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