1

CONFÉRENCE À SUCCÈS EN SCIENCES DE

LA VIE : ENDOCEUTICS

13 Septembre 2018

Quebec, Canada

ENDOCEUTICS

No. 1 Innovative pharmaceutical

company in menopausal women’s

health in the world

FL220818 – QC int.2

3

FacilitiesHead Office

Laboratory ManufacturingFL220818 – QC int.

1

1980

↓US patent 5,389,613

↓

Medical castration with

GnRH agonists1

Suprefact®

Lupron®

Zoladex®

Decapeptyl®

Synarel®

Factrel®

Gonazon®

Suprelorin®

Ovalyse®

Vantas®

Dalmarelin®

Maprelin®

Fernand Labrie

Laval University and

Laval University Medical Research Center, Quebec, Canada.

Leader of major discoveries in fundamental research followed by clinical

developments which save lives and improve the quality of life of millions of

men and women worldwide.

4

3

1984

↓US patent 4,472,382

↓

Combined androgen

blockade in prostate

cancer2,3

Euflex®

Anandron®

Casodex®

Xtandi®

Erleada®

5- Labrie, Bélanger et al. (2017) Menopause 24: 702-712

6- Labrie, Archer et al. (2016) Menopause 24:1246-1256

7- Intrarosa® Prescribing Information

1- Labrie, Bélanger et al. (1980) J Androl 1: 209-228

2- Labrie, Dupont et al. (1982) Clin Invest Med 5: 267-275

3- Labrie, Dupont et al, Important Adv Oncol, 193-217,

1985

4- Labrie (1991) Mol Cell Endocrinol 78:C113-118

2

1982-

↓Intracrinology2-5

DHEA, mainly secreted by

the adrenals, is

transformed intracellularly

into small amounts of

estrogens and androgens

which are also inactivated

intracellularly and locally

without influencing the

other tissues.

4

2008-2016

↓US patent 8,957,054

↓

Vulvovaginal atrophy or

genitourinary syndrome

of menopause (2015) 6,7

Intrarosa®

At least 18 drugs have been commercialized worldwide based upon the original

data of Dr Labrie’s research team.

Author and co-author of 1360 publications

5

When and how

Intracrinology was first

recognized.

1- First demonstration in

prostate cancer in 1982

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ANDROGENRECEPTORAR

GnRHsuperagonist

CRF

LH

PITUITARY

TESTIS

PROSTATIC CELL

17b-HSD 3b-HSD

4-DIONEDHEAT

TESTOSTERONE

DEHYDROEPI-ANDROSTERONE

ACTH

ADRENAL

FLUTAMIDE

NILUTAMIDE

BICALUTAMIDE

ENZALUTAMIDE

5a-DIONE

ABIRATERONE

5α - reductases

APALUTAMIDE

DAROLUTAMIDE

1- Labrie, Dupont et al, Clin. Invest. Med. 5, 267-275, 1982;2- Labrie, Dupont et al, Important Adv Oncol, 193-217, 1985;

3- Smith et al, N. Engl. J. Med. 378, 1408-1418, 2018.

Combined androgen blockade (1982)

First

demonstration of

the role of DHEA

and Intracrinology

(Unique to the

human) Demonstration of the

role of DHEA in the

formation of

androgens in the

prostatic tissue

(normal and cancer)1-3

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2- New technology : Mass

spectrometry and molecular

biology

Development of validated mass

spectrometry for the assay of

steroids and molecular biology

for the cloning and

characterisation of the intracrine

enzymes.FL220818 – QC int.

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DHEA-S

DHEA

3b HSD-1

3b HSD-1

3(a b)-HSE

3bHSD-1

3a HSD-1, 3 RoDH-1

(3a HSD-4)

5a reductase-1, 2, 3 5a reductase-1, 2, 3

DHEASulfotransferase

4-DIONE

A-DIONE

ADT

epi-ADT

3a-DIOL

3b-DIOL

17b HSD-1

3a HSD-13a HSD-3

TESTO

DHT

UGT2B7UGT2B15

Aromatase

3a-DIOL-GADT-G

E1-G3b-Diol-S

Aromatase

E1-S E2-S

E1 E2

Sulfo-transferase

17b HSD-2, 4

17b HSD-5

17b HSD-2, 10

17b HSD-1, 7, 12

Sulfatase Sulfo-Transferase

Sulfatase

RoDH-1

(3a HSD-4)

AR

Estrogenicresponse

Androgenicresponse

3b HSD-117b HSD-7

3(a b)-HSE

Sulfatase

17b HSD-5, 15

17b HSD-2, 9, 10

17b HSD-5, 15

17b HSD-2, 9, 10, 14

17b HSD-2, 9, 10, 14

17b HSD-2, 4, 8, 14

3(a b)-HSE

ADT-S

Elimination of steroids

E2-G

UGT2B17

Sult2B1

UGT1A1

Sult2B1

UGT1A1

17b HSD-73(a b)

-HSE

17b HSD-5, 15

5-DIOL

ADRENAL

ER

9

DHEAExogenousIntravagina

lIntrarosa

TM

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UNIQUE TO THE HUMAN SPECIES

AND PRIMATES:

Adrenals whichsecrete large amounts

of DHEA

Intracrinology

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3- Novel

understanding of the

physiology of sex

steroids in women:

Intracrinology

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New understanding of sex steroid physiology

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Hot flushes

Night sweats

Insomnia

Nervousness

Lack of

concentration

Depression

Vulvovaginal atrophy

Sexual dysfunction

Muscle loss

Bonne loss – fractures

Loss of memory

Loss of cognition

Possibly Alzheimer’s disease

Symptoms and signs of sex steroid deficiency

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Endogenous DHEA : Summary of role and action in VVA/GSM – Low DHEA is the essential cause of VVA

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Systemic Exposure to E2

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Renaissance/Revolution in the treatment of

menopause

The cause of VVA is not

the lack of estrogens but

the lack of DHEA

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ERC – 213 J. Ster Biochem. Mol. Biol. 138, 359-367, 2013

ERC – 210 Menopause 16, 907-922, 2009; Climacteric 14, 282-288, 2011

ERC – 230 Maturitas 81, 46-56, 2015

ERC – 231 Menopause 22, 950-963, 2015

ERC – 234 Climacteric 18, 590-607, 2015

ERC – 238 Menopause 23, 243-256, 2016

Acceptability Intravaginal Gynecol Endocrinol 32, 240-245, 2016

Application

Influence on Male Partner Climateric 18, 817-825, 2015

Safety- Endometrium Menopause 22, 1289-1295, 2015

Sexual Function : Menopause 16, 923-931, 2009

Horm. Mol. Biol. Clin. Invest 25, 181-190, 2016

J. Sex Medecine 12, 2401-2412, 2015

Serum Steroids : Menopause 16, 897-906, 2009

J. Ster Biochem. Mol. Biol. 154, 186-194, 2015

Horm. Mol. Biol. Clin. Invest 24, 117-129, 2015

J. Ster Biochem. Mol. Biol. 159, 142-153, 2016

Approval – US FDA, Nov. 2016/ European EMA, Q1 2018

1552 women treated with

intravaginal DHEA-

Clinical Program completed

according to FDA recommendations

4- Clinical Program Performed for the approval of Intrarosa®

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Parabasal cells

0

70

80

0% 0.25% 0.5% 1.0%

Prasterone dose

%

Day 1

2 weeks

4 weeks

8 weeks

12 weeks60

NS

p=0.83

p<0.0001

p<0.0001

p<0.0001

vs PLACEBO

vs PLACEBO

vs PLACEBO

40

50

30

20

10

vs BASELINE

Labrie, Archer et al , Menopause 16, 907-922, 2009

Example of effect of DHEA on

vulvovaginal atrophy

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INFLUENCE ON THE MALE PARTNER AT 12 WEEKS

FEELING OF VAGINAL DRYNESS:ALMOST NEVER OR NEVER

PLACEBODHEA(n=34)(n=66)

8%36%

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All serum steroids remain

within normal values with no

systemic effect

Only the inactive estrogen

and androgen metabolites

appear in the blood

Premenopause Postmenopause Postmenopause +

DHEA

Prasterone (DHEA)

DHEA

Estradiol Testosterone

Estrogen

Metabolit

e

Androgen

Metabolite

1- Labrie, Menopause, In press, 2018.

Intravaginal DHEA: Summary of its intracellular transformation and effects

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5- SEXUAL DYSFUNCTION

(A second indication for Prasterone)

Unmet medical need (FDA)

MAJOR

DIFFERENTIATING FACTOR

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Arousal / lubrication

Sensitive fibers

DesireArousal / sensation

Orgasm

Prasterone-(androgenic)

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1- Intrarosa® US Prescribing Information.

• All serum steroids remain within normal postmenopausal values (Martel et al, J. Ster. Biochem. Mol. Biol. 159, 142-153, 2016)

• The only observation more frequent in the prasterone group is vaginal discharge due to the stimulation of vaginal secretions by prasterone

• Given the safety observed with Intrarosa®, the product has been approved without a black box.

• No limitation to the duration of treatment.

This is a major differentiation for Intrarosa® relative to all the available estrogen-based therapies for vulvovaginal atrophy which all have a black box while Intrarosa® has no black box warning.

6- Intrarosa® : Summary of Safety

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(Baseline) (0.5% DHEA, 52 weeks)

No effect of DHEA on the endometrium

Portman, Labrie et al, Menopause 22, 1289-1295, 2015

(n = 389)

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1- Labrie, Mol. Cell. Endocrinol. 78, C113-118, 1991; 2- Labrie et al, Menopause 24, 702-712, 2017;

8- What is

Intracrinology?

(First step):

A- Intracellular

formation of

estradiol and

testosterone from

inactive DHEA

(prasterone) …

followed by their

intracellular action in

the same cells1-2

Estradiol

Testosterone

Estrogenreceptor

Androgenreceptor

Peripheral cell

DHEA

(Endogenous from the adrenals or

exogenous (Intrarosa®))

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1- Bélanger et al, Trends Endocrinol Metab 14, 473-9, 2003; 2- Ke et al, Horm. Mol. Biol. Clin. Invest. 24, 117-29, 2015;

3- Labrie et al, Horm. Mol. Biol. Clin. Invest. 29, 39-60, 2017; 4- Martel et al, J. Steroid. Biochem. Mol. Biol. 159, 142-53, 2016.

What is Intracrinology?

(Second step):

B- The estrogens and

androgens made

intracellularly are

inactivated locally in the

same cells by steroid-

inactivating enzymes1

Consequence:

Only inactive metabolites

appear in the blood2-4,

thus avoiding action in

other tissues

Estradiol

Testosterone

Estrogenreceptor

Androgenreceptor

Both inactivated inside the same cells

Peripheral cell

Only inactive metabolites are released in the circulation

DHEA

(Endogenous from the adrenals or

exogenous (Intrarosa®))

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Product IndicationPre-

ClinicalPhase

IPhase

IIPhase

IIIUS NDA

ApprovalVulvovaginalatrophy

Sexual dysfunction

Prasterone + Acolbifene

(Oral)

Vasomotorsymptoms

Osteoporosisprevention

AcolbifeneBreast cancertreatment

Acolbifene + Prasterone + GnRH agonist

Endometriosis

Prasterone + Acolbifene

Male hypogonadism & Loss of libido

AntiandrogensProstate cancer treatment

Over $320M investment to date

Endoceutics’ Drug Pipeline

ERC-249

ERC-407

ERC-242

IntrarosaTM

(Prasterone Intravaginal)

Prasterone(Intravaginal)

Approved US FDA–Nov. 2016, EMA–Jan, 2018

2022

2020

2016

2023

2023

2024

2025

2025

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“Scientific research is one

of the most exciting and rewarding of

occupations.”

Frederick Sanger (1918-2018),

Biochemist and two time Nobel Prize recipient

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“Conformity is the jailer of freedom and the enemy of

growth.”-John F. Kennedy, 35th U.S President

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Date

Merci beaucoup

Pour plus d’information

www.endoceutics.com

fernand.labrie@endoceutics.com

www.fernandlabrie.com