2019-01-04-investor presentation mithra-january€¦ · phase iii (e4 monotherapy) submission h2...

Investor PresentationJanuary 2019

© 2019 | Mithra Investor Presentation | January 2019 2

This presentation contains forward looking statements including, but not limited to, statements concerning the outcome or success of Mithra Pharmaceuticals’ clinical trials; its ability to successfully gain regulatory approvals and commercialize products; its ability to successfully advance its pipeline of product candidates; the rate and degree of market acceptance of its products ; and its ability to develop sales and marketing capabilities. Forward looking statements are subject to a number of risks, uncertainties and assumptions. Moreover, Mithra Pharmaceuticals operates in a very competitive and rapidly changing environment. New risks emerge from time to time. It is not possible for Mithra Pharmaceuticals’ management to predict all risks, nor can Mithra Pharmaceuticals assess the impact of all factors on its business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward looking statements it may make. In light of these risks, uncertainties and assumptions, the forward looking events and circumstances discussed in this presentation may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward looking statements. You should not rely upon forward looking statements as predictions of future events. Although Mithra Pharmaceuticals believes that the expectations reflected in the forward looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward looking statements will be achieved or occur. Moreover, except as required by law, neither Mithra Pharmaceuticals nor any other person assumes responsibility for the accuracy and completeness of the forward looking statements. Forward looking statements in this presentation represent Mithra Pharmaceuticals’ views only as of the date of this presentation. Mithra Pharmaceuticals undertakes no obligation to update or review any forward looking statement, whether as a result of new information, future developments or otherwise, except as required by law. This presentation has been prepared by the management of Mithra Pharmaceuticals. It does not constitute or form part of, and should not be construed as, an offer, solicitation or invitation to subscribe for, underwrite or otherwise acquire, any securities of Mithra Pharmaceuticals or any member of its group nor should it or any part of it form the basis of, or be relied on in connection with, any contract to purchase or subscribe for any securities of Mithra Pharmaceuticals or any member of its group, nor shall it or any part of it form the basis of or be relied on in connection with any contract or commitment whatsoever. The information included in this presentation has been provided to you solely for your information and background and is subject to updating, completion, revision and amendment and such information may change materially. No person is under any obligation to update or keep current the information contained in this presentation and any opinions expressed in relation thereto are subject to change without notice. No representation or warranty, express or implied, is made as to the fairness, accuracy, reasonableness or completeness of the information contained herein. Neither Mithra Pharmaceuticals nor any other person accepts any liability for any loss howsoever arising, directly or indirectly, from this presentation or its contents.

Disclaimer

We help transform women’s health by offering new choices through innovation

with a particular focus on fertility, contraception and menopause

Management team– Co-founders

4

François FornieriChief Executive Officer Co-founder• Over 30 years in the Pharma industry• Founder & CEO of Uteron Pharma

(sold to Watson/Actavis)• Master in Chemical Engineering

Jean-Michel FoidartScientific Committee & Board memberCo-Founder• Former CSO of Uteron Pharma & Actavis Belgium• Former Head of the Gynecology and Obstetrics

Department of the University of Liège• MD & PhD in Cell Biology & Biochemistry

© 2019 | Mithra Investor Presentation | January 2019

5

Transforming Women’s Health through innovation

Clear growth strategy

• Multiple mid- to near-term catalysts

• Several revenue-generating partnerships in place

5Mithra CDMO

• Develop products from POC to market,

• For own product portfolio and partners

Leveraging know-how in Complex

Therapeutics

• Pipeline of complex, polymer-based generics

• International launches of Tibelia® (2017) and MyringTM

(2019)

E4: two potential blockbusters in late-stage development

• Estelle® - 5th generation oral contraceptive in Phase III

• Donesta ® - next-generation HT Phase III ready

Expert in Women’s Health

• Markets characterized by a lack of innovation, with recent return of interest from Big Pharma

• Unique portfolio based around (1) E4 natural estrogen with improved benefit / risk profile and (2) Complex Therapeutics

1 2 3 4


6





5Mithra CDMO




Therapeutics


• International launches of Tibelia® (2017) and MyringTM (2019)







1 2 3 4


*Based on Datamonitor 2014; Transparency Market Research 2017. / Menopause market expected to reach > 16bn by 2025

Expert in Women’s Healthre-energizing the $22bn Contraceptive and $8.6bn Menopause market*


• Women’s Health Market characterized by lack of innovation; recent return of interest from Big Pharma

• Unique Women’s Health portfolio of E4-based pipeline and Complex Therapeutics

• Highly innovative new approaches based on E4, a native estrogen with improved benefit/risk profile

• Complex Therapeutics: leveraging polymer science & formulation expertise to develop complex generics

• Powered by Mithra CDMO (Contract Development & Manufacturing Organization)

Complex TherapeuticsEstetrol (E4)

Advanced pipeline offering multiple near- to mid-term catalysts


Product

Product Phase 1 Phase 2 Phase 3 Market Appr. Key milestonesIndication

Contraception

Menopause

2018: Positive Phase III results in EuropeCompletion of Estelle Phase III US/Canada study programme, CSR top line results expected Q1 2019

2018: positive Phase IIb resultsPhase III (E4 monotherapy) submission H2 2019

Formulation Clinical/BioEq Filing Market Appr. Key milestonesIndication

Contraception

Menopause

MA EU Q3 2018

2019 / 20 clinical trials for one and three-month injectable formulationZoreline® Oncology

Additional launches

PeriNesta1

E4Perimenopause

Estelle®

Donesta®

Under development

CNS, dermatology,oncology, etc.

Various stages of development of future E4-based pipeline

Development of perimenopause E4 product, leveraging on Estelle & Donesta studiesPhase III scientific advice submission: Q1 2019

MyringTM

Tibelia®

(Pre-) Clinical Development: Neuroprotection (ODD in encephalopathy), wound healing and hormone therapy in breast and prostate cancer

Complex Therapeutics

EU / RoW

US MA US 2020

1 : See Press Release of 7/01/19 : New potential E4 blockbuster indication development in

perimenopause, Acceleration of Donesta Phase III program

https://investors.mithra.com/en/press-releases/

9





5Mithra CDMO




Therapeutics









1 2 3 4


E4 (Estetrol)

E4: native estrogen produced by human fetus around week 9

Fetal plasma levels 12x higher than those of mother

E4’s broad potential for use in Women’s Health validated in multiple peer-reviewed academic journals1-8

E4-based programs protected by 30 patent families, including synthesis pathway until 2032

E4 (Estetrol) Answer from Nature with Unique Potential

11

1 Kluft C et al., Contraception 2016.; 2 Gerard C et al., Oncotarget 2015;6(19):17621-36.; 3 Visser M et al., Horm Mol Biol Clin Invest. 2012;9:95-103.; 4 Visser M et al., Climacteric 2008; 11 Suppl 1:64-8.; 5 Mawet M et al., Eur. J. Contracept. Reprod. Healthcare 2015:1-13.; 6 Apter D. et al., Contraception 2016;94(4):366-73; 7 Abot et al., EMBO 2014: 6 (10); 8 Apter et al., Eur. J. Contracept. Reprod. Healthcare 2017:22(4) © 2019 | Mithra Investor Presentation | January 2019

E4 (Estetrol) Unique Agonist-Antagonist Mode of Action

12© 2019 | Mithra Investor Presentation | January 2019

Cells exhibit 2 types of estrogen receptors (ERα): membrane and nuclear receptors

Depending on the tissue either the membrane or the nuclear receptor is predominantly active

E4 acts differently compared to other estrogens depending on the tissue:

• E4 activates the nuclear Estrogen receptor in bone, vagina, endometrium stability & heart to providebeneficial effects (as other estrogens)

• Antagonist on the membrane receptor: E4 blocks the estrogen receptor in breast and has a neutral effecton the liver (unlike other estrogens)

Safety concerns of estrogens: an unmet clinical need potentially addressed by E4

13

• 1 Kluft C et al., Contraception 2016.; 2 Gerard C et al., Oncotarget 2015;6(19):17621-36.; 3 Visser M et al., Horm Mol Biol Clin Invest. 2012;9:95-103.; 4 Visser M et al., Climacteric 2008; 11 Suppl 1:64-8.; 5 Mawet M et al., Eur. J. Contracept. Reprod. Healthcare 2015:1-13.; 6 Apter D. et al., Contraception 2016;94(4):366-73; 7 Abot et al., EMBO 2014: 6 (10); 8 Apter et al., Eur. J. Contracept. Reprod. Healthcare 2017:22(4)

E4 has the potential to address most of these concerns:

+ Favorable VTE risk profile¹,#

+ Favorable drug-drug interaction profile⁴+ Minimal increase of triglycerides5, ‡

+ Lower breast pain6 and lower carcinogenicpotential in the presence of E2*,2,3,7

+ Good user acceptability, body weight control, excellent cycle control, improved spotting and general well-being6,8

Estrogen’ssystemic effects:

- Heart and liver: increased risk of Myocardial infarction, Thromboembolism

- Brain: increased risk of Stroke- Uterus: increased risk of Endometrial

cancer- Breast: increased risk of Breast cancer- Quality of life: bleeding, cycle control

*E2: Estradiol# https://investors.mithra.com/wp-content/uploads/2018/03/2018-03-08-Hemostasis-ISGE-en-final.pdf‡ https://investors.mithra.com/wp-content/uploads/2018/06/e-Poster-Mithra-IMS-2018.pdf


https://investors.mithra.com/wp-content/uploads/2018/03/2018-03-08-Hemostasis-ISGE-en-final.pdf

https://investors.mithra.com/wp-content/uploads/2018/06/e-Poster-Mithra-IMS-2018.pdf

Estelle®

Promising clinical study results in over 4,400 women

Estelle® for Contraceptiona $22bn blockbuster market1

15

• 1 Transparency market research 2017. $22bn is total hormonal contraceptive market. The oral contraceptive market stands at $9.6bn. • 2 IMS Health Data • 3 In the 8 biggest markets: US, France, Germany, UK, Spain, Italy, Belgium & Netherlands. United Nations, Department of Economic and Social Affairs, World Bank• 4 K. Daniels et al., National Health Statistics report n° 62, 2013

Regulators are encouraging new approaches throughnon-reimbursement, market withdrawal and warnings for existing products

Generation pillBetter user

acceptabilityImproved

safety profile

1st & 2nd generation

3rd & 4th generation

(e.g. Yaz family: peak sales €1.2bn; EE +

DRSP)1

Potential 5th generation

(E4 + DRSP)

24%use alternative

methods1

27%use no

contraceptive at all2

30%of US women not

taking pill mainly due to safety or

convenience4


Estelle® Phase IIa: no ovulation

16

• Note: Hoogland score is a validated tool to assess ovarian function and evaluate ovulation inhibition, which is assessed by transvaginal ultrasounds (TVUS) monitoring of follicle size and analysis of serum E2 and progesterone levels, and consequently classified according to a 6-point scoring (1 = no ovarian activity; 2 = potential activity; 3 = non-active follicle-like structure (FLS); 4 = active FLS; 5 = luteinised unruptured follicle (LUF); 6 = ovulation).

• 1 Duijkers et al. 2015, Eur.J. Contracept. Reprod. Healthcare

Evaluation of ovulation inhibition: % of patients scored according to Hoogland score (treatment cycle 3; n= 109 healthy premenopausal women of child bearing age)1

0

20

40

60

80

100

5 mg E4/DRSP(n=17)

10 mgE4/DRSP

(n=19)

20 µg EE/3 mgDRSP (Yaz)

(n=20)

5 mg E4/LNG(n=18)

10 mg E4/LNG(n=17)

20 mg E4/LNG(n=18)

No activity Potential activity Non-active FLS Active FLS LUF Ovulation

E4 inhibits ovulation in association with a progestin and allows rapid & complete return to fertility


0

10

20

30

40

50

60

70

80

90

100

E2V/DNG(n=78)

15 mgE4/DRSP

(n=79)

20 mgE4/DRSP

(n=79)

15 mgE4/LNG(n=80)

20 mgE4/LNG(n=77)

Higher rates of withdrawal bleeding

0

10

20

30

40

50

60

70

80

90

100

E2V/DNG(n=78)

15 mgE4/DRSP

(n=79)

20 mgE4/DRSP

(n=79)

15 mgE4/LNG(n=80)

20 mgE4/LNG(n=77)

% o

f subje

cts

Unscheduled bleeding / spotting after6 treatment cycles

Estelle® Phase IIb: Dose-finding study shows well-controlled bleeding pattern1

171 Apter D. et al., Contraception. 2016;94(4):366-73

75)

% o

f subje

cts

75)

QIairaTM

Natazia®Estelle® Estelle®


QIairaTM

Natazia®

Estelle® Phase II substudy: Reduced VTE* risk profile

18

Effect of COCs on VTE Risk FactorsCycle 6 – Baseline (Mean % change)

• Limited hemostatic impact for Estelle® (E4/DRSP)

• Comparable to EE/LNG (Melleva®), the ‘safest’ 2nd generation pill

• Much lower than 4th generation benchmark EE/DRSP (Yaz®)

Yaz®Estelle®© 2019 | Mithra Investor Presentation | January 2019

*Venous Thromboembolism

Pro-coagulant Anticoagulant

Nordette® /

Microgynon 30®

Estelle® Phase II substudy: Reduced VTE risk profile

19

Change of SHBG (Sex-hormone binding globulin) plasma levels as marker of VTE risk1

Cycle 6 – Baseline (Mean change)

1Change of APC resistance (Thrombin generation).

• Limited impact on SHBG levels for Estelle® (E4/DRSP)

• In line with EE/LNG (Microgynon -30®), the ‘safest’ 2nd generation pill

• Much lower than 4th generation benchmark EE/DRSP (Yaz®)

Yaz®Nordette®

Microgynon 30®

Estelle®


EU / Russia : June 2016 (Results obtained: Q3 2018)

Contraceptive Efficacy Study

1,577 subjects, 18-50 years


Endometrial Safety Substudy 175 subjects, 18-50 years

20

Estelle® - Phase III program

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

US / Canada : Sept 2016 (Completed - Results expected: Q1 2019)

Contraceptive Efficacy Study



PK Substudy(body weight, race, smoking) 500 subjects, 16-50 years

Study objectives

Primary objective:

Contraceptive efficacy based on the Pearl Index (PI)

Secondary Endpoints: Cycle control – bleeding pattern; Safety – S(AE) reporting; Subject’s well being; Population PK substudy (US/CA); Endometrial safety (EU)


Estelle Phase III Europe/Russia : Positive Top-line results1

• Primary efficacy endpoint indicates excellent contraceptive efficacy, with a Pearl Index (PI) of 0.47 per 100 women, exceeding efficacy goals

• Efficacy rate > 99,5 %

• Key secondary endpoints achieved:• Outstanding cycle control with an excellent regular bleeding pattern

• Quality of life maintained

• Well tolerated with no unexpected safety events

• Estelle® Phase III study in US/Canada completed2 and on track to report top-line results in Q1 2019


Ref: 1) Press Release, 8/08/18 : Mithra Announces Positive Top-Line Results of Estelle® Phase III Oral Contraceptive Study in EU/Russia

2) Press Release, 14/11/18 :Mithra Announces the Completion of its Lead Clinical Phase III Programme for Estelle®

https://investors.mithra.com/wp-content/uploads/2018/08/2018-08-08-Estelle-Phase-III-EU-RU-en.pdf

https://investors.mithra.com/wp-content/uploads/2018/11/2018-11-14-Completion-estelle-study-en.pdf

Program Trial Subjects Characteristics Objectives Results

Estelle® Phase III

European / Russia study

1,577 • Healthy premenopausal women of childbearingpotential

• 18-50 years

• Contraceptive efficacy -Pearl Index (PI)

• Cycle control, general safety and acceptability

• Endometrial safety (EU)

• Excellent efficacy pearl index of 0.47 (0.15-1.11)

• Efficacy rate > 99,5 %

• Excellent regular bleeding pattern

• Well tolerated - Safety profile: no unexpected events

• QoL maintained

Estelle® Phase II

Hemostasisstudy

98 • Healthy premenopausal women of childbearing potential

• 3 treatment groups:

15 mg E4/3 mg DRSP

30 µg EE/150 µg LNG

20 µg EE/3 mg DRSP

• Analyze impact on coagulation (blood clotting) and fibrinolysis (breakdown of clots) of Estelle®,

• Determine the risk profile of a novel COC for deep venous thrombosis (DVT) and pulmonary embolism.

• Less pronounced effects of E4/DRSP and EE/LNG on hemostasis parameters than those of EE/DRSP.

• Comparable effects of E4/DRSP to EE/LNG (second generation COC).

• Lower impact of E4/DRSP vs EE/DRSP on a number of hemostatic parameters confirms the importance of the estrogen selected for COC use

Estelle® Phase IIb 389 • Healthy premenopausalwomen of childbearing potential

• Vaginal bleeding profile

• Cycle control

• Well controlled bleeding pattern

• Indications of reduced VTE risks

Estelle® Phase IIa 109 • Healthy premenopausalwomen of childbearing potential

• Ovulation inhibition

• Effect on liver function (surrogate markers of VTE)

• No ovulation

• Only slight increase vs EE of SHBG* plasmatic concentration (surrogate marker of VTE risk)

E4 – Promising clinical study results in over 2,400 womenand up to 12 months for subjects in Phase III for Estelle®

22© 2019 | Mithra Investor Presentation | January 2019* Sex Binding Hormone Globulin

Donesta®

Promising clinical study results inover 300 postmenopausal women with E4 only

6.3

4.1

2002 2005 2016 2025

Menopause market (in $bn)³,⁴

16

Donesta® for Menopause and HT a $8.6bn blockbuster market1

• 78%¹ of menopausal women suffer VMS (hot flushes) - only 7.8% receive HT²

• Increased safety issues: VTE, stroke, breast cancer risks

• No new estrogen-based products for more than 10 years, but renewed interest & developments (hormonal & non-hormonal)

• $16bn billion potential HT Market in 2025 –VMS potential with safer alternative

24Sources: (1) Transparency Market Research 2017; (2) KBC company report Aug 2015; (3) IMS link Q2 2016; (4) Datamonitor 2014

8.6

potential valueachieved value


Donesta® Phase IIb: Positive Topline Results (Q2 2018)

25

Study Design:> Apprx. 260 subjects> Non-hysterectomized and hysterectomized

women> Aged 40 to 65 years> Presenting at least 7 moderate to severe hot

flushes / day or at least 50 moderate to severe hot flushes / week

> 4 dose levels of E4 or Placebo up to 13 weeks (2.5 – 5 – 10 – 15 mg)

> In non-hysterectomized women, E4 therapy is followed by a Progestin therapy (Dydrogesterone 10 mg) for 2 weeks

Secondary Endpoints:

> Genitourinary syndrome of menopause (GSM) or vulvovaginal atrophy (VVA)

> Vaginal maturation index (MI)> Vaginal pH> Change in the Menopause Rating Scale

(MRS)> Lipid and glucose metabolism> Hemostatic and bone laboratory

variables> E4 concentrations at baseline and steady

state

Key safety objectives:

> Transvaginal ultrasonography (TVUS) change of endometrial thickness at each study visit during the E4/placebo treatment period

> Serious adverse event (SAE) monitoring> Electrocardiogram (ECG)> Bleeding control

Primary objective:

Minimum effective dose of E4 for vasomotor symptoms (VMS) or hot flushes

A Multicenter Dose-Finding, Randomized, Double-Blind, Placebo-Controlled Study to Select the Daily Oral Dose of E4 for the Treatment of Vasomotor Symptoms (VMS) in Postmenopausal Women


Donesta® Phase IIb: Positive Results Optimal minimal dose & significant effect on VMS


• Primary study objective reached: optimal minimal effective dose defined at 15 mg

• Frequency and severity endpoints met, despite not being powered for statistical significance:

o Significant % of reduction of VMS frequency at Week 4 & Week 12 (p < 0.05)

˗ Reduction of over 80% vs baseline, vs. 65% for placebo at week 12*

o Significant reduction of severity of VMS at Week 4 and Week 12 (p < 0.05)

˗ Reduction of over 40% vs baseline for moderate to severe VMS, vs. approx. 25% for placebo at week 12 *

* Note: High placebo effect well-documented in VMS studies (see e.g. Maclennan et al. 2009)

26

Donesta® Phase IIb: Positive Top-line Results: Significant effect on frequency of hot flushes


-90%-80%-70%-60%-50%-40%-30%-20%-10%

0%

0 2 4 6 8 10 12

MEA

N%

OF

CHAN

GE

FRO

MBA

SELI

NE

WEEKS

E4 2,5 mg E4 5 mg E4 10 mg E4 15 mg Placebo

P < 0.05 P < 0.05

MEAN % OF CHANGE IN WEEKLY FREQUENCY OF MODERATE-TO-SEVERE VMS

-65%

-84%

Donesta® Phase IIb: Positive Top-line Results: Significant effect on severity of hot flushes


-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

MEA

N C

HAN

GE

FRO

M B

ASEL

INE

WEEKS

E4 2,5mg E4 5mg E4 10mg E4 15mg Placebo

MEAN CHANGE IN VMS SEVERITY ( ITT POPULATION: MODERATE VS SEVERE)

P < 0.05

P < 0.05

Donesta® Phase IIb: Positive Results Efficacy on Secondary endpoints & promising safety profile (1/2)

• Highlights secondary efficacy endpoints:o Statistically significant result for vaginal maturation index (VVA/vulvo-vaginal atrophy; p < 0.001)

o Strong improvement in Menopause Rating Scale (Quality of life)

o 15 mg dose shows lower bone turnover vs placebo at Week 12

Near-significant decrease for CTX-1 & significant decrease for osteocalcin marker (p < 0.05) vs placebo

• At 15 mg, need to add progestin for non-hysterectomized women to curb endometrial proliferation

• However, no endometrial hyperplasia detected in any of the study subjects



• Safety parameters confirming published results on hemostatic profile of E4:• Limited impact on pro- and anti-coagulant factors• Encouraging limited increase in SHBG levels (Sex-hormone binding globulin), as marker of hepatic

estrogenicity

• Significant improvement in metabolic factors, especially for 15 mg dose, pointing to promising cardiovascular safety profile:• Glucose levels significantly improve, as measured by hemoglobin A1C (p < 0.001 vs placebo)• Metabolism of lipids also significantly improved (p < 0.05 for increase in cholesterol-HDL levels vs

placebo for 10 & 15 mg)• Only very slight increase in triglyceride levels

Donesta® Phase IIb: Positive Results Efficacy on Secondary endpoints & promising safety profile (2/2)

30

Donesta® Phase IIb: Summary and Next steps


• 15mg E4 efficacious for relieving most bothersome symptoms of menopause; with promising safety profile

• European and American KOL Boards very supportive to progress Donesta; • Phase III development plan:

o Launch of both an E4 alone and a combination trial (E4 + progestin) in order to maximize market potential of Donesta

o Preparatory/bridging studies to commence as early as Q4 2018 (e.g. food effect study), followed by initiation of recruitment for Phase III trials

o Detailed Phase III design is being discussed with KOLs and agencies

> Positive top line Phase IIb data strongly support further Donesta® development, as a unique next-generation hormone therapy

Program Trial # Subjects Characteristics Objectives Results

Donesta® Phase IIb 260 Healthy postmenopausal women E4 Dose-finding study placebo/2.5 /5/10/15 mg

Frequency & severity of hot flushes

15 mg minimally effective doseSignificant reduction in VMS & VVA

Donesta® Phase Ib 49 Healthy postmenopausal women Safety and tolerability

Number of hot flushes & sweating

Decrease in number of hot flushes

Effective reduction of hot flushes with E4 – first efficacy evidence

Donesta® Phase Ia 32 Healthy postmenopausal women Safety and tolerability Fast oral absorption

Half life +/- 28 hours

E4 – Promising clinical study results in over 300 postmenopausal women with E4 only

• 1Sex hormone-binding globulin


Excellent safety and efficacy results for Estelle® (15 mg E4/3mg DRSP) & Donesta® (E4 alone)

33





5Mithra CDMO




Therapeutics


• International launches of Tibelia®

(2017) and MyringTM

(2019)







1 2 3 4


Leveraging know-how of Complex Therapeutics

• Expertise in developing complex and innovative polymer products • Targeting safer, long-lasting delivery and controlled release of trusted,

established approaches to contraception, menopause and hormone-dependent cancers

• Duration ranging from 1 month to 5 years• One of handful of companies that can deliver multiple drug delivery

strategies including vaginal rings, implants and intra-uterine systems (IUS)• To be developed and manufactured in-house at Mithra‘s dedicated

CDMO research, development and specialist manufacturing center


35

Targeted market Development path

Product description Opportunity 2015 2016 2017 2018 2019

MyringTM

ContraceptionNon-biodegradable,

flexible, transparent,

combination contraceptive

vaginal ring

Made of ethylene vinyl-

acetate copolymers

Circa $960m1

Original product:

NuvaRing® from

Merck (patent

expiry: April 2018)

Zoreline®

Prostate & breast cancer and benign women’sconditions

Biodegradable

subcutaneous implant

For prostate & breast

cancer and benign

gynecological indications

(endometriosis, uterine

fibroids)

Circa $816m2

Original product:

Zoladex® from

AstraZeneca

Tibelia®

HT and Osteoporosis24 months stability

Synthetic steroid (tibolone)

intended to be used for HT

Used especially for the

relief of symptoms

occurring after

menopause

Circa $127m1

Original product:

Livial® from

Merck

Bioequivalence study

3 month formulation upgrade

EU MA submissionMyringTM first launches

36 month shelf life evaluation results

PK 1 & 3 month formulation

Q1 2016: Product launched in Europe Additional MAs &

product launches

Q2: GMP Approval

International launches of Tibelia® as of 2017 and MyringTM potentially as of 2018

1 IMS Health 2016; 2Astrazeneca Annual Report 2016

US MA submission

MyringTM EU MA

© 2019 | Mithra Investor Presentation | January 2019Achieved Expected

Pivotal clinical trials

Additional MAs & product launches

expected

36





5Mithra CDMO




Therapeutics









1 2 3 4


Mithra CDMO: Fully Integrated R&D & manufacturing platform

Specialized pharmaceutical ecosystem, to take products from POC to market

37

Rationale for CDMO:> Keep quality control, IP & expertise in-house> Operate independently from 3rd parties using its own proprietary production

technology> Additional source of revenue via production of (partnered) programs> Leverage development expertise through 3rd party production contracts

2-Phase construction process:> H2 2016: R&D facility and polymeric forms, implants and sterile

injectables production line facilities> Received European GMP approval for MyringTM (May 2017)> H1 2019: Production line for tablets to be completed


38





5Mithra CDMO




Therapeutics









1 2 3 4


Partnering with leaders in Women’s Healthat key value inflection points

Accelerating business development while strengthening in-house expertise


Develop concepts internally until market commercialization

Selecting specialist, regional partners e.g. Myring™: Mayne Pharma in the US (2017);Gynial in Austria (2017); Adamed in Czech Republic (2017); Alvogen in Russia (2018); Orifarm in Denmark (2018); Neo Health in Australia & New Zealand (2018), GSP (2017) and Midas Pharma (2018) or injectables

E4 Partnering Strategy*

Estelle® intended partnering after Phase IIIPartnering for world-wide commercialization

Donesta® intended co-development for Phase III

Gedeon-Richter: partnering agreements for Estelle® (2018) Fuji Pharma: partnering agreements for Estelle® (2016) and Donesta® (2017) in Japan & ASEAN; Libbs for Estelle® in Brazil (2017); Searchlight for Estelle® in Canada (2018), Hyundai Pharm for South-Korea (2018), Ceres** for BeLux(2018), Adcock Ingram for Southern Africa (2018)

39

* Preclinical research in neuroprotection (ODD received for neonatal encephalopathy in Q2 2017): Partnering intended for clinical development** Ceres has a non-exclusive license for Estelle® in BeLux

Mithra CDMO


EU US RoW

Estelle®Partnering ongoing

Donesta® Partnering intended for co-development Phase IIIPartnering ongoing

Japan & ASEAN

Myring™Partnering discussions ongoing

Austria Czech Republic Russia Denmark

Partnering discussions ongoing

Other products(incl. Zoreline®; Tibelia®)

Partnering discussions ongoing** Partnering discussions

ongoing

Partnering discussions ongoing

Partnering with leaders in Women’s Health at key value inflection points

40

*Non-exclusive license; **Tibelia® distribution partners include Gedeon, Mercury, Procare, Campus


Partnering intended for commercialization

Chile

(Brazil)

(Japan & ASEAN) (Canada)

(BeLux*)

(South Korea) (South Africa)

Australia & NZ

Estelle: Results hemostasis study Ѵ

Estelle: Results PK ethnobridging study (Fuji) Ѵ

Donesta: Ph IIb topline results Ѵ

Estelle: Start DDI PK study Ѵ

Estelle: Topline results Ph III EU/Russia Ѵ

Estelle: Ovarian function inhibition Ѵ

Estelle: Topline results Ph III US/CanadaEstelle: Results DDI PK study

2018 2019

Zoreline 1 month: PK results Ѵ

Myring: FDA Submission (Mayne Pharma) Ѵ

Tibelia®: Launch Sweden Ѵ

Zoreline 3 month: PK results Ѵ

Myring: MA Europe Ѵ

2018 2019

H1 H2 H1

News Flow – Key inflection points in 2018/19

CDMO: Phase IIZoreline: Start clinical trialsMyring: Launch EU

41© 2019 | Mithra Investor Presentation | January 2019Ѵ achieved

HY 2017 HY 2018

Revenues 12.7 12.6

R&D Expenses (25.5) (19.4)

G&A (5.2) (4.5)

Selling expenses (2.4) (2.4)

REBITDA (23.2) (11.5)

* Shareholdership in accordance with transparency declarations received by the company and notified managers’ transactions. Market Cap: €1.1bn as of June 2018 (Euronext: MITRA)** CEO (François Fornieri) holds warrants for 1,023,000 additional shares of Mithra

28.18%CEO**

16.48%Alychlo / Mylecke

33.73% Free Float

4.10% Scorpiaux/Versluys BVBA

3.14% OGESIPInvest SA

14.37%Meusinvest

Share capital as of June 2018* IFRS P&L and cash balance (in m€, FY as of 06/30/2018)**

42

Revenues stable : Decreased Benelux sales

compensated by

Increased Licensing revenues

Libbs - Estelle

Costs controlled; lower R&D Expenses because end of clinical studies Phase III for Estelle

Cash: EUR 77.5m private placement in May 2018

Summary Financial Information

Dec 2017 June 2018

Cash & Equivalents 36.2 85.8


Building a transformative Women’s Health company

• Multiple prospective near- and mid-term milestones and launches to drive long-term growth

• Estelle® and Donesta® – late-stage potential blockbusters built on unique E4 platform

• Acceleration of business development including partnerships for E4-based programs

• Industry partner with specialist research, development and manufacturing capabilities

• Diversified model spreads risk and maximizes product opportunities through collaborations

2017


2018 -2020

Estelle®


> 2020


Estelle®

Donesta®

Additional indications(e.g. neuroprotection)


Contact Us

Mithra

MITRA (Euronext)Rue Saint-Georges 5/7

4000, LiègeBelgium

Website: investors.mithra.com

François Fornieri, CEO

Jean-Manuel Fontaine, PRO

+32 4 349 28 [email protected]

https://investors.mithra.com/en/

mailto:[email protected]

Thank youinvestors.mithra.com

https://investors.mithra.com/en/

Appendices


Estelle® Phase IIa: Reduced VTE risk profile


Low increase in SHBG demonstrating significantly reduced VTE risk as compared to Yaz®1

• 1 Kluft C et al., Contraception. 2016

0

50

100

150

200

250

300

350

400

450

Day 3 Day 3 Day 24 Day 3 Day 24 Follow-up

Change of sex hormone-binding globulin (SHBG)plasma levels, as marker of VTE risk

20µg EE/DRSP (Yaz)(n=20)

5mg E4/3 mg DRSP(n=17)

10mg E4/3 mg DRSP(n=19)

Compound CYP 1A2 CYP 2C9 CYP 2C19 CYP 2D6 CYP 3A4

EE <10 <10 82 <10 45

E2 19 <10 63 <10 <10

E4 <10 <10 <10 <10 <10

% inhibition of cytochrome P450 enzymes

• 1 Visser M et al., Horm Mol Biol Clin Invest. 2012;9:95-103

Pre-clinical results: Lower risk of drug-drug interaction

Minimal interference with liver cells and drug degradation processNo unwanted inhibition of cytochrome P450, major family of drug degradation enzyme1


49

Donesta® Phase Ib: Minimal increase of triglycerides,a key marker for coronary heart disease

Elevated triglyceride levels are associated with coronary heart disease

Different dose levels of E4 show minimal impact on triglyceride levels1


1 C o e l i n g h B e n n i n k e t , a l . M e n o p a u s e . 2 0 1 7 .

Donesta® Phase Ib: Dose-dependent effect on number of hot flushes

50

Consistent decrease in the mean number ofhot flushes was observed in all dose groups(49 subjects with 35+ hot flushes per week atscreening)

0

2

4

6

8

10

12

14

2mg E2V 2 mg E4 10 mg E4Me

an

nu

mb

er

of h

ot flush

es p

er

da

y (

ran

ge

)

Screening Day 14 Day 28 Day 56 (follow up)

11.5

(5-18)

8

(4-16)6.8

(2-14)

1.8

(0-5)

9

(6-16)

5

(2-8)

5.6

(5-6)

1.8

(0-6)

1.8

(0-6)

8.4

(2-14)6.5

(1-17)5

(0-15)


51

• 1 Yagi E et al., Carcinogenesis. 2001;22(9):1505-10.• 2 Gerard C et al., Oncotarget. 2015;6(19):17621-36.;• 3 Visser M et al., Horm Mol Biol Clin Invest. 2012;9:95-103.11 Suppl 1:64-8.

E4: Low carcinogenic potential (preclinical)

Lower carcinogenic potential¹

No stimulation of normal or malignant breast cell growth at therapeutic dosesAnti-estrogenic effects in the presence of E2²,³

•

In the laboratory, E4 was shown to protect against breast cancer

development and to decrease size of already existing tumors

Female rats exposed to DMBA for 8 weeks and

receiving E4 in parallel


52

1990-2001: HT widely use for menopause symptoms and

prevention

2003-2006: Impact of HERS & WHI => No HT

2006: Low dose HT reintroducedfor symptomatic women

2007-2016: Multiples safety/efficacy studies

(DOPS, KEEPS, ELITE, EPAT, COMPREHEND,

REGISTRY, FINNISH Study,Cochrane...)

=> HT safe for healthy, recentlypostmenopausal women

2016: Pharma Industry reinvests in menopause

Bazedoxifene/Estrogen conjugate (e.g. Pfizer)

Estradiol/Progesterone (e.g. TherapeuticsMD)

NK3R antagonists for the 5% women in whom Estrogen are contraindicated (e.g. Ogeda)

Hormone Replacement Therapy: Back to the Future

DonestaTM (E4)


Advisory boards and clinical collaborations1

• EU and US-based advisory boards of key opinion leaders for both Donesta® and Estelle®

• Endorsement of the major potential of E4, providing strategic guidance on clinical programs• Clinical collaborations with world renowned leaders in women’s health

• 1Non-exhaustive list


http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjkzbWqxfbSAhUHXhQKHXSJCZQQjRwIBw&url=http://www.facmed.ulg.ac.be/cms/c_252991/fr/organisation-de-la-faculte&psig=AFQjCNFHVWPVxo5qWTbex3CUAtW-fkx3zA&ust=1490699179614381

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjkzbWqxfbSAhUHXhQKHXSJCZQQjRwIBw&url=http://www.facmed.ulg.ac.be/cms/c_252991/fr/organisation-de-la-faculte&psig=AFQjCNFHVWPVxo5qWTbex3CUAtW-fkx3zA&ust=1490699179614381

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiL2NDAxfbSAhXJ6RQKHU41Bq4QjRwIBw&url=http://www.family-hope.be/fr/centers/bruxelles-brussel-chu-saint-pierre-fr/&psig=AFQjCNHElFPfRPN_UbcaFNv2KVNSHcUapQ&ust=1490699207465965

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiL2NDAxfbSAhXJ6RQKHU41Bq4QjRwIBw&url=http://www.family-hope.be/fr/centers/bruxelles-brussel-chu-saint-pierre-fr/&psig=AFQjCNHElFPfRPN_UbcaFNv2KVNSHcUapQ&ust=1490699207465965

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0ahUKEwj2_-D6xfbSAhXGwxQKHdLzBPgQjRwIBw&url=http://www.thalea-pcp.eu/northern-ostrobothnia-hospital-district&psig=AFQjCNHwxb1iLNm7MCgmlafUcn9X1g3ilQ&ust=1490699337265421

http://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0ahUKEwj2_-D6xfbSAhXGwxQKHdLzBPgQjRwIBw&url=http://www.thalea-pcp.eu/northern-ostrobothnia-hospital-district&psig=AFQjCNHwxb1iLNm7MCgmlafUcn9X1g3ilQ&ust=1490699337265421

https://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwi1vKXQx_bSAhWEshQKHWcZCucQjRwIBw&url=https://www.pinterest.com/pin/268456827762070791/&psig=AFQjCNHbnmhUabFwycb8I4iyusYECBBZ2A&ust=1490699792359587

https://www.google.be/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwi1vKXQx_bSAhWEshQKHWcZCucQjRwIBw&url=https://www.pinterest.com/pin/268456827762070791/&psig=AFQjCNHbnmhUabFwycb8I4iyusYECBBZ2A&ust=1490699792359587

2019-01-04-investor presentation mithra-january€¦ · phase iii (e4 monotherapy) submission h2...

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