CONFÉRENCE À SUCCÈS EN SCIENCES DE LA VIE : ENDOCEUTICS

13 Septembre 2018 1 Quebec, Canada ENDOCEUTICS No. 1 Innovative pharmaceutical company in menopausal women’s health in the world

2 FL220818 – QC int. Facilities Head Office

Laboratory Manufacturing 3 FL220818 – QC int. 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. 1 2 3 4 1980 1982- 1984 2008-2016 ↓ ↓ ↓ ↓ US patent 5,389,613 Intracrinology2-5 US patent 4,472,382 US patent 8,957,054 DHEA, mainly secreted by ↓ the adrenals, is ↓ ↓ Medical castration with transformed intracellularly Combined androgen Vulvovaginal atrophy or GnRH agonists1 into small amounts of blockade in prostate genitourinary syndrome Suprefact® estrogens and androgens cancer2,3 of menopause (2015) 6,7 Lupron® which are also inactivated Euflex® Intrarosa® Zoladex® intracellularly and locally Anandron® Decapeptyl® without influencing the Casodex® Synarel® other tissues. Xtandi® Factrel® Erleada® Gonazon® Suprelorin® Ovalyse® Vantas® At least 18 drugs have been commercialized worldwide based upon the original Dalmarelin® data of Dr Labrie’s research team. Maprelin® Author and co-author of 1360 publications

1- Labrie, Bélanger et al. (1980) J Androl 1: 209-228 5- Labrie, Bélanger et al. (2017) Menopause 24: 702-712 2- Labrie, Dupont et al. (1982) Clin Invest Med 5: 267-275 6- Labrie, Archer et al. (2016) Menopause 24:1246-1256 3- Labrie, Dupont et al, Important Adv Oncol, 193-217, 7- Intrarosa® Prescribing Information 4 1985 4- Labrie (1991) Mol Cell Endocrinol 78:C113-118 When and how Intracrinology was first recognized. 1- First demonstration in prostate cancer in 1982

5 FL220818 – QC int. Combined androgen blockade (1982)

GnRH CRF superagonist PITUITAR First Y ACT demonstration of LH H ADRENAL TESTI the role of DHEA S DEHYDROEPI- and Intracrinology TESTOSTERONE ANDROSTERONE ABIRATERONE (Unique to the 17b-HSD 3b-HSD DHEA human) T 4-DIONE 5α - reductases Demonstration of the 5a-DIONE FLUTAMIDE role of DHEA in the NILUTAMIDE ANDROGEN BICALUTAMIDE AR formation of RECEPTOR ENZALUTAMIDE APALUTAMIDE androgens in the DAROLUTAMIDE prostatic tissue 1-3 PROSTATIC CELL (normal and cancer) 6 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. FL220818 – QC int. 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.

7 FL220818 – QC int. 8 ADRENAL DHEA-S

Sulfatase DHEA Sulfotransferase 17b HSD-1 Androgenic DHEA 5-DIOL DHEA response Exogenous 17b HSD-2, 4 AR Intravagina 3b HSD-1 3bHSD-1 l TM 17b HSD-5 Estrogenic Intrarosa 4-DIONE TESTO 17b HSD-2, 10 response 5a reductase-1, 2, 3 5a reductase-1, 2, 3 ER

Aromatase 17b HSD-5, 15 A-DIONE DHT Aromatase 17b HSD-2, 9, 10 3a HSD-1, 3 RoDH-1 3a HSD-1 RoDH-1 17b HSD-7 a 3(a b) (3a HSD-4) 3 HSD-3 (3a HSD-4) 17b HSD-7 -HSE UGT2B7 3(a b)-HSE 3b HSD-1 17b HSD-5, 15 3b HSD-1 UGT2B15 ADT 3a-DIOL 3a-DIOL-G 17b HSD-2, 9, 10, 14 3(a b)-HSE 3(a b)-HSE UGT2B17 ADT-G Sult2B1 b ADT-S 17 HSD-5, 15 Sult2B1 epi-ADT 3b-DIOL b 17b HSD-2, 9, 10, 14 UGT1A1 3 -Diol-S UGT1A1 E1-G E -G 17b HSD-1, 7, 12 2 E1 E2 Elimination 17b HSD-2, 4, 8, 14 of steroids Sulfatase Sulfo- Sulfatase Sulfo- transferase Transferase

E1-S E2-S

9 FL220818 – QC int. Intracrinology

UNIQUE TO THE HUMAN SPECIES AND PRIMATES: Adrenals which secrete large amounts of DHEA

10 FL220818 – QC int. 3- Novel understanding of the physiology of sex steroids in women: Intracrinology

11 FL220818 – QC int. New understanding of sex steroid physiology

12 FL220818 – QC int. Symptoms and signs of sex steroid deficiency

 Hot flushes  Vulvovaginal atrophy  Night sweats  Sexual dysfunction  Insomnia  Muscle loss  Nervousness  Bonne loss – fractures  Lack of  Loss of memory concentration  Loss of cognition  Depression  Possibly Alzheimer’s disease

13 FL220818 – QC int. Endogenous DHEA : Summary of role and action in VVA/GSM – Low DHEA is the essential cause of VVA

14 FL220818 – QC int. Systemic Exposure to E2

15 FL220818 – QC int. The cause of VVA is not the lack of estrogens but the lack of DHEA Renaissance/Revolution in the treatment of menopause

16 FL220818 – QC int. 4- Clinical Program Performed for the approval of Intrarosa®

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 1552 women ERC – 238 Menopause 23, 243-256, 2016 treated with Acceptability Intravaginal Gynecol Endocrinol 32, 240-245, 2016 intravaginal DHEA Application - Influence on Male Partner Climateric 18, 817-825, 2015 Safety- Endometrium Menopause 22, 1289-1295, 2015 Clinical Program Sexual Function : Menopause 16, 923-931, 2009 completed Horm. Mol. Biol. Clin. Invest 25, 181-190, 2016 according to FDA J. Sex Medecine 12, 2401-2412, 2015 recommendations 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 17 FL220818 – QC int. Example of effect of DHEA on vulvovaginal atrophy

Parabasal cells 80 Day 1 vs BASELINE 2 weeks 70 NS 4 weeks p=0.83 60 8 weeks 12 weeks 50 vs PLACEBO % p<0.0001 40 vs PLACEBO p<0.0001 30 vs PLACEBO p<0.0001 20

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0 0% 0.25% 0.5% 1.0% Prasterone dose Labrie, Archer et al , Menopause 16, 907-922, 2009 18 FL220818 – QC int. INFLUENCE ON THE MALE PARTNER AT 12 WEEKS FEELING OF VAGINAL DRYNESS: ALMOST NEVER OR NEVER DHEA PLACEBO (n=66) (n=34) 36% 8%

19 FL220818 – QC int. Intravaginal DHEA: Summary of its intracellular transformation and effects Prasterone (DHEA) All serum steroids remain within normal values with no DHEA systemic effect Estradiol Testosterone Estrogen Only the inactive estrogen Androgen and androgen metabolites Metabolit Metabolite e appear in the blood

Premenopause Postmenopause Postmenopause + DHEA

20 1- Labrie, Menopause, In press, 2018. FL220818 – QC int. 5- SEXUAL DYSFUNCTION (A second indication for Prasterone) Unmet medical need (FDA) MAJOR DIFFERENTIATING FACTOR

21 FL220818 – QC int. Desire Arousal / sensation

Sensitive fibers Prasterone- Arousal / lubrication (androgenic) Orgasm

22 FL220818 – QC int. 6- Intrarosa® : Summary of Safety

• 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.

1- Intrarosa® US Prescribing Information.

23 FL220818 – QC int. No effect of DHEA on the endometrium

(Baseline) (0.5% DHEA, 52 weeks) (n = 389)

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

24 FL220818 – QC int. 25 FL220818 – QC int. 8- What is Intracrinology(Endogenous ?from the adrenals or DHE exogenous (Intrarosa®)) A (First step): Estradiol A- Intracellular formation of Testosterone estradiol and testosterone from Estrogen inactive DHEA receptor (prasterone) … Androgen followed by their receptor intracellular action in the same cells1-2 Peripheral cell

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

26 FL220818 – QC int. What is Intracrinology? (Endogenous from the adrenals or DHE exogenous (Intrarosa®)) A (Second step): Estradiol B- The estrogens and androgens made intracellularly are Testosterone inactivated locally in the Estrogen same cells by steroid- receptor inactivating enzymes1 Both inactivated Androgen receptor Consequence: inside the Only inactive metabolites same cells Peripheral cell appear in the blood2-4, thus avoiding action in Only inactive metabolites are other tissues released in the circulation 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. 27 FL220818 – QC int. 28 FL220818 – QC int. Endoceutics’ Drug Pipeline

Pre- Phase Phase Phase US NDA Product Indication Clinical I II III Approval TM Vulvovaginal Intrarosa Approved US FDA–Nov. 2016, EMA–Jan, 2018 (Prasterone Intravaginal) atrophy 2016 Prasterone Sexual (Intravaginal) dysfunction ERC-242 2020

Vasomotor ERC-249 2022 Prasterone + symptoms Acolbifene Osteoporosis (Oral) prevention 2023 Breast cancer 2023 Acolbifene treatment Acolbifene + Prasterone + Endometriosis 2024 GnRH agonist Prasterone + Male hypogonadism 2025 Acolbifene & Loss of libido Prostate cancer Antiandrogens treatment ERC-407 2025

29 Over $320M investment to date FL220818 – QC int. “Scientific research is one of the most exciting and rewarding of occupations.”

Frederick Sanger (1918-2018), Biochemist and two time Nobel Prize recipient

30 FL220818 – QC int. “Conformity is the jailer of freedom and the enemy of growth.”

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

31 FL220818 – QC int. Merci beaucoup

Pour plus d’information www.endoceutics.com [email protected] www.fernandlabrie.com

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