CONFÉRENCE À SUCCÈS EN SCIENCES DE LA VIE : ENDOCEUTICS 13 Septembre 2018 Quebec, Canada 1
ENDOCEUTICS No. 1 Innovative pharmaceutical company in menopausal women s health in the world 2
Facilities Head Office 3 Laboratory Manufacturing
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 1980 US patent 5,389,613 Medical castration with GnRH agonists 1 Suprefact Lupron Zoladex Decapeptyl Synarel Factrel Gonazon Suprelorin Ovalyse Vantas Dalmarelin Maprelin 2 1982- Intracrinology 2-5 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. 3 1984 US patent 4,472,382 Combined androgen blockade in prostate cancer 2,3 Euflex Anandron Casodex Xtandi Erleada 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 4 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 5- Labrie, Bélanger et al. (2017) Menopause 24: 702-712 6- Labrie, Archer et al. (2016) Menopause 24:1246-1256 7- Intrarosa Prescribing Information
When and how Intracrinology was first recognized. 1- First demonstration in prostate cancer in 1982 5
Combined androgen blockade (1982) 6 GnRH superagonist PITUITAR Y TESTI S AR LH TESTOSTERONE T 17b-HSD ANDROGEN RECEPTOR CRF ACT H PROSTATIC CELL ABIRATERONE 3b-HSD 4-DIONE 5α - reductases 5a-DIONE FLUTAMIDE NILUTAMIDE BICALUTAMIDE ENZALUTAMIDE APALUTAMIDE DAROLUTAMIDE DEHYDROEPI- ANDROSTERONE DHEA ADRENAL 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 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.
7 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.
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ADRENAL DHEA Exogenous Intravagina l Intrarosa TM Sulfatase 3b HSD-1 DHEA-S DHEA 4-DIONE DHEA Sulfotransferase 17b HSD-1 17b HSD-2, 4 17b HSD-5 17b HSD-2, 10 5-DIOL TESTO 3bHSD-1 5a reductase-1, 2, 3 5a reductase-1, 2, 3 AR ER Androgenic response Estrogenic response Aromatase 17b HSD-7 3(a b)-hse A-DIONE 3a HSD-1, 3 RoDH-1 (3a HSD-4) 3b HSD-1 ADT 3(a b)-hse Sulfatase epi-adt 17b HSD-5, 15 DHT 17b HSD-2, 9, 10 3a HSD-1 RoDH-1 3a HSD-3 (3a HSD-4) 17b HSD-5, 15 3b HSD-1 3a-DIOL 17b HSD-2, 9, 10, 14 3(a b)-hse 3b-DIOL E 1 E 2 17b HSD-5, 15 17b HSD-2, 9, 10, 14 17b HSD-1, 7, 12 17b HSD-2, 4, 8, 14 Sulfatase E 1 -S E 2 -S Sulfotransferase Sulfo- Transferase 17b HSD-7 3(a b) -HSE Aromatase UGT2B7 UGT2B15 UGT2B17 Sult2B1 Sult2B1 UGT1A1 UGT1A1 3a-DIOL-G ADT-G ADT-S 3b-Diol-S E 1 -G E 2 -G Elimination of steroids 9
Intracrinology UNIQUE TO THE HUMAN SPECIES AND PRIMATES: Adrenals which secrete large amounts of DHEA 10
3- Novel understanding of the physiology of sex steroids in women: Intracrinology 11
New understanding of sex steroid physiology 12
Symptoms and signs of sex steroid deficiency Hot flushes Vulvovaginal atrophy Night sweats Sexual dysfunction Insomnia Muscle loss Nervousness Bonne loss fractures Lack of concentration Depression Loss of memory Loss of cognition Possibly Alzheimer s disease 13
Endogenous DHEA : Summary of role and action in VVA/GSM Low DHEA is the essential cause of VVA 14
Systemic Exposure to E 2 15
The cause of VVA is not the lack of estrogens but the lack of DHEA Renaissance/Revolution in the treatment of menopause 16
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 17 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
Example of effect of DHEA on vulvovaginal atrophy 80 70 60 vs BASELINE NS p=0.83 Parabasal cells Day 1 2 weeks 4 weeks 8 weeks 12 weeks % 50 40 30 20 vs PLACEBO p<0.0001 vs PLACEBO p<0.0001 vs PLACEBO p<0.0001 10 18 0 0% 0.25% 0.5% 1.0% Prasterone dose Labrie, Archer et al, Menopause 16, 907-922, 2009
INFLUENCE ON THE MALE PARTNER AT 12 WEEKS FEELING OF VAGINAL DRYNESS: ALMOST NEVER OR NEVER DHEA (n=66) 36% PLACEBO (n=34) 8% 19
Intravaginal DHEA: Summary of its intracellular transformation and effects Prasterone (DHEA) Estradiol Estrogen Metabolit e DHEA Testosterone Androgen Metabolite 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 20 1- Labrie, Menopause, In press, 2018.
5- SEXUAL DYSFUNCTION (A second indication for Prasterone) Unmet medical need (FDA) MAJOR DIFFERENTIATING FACTOR 21
Desire Arousal / sensation Sensitive fibers Prasterone- (androgenic) Arousal / lubrication Orgasm 22
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
No effect of DHEA on the endometrium (Baseline) (n = 389) (0.5% DHEA, 52 weeks) Portman, Labrie et al, Menopause 22, 1289-1295, 2015 24
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(First step): A- Intracellular formation of estradiol and testosterone from inactive DHEA (prasterone) followed by their intracellular action in the same cells 1-2 8- What is Intracrinology? DHE A (Endogenous from the adrenals or exogenous (Intrarosa )) Testosterone Peripheral cell Estradiol Estrogen receptor Androgen receptor 1- Labrie, Mol. Cell. Endocrinol. 78, C113-118, 1991; 2- Labrie et al, Menopause 24, 702-712, 2017; 26
27 (Second step): B- The estrogens and androgens made intracellularly are inactivated locally in the same cells by steroidinactivating enzymes 1 Consequence: Only inactive metabolites appear in the blood 2-4, thus avoiding action in other tissues What is Intracrinology? DHE A (Endogenous from the adrenals or exogenous (Intrarosa )) Testosterone Estradiol Both inactivated inside the same cells Peripheral cell Only inactive metabolites are released in the circulation Estrogen receptor Androgen receptor 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.
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Endoceutics Drug Pipeline Product Intrarosa TM (Prasterone Intravaginal) Prasterone (Intravaginal) Prasterone + Acolbifene (Oral) Acolbifene Acolbifene + Prasterone + GnRH agonist Prasterone + Acolbifene Antiandrogens Indication Vulvovaginal atrophy Sexual dysfunction Vasomotor symptoms Osteoporosis prevention Breast cancer treatment Endometriosis Male hypogonadism & Loss of libido Prostate cancer treatment Pre- Clinical ERC-407 Phase I ERC-242 ERC-249 Phase II Phase III Approved US FDA Nov. 2016, EMA Jan, 2018 US NDA Approval 2016 2020 2022 2023 2023 2024 2025 2025 29 Over $320M investment to date
Scientific research is one of the most exciting and rewarding of occupations. Frederick Sanger (1918-2018), Biochemist and two time Nobel Prize recipient 30
Conformity is the jailer of freedom and the enemy of growth. -John F. Kennedy, 35 th U.S President 31
Merci beaucoup Pour plus d information www.endoceutics.com fernand.labrie@endoceutics.com www.fernandlabrie.com Date