10/07/18

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Male Contraception: The Male Pill

D ia n a B lith e , P h DChief, Contraceptive Development Program

NICHD, NIH

DisclosuresNICHD has a Cooperative Research and Development Agreement (CRADA) with HRA Pharma (Paris, France). The goal of the CRADA is to develop Ulipristal Acetate (CDB-2914) for therapeutic indications. Products to date include ella® and esmya®. P rin c ip a l Inve stigato rs : D ia n a B lith e , P h D & Ly n n e tte N ie m a n , M D

M ethods of Contraceptive Usage in the USA

Percentage Pill Sterilized IUD Other

Fem ale M ethods 72% 26% 25% 11% 10%Male Methods 28%

Male Condoms 15%Vasectomy 8%Withdrawal 5%

Contraceptive Use in the United States | Guttmacher Institutehttps://www.guttmacher.org/fact-sheet/contraceptive-use-united-states

CONTINUATION RATE

C o m p a r in g T y p ic a l E f f e c t iv e n e s s o f C o n t r a c e p t iv e M e t h o d s

M o r e e f fe c t iv e

Injectable Pills

Female Condom

Spermicides

Female SterilizationVasectomy

Ring Patch

Male Condom

Implant

Diaphragm

Fertility Awareness-Based Methods

Source: Sundaram A, Vaughan B, Kost K, BankoleA, Finer L, Singh S, Trussell J. Perspect Sex ReprodHealth. 2017;49:7-16

WithdrawalSponge

> 9 9 %NOT REVERSIBLE

84%>99.9% 99.2%

78% 80%CONTINUATION RATE at 1 YR

47%

56% 67% 67% 67% 57%

43% 41% 36% 46%42%

96% 93%

CONTINUATION RATE

87% 80%

99.8%IUD IUS

L e s s e f fe c t iv e

< 1 % F a i lu r e r a te

4 % F a i lu r e r a te

> 2 0 % F a i lu r e r a te1 3 % F a i lu r e r a te

> 7 % F a i lu r e r a te

Men need and want more options!

Development of Safe, Effective, Affordable, Acceptable Products

• B a s ic re s e a rc h – Id e n t ify d ru g .• To x ic o lo g y – H IG H b a r o f s a fe ty ! H o w h ig h ? ? ?• C lin ic a l s tu d ie s in n o rm a l v o lu n te e rs … H o w m a n y s u b je c ts ? H o w lo n g ?

Start FinishThe Road to a Male Contraceptive Product

Injectables

Pills

IUD IUS

Rings Patch

basic research clinical research

2 0 ,0 0 0 c y c le s

Valley of Death

Pipeline

For WomenSperm Numbers

Men make 1000 sperm per heartbeat!

Average volume of ejaculate ~ 4 ml ( 1 teaspoon = 5 ml )

Normal number of sperm = 15-200 million/ml (60 million –800 million sperm per ejaculate)~ 1out of 10 million spermenters the Fallopian Tube! ~ 10-100 sperm enter the Fallopian Tube? U n d e r g o c a p a c i t a t i o n . R e m a i n v i a b l e f o r s e v e r a l d a y s .

It only takes one??? < 1 million sperm/ml is considered contraceptive,so 4 million sperm isn’t enough.

https://www.guttmacher.org/fact-sheet/contraceptive-use-united-states

10/07/18

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S p e rm a to g e n e s is

Oocyte

DifferentiationStem cells

Meiosis

Spermiogenesis

M a tu ra tio nTrimming

GlycoprocessingEnvironment

F u n c tio nMotility

OrientationCapacitation

BindingSperm-Zona Interaction

Acrosomal ReactionFusion

Intervention Points for Male Contraceptives

Horm

ones

(Gottwald et al 2006 Mol Cell Endocrinol)

Hormonal Approach to Male ContraceptionHypothalamic-Pituitary-Testicular Axis

hypothalamus

pituitary

testisLHFSH

T

GnRH

X

T

ProgestinX

T

Spermatogenesis

T

Libido, muscle mass

XXT

C hallenges for the “M A LE P ILL”: To deliver a daily safe, effective ora l dose of

TestosteroneØNatural Testosterone as an oral pill is

cleared too rapidly from the blood-- requires multiple doses per day

L e a d

O p t im iz a t io n

R e d F o n t indicates CCTN Clinical Trial

Male Method Research in NICHD in 2018

Non-

horm

onalM

ale

•DMAU injectable

D is c o v e r y p r o je c ts D e v e lo p m e n t p r o je c ts

§ indenopyridines

Horm

onal

•SpermCheck® - Vasectomy •SpermCheck® - Fertility

• Adjudin• LDH C • CatSper• STYX• α-adrenoreceptor• Ubiquitinase• MOV10l-PIWIL1/2• MEIOB-SPATA22• GAPDHS• TEX14• GASZ• VASA• DMRT• Non-invasive laser vasectomy

• H2-Gamendazole• TSSK 1, 2, 6• ANT4

§ BRDT -JQ1-analogs§ ALDH1A2 inhibitors§ Na, K-ATPase α4 inhibitors (Cardenolides) § CDK2 inhibitors§ RARα inhibitors§ Eppin inhibitors

Discovery, Target ID, Target Validation, Proof-of-principle

Phase I –first-in-

manPhase III

Phase II –safety & efficacy

Launched Products

Early Development(Pre-clinical)

NDA / PMApreparation

Phase I –repeat dose

•NES/Tes gel•DMAU oral

•11�MNTDC oral

New Androgens with Progestin Activity

Backbone Structure of Progesterone, TestosteroneCompound Name R1 (C7) R2 (C11) R3 (C17) R4 (C19) R5 (C17)

Progesterone H H H CH3 C(O)CH3Testosterone H H H CH3 OH 7a ,11β-Dimethyl-19-nortestosterone (DMA) CH3 CH3 H H OH

11β-Methyl-19-nortestosterone (11β-MNT) H CH3 H H OH

A d d p ro g e s tin a c tiv ity to a n d ro g e n ic a c tiv ity - fu n c tio n a l g ro u p s a lte r ra tio o f p ro g e s tin to a n d ro g e n a c tiv ity

, DMA and11β-MNT

CCTN-SCG

DMAU 11b-MNTDC

Progestogenic Androgens in M ale CCTN Trials

W h a t a re w e lo o k in g fo r ?S a fe ? O ra l ly a c t iv e ? L a s t fo r 2 4 h ?

D o e s p ro g e s t in a c t iv it y s h u t d o w n g o n a d o t ro p in s a n d e n d o g e n o u s te s to s te ro n e p ro d u c t io n ?D o e s a n d ro g e n a c t iv it y m a in ta in a n d ro g e n - d e p e n d e n t f u n c t io n s ?F irs t s te p : S in g le d o s e f ir s t- in - m a n .

10/07/18

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P. Surampudi et al Andrology , 2014

400 mg

0 4 8 12 16 20 24

200 mg

Time (h)0 4 8 12 16 20 24

LH (IU

/L)

0123456

FastingWith food

800 mg

0 4 8 12 16 20 24

Placebo

0 4 8 12 16 20 24

0 4 8 12 16 20 24Time (h)

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

0 4 8 12 16 20 24Time (h)

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

0 4 8 12 16 20 24Time (h)

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

0 4 8 12 16 20 24Time (h)

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

0 4 8 12 16 20 24Time (h)

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

0 4 8 12 16 20 24Time (h)

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24

* *****

200 mg

FSH (

IU/L)

1

2

3

4

5

FastingWith food

400 mg 800 mg Placebo

* * * * **

200 mg

T (nM

)

0

5

10

15

20

25

FastingWith food

400 mg 800 mg Placebo

* ** * **

*

* ***

**

200 mg

Calcu

lated

freeT

(nM)

0.00.10.20.30.40.50.6

FastingWith food

400 mg 800 mg Placebo

*******

**

400 mg200 mg

DHT (

nM)

0.0

0.5

1.0

1.5

2.0 800 mg Placebo

FastingWith food

* ** **

***

* *

400 mg200 mg

E2 (p

M)

25

50

75

100

125

FastingWith food

800 mg Placebo

* **** ****

*

400 mg200 mg

SHBG

(nM)

1020304050607080

800 mg PlaceboFastingWith food

(A)

(B)

(C)

(D)

(E)

(F)

(G)

Figure 2 Serum LH (A), FSH (B), T(C), free T (D), DHT (E) and estradiol (F) concentrations after administration of a single dose 200, 400 or 800 mg of di-methandrolone undecanoate (DMAU) (n = 10) or placebo after fasting (closed circles) or a high-fat meal (50% fat, open circles). The right panel shows hor-mone levels in two participants taking the same number of capsules as the active drug studied while fasting or after a high-fat meal on three occasions.Hormone concentrations at 12 or 24 h that were significantly different from baseline hormone concentration were marked with *p < 0.05 and **p < 0.001at each dose level by mixed model analysis.

584 Andrology, 2014, 2, 579–587 © 2014 American Society of Andrology and European Academy of Andrology

P. Surampudi et al. ANDROLOGY

•DMAU lasts for 24 hours

Single Oral Dose of Dimethandrolone Undecanoate in Men400mg

0 4 8 12 16 20 24

800mg

0 4 8 12 16 20 24

200mg

Time (h)0 4 8 12 16 20 24

DMAU

(ng/m

l)

0.1

1

10

100

1000FastingWith Food

•Single oral dose suppresses production of LH

•Better absorption of drug if taken with food

and Testosterone200mg

Time(h)0 4 8 12 16 20 24

T(ng/d

l)

0

100

200

300

400

500

600

700

800

FastingWith Food

400mg

0 4 8 12 16 20 24

800mg

0 4 8 12 16 20 24

Placebo

0 4 8 12 16 20 24

T (n

g/dl

)

Time (hr)

Time (hr)

Time (hr)

100mg

0 12 24

200mg

Time(hr)0 12 24

400mg

0 12 24

800mg

0 12 24

Placebo

0 12 24

T(ng/dl)

0

100

200

300

400

500

600

700

FastingFed

Single Oral Dose of 11β-MNTDC (1 1 β -M e t h y l N o r -Te s to s te ro n e D o d e c y l-C a r b o n a te )100mg

Hour0 4 8 12 16 20 24

200mg

Hour0 4 8 12 16 20 24

400mg

Hour0 4 8 12 16 20 24

800mg

Hour0 4 8 12 16 20 24

Placebo

Hour0 4 8 12 16 20 24

11 B

eta

MNT

(ng/

ml)

0

10

20

30

40

FastingFed

Time (hr)

Time (hr)

Could DM AU or 11β-M NTDC becom e the M ale Pill? (or capsule?)

Next Step: Daily oral dosing for 28 days.• Evaluate safety and side effects.• Will daily dosing suppress LH and Testosterone?• Will androgenic activity compensate for Testosterone deficiency?

Followup

DayD49-5

6

D70-7

6

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/ml

)

0

1

2

3

4

5

6

7Day 28

Hour0 4 8 12 16 20 24

Placebo C100 C200 P200 P400 C400

Repeat Dosing of DMAU for 28 Days in Men

Followup

DayD49-5

6

D70-7

6

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/d

l)

0

200

400

600

800Day 28

Hour0 4 8 12 16 20 24

Placebo C100 C200 P200 P400 C400

Placebo

Placebo

Could DM AU becom e the M ale Pill? (or capsule?)

In the 28-day study of DMAU, men had VERY low Testosterone, but did not show signs of testosterone deficiency.

No significant safety concerns were identified at any dose tested.

M aybe!

N e x t S t e p : L o n g e r s t u d y o f D M A U t o m o n i t o r s a fe t y a n d s p e r m s u p p r e s s i v e a c t i v i t y !

Early Development(Pre-clinical)

IND and Clinical Batch

Formulation

Min LeeDrug Discovery & Optimization:M edicinal Chem istry & Crystallography

Discovery Development

Discovery Target ID,

Target Validation,

Proof-of-principle

C lin ic a l

E v a lu a t io n

• BRDT inhibitors

Contraceptive Effectiveness

Target Drug

Screening

M e d ic in a l

C h e m is tr y & L e a d

O p t im iz a t io n

Optimize

• BRDT gene

JQ1

JQ35for cancer

treatment

Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE. Small-molecule inhibition of BRDT for male contraception. Cell 2012 17;150(4):673-84.

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Drug Discovery & Optimization: BromodomainInhibitors BRD4BRDT (testis specific)

In h ib ito r IC 5 0 (B R D T ) IC 5 0 (B R D 4 )

J Q 1 11 0 n M 3 5 n M

C o m p o u n d 6 2 2 0 n M 4 7 0 n M

Ernst Schönbrunn, Gunda Georg, Jun Qi, Min Lee

M ale Contraceptive Pills on the Horizon?

•N E S /Te s g e l

NDA / PMApreparation

Clinical Contraceptive Development Timeline

Ma

le

•D M A U in je c ta b le

D e v e lo p m e n t p r o je c ts

• D M A U oral•11 � M N T D C o r a l

• H2-Gamendazole• TSSK 1, 2, 6• ANT4

P h a s e I I I

s a fe ty & e f f ic a c y

P h a s e I Ia – P h a s e I Ib

s a fe ty & e f f ic a c y

Early Development(Pre-clinical)

Phase I –repeat dose

Phase I –first-in-man

Launched Products

Non-

horm

onal

§ indenopyridines

§BRDT§ALDH1A2§Na, K-ATPase α4 §RARα§Eppin

2 y e a r s 2 y e a r s 2 y e a r s 2 y e a r s 4 y e a r s 2 y e a r s4 y e a r s

? ? ?

? Y e a r s

F o r m u la t io n

B r id g e S tu d ie s

L o n g e r To x s tu d ie s

? Y e a r s

F in a l F o r m u la t io n

A d d it io n a l S a fe ty S tu d ie s

? ? ?

2 0 1 8

L o n g e r To x s tu d ie s

1 6 – 2 0 + y e a r s ? ? ?

2 0 2 5 2 0 3 0 2 0 3 2

Oocyte

S p e r m a to g e n e s isDifferentiation

MeiosisSpermiogenesis

M a tu r a t io n

TrimmingGlycoprocessing

F u n c t io n

MotilityOrientation

CapacitationHyperactivation

Sperm-Zona InteractionAcrosomal Reaction

FusionhO

R 17-

4Ca

tSpe

r

GAPD

HS

Fertilins

PKA

Cα2

Inden

opyr

idine

s

LNG

Testase

Horm

ones

, Nes

toron

e/T,

DMAU

, MEN

T, 11

ßMDC

Retin

oicAc

id Re

cepto

r

regula

tors B

DADs

, BMS

1894

53

H-2 G

amen

dazo

lePr

oges

teron

e Rec

eptor

Mod

ulator

B in d in gEppin

Aden

ine nu

cleoti

de tra

nsloc

ase-4

TSS

Kina

ses 1

,2

STYX

BRDT

, GAS

Z, VA

SA, T

EX14

Adjud

in

Dmrt1

Na K

-ATPa

se α4

inhib

itors,

carde

nolid

esTS

SKina

se6

Izumo

- 1

Cycli

n A1/c

dk2

CCTN Sites - Male MethodsU n iv e r s ity o f W a s h in g to n¢ Stephanie Page

¢ William Bremner¢ Brad Anawalt¢ John Amory¢ Arthi Thirumalai¢ Sherry Wu

LA B iom ed at H arbor-U C L A M e d ic a l C e n te r

¢ Christina Wang ¢ Ronald Swerdloff¢ Peter Liu¢ Brian Nguyen¢ Fiona Yuen¢ Prasanth Surampudi¢ Janos Ceponis

C C TN Partner Investigators & Institu tions¢Kristina Gemzell Danielsson, Karolinska Inst¢Gabriela Noe, University of Chile¢Ajay Nangia, University of Kansas ¢Cheryl Fitzgerald, Fred Wu, U. of Manchester¢Cristina Meriggiola, University of Bologna¢Richard Anderson, University of Edinburgh

¢John Kinuthia, University of Nairobi

CO N T R A C E P T IV E RE S E A R C H CO L L A B O R AT O R S

Population Council ¢Regine Sitruk-Ware¢Narendar Kumar¢Ruth Merkatz¢Dan Loeven¢John Townsend

University of Minnesota

¢Gunda GeorgMoffitt Cancer Center¢Ernst Schonbrunn

C o n tra ce p tive Ta rge t D a ta b a se W e b site -Construction in ProgressCheck for updates at: www.nichd.nih.gov/about/org/diphr/officebranch/cdp

Male Contraceptive Development Program

¢John Amory, University of Washington¢Martin Matzuk, Baylor College of Medicine¢Debra Wolgemuth, Columbia University¢James Bradner, Novartis¢Jun Qi, Harvard University

C o n tra c e p tiv e D e v e lo p m e n t P ro g ra m¢ M in L e e¢ J ill L o n g

http://www.nichd.nih.gov/about/org/diphr/officebranch/cdp