Powder400
Castor40
0
LH(m
Iu/m
l)
0
1
2
3
4
5
Day 1Day 28
LH C Min
Placeb
o
Castor10
0
Castor20
0
Powder200
Powder400
Castor40
0
7
Followup
DayD49-
56
D70-
76
Day 3-26
Day
D4 D7 D10
D14
D17
D21
D24
T (ng/dl) Mean +/- SEMDay 1
Hour0 4 8 12 16 20 24
T(ng
/dl)
0
200
400
600
800Day 28
Hour0 4 8 12 16 20 24
Placebo C100 C200 P200 P400 C400
T C Average
Placeb
o
Castor10
0
Castor20
0
Powder200
Powder400
Castor40
0
T (n
g/dl
)
0
100
200
300
400
500
600Day 1Day 28
T C Min
Placeb
o
Castor10
0
Castor20
0
Powder200
Powder400
Castor40
0
Suppression of Serum T after 28 days dosing of oral DMAU
Adverse Events after Oral Dosing of DMAU
– No Serious Adverse Event– No changes in mood , some men had
changes in libido– As anticipated decreases in SHBG and
HDL- cholesterol were observed
Next Steps for DMAU and other SARM
• Completed longer term primate toxicology
studies• Started Single IM/SC injection of DMAU dose
escalating study in castor oil with benzyl benzoate
• Spermatogenesis suppression study in 2018• Single dose, dose-
esc17-β dodecylcarbonatealating of second
novel androgen 11β-
methyl-19-nortestosterone CDB-4746, 11β-MNT11β-methyl-19-nortestosterone
CDB-4754, 11β-MNTDC11β-methyl-19-nortestosterone 17β-dodecylcarbonate
Esterases
Are Men Willing to Use New Male Contraception Method?
62.7
49.2
57.6
28.5
55.2
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
E ur op e U .S .A . L at in A mer ic a In d on e si a A llR es p on d en ts
%
Heinemann K et al. Human Reprod. 20(2): 549-556 (2005)
Yes, the time as come for male to have a reversible user friendly effective, safe contraceptive