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Home , Estetrol (medication), Promegestone

investor day 2016

29 June 2016 09 :30 – 09 :55 : Registration 09 :55 – 10 :00 : Welcome 10 :00 – 10 :30 : The unique potential of

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 in the “pill” a very limited family

. . Synthetic progestin . Over 95% of oral contraceptives contain ethinylestradiol

6 Synthetic Progestins : a very large family

First First Second Third New” COCs generation: generation: generation: progestins: > > Norethynodrel > > > > Norethinodrel > Nortestosterone > > > > High doses of derivatives > > Trimestone synthetic >Pregnanes > Nesterone and androgenic > > 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 and at only 1% of the human plasma levels.

Cynomologus What is Estetrol (E4)?

17-estradiol (E2) (E1)

Widely distributed among animal

species Primate specific, essentially human

Estriol (E3) Estetrol (E4) The two forms of the Estrogen -α (ER-α) The two forms of the -α (ER-α) E2 activates two types of ERas

Palmytoylated Estradiol cysteine 451 ERa Membrane Initiated (E2) 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 synthesis of proteins, also proteins involved in the

. ↑ 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 family, this is the case of current estrogens

. Some drugs activate CYP450 (antibiotics, anti-epileptics) => ↓ drug efficacy

Lower risk of drug- 25 What are the potential benefits of using E4 in comparison to currently available estrogens?

% INHIBITION OF 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 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 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- 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 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

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 . 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 Hormonal Replacement Therapy Dermatology Endometriosis ...

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 made of ethylene vinylacetate copolymers

Complex formulation

synthetic steroid () intended to be used for 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

Know-how and Mithra’s 3rd parties expertise in-house R&D projects projects Master Plan

Polymeric forms Sterile Hormonal and implants injectables Tableting

Production QC QC laboratories

R&D

Warehouse R&D platform Admin Timeline

Polymeric forms Sterile Hormonal and implants injectables Tableting

QC laboratories

Phase 1: Inauguration on September 30th, 2016

Phase 2: Completed by 2019 R&D platform Mithra‘s growth potential

E4 + + 2 projects in mid-late Partnering Technological platform stage development and innovation for Mithra and partners 25 patent families

SIGNIFICANT POTENTIAL

Broad intellectual property portfolio

2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032

+6 Month PIP Extension

Patent* Supplementary Patent Certificate (5 years)

Estelle® Exclusivity 10 years from MA date Combined Oral 0-5 years depending on FDA review contraceptive Patent PTA PTE Exclusivity 5 years from MA date

Patent* Supplementary Patent Certificate (5 years)

Donesta® Exclusivity 10 years from MA date HRT 0-5 years depending on FDA review Patent PTA PTE Exclusivity 5 years from MA date

Patent

Estetrol synthesis

Patent

* In a selection of countries

Achievements

2015 Innovation

In 2015, Mithra strengthens its R&D portfolio:

. Acquisition of 4 innovative projects from Actavis including Estelle®

. Acquisition of all rights held by Pantarhei Bioscience on Estetrol (25 patent families); including Menopause (Donesta®)

. Estelle® and Donesta® become Mithra’s lead R&D projects

. Mithra acquires all worldwide and property rights regarding Zoreline® and Myring (100% of Novalon)

. In 2015, Mithra continues to build its Mithra CDMO Commercial Achievements . Belgium leader on the oral contraception market 2015 45,24% of market shares (in number of blisters) in 2015 1,4% increase compared to 2014 . The Netherlands Mithra dominates the oral contraception market 32% of market shares (in volume in counting units) in 2015, 5% increase . Germany (launch of 2 COC products : Midien and Midesia)

. (MA for 2 COC products: Milevoni 20/100 and Milevoni 30/100) —> commercialisation Q4 2016

. Brazil Mithra prepared to enter the Brazilian market (market study on KOL’s) Achievements

2015 Corporate . Strenghtening management teams ( group controller, CLO, Estetrol and clinical developments)

. ERP solution

. European business awards 2015

. Finalist in « Entreprise de l’année 2015 „

. Business developer Executive of the year 2015

. Unique survey: Women Consulting Board

. Social Responsibility Outlooks Expected read outs in 2016

. PD study of Zoreline® 3-month 2016 . PK study of Zoreline® 3-month . PK study on Estetrol alone . Mass balance study of Estelle® in women

Further developing pipeline

. Donesta® phase II dose-finding study . Estelle® phase III . Myring clinical batches and start of bioequivalence study . Start-up of CDMO PQ Phase I 3 months ahead of schedule . Pre-clinical proof of concept in other indications of Estetrol Commercial

. Marketing Authorisations for Tibelia® . Strategic commercial portfolio development . Potential milestones payments and collaborative deals Financial Highlights

Estetrol programmes Complex Therapeutical Solutions programmes Thank you for your attention Programme de la journée

Q&A investor day 2016 Dr Karina Putineanu Head of Clinical Development Mithra Why doing a ? What’s a clinical trial?

. Out of 10000 mollecules, only one become a drug . Long path (10-15 years) governed by strict rules . Clinical trials are building the evidence . Optimal intercontinental and intermodal connectivity

- Safety and efficacy - Drug-drug/ drug- substance interactions - Potential adverse events - Dose and administration route - Most appropriate patient profile What does the R&D market means?

. The global R&D market represents 50-80 billion USD;

. 38599 recruiting studies (global); 55% in Europe

. The R&D pharma investment in Europe was 30.63 billion Euros (2013 EFPIA)

. Belgium 2.343 bilion Euros

. R&D employment in Europe represents 115000 FTE What do we mean by research?

Translational Fondamental research Clinical Research (bench side) (bench to (patients, subjects ) research bed) Clinical research, what do we do on human subjects ?

MAA Phase I Phase II Phase III Phase IV

• Healthy subjects • Dose finding • Pivot studies • Long term follow up (<100) • PK; PD • Randomised, • Real life • Tolerance • Efficacy blinded • • Initial safety data • patients 100- 500 • Comparison with • Higher patient variability golden standards • PK; PD; food effect; • Short (months) • Post marketing • Efficacy and safety • Intense schedule • Can be required / • Short (days), • 1000-5000 patients • Clinical centers mandated by authorities intense schedule • Long duration (years) • Dedicated specialised centers How do we do our studies? Estetrol programmes How does Mithra fit into this landscape?

• Insert here the slide with the timelines for clin dev Estelle® (E4 DRSP) Global Development Plan

Non-Clinical Clinical Agency feed-back

2005-2007: E4 only • PR3050: Single oral dose • Safety Pharmacology • PR3054: Multiple oral dose 2012 NCAs: MEB & MHRA • ADME & PK 2007-2011: EMA: Scientific advice • PR3081: Proof of concept study FDA: End of Phase 2 meeting • Drug-drug interactions E4 Combined • ES-C01: Dose-finding inhibition study • Acute and repeated toxicity with a • ES-C02: Dose-finding bleeding profile and cycle studies progestin control study

• Genotoxicity 2015-2020: • Phase 1: Mass Balance, early QT assessment, SD-MD 2015: • Reprotoxicology PK studies, …. 15 mg EMA: Follow-up SA clinical • 2 Phases 2: Hemostasis – Ovulation Inhibition with • E4/DRSP Carcinogenicity MED 2015/2016 • 2 Pivotal Phase 3 Contraceptive studies US/Canada FDA: Special Protocol – EU/Russia Assessment (SPA Phase II results show good efficacy in inhibiting ovulation

Evaluation of ovulation inhibition: % of patients scored according to Hoogland score (treatment cycle 3) Not a single ovulation in any of the E4/DRSP groups

100 Note: Hoogland score is a validated

90 tool to assess ovarian function and evaluate ovulation inhibition, which 80 is assessed by transvaginal

70 ultrasounds (TVUS) monitoring of follicle size and analysis of serum E2 60 and levels, and 50 consequently classified according to a 6-point scoring (1 = no ovarian 40 activity; 2 = potential activity; 3 = 30 non-active follicle-like structure

20 (FLS); 4 = active FLS; 5 = luteinised unruptured follicle (LUF); 6 = 10 ovulation).

0 5 mg E4/DRSP 10 mg E4/DRSP 20 µg EE/3 mg DRSP (Yaz) 5 mg E4/LNG 10 mg E4/LNG 20 mg E4/LNG (n=17) (n=19) (n=20) (n=18) (n=17) (n=18) Source:Duijkers I et al., Eur J Cont Reprod Health Care, 2015;20(6):476- 89 No activity Potential activity Non-active FLS Active FLS LUF Ovulation Impact of E4/DRSP on surrogate markers of VTE (reference COC: YAZ®)

change versus baseline

EE 20 µg / DRSP 3 mg

E4 / DRSP mg

Data Submited Bleeding pattern (reference COC: Qlaira®)

Absence of withdrawal bleeding and unscheduled bleeding at Cycle 6

40 Endpoint of the study: 35

30 « Find a dosing combination 25 with not more than 20% absence 20 of withdrawal bleeding, and not more than 20% 15 unscheduled intracyclic

10 bleeding in Cycle 6 »

5

1. Apter D et al., Bleeding pattern and 0 15E4/DRSP 20E4/DRSP 15E4/LNG 20E4/LNG E2V/DNG 15E4/DRSP 20E4/DRSP 15E4/LNG 20E4/LNG E2V/DNG cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose- finding study (FIESTA). Contraception Absence of withdrawal bleeding Unscheduled bleeding on line: http://www.contraceptionjournal.org/a rticle/S0010-7824(16)30050-6/pdf Conclusion post completed studies

Evaluation of ovulation inhibition: % of Based on both dose- patients scored according to Hoogland finding studies the score (treatment cycle 3) combination selected for phase 3 development is: . Complete inhibition of ovulation 1,2 . Low incidence of unscheduled bleeding 3 . Very low incidence of absence of withdrawal bleeding 3 15 mg E4 and 3 mg . Good safety profile 1,2,3 DRSP 24/4 (Estelle®)

1. Duijkers I et al., Eur J Cont Reprod Health Care, 2015;20(6):476-89 2. Mawet M et al., Eur J Cont Reprod Health Care, 2015;20(6):463-75 3. Data on file Pivotal Phase 3 studies: Design

Two multicenter, open-label, single arm studies, 13 cycles

EU/Russia US/Canada

1550 subjects 2000 subjects 18-50 years 16-50 years Contraceptive Contraceptive  1350 subjects  1800 subjects Efficacy Study Efficacy Study 18-35 years 16-35 years

PK Substudy  500 subjects (body weight, Endometrial  16-50 years 167 subjects race and Safety 18-50 years Substudy smoking Menopause: Hormonal Replacement Therapy (HRT)

Non-Clinical Clinical Agency feed-back

Phase 1: 2005-2007: PR 3054 E4 only • Pharmacology (hot flushes VMS: Effect on hot flushes & cytology parameters) VVA: Effect on cytology of epithelial cells 2015 • Safety Pharmacology NCAs: MEB & MPA 2016-2017 : FDA: Pre-IND meeting • ADME & PK Based on • Dose finding per os to define the MED for VMS as effect on primary objective based on frequency and in severity • Drug-drug interactions of moderate to severe vasomotor symptoms • VVA (secondary objectives): on vaginal maturation • Acute and repeated toxicity index (MI), on vaginal pH, on change in the studies Menopause Rating Scale (MRS), on lipid and glucose metabolism, on haemostatic and laboratory • Genotoxicity variables Use of progestin in sequential way • Reprotoxicology or topic 2017-2019: formulation • Carcinogenicity • Phase 1: early QT assessment, SD-MD PK studies, …. • 2 Pivotal Phase 3 studies ESTETROL (E4) for Vasomotor Symptoms (VMS) relief

Phase 1/2 Program :

PR3050 study: PR3054 study: Phase 1, randomized, double-blind, Phase 1, partly randomized, placebo-controlled open-label

> Primary Objective: >> Results: To evaluate safety, tolerability, (PD) and - Safe and well-tolerated (PK) of E4 - Dose-dependent inhibition of plasma LH Intervention: Single ascending dose - Profound inhibition of FSH at 100mg Groups: • Placebo : 8 >> strong central inhibiting • 0.1 mg E4 : 6 • 1 mg E4 : 6 of the compound • 10 mg E4 : 6 • 100 mg E4 : 6 Population : Healthy postmenopausal women ESTETROL (E4) for Vasomotor Symptoms (VMS) relief

Phase 1/2 Program :

PR3050 study: PR3054 study: Phase 1, randomized, double-blind, Phase 1, partly randomized, placebo-controlled open-label

> Primary Objective: >> Results: To evaluate safety, tolerability, PK and PD of E4 - Safe and well-tolerated Intervention: multiple ascending doses for 28 days - PR 3050 PD conclusions confirmed Groups: 2 mg E2V : 10 ® 2 mg E4 : 10 Progestin (Lynestrol ) for 14 days after E4 treatment 10 mg E4 : 10 20 mg E4 : 10 Hysterectomized women 40 mg E4 : 9 Population : Healthy postmenopausal women ESTETROL (E4) for Vasomotor Symptoms (VMS) relief

Phase 1/2 Program :

PR3050 study: PR3054 study: Phase 1, randomized, double-blind, Phase 1, partly randomized, placebo-controlled open-label

Population: subjects with 35 or more hot-flushes per week at screening

>> Results: >> VMS consistent decrease in the mean number of hot flushes was observed in all dose groups ESTETROL (E4) for Vulvo-Vaginal Athrophy (VVA) treatment

Phase 1/2 Program :

PR3050 study: PR3054 study: Phase 1, randomized, double-blind, Phase 1, partly randomized, placebo-controlled open-label

>> Results: Parabas Intermediate Superficial al (%) (%) (%) VVA E2-val - 2mg 0 (0-3) 74 (51-92) 26 (15-49)

E4 - 2 mg 2 (0-15) 80 (53-94) 18 (6-47)

E4 - 10 mg 8 (0-17) 45 (23-78) 47 (5-77)

E4 - 20 mg 0 (0) 60 (17-88) 40 (12-83) Disclosures

• The information contained in this document has been provided by MITHRA PHARMACEUTICALS (the “Company”). No, representation, warranty or undertaking, express or implied, is made as to, and no reliance should be placed on the fairness, accuracy, completeness or correctness of the information or the opinions herein. Neither the Company nor any of its affiliates, advisors or representatives shall have any liability whatsoever (in negligence or otherwise) for any loss whatsoever arising from any use of this document or its contents. • Any projections and expectations presented in this document are provided without any guarantee as to their future realization. This document may contain certain statements, estimates, targets or projections that constitute forward-looking statements regarding the financial condition and other matters relating to the Company. Such forward-looking statements are necessarily based on assumptions reflecting current views and assumptions and involve a number of risks and uncertainties that could cause actual results to differ materially from those suggested by the forward-looking statements. Readers are cautioned not to place undue reliance on such forward- looking statements, which reflect expectations only as of the date of this document. Past performance cannot be relied on as guide to future performance. • The information in this document has not been independently verified. The information in this document, including but not limited to any forward-looking statements, applies only as of the date of this document and is not intended to give any assurances as to future results. The Company expressly disclaims any obligation or undertaking to disseminate any updates or revisions to the information, including any financial data or any forward-looking statements, contained in this document, and will not publicly release any revisions it may take to this document that may result from events or circumstances arising after the date of this document. • Certain financial and statistical information in this document may have been subject to rounding off adjustments. Accordingly, the sum of certain data may not conform to the expressed total.

This document is strictly confidential and must not be disclosed or distributed to third parties. By accepting this document you agree to be bound by the foregoing limitations. Thank you for your attention Plural Polymer Technology for targeted long acting drug development :

Interview with Valerie Gordenne and Rudi Meurs Valérie Gordenne Chief Scientific Officer Mithra Rudi Meurs Mithra CDMO site Director Mithra CDMO Phase I + II . Mithra has over 16 years of experience to We offer our partners an integrated R&D support your product development from and manufacturing platform to innovate “proof of concept” to market in long acting drug development . Qualified facilities to meet international industry quality standards

. Pharmaceutical eco-system to cross- fertilize and benefit from Mithra’s assets and capabilities to support your Polymeric forms Sterile Hormonal development and implants injectables Tableting . Optimal intercontinental and intermodal connectivity

. Wide range of technical, regulatory and QC laboratories scientific support for partners looking for a global expertise in the field of pharmaceutical polymer delivery systems R&D platform Overview

. 15,000m² in Liège (Belgium)

. 55,000m² land

. Production unit for sterile injectables, polimeric forms, hormonal tablets

. On-site analytical laboratories & Regulatory support

. Pilot batches, Clinical batches and Commercial batches

. GMP standards compliance (EMA and FDA) 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 Polymer Technology offers a wide range of opportunities in drug delivery development for multiple therapeutic fields

Multiple therapeutic fields and APIs

Extensive Non / Various polymer administration Biodegradable routes technology forms expertise

Flexible durations Strong experience for developing multiple drug/device delivery strategies

Non/biodegradable (co)polymers

PEG PCL PVP Multiple Multiple administration routes EVA PLGA Drug / Device PLA Delivery Strategies PDMS PGA

Broad API’s compatibility

Virology Oncology Sexual CNS Others Polymers help achieve a controlled release of a given drug or/and a targeted delivery and improved drug

Important patient and social benefits . Better compliance, tolerability and safety

Toxicity range . Significant decrease in API use

. Local treatment

Therapeutic range . Quality of life . Improved treatment effectiveness enhances the positive impact on Sub therapeutic range population health . Improved adherence to medication 1: Controlled Active Pharmaceutical Ingredient Release lowers healthcare costs Long acting product – complex therapeutical solution programs

Our expertise / knowledge is based on preliminary successful development programs

. Formulation

. Process

. Clinical development

. Regulatory requirements Long acting product – complex therapeutical solution programs

Diffusion profiles Long acting product – complex therapeutical solution programs

Our expertise / knowledge is based on preliminary successful development programs

. Formulation

. Process

. Clinical development

. Regulatory requirements ZORELINE® MYRING™ Zoreline® :biodegradable SC implant

Zoreline Hybrid analogue of Zoladex®

. Zoreline is a biodegradable subcutaneous implant preloaded in a single use safety syringe for prostate and breast cancer Gosereline acetate and benign gynaecological indications

. Releases 3,6mg or 10,8mg of gosereline acetate per injection for 1 or 3 months

Two different formulations release over

Lactide/glycolide copolymer 1 month 3 months Zoreline® : biodegradable SC implant

3 months controlled release Myring™ : vaginal ring – contraception 21 days delivery

MYRING™ 4 mm Hybrid analogue of NuvaRing® Core Membrane System (120μg ENG – 15µg EE/24h) . MyRing is a combined hormonal contraceptive vaginal ring 54 mm . Releases 120µg of etonogestrel and 15µg of ethinylestradiol per day for a menstrual cycle of 21 days

Ethylene vinyl acetate copolymer

Ethylene vinyl acetate copolymer Ethinylestradiol (EE) 2,7 mg Etonogestrel (ENG) 11,7 mgs Myring™ : vaginal ring – contraception 21 days delivery

21 days ENG / EE controlled release (µg/24h) Complex Therapeutical Solutions programmes . Mithra has over 16 years of experience to We offer our partners an integrated R&D support your product development from and manufacturing platform to innovate “proof of concept” to market in long acting drug development . Qualified facilities to meet international industry quality standards

. Pharmaceutical eco-system to cross- fertilize and benefit from Mithra’s assets and capabilities to support your Polymeric forms Sterile Hormonal development and implants injectables Tableting . Optimal intercontinental and intermodal connectivity

. Wide range of technical, regulatory and QC laboratories scientific support for partners looking for a global expertise in the field of pharmaceutical polymer delivery systems R&D platform Mithra CDMO Phase I + II State of the art R&D and production platform for complex therapeutical entities (NTEs)

Plural Polymer Technology Sterile Injectables Mithra has a strong heritage in Polymer Mithra offers the latest generation, highly Flexible, Multiform Technology for Long Acting Drug Developement Sterile Injectables manufacturing platform to its partners

. Experience with mutilple drug delivery strategies for drug . Nested Technology / device combinations product developements . Flexible aseptic manufacturing process . Broad range of APIs and durations (from 1 month to 5 years release) . Adaptable to multiple pharmaceutical forms and Aps (hormones, non hormones) . Multiple therapeutic fields Vials, Cartridges, Ready-to-use Syringes . Flexible processes of extrusion and co-extrusion

Rings, Intra Uterine Systems, Implants Sterile injectable

Key figures:

. Volume: max. 5 mio units/year

. Production in batch and/or campaign

. Maximum 2 shifts/day

. High speed filling line in Class A under isolator

. Final sterilization (autoclave)

. Cold Storage Plural Polymer Technology

Key figures . Maximum volume of 5 million units /year . Maximum 2 shifts/day . Sampling and weighing grade C classification under isolation and flow booth

. Cold storage Phase II : Hormonal Tableting

Resources & Equipments

. Products . Production at an industrial scale of hormonal and non- hormonal tablets . Highly flexible production line able to produce more than 10 different types of tablets

. Forms . Coated and uncoated tablets

. Processes . Full range of tablets using a wet granulation process in combination with a direct compression process Hormonal Tableting

Key figures . Maximum volumes of 1,5 billion units/year

. Production in batch and/or campaign

. Maximum 3 shifts/day

. Tablet Manufacturing in grade D environment

. Sampling and weighing under isolation and down flow booth in grade D environment

. Secondary packaging in a not classified area

. Multi-products facility design

Master Plan Timing Phase I+II Drug life cycle

. Technology transfer . Long acting . Technology transfer . Process validation /Injectable/ Oral . Process . GMP commercial batches solid qualification/optimization . Long . Formulation . Clinical (GMP) acting/Injectables/Oral . Analytical manufacturing of solid Services formulations . Hormones & . Lab scale process . Clinical trial packaging & development supply

Clinical supply Pharmaceutical Stability Contract manufacturing Packaging development Logistics capabilities studies manufacturing

+ Analytics + Regulatory services Thank you for your attention Programme de la journée

Q&A Q&A