MENT: ICCR’s contribution to male contraceptionMENT: ICCR’s contribution to male contraception...

MENT: ICCR’s contribution to male contraception

Vision for Contraceptive Research & Development The 100th Meeting of the ICCR

New York, April 20, 2012

E. Nieschlag, Center for Reproductive Medicine and Andrology

University of Münster N. Kumar, R. Sitruk-Ware Center for Biomedical Research Population Council, New York

Hypothalamus

-

Pituitary

GnRH

Testes Leydig cells

Testosterone

Sertoli cells Spermatogenesis

LH FSH

Androgen effects Fertility

DHT

Testosterone

Estradiol

+

+ +

+ Spermien

+

F 1995 E

(Nieschlag, Behre, Nieschlag „Andrology“ 3rd ed, Springer 2010)

Hypothalamus

Pituitary

GnRH

Testes Leydig cells

Testosterone

Sertoli cells Spermatogenese

LH FSH


DHT

Testosterone

Estradiol +

Testosterone -

-

F 1996E


Hypothalamus

Pituitary

GnRH

Testes Leydig cells

Testosterone

Sertoli cells Spermatogenese

LH FSH


DHT

Testosterone

Estradiol +

Gestagen -

- Testosterone

-

-

F 1996 E


Clinical trials for hormonal male contraception 1972 – 2011

- 60 surrogate trials counting sperm - 8 real contraceptive efficacy trials - 71 reviews

Assessed for eligibility(n=589)

Randomized(n=354)

Excluded (n=235)Not meeting inclusion/exclusion: n=158Refused to participate: n=53Other reasons: n=24

High release ENG implant(n=152)

Low release ENG implant(n=149)

Placebo(n=53)

1 withdrew IC 2 withdrew IC, 1 switch1 1 switch1

Treated(n=52)

Discontinued treatment (n=36)Due to (S)AE: n=24Other reason: n=12



Completed treatment(n=112)



Did not start follow up (n=7)2

Discontinued follow up (n=5)Due to (S)AE: n=1Other reason: n=4





Treated (n=148)TU 1: n=47TU 2: n=50TU 3: n=51

Treated (n=149)TU 1: n=50TU 2: n=50TU 3: n=49

Completed follow up2

(n=136)Completed follow up2

(n=144)Completed follow up2

(n=49)

Phase II-b trial of TU i.m. and ENG implants for male contraception (Schering-Organon trial, 2008)

F 2061

Sperm concentration (mill/ml) in 23 normal and 18 subnormal volunteers under testosterone undecanoate

(Nieschlag et al Int J Androl 34: 556-67, 2011)

0,0

0,1

1,0

10,0

100,0

1000,0

-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

normals

subnormals

0,01

0,1

1

10

100

-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

F 2093

Male contraceptive efficacy trials based on hormones

PopCouncil 1977 TE + DMPA 100 WHO I 1990 TE 271 WHO II 1996 TE 225 Gu et al 2003 TUch 305 Gu et al 2009 TUch 898 Soufir et al 2011 Tgel + MPA 35 Turner et al 2003 TI + DMP 53 WHO/CONRAD 2011 TUeu + NETE (440) TUch = TU chinese = TU in tea seed oil

TUeu = TU european = TU in castor oil

Multicenter clinical trial of DMPA and TE or TI for male contraception: Sperm concentrations (million/ml) in 9 / 100 men

around the time their wives became pregnant. (Barfield et al Contraception 20: 121-127, 1979)

Preg

nanc

y ra

te (p

er 1

00 p

erso

n-ye

ars)

0

2

3

4

5

6

1

Azoospermia <=1.0 M/ml <=2.0 M/ml <=3.0 M/ml <=4.0 M/ml <=5.0 M/ml All sperm concentrations

Contraceptive efficacy of testosterone enanthate (200 mg biweekly) in 346 men: pregnancy rates per 100 person-years in

relation to sperm concentration. (WHO, Fertil. Steril. 65; 821, 1996)

Cumulative sperm concentration F 1846E

enanthate implants

undecanoate

buciclate

OHCH3

CH3

O

Testosterone

19-Nortestosterone

The search for long-acting testosterone preparations

Phase III trial of TU in tea seed oil in 10 Chinese centres

(Gu et al J Clin Endocr Metab 94: 1910-15,2009) Design: 1000 mg TU loading, 500 mg TU / month If sperm < 1 million/mL, efficacy phase for 2 years Volunteers: 1045 men recruited, 733 men completed efficacy and recovery phase Pregnancies:

F 2143/1

Copyright ©2009 The Endocrine Society

The changes in sperm concentration with log scale during the study period

F 2143


(Gu et al J Clin Endocr Metab 94: 1910-15, 2009)


(Gu et al J Clin Endocr Metab 94: 1910-15, 2009) Design: 1000 mg TU loading, 500 mg TU / month If sperm < 1 million/mL, efficacy phase for 2 years Volunteers: 1045 men recruited, 733 men completed efficacy and recovery phase Pregnancies: 1.1 in 100 men years (6 with sperm between 2-8 million/mL 3 with sperm < 1 million/mL)

F 2143/1

FE 679

Germany 2004

Nether- lands 1975 China 1993

O

OCO(CH2)9CH3

Testosterone undecanoate FH 118

F1621E

T U ( 1 0 0 0 m g i . m . e v e r y 6 w e e k s ) / N E T E ( 2 0 0 m g i . m . e v e r y 6 w e e k s )

s t u d y w e e k A B 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 4 5 2

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

T U ( 1 0 0 0 m g i . m . e v e r y 6 w e e k s ) / P l a c e b o p . o .

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

T U ( 1 0 0 0 m g e v e r y 6 w e e k s i . m . ) / L N G ( 0 , 2 5 m g p . o . / d )

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

I n j e c t a b l e t e s t o s t e r o n e u n d e c a n o a t e a l o n e o r w i t h o r a l l e v o n o r g e s t r e l o r i n j e c t a b l e n o r e t h i s t e r o n e e n a n t h a t e i n a c o n t r o l l e d c l i n i c a l t r i a l f o r m a l e c o n t r a c p n

s p e r m c o n c e n t r a t i o n > 1 - < 3 m i l l / m l s p e r m c o n c e n t r a t i o n > 3 m i l l / m l

a z o o s p e r m i a s p e r m c o n c e n t r a t i o n < 0 , 1 m i l l / m l

s p e r m c o n c e n t r a t i o n 0 , 1 - 1 m i l l / m l

Injectable testosterone undecanoate alone or with oral levonorgestrel or injectable norethisterone enanthate in a controlled clinical trial for male contraception

%

%

%

(Kamischke, Nieschlag et al. 2001 & 2002)

Treatment schedule:

1000 mg testosterone undecanoate (TU) plus 200 mg norethisterone enanthate (NETE)

intramuscular every 8 weeks in 440 male partners of fertile couples

F 2304

10 centers worldwide 487 couples screened since July, 2008 321 couples enrolled 260 entered efficacy phase 6 failed to suppress 55 discontinued before suppressing 114 couples completed efficacy

No further injections after April 6, 2011 F 2305

enanthate implants

undecanoate buciclate

OHCH3

CH3

O

Testosterone

O

OH

CH3

CH3

MENT (7α-Methyl-19- nortestosterone)

F 1818

19-Nortestosterone

The search for long-acting testosterone preparations

(Lyster & Duncan [Upjohn] Acta endocrinol 43: 399 - 411, 1963)

„Anabolic, androgenic and myotropic activi- ties of derivatives of 7α-methyl-19-nortestosterone“

20 µg MENT / day ------ 100 µg TP / day (Lyster & Duncan (Upjohn) Acta endocrinol 43: 399 - 411, 1963)

Development of MENT by the Population Council

1963 MENT first described by Lyster & Duncan (Upjohn)

1988 C.W. Bardin and B. Monder identified MENT as suited for replacement therapy and male contraception

1990 RIA for MENT by Kumar et al.

1990- Pharmacology, modes of application and toxicology 1995 by Kumar & Sundaram since 1995 Clinical trials for treatment of hypogonadism since 2000 2001- 2004 2006

F 2325

at start

TE 24 wks

MENT 24 wks

Serum androgen levels, prostate volumes and lumbar bone density in 2 x 8 hypogonadal men receiving

one (group 1) or two (group 2) MENT implants (Anderson et al. JCEM 88: 2784, 2003)

Prostate volume

Bone density

FE 646

FE 930

MENT (12 ug/day) vs. testosterone implants (72 ug/day) over 4 months for hypogonadal osteoporosis:

a preclinical study in the aged orchidectomized rat model

(Sinnesael et al Int J Androl 34: e601-e611, 2011)

Trabecular bone volume

Trabecular bone number

Trabecular thickness

Trabecular microstructure



1988 C.W. Bardin identifies MENT as suited for replacement therapy and male contraception


1990- Pharmacology, modes of application and toxicology 1995 by Kumar & Sundaram since 1995 Clinical trials for treatment of hypogonadism since 2000 Clinical trials for male contraception 2001- 2004 2006

F 2325

F 2317

Effect of 100 μg MENT/day Silastic implants on sperm counts in Bonnet monkeys: no pregnancy

(Ramachandra et al. Reproduction 124: 301-309, 2002)

5 controls 10 treated monkeys

Clinical trials using MENT Silastic implants for suppression of spermatogenesis

MENT applied to bonnet monkeys

MENT applied to 35 volunteers in 3 centres (Münster, Santiago de Chile, Santo Domingo)

F 2326

(Ramachandra et al. 2002)

(von Eckardstein et al. 2003)

Suppression of spermatogenesis and LH, FSH in 34 men treated with 1, 2 or 4 MENT implants

0.001

0.010

0.100

1.000

10.000

100.000

1000.000

Spe

rmco

ncen

trat

ion

(Mill

/mL)

0.001

0.010

0.100

1.000

10.000

100.000

1000.000

Spe

rmco

ncen

trat

ion

(Mill

/ m

l)

0 30 60 90 120 150 1800.001

0.010

0.100

1.000

10.000

100.000

1000.000

10000.000

days

Spe

rmco

ncen

trat

ion

(Mill

/ m

l)

Sperm concentration

0

1

2

3

4

5

6

LH (I

U/ L

)

0 60 120 1800

1

2

3

4

1 implant 2 implants 4 implants

Values below detection limitstudy day

FSH

(IU

/ L)

Gonadotropins

1 implant Azoo: 0 / 12

2 implants Azoo: 2 / 11

4 implants Azoo: 8 / 11

(von Eckardstein et al. JCEM 88:5232-39, 2003)

F1750




Etonogestrel combined with MENT or testosterone implants in 29 volunteers (Edinburgh)

F 2326


von Eckardstein et al. 2003

(Walton et al. 2007)

F 2314

Serum hormone concentrations in men receiving 2 etonogestrel implants either with testosterone (closed circles) or MENT implants (open circles) (Walton et al. J Androl 28: 679-688, 2007)

http://www.andrologyjournal.org/content/vol28/issue5/images/large/andr-28-5-679-f01.jpeg�

F 2315

Sperm concentrations in 29 men receiving 2 etonogestrel implants either with testosterone (closed circles) or

MENT implants (open circles) (Walton et al. J Androl 28: 679-688, 2007)

F 2316

Blood pressure in 29 men receiving 2 etonogestrel implants either with testosterone (closed circles) or

MENT implants (open circles) (Walton et al. J Androl 28: 679-688, 2007)




Etonogestrel combined with MENT or testosterone implants in 29 volunteers (Edinburgh)

MENT plus levonorgestrel implants in 72 volunteers in 3 centres (Los Angeles, Münster, Santiago de Chile)

F 2326


von Eckardstein et al. 2003

(Walton et al. 2007)

(Wang et al. in preparation)



1988 C.W. Bardin identifies MENT as suited for replacement therapy and male contraception


1990- Pharmacology, modes of application and toxicology 1995 by Kumar & Sundaram since 1995 Clinical trials for treatment of hypogonadism since 2000 Clinical trials for male contraception 2001- MENT licensed to Schering AG: 2004 eF-MENT gel in phase I studies 2006 MENT back to Population Council for contraception

F 2325

T undecanoate

T implant

T implant

T implant/MENT

T undecanoate

Transdermal T

MENT implant

NETA

DSG

DMPA

ETN

NETE

Oral MDP

LNG / DMPA

+

+

+

+

+

+

+

Most promising testosterone/progestin combinations

Paris

Münster / Bologna WHO-CONRAD Schering

Edinburgh / Organon / PopCcl

Popul. Council

F 1823

T undecanoate ETN + Schering-Organon

implants intramuscular oral

transdermal

Sydney / Melbourne

• MENT has high androgenic potency (5 – 10 times T).

• Suited for long-lasting implants (one year and longer).

• However, implantation & removal require minor surgery.

• Needs to be combined with progestin for contraception in Caucasian men.

• No 5α-reduction i.e. little effect on prostate.

• At adequate doses bone mass is maintained.

• Minor effect on blood pressure needs to be resolved.

• MENT and eF-MENT has potential for substitution therapy.

• A male contraceptive is still a long way off.

MENT for male contraception: key messages

The End

MENT: ICCR’s contribution to male contraceptionMENT: ICCR’s contribution to male contraception...

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