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29 June 2016 09 :30 – 09 :55 : Registration 09 :55 – 10 :00 : Welcome 10 :00 – 10 :30 : the Unique Potential of Estetrol

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29 June 2016 09 :30 – 09 :55 : Registration 09 :55 – 10 :00 : Welcome 10 :00 – 10 :30 : the Unique Potential of Estetrol investor day 2016 29 June 2016 09 :30 – 09 :55 : Registration 09 :55 – 10 :00 : Welcome 10 :00 – 10 :30 : The unique potential of Estetrol 10 :30 – 11 :45Programme: Mithra’sde la journée strategy 11 :45 – 12 :00 : Q&A 12 :00 – 13 :30 : Drink and lunch with Executive Management 13 :30 – 14 :15 : Focus on Estetrol-based projects 14 :15 – 14 :30 : Coffee break 14 :30 – 15 :15 : Focus on long-acting drugs and Mithra CDMO 15 :15 – 15 :30 : Q&A and wrap-up session 15 :30 – 16 :30 : Drink and networking What is Estetrol ? Interview with Professor J.M. Foidart MD. Member of scientific committee Mithra Professor J.M. Foidart MD. Member of scientific committee Mithra 4 Estrogens in the “pill” a very limited family . Estradiol . Synthetic progestin . Ethinylestradiol Over 95% of oral contraceptives contain ethinylestradiol 6 Synthetic Progestins : a very large family First First Second Third New” COCs generation: generation: generation: progestins: > Norethisterone > Norethynodrel > Norgestrel > Desogestrel > Drospirenone > Norethinodrel > Nortestosterone > Levonorgestrel > Etonogestrel > Dienogest > High doses of derivatives > Gestodene > Trimestone synthetic estrogen >Pregnanes > Nesterone and androgenic > Norgestimate > Nomegestrol Ac. progestin > Promegestone Jan 2014 EMA classification progestins by type . Structural modification: to reduce androgenic side-effects but maintain strong progestational activity . Wider health benefits depending on progestin properties Reviewed in Brynhildsen J. Ther Adv Drug Saf. 2014;5(5):201-13; Benagiano7 G, et al. Eur J Contracept Reprod Health Care. 2004;9(3):182- 93; Sitruk-Ware R. Hum Reprod Update. 2006;12(2):169-78; Micks E, et al. Endocr Connect. 2015;4(4):R81-92 The third and fourth generation progestins and pills are not androgenic. Some have an anti-androgenic activity No acne No oily hair + No weight gain 1985 - 2011 8 The pill increases the risk of deep venous thrombophelbitis and pulmonary embolism The third and fourth generation progestins and pills are not androgenic. Some have an anti-androgenic activity Ethinyl-estradiol (thrombogenic risk +++) - Don’t protect against the Thrombogenic effect of EE. The risk is multiplied by 4-6 2012 - present 9 What is Estetrol (E4)? Estrone (E1) 17-estradiol (E2) Estriol (E3) Estetrol (E4) Natural estrogens Darwin and evolution “ It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is most adaptable to change. “ Darwin and evolution Primates display E4 only at the term of pregnancy and at only 1% of the human plasma levels. Cynomologus What is Estetrol (E4)? 17-estradiol (E2) Estrone (E1) Widely distributed among animal species Primate specific, essentially human Estriol (E3) Estetrol (E4) The two forms of the Estrogen Receptor -α (ER-α) The two forms of the Estrogen Receptor -α (ER-α) E2 activates two types of ERas Palmytoylated Estradiol cysteine 451 ERa Membrane Initiated (E2) Steroid Signals (MISS) Plasma membrane ERa Nucleus AFAF1-1 DBD LBD AFAF2-2 N-Ter C-Ter Cofactors => Gene transcription Genomic effects E4 activates the nuclear Era but inhibits the membrane Era Palmytoylated cysteine 451 E4 ERa MISS blockade ERa AFAF1-1 DBD LBD AF2AF-2 N-Ter C-Ter Cofactors => Gene transcription Genomic effects E4 is an estrogen with a distinctive profile of ERα activation. It activates nuclear ERα, but devoid of Membrane signaling, and is an antagonist of the Membrane effects. Thus, E4 is a natural Selective ER Modulator (SERM) of human pregnancy that could also be considered for HT. Usual E4 criticism: E4 is a very weak Estrogen E4 E2 E2 What are the potential benefits of using E4 in comparison to currently available estrogens? 20 What are the potential benefits of using E4 in comparison to currently available estrogens? . Estrogens modify liver synthesis of proteins, also proteins involved in the coagulation . ↑ pro-coagulation and ↓ anti-coagulation → VTE risk ↑(complication pulmonary embolism) . VTE risk ↑ with estrogen dose Reduced venous thromboembolism (VTE) risk profile 21 What are the potential benefits of using E4 in comparison to currently available estrogens? Reduced venous thromboembolism (VTE) risk profile 22 What are the potential benefits of using E4 in comparison to currently available estrogens? Reduced venous thromboembolism (VTE) risk profile 23 What are the potential benefits of using E4 in comparison to currently available estrogens? Reduced venous thromboembolism (VTE) risk profile 24 What are the potential benefits of using E4 in comparison to currently available estrogens? . Many drugs are metabolized by the CYP450 enzymes family, this is the case of current estrogens . Some drugs activate CYP450 (antibiotics, anti-epileptics) => ↓ drug efficacy Lower risk of drug-drug interaction 25 What are the potential benefits of using E4 in comparison to currently available estrogens? % INHIBITION OF CYTOCHROME P450 ENZYMES Compound CYP CYP CYP CYP CYP 1A2 2C9 2C19 2D6 3A4 EE <10 <10 82 <10 45 E2 19 <10 63 <10 <10 E4 <10 <10 <10 <10 <10 Lower risk of drug-drug interaction What are the potential benefits of using E4 in comparison to currently available estrogens? In laboratory, E4 was shown to protect against breast cancer development and to decrease size of already existing tumors Lower carcinogenic potential 27 What are the potential benefits of using E4 in comparison to currently available estrogens? . Elevated triglycerides levels are associated with coronary heart diseases . E4 has minimal impact on triglycerides levels DINOX Study Minimal increase of triglycerides Estetrol (E4 ) Reduced venous thromboembolism (VTE) risk profile Potential benefits Lower carcinogenic potential Natural estrogen produced by fetal liver Lower risk of drug-drug interaction Minimal increase of triglycerides 29 The unmet need: a sate and well-tolerated pill MITHRA solution: ESTELLE (E4/Drospirenone) Drospirenone pure progestin with anti-androgenic and anti-mineralocorticoid activity ESTETROL Expected minimal or no increased risk of DVT Lower Excellent tolerance expected : thrombogenic risk no acne, no oily hair, no weight gain, no oedema, no breast tension, excellent control of spotting/bleeding Vaginal bleeding profile and cycle control Occurence of bleeding by cycle day 15 mg E4/DRSP 20 mg E4/DRSP E2V/DNG (Qlaira) Finnish Study Estelle® Novel combination containing the new naturally occurring estrogen (E4) with DRSP Innovative combination Good Robust tolerability contraceptive profile efficacy Estelle® Good Minimal vaginal CYP450 bleeding interaction pattern Low impact on liver enzymes Donesta® Estetrol for the relief of Vasomotor Symptoms of menopause Innovative Low or no risk of Suppression breast of hot flushes cancer Donesta® Minimal Minimal CYP450 impact on interaction lipids Low risk of DVT and pulmonary embolism Other potential indications Acceleration of wound healing? Burn War Wound Ulceration Neuroprotection Neuroprotection 37 Neuroprotection par E4 Ligature carotide Placebo Estetrol 5mg/kg 8% O2 pendant 35 minutes Thank you for your attention investor day 2016 Mithra’s Strategy: Interview with François Fornieri Our mission is to support women at every cycle of their life, providing innovative and accessible pharmaceutical solutions Personalised medicine is the future Early 2000s, studies on HRT : . Women’s Health Initiative in US . Million Women Study in UK Learnings Higher safety issues Menopause . VTE . Stroke . Breast cancer risks Pill generations 1 - 2 : Pill generations 3 - 4 : non-contraceptive side effects higher safety issues . Weight gain . VTE risks . Acne Learnings Contraception Market Needs Higher security profile More comfort Mithra focuses on innovation Innovation Contraception Estetrol (E4) Indications Menopause What is Estetrol ? A potential answer from nature A selective natural estrogen Reduced venous thromboembolism (VTE) risk profile Estetrol (E4 ) Lower carcinogenic potential Natural estrogen produced by fetal liver Lower risk of drug-drug interaction Minimal increase of triglycerides Estetrol-based projects Contraception Menopause Other potential indications Estelle® (E4/Drospirenone) Donesta® (E4) Breast cancer CNS Combined Oral Contraceptive Pill Hormonal Replacement Therapy Dermatology Endometriosis Osteoporosis ... 25 PATENT FAMILIES Mithra’s multiple shots on goal A high potential buisness model What is a long acting drug Example: Intra-Uterine Device. 24 hour delivery system for 5 years Plural Polymer Technology for targeted long-acting drug development What is a long acting drug ? . Prolonged drug delivery technology . Predetermined rate of API distribution . Controled release / Targeted delivery Complex Long acting drug development Therapeutical biodegradable subcutaneous implant for prostate ® Solutions Zoreline project and breast cancer and benign gynecological conditions (endometriosis, uterine fibroids) Projects Long acting drug development non-biodegradable, flexible, transparent, Myring project combination contraceptive vaginal ring made of ethylene vinylacetate copolymers Complex formulation synthetic steroid (tibolone) intended to be used for hormone replacement therapy (used Tibelia® project especially for the relief of symptoms occurring after menopause) Mithra‘s growth potential E4 Multiple Long acting drug Integrated R&D therapeutic field + development + & production potential expertise & technology technological platform Mithra CDMO Mithra’s integrated development and production platform A unique pharmaceutical ecosytem for successful co-development
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