KOL DAY PRESENTATION June 27 th , 2017 FOCUS ON QUANTUM GENOMICS - - PowerPoint PPT Presentation

KOL DAY PRESENTATION

June 27th, 2017

FOCUS ON QUANTUM GENOMICS

www.quantum-genomics.com

This presentation and the information contained herein does not constitute or form part of, and should not be construed as, an

• ffer or invitation to sell or subscribe for, or a solicitation of any offer or invitation to acquire, dispose of or subscribe for, securities
• f Quantum Genomics S.A. (the « Company») in any country where such offer, invitation or subscription would be prohibited by
• law. The publication of this presentation in certain countries may violate applicable regulations.

The new securities referred to herin have not been, and will not be, registered under the United States Securities Act of 1933, as amended (the « Securities Act ») or any securities laws of any state within the US and may not be offered or sold, directly or indirectly, in or into the US, except pursuant to an available exemption from, or a transaction not subject to, the registration requirements of the Securities Act and in compliance with any applicable state securities laws of the US. Any offering of the Shares to be made in the US will be made only to a limited number of persons who: (i) are reasonably believed to be qualified institutional buyers (as defined in Rule 144A under the Securities Act) and/or institutional accredited investors (as defined in Regulation D under the Securities Act), and (ii) have executed and returned an investor issuance agreement, in designated form, to the Company. With respect to the member states of the European Economic Area which have implemeted the Directive 2003/71/EC of the European Parliament and the Council of November 4, 2003, as amended in particular by Directive 2010/73/EC of the European Parliament and of the Council of November 24, 2010 (the «Prospectus Directive»), no action has been undertaken or will be undertaken to make an offer to the public of the securities referred to herin requiring a publication of a prospectus in any relevant member state. As a result, the securities may not and will not be offered in any relevant member state, or under any

• ther circumstances which do not require the publication by the Company of a prospectus pursuant to Article 3 of the

Prospectus Directive and/or to applicable regulations of that relevant member state. In accordance with Article 211-3 of the General Regulation of the Autorité des marchés financiers, no prospectus has been prepared nor will be disclosed by the Company or filed with the Autorité des marchés financiers in relation to the issuance of the new securities referred to herein. This presentation contains certain forward-looking statements. No guarantee can be given as to any of the events anticipated by the forward looking statements, which are subject to inherent risks, including those described the Prospectus registered with the Autorité des marchés financiers under number 15-036 on January 26, 2015, and the rapport financier semestriel disclosed by the Company on October 13, 2016, changes in economic conditions, the financial markets or the markets in which the Company operates.

Disclaimer

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11:00 – 11:15 Welcome and Introduction

Lionel Segard, CEO Quantum Genomics (Paris, France)

11:15 – 11:40 Management of Hypertension : view from 25,000 feets

Pr Henry Black, NYU Langone School of Medicine (New-York, NY)

11:40 – 12:05 Complicated, Resistant Hypertension and Minorities

Pr Keith Ferdinand, Tulane University School of Medicine (New-Orleans, LA)

Lunch Break (15 minutes) 12:20 – 12:50 QGC001 : Phase IIa Results and Next steps

Dr Bruno Besse, CMO Quantum Genomics (Paris, France)

12:50 – 12:55 Opening the Panel discussion

Max Jacobs, Analyst Edison (New-York, NY)

13:00 – 13:45 Panel Discussion

All

13:45 – 14:00 Conclusions and Take-home Messages

Lionel Segard, CEO Quantum Genomics (Paris, France)

Agenda

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DEVELOPING FIRST IN CLASS CARDIOVASCULAR DRUGS

Our mission

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SAVE LIVES OF PATIENTS SUFFERING FROM RESISTANT HYPERTENSION Our vision

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www.quantum-genomics.com

Lionel Ségard - President & CEO

• Former CEO of’Inserm-Transfert, subsidiary of INSERM (French National Institute for Health and Medical Research)
• Founder and former president of Inserm Transfert Initiative (seed fund dedicated to young, innovative healthcare companies)
• Founder of the Strategic Council for Innovation (Secretary General in 2003-2005), who’s goal is to boost French efforts in research and high

technologies and included key figures from France's science, industry and financial community

• Biochemist by training (University of South Paris - Orsay)

Jean-Philippe Milon, PhD - Chief Operating Officer

• Several management positions at Bayer Healthcare, member of the Worldwide Executive Committee as Head
• f WW Business Development, Licensing, Mergers & Acquisitions
• Previously head of the cardiovascular business at Sandoz
• More than 25 years of experience in healthcare and pharmaceuticals

Marc Karako - Chief Financial Officer

• Previously Executive Vice President & Chief Financial Officer of Carlson Wagonlit Travel
• Former Chief Financial and Legal Officer of Vallourec and former Vice President Finance at Thomson Multimedia
• 10 years at IBM in various financial management positions
• Master of engineering (Ecole des Ponts ParisTech) and MBA from the University of Chicago

Bruno Besse- Chief Medical Officer

• More than 20 years experience in the pharmaceutical industry
• Held several R&D and Medical Affairs positions in big pharma companies (Aventis, BMS) incardiology

and thrombosis as well as in a start-up company (medical device)

• MD, cardiologist and graduated in Biostatistics

Fabrice Balavoine - Vice President Research & Development

• 15 years of experience in drug discovery and development
• Developed several clinical-stage drug candidates (new chemical entities, peptides and recombinant proteins) across various therapeutic areas
• Ph.D. in Organic Chemistry from the University Paris-Sud, M.Sc. from Ecole Supérieure de Physique et de Chimie Industrielle of Paris (ESPCI) and Executive MBA from

the ESSEC & Mannheim Business School

Experienced Management Team

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www.quantum-genomics.com

Company Highlights

Targeting highly unmet medical needs

Strategy targets prevalent indications such as hypertension and heart failure

High blood pressure: QGC001 clinical program

Disclosed positive Ph.2a results (June 2017) and will launch U.S. targeted Ph.2 study

Heart failure: QGC101 clinical program

Multicenter, pan-European Ph.2a clinical study results expected in H1 2018

Broad intellectual property portfolio

multiple patent families granted or filed, up to 2033

Novel therapeutic class to treat cardiovascular diseases:

Brain Aminopeptidase A Inhibitors (BAPAIs) provide antihypertensive effects and cardioprotection

Experienced management and Scientific/Clinical Advisory Boards

composed of top experts in their fields

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www.quantum-genomics.com

Key Figures

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€ 26.1 million

Cash expenses (primarily R&D)

€ 32.1 million

Equity financing

€ 2.4 million

Subsidies from Bpifrance (Public Innovation Bank) and ANR (National Research Agency)

€ 2.8 million

Research Tax Credits (RTC) Alix AM (Singapore)

14.9%

Management

10.6%

Float

63.1% Capital breakdown:

(8,754,491 shares)

Cash from inception:

December 23, 2005 to December 31, 2016

Cash in December 31, 2017

11,197 €

www.quantum-genomics.com

Key Upcoming Clinical Milestones

Heart failure Hypertension

2017 2018

June: Présentation des résultats de l’étude Phase IIa (ESH meeting, Milan) July: U.S. Phase II IND submission H2: First patient recruitment for U.S. Phase II Completion

• f

clinical part of European Phase IIa by year-end U.S. Phase II completion by year-end H1: U.S. Phase II results H2: Phase IIb initiates

2019

H1: European Phase IIa Results 10

www.quantum-genomics.com

Market Data

9.4 million

deaths worlwide, every year due to complications of high blood pressure (1)

Sources : (1) WHO (World Health Organization) - A global brief on hypertension, Silent killer, global public health crisis (2013), (2) The pharmaletter (June 2014), (3) National Hospital Discharge Survey, CDC/NCHS and NHLBI, (4) Heidenreich et al, Circulation Heart Failure (2013).

23 million

people suffer from heart failure worldwide

50% Survival Rate

• f

patients die within 5 years

• f

diagnosis, worse survival rate than any cancer, except lung cancer(3)

$39 billion

global heart failure drugs market estimate for 2015 (4)

$40 billion

Global anti-hypertensive drug market in 2013 (2)

HIGH BLOOD PRESSURE HEART FAILURE

1/3 people worldwide die due to cardiovascular diseases Main cause of death with 17 million deaths per year

1/3 of adults

Have high blood pressure. The proportion increases to one-in- two for people above age 50 (1) 11

www.quantum-genomics.com

BLOCKBUSTERS UNDER PRESSURE OF GENERICS

Main patent expired for the five top-selling antihypertensive drugs, each with annual sales >$1 billion

Significant Industry Need for Innovative Therapies

Research for innovation in the cardiovascular field

PHARMACEUTICAL INDUSTRY LACKS INNOVATION Most late stage programs focus on combination therapies using existing drugs

Blockbuster (I.N.N.) Company Diovan (valsartan) Micardis (telmisartan) Benicar, Olmetec (olmesartan) Avapro, Aprovel (irbesartan) Blopress (candesartan)

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BAPAI: novel therapeutic class

www.quantum-genomics.com

Brain Aminopeptidase A Inhibitors (BAPAIs)

Quantum Genomics, the BAPAI company, is developing first-in-class treatments targeting a new pharmacological pathway in the brain

Hypertension Heart failure Other diseases

Catherine Llorens-Cortes, Ph.D. PhD in Neurobiology, Director of the Central Neuropeptides and cardio-vascular hydro- regulation research team – College de France CIRB-CNRS UMR U1050 7241/INSERM

Novel Therapeutic Approach to Treat Hypertension and Associated Cardiovascular Diseases

BAPAI: Brain Aminopeptidase A Inhibitors

More than 20 years of leading European academic research

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www.quantum-genomics.com

BAPAI Pathway Mechanics

A triple mechanism of action with a single drug

Increase of the diuresis (urinary elimination) Inhibition of Aminopeptidase A Innovative novel drugs target a new central pharmacological pathway leading to both antihypertensive effects and cardioprotection Lowering vascular resistance Controlling heart rate

Angiotensin II

BAPAI

Angiotensin III

Vasopressin release Sympathetic nerve activity Baroreflex

Mechanism of action described in several peer-reviewed academic publications:

Bodineau & al – Hypertension – 2008 Marc & al – ProgNeuroscience – 2011 Marc & al – Hypertension - 2012

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www.quantum-genomics.com

Development Pipeline

Four R&D Programs based on BAPAI Platform

CONGESTIVE HEART FAILURE HYPERTENSION

First-in-class

Prevention and treatment of congestive heart failure

QGC101

Proof of efficacy (single dose) in hypertensive rats Regulatory Preclinical results Pharmacokinetics and toxicology (rats and dogs)

First-in-class

Treatment of hypertension as monotherapy

QGC001

Combination

Treatment of hypertension in combination

QGC011

Best-in-class

Optimized treatment

• f hypertension

as monotherapy

QGC006

Identification of active compounds Preclinical studies Clinical studies Phase I Clinical studies Phase IIa Clinical studies Phase IIb Clinical studies Phase III New drug approval (NDA) Commercia- lization

Proof of efficacy repeated doses (post infarction rat and dog models) and start of phase II

Quantum Genomics Partner

Typically, identification and preclinical phases last 2-3 years, a phase I 1-2 years, a phase IIa 1-2 years , a Phase IIb 1-2 years, a phase III 2-3 years and new drug approval and commercialization 2-3 years.

Tolerance, safety and efficacy in hypertensive patients in Phase IIa

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QGC001, for the treatment of hypertension

www.quantum-genomics.com

Overexpressed in elderly, Asian, African American and Hispanic populations ACEs and ARBs drugs are not effective for LRHV patients

QGC001

Targeting Low Renin High Vasopressin (LRVH) Patients 30%

LRVH Patients

LRHV patients have mostly uncontrolled or poorly- controlled high blood pressure

• ~30% of total hypertensive population

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MANAGEMENT OF HYPERTENSION VIEW FROM 25,000 FEET

Professor Henry Black

Adjunct Clinical Professor of Medicine and member of the Section of Cardiology at the New York University School of Medicine, New York

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Global Burden of Disease

Mortality Attributable to Selected Behavioral and Dietary Risk Factors (2010)

2 000 000 4 000 000 6 000 000 8 000 000 10 000 000 Diets Low in Fish/Seafood Diets Low in Vegetables Diets Low in Nuts & Seeds High Dietary Salt High Plasma Glucose Diets Low in Fruits High Blood Pressure Number of Deaths

High Income Regions Central Asia & Central/Eastern Europe Latin America & Caribbean Middle East & North America East/Southeast Asia & Oceania South Asia Sub-Saharan Africa

Adapted from: Ezzati M, Riboli E. N Engl J Med. 2013;360:954-964.

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Deaths Attributable to Diseases of the Heart* United States: 1900–2014

200 400 600 800 1000 190019101920193019401950196019701980199020002010 Number of Deaths, in Thousands Year

Before 1933, data are for a death registration area and not the entire United States. In 1900, only 10 states were in the death registration area, and this increased over the years, so part of the increase in numbers of deaths is attributable to an increase in the number of states.

* Includes acute rheumatic fever/chronic rheumatic heart diseases (I00–I09), hypertensive heart disease (I11), hypertensive heart and renal disease (I13), CHD (I20-I25), pulmonary heart disease and diseases of pulmonary circulation (I26–I28), heart failure (I50), and other forms of heart disease (I29–I49, I50.1–I51). “Diseases of the heart” are not equivalent to “total cardiovascular disease” Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

2014

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Cardiovascular Disease (CVD):

Approximately 2200 Americans die of CVD daily

* Estimates were extrapolated to the US population from the National Health and Nutrition Examination Survey (NHANES) 2014 data.

CLRD=chronic lower respiratory disease

In 2014, more than 807,775 (30.8%) of deaths were attributed to heart disease; 133,103 of these were attributed to stroke

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

806,7 591,6 166,0 134,5 91,7 63,6 250 500 750 1000 CVD Cancer Accidents CLRD Diabetes Alzheimer's Disease Mortality (in thousands)

23 CLRD=chronic lower respiratory disease

407,7 311,2 85,4 69,4 41,1 28,3 399,0 280,4 77,6 65,1 50,6 35,3 0,0 50,0 100,0 150,0 200,0 250,0 300,0 350,0 400,0 CVD Cancer Accidents CLRD Diabetes Alzheimer's Disease Men Women

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Mortality by Disease by Gender

NHANES, 2014

Mortality (in thousands)

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Cardiovascular Disease Mortality United States, 2014 Coronary Heart Disease, 45.1% Stroke, 16.5% Hypertension, 9.1% Heart Failure, 8.5% Diseases of the Arteries, 3.2% Other, 17.6%

Total may not add to 100 because of rounding

Adapted from: Yang Q, et al. JAMA. 2012;307:1273-1283. Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

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Causes of Cardiovascular Disease Mortality

United States - 2014

High Blood Pressure, 40.6% Smoking, 13.7% Poor Diet, 13.2% Insufficient Physical Activity, 11.9% Abnormal Glucose Levels, 8.8%

Total may not add to 100 because of rounding

Adapted from: Yang Q, et al. JAMA. 2012;307:1273-1283. Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

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Remaining Lifetime Risks for Various Diseases by Gender and Age

Diseases Remaining Lifetime Risk at Age 40 Years Remaining Lifetime Risk at Age 70 Years Men Women Men Women Any CVD 2 in 3* 1 in 2* 2 in 3† 1 in 2 CHD 1 in 2 1 in 3 1 in 3 1 in 4 Atrial Fibrillation 1 in 4 1 in 4 1 in 4 1 in 4 CHF 1 in 5 1 in 5 1 in 5 1 in 5 Stroke 1 in 6‡ 1 in 5‡ 1 in 6 1 in 5 Dementia

• 1 in 7

1 in 5 Hip Fracture 1 in 20 1 in 6

• Breast Cancer

1 in 1000 1 in 8

• 1 in 14

Prostate Cancer 1 in 6

• Lung Cancer

1 in 12 1 in 17

• Diabetes

1 in 3 1 in 3 1 in 9 1 in 7

Hypertension 9 in 10‡ 9 in 10‡ 9 in 10† 9 in 10†

Obesity 1 in 3 1 in 3

• *

Age 45 years † Age 65 years ‡ Age 55 years CHD=coronary heart disease CHF=congestive heart failure CVD=cardiovascular disease

• --, not estimated

Adapted from: Writing Group Members, et al. Heart Disease And Stroke Statistics--2014 update. Circulation. 2014.

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Factors Determining Blood Pressure Vasoconstrictors AII, Catechols, Endothelin, etc. Vasodilators NO, PG, etc. Peripheral Nervous System Central Nervous System Volume Local Factors Renal, Cardiac, Adrenal

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• Packer. Prog Cardiovasc Dis. 1998;41(suppl 1):39.

 CNS Sympathetic Outflow

1- Receptors

 Cardiac Sympathetic Activity  Sympathetic Activity To Kidneys + Blood Vessels

2- Receptors 1- Receptors Activation Of RAS

Vasoconstriction Sodium Retention Myocyte Death Increased Arrhythmias Disease Progression

1- Receptors 1- Receptors

Sympathetic Activation And Cardiovascular Disease

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Prevalence of Hypertension*

NHANES 2011-2014

10,7 23,1 35,1 57,6 63,6 73,4 7,8 22,8 33,2 55,5 65,8 81,2

10 20 30 40 50 60 70 80 90 100 20-34 35-44 45-54 55-64 64-74 ≥ 75 Percent (%) of Population Age, years Men Women

* Defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, if the subject said “yes” to taking antihypertensive medication, or if the subject was told on 2 occasions that he or she had hypertension.

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

30

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Prevalence of Stroke

NHANES 2011-2014 0,3 1,8 8,5 13,8 0,8 2,4 8,1 14,9

2 4 6 8 10 12 14 16 20-39 40-59 60-79 ≥ 80

Men Women

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Percent (%) of Population Age, years

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Age-adjusted Mortality Rates for Stroke by Gender and Ethnicity NHANES 2014

35,1 56,5 29,6 32,1 32,1 35,0 46,3 27,4 31,4 28,3 10 20 30 40 50 60 70

White Black Asian/Pacific Islander American Indian/ Alaskan Native Hispanic

Mortality Rate, per 100,000 Men Women

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

33

Hypertension* in the U.S.

NHANES 20011-2014

69,0 82,6 87,5 49,7 74,2 82,9 40,1 58,3 54 20 40 60 80 100 20-39 40-59 ≥60

Percent (%) of Population Age, years Awareness Treatment Control

* Defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, if the subject said “yes” to taking antihypertensive medication, or if the subject was told on 2 occasions that he or she had hypertension.

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

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Hypertension in the United States By Race/Ethnicity and Gender

NHANES 20011-2014

83,1 87,0 79,6 90,0 74,0 70,6 79,6

73,6 82,1 68,0 81,9 60,3 76,8 70,7 54,9 59,1 42,7 54,0 40,9 54,9 40,0 49,9

10 20 30 40 50 60 70 80 90 100 NH White Men NH White Women NH Black Men NH Black Women Mexican American Men Mexican American Women NH Asian Men NH Asian Women Percent of Population with Hypertension

Awareness Treatment Control

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

NH=non-Hispanic

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Age-standardized Prevalence Estimates* for Cardiovascular Health

U.S. Adults by Age Ranges

24 16,2 36,1 40 42 54,5 82 69,1 9,8 12,4 7 24,2 4,2 16,7 2,9 1,1 31,2 34,5 16 16,6 17,8 30,4 26,5 57,5 31,9 53,6 22,2 41,7 73,1 82,6 32,6 25,4 42 28,9 0,2 0,5 63,2 30,1 61 21,7 73,6 41,6 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 20-49 50+ 20-49 50+ 20-49 50+ 20-49 50+ 20-49 50+ 20-49 50+ 20-49 50+

Poor Intermediate Ideal

* reflects 2011-2012 NHANES data Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Current Smoking Body Mass Index Physical Activity Healthy Diet Score Total Cholesterol Blood Pressure Fasting Plasma Glucose

36

Incidence of Cardiovascular Disease according to # Ideal health behaviors/factors

# of ideal health factors=3 # of ideal health factors=2 # of ideal health factors=1 # of ideal health factors=0

5 10 15 20 25 30 35 1 2 3 to 4

Age, Sex, and Race-adjusted incidence rate (/1000 person-years) # of Ideal Health Behaviors

Yang Q, et al. JAMA. 2012;307:1273–1283.

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10-year Cardiovascular Disease Risk by Levels of Risk Factors Adults 50-54 Years of Age

7,9 11,2 21,6 30,0 4,5 7,3 15,9 24,8

5 10 15 20 25 30 35 40

Men Women

BP: blood pressure HDL-C: high density lipoprotein cholesterol 45-59 45-49 35-44 35-44 160-199 200-239 200-239 200-239 120-129 130-139 130-139 130-139 No No Yes Yes No No No Yes

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Estimated 10-year Risk (%)

HDL-C (mg/dL) Total Cholesterol (mg/dL) Systolic BP (mmHg)* Diabetes Smoker

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Blood Pressure* (mmHg) 95-105 138-148 138-148 138-148 138-148 138-148 Diabetes No No Yes Yes Yes Yes Cigarette Smoking No No No Yes Yes Yes Prior AF No No No No Yes Yes Prior CVD No No No No No Yes

10-year Stroke Risk by Levels of Risk Factors Adults Age 55

2,6 4,0 5,4 8,4 14,8 22,4 1,1 2,0 3,8 6,3 18,1 27,0 5 10 15 20 25 30 35 Men Women

* Closest ranges for women are: 95-104 and 115-124 (mmHg) Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Estimated 10-year Risk (%)

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Age-standardized Death Rates From Cardiovascular Diseases (CVD) Over Time 50 100 150 200 250 300 350 400

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Total CVD Stroke CHD Other CVD

CHD=coronary heart disease

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2016;133:338-e360.

Deaths per 100,000

Year

40

Cardiovascular Disease Mortality Trends 350 370 390 410 430 450 470 490 510 530 550 1979 1980 1985 1990 1995 2000 2005 2011 2013 Men Women

* CVD excludes congenital cardiovascular defects

Adapted from: Mozaffarian D, et al. Heart Disease and Stroke Statistics—2016 Update. Circulation. 2016;133:e38-e360.

Deaths, in Thousands

Year

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Antihypertensive Drugs in the USA

DIURETICS THIAZIDES THIAZIDE-TYPE LOOP ACTIVE ALDOSTERONE ANTAGONISTS SYMPATHETIC BLOCKERS PERIPHERAL CENTRAL BOTH β-BLOCKERS α-BLOCKERS CALCIUM CHANNEL BLOCKERS ANGIOTENSIN CONVERTING ENZYME INHIBITORS ANGIOTENSIN RECEPTOR BLOCKERS VASODILATORS

42

Sites of Action of Antihypertensive Drugs

MAP = CO x SVR

Baroreflex Suppression

HR x SV

Blood Volume Venoconstriction

SNS Activation RAAS Activation

Arteriolar Constriction CCBs Vasodilators ACEIs ARBs Renin Inhibitors Aldosterone Antagonists α-blockers β-blockers β-blockers

Izzo JL, Sica DA, Black HR, eds, and the Council for High Blood Pressure Research (American Heart Association). Hypertension Primer: The Essentials

• f High Blood Pressure. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:126–132, 443–450, 455–464.

Diuretics

43

JNC 7 Algorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

With Compelling Indications Lifestyle Modifications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combinations for most (usually thiazide- type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB,

• r combination.

Without Compelling Indications

Chobanian AV et al. Hypertension. 2003;42:1206-1252.

44 AA: aldosterone antagonist ACEI: angiotensin-converting enzyme inhibitor ARB: angiotensin II-receptor blocker βB: ß-blocker

The Seventh Report of the Joint National Committee (Updated)

Compelling Indications Diuretic βB ACEI ARB CCB AA Heart failure ✓ ✓ ✓ ✓ ✓ Post-MI ✓ ✓ ✓ High CAD risk ✓ ✓ ✓ ✓ ✓ Diabetes ✓ ✓ ✓ ✓ ✓ CKD ✓ ✓ Recurrent stroke prevention ✓ ✓

CAD: coronary artery disease. CCB: calcium channel blocker CKD: chronic kidney disease MI: myocardial infarction

Chobanian AV, et al. JAMA. 2003;289(19):2560-2572.

45

Drug adherence in hypertension:

Persistence is more problematic than daily compliance

46

Ho et al., Am Heart J 2008;155:772-9

Beta-blockers

Non-adherence is associated with adverse outcomes

ACE-inhibitors

47

Ho et al, Circulation. 2009;119:3028-3035

Reasons For Medication Non-adherence Health system: poor quality of provider-patient relationship; poor communication; lack of access to healthcare; lack of continuity

• f care

Condition: asymptomatic chronic disease (lack of physical cues); mental health disorders (e.g., depression) Patient: physical impairments (eg, vision problems); cognitive impairment; psychological/behavioral; younger age; Therapy: complexity of regimen; side effects

48

Direct Health Expenditures by Top 22 Leading Diagnoses

National Heart, Lung, and Blood Institute 2012-2013

17,9 18,1 20,1 23,6 25,5 30,2 31 31,1 34,7 34,7 34,8 36,2 37,1 41,4 41,7 47,3 61,2 73,7 74,1 81,2 84,8 95,1 98,7

20 40 60 80 100 120 Stroke Other care and screening Other circulatory conditions Skin disorders Other Central CNS Disorders Hyperlipidemia Systemic Lupus/Connective Tissue Disorders Normal Live Births Diabetes Mellitus Osteoarthritis Mental Disorders Heart Conditions U.S. Dollars ($), in Billions

COPD: chronic obstructive pulmonary disease GI: gastrointestinal

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

49

Hospital Discharges for 10 Leading Diagnostic Groups

NHANES, 2010 1,6 1,8 2,1 2,2 2,3 3,0 3,4 3,5 4,0 5,8 1 2 3 4 5 6 7 Neoplasms (140-239) Endocrine System (240-279) Mental (290-319) Genitourinary System (560-629) Musculoskeletal System (710-739) External: Injuries, etc (800-999) Respiratory System (460-519) Digestive System (520-579) Obstectrical (V27) Cardiovascular (390-459) Discharges, in Millions

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

50

Hospital Discharges in the United States for Cardiovascular Disease* 1 2 3 4 5 6 7 1970 1975 1980 1985 1990 1995 2000 2005 2010 Year

* include people discharged alive, dead, and “status unknown.”

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Discharges, in Millions

51

Costs* of Cardiovascular Disease†

NHANES, 2012-2013

189,7 98,8 90,9 91,6 98,1

$126,4 $94,1 $32,3 $107,9 $18,5

20 40 60 80 100 120 140 160 180 200 U.S. Dollars ($), in Billions

Direct Indirect Mortality

All Patients Men Women <65 Years >65 Years Gender Age

† include cardiovascular disease and stroke

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

52

Total (Direct and Indirect) Costs* of All Cardiovascular Disease (CVD) by Age Range

100 200 300 400 500 600

2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030

18-44 Years 45-64 Years 65-79 Years ≥80 Years

* In Billions (in 2012 $)

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

U.S. Dollars in Billions Year

53

Trends in Cardiovascular Procedures Over Time in the United States

200 400 600 800 1000 1200 1400 1979 1980 1985 1990 1995 2000 2005 2010 Year

Catheterizations Bypass Percutanous Coronary Intervention Carotid Endarterectomy Pacemakers

Adapted from: Benjamin EJ, et al. Heart Disease and Stroke Statistics—2017 Update. Circulation. 2017;135:e146-e603.

Procedures (N), in Thousands

54

Treatment Of Hypertension 1937 “The treatment of hypertension itself is a difficult and almost hopeless task in the present state of knowledge, and in fact for aught we know ... hypertension may be an important compensation mechanism which should not be tampered with, even were it certain that we could control it.”

Paul Dudley White, 1937

COMPLICATED,RESISTANT HYPERTENSION AND MINORITIES

Professor Keith C. Ferdinand Professor of Medicine at the Tulane University School of Medicine

56

Only Half of Americans with Hypertension Have It Under Control

48% 52% Uncontrolled Controlled

72 million adults with hypertension (31%)

BP: Blood Pressure

1National Health and Nutrition Examination Survey 2011-2012.

2Keith C. Ferdinand, Samar A. Nasser. Current Cardiovascular Risk Reports, 8 June 2012 – Springer 3Calhoun, David A., et al. Circulation 117. 25 (2008): e510-e526.

• 4T. Denolle, B. Chamontin and al. Journal of Human Hypertension advance online publication, 28 January 2016; doi:10.1036/jhh.2015.122

Resistant hypertension is defined as: BP above goal (≥ 140/90 mmHg for

• verall population)2. Despite adhering

to optimal doses of 3 antihypertensive agents (including a diuretic), for at least 4 weeks, in addition to appropriate lifestyle and dietary measures3-4. OR Individuals with controlled BP using more than 4 drug classes2.

1

57

Epidemiology of Resistant Hypertension True prevalence of resistant hypertension is not known1 10-30% in general practice, ≥50% in nephrology referral clinics2 NHANES (2003-2008) estimated prevalence of resistant hypertension 8.9% (1 in 11) of US adults with hypertension 12.8% (1 in 8) of all antihypertensive drug-treated US adults with hypertension3 The prevalence of resistant hypertension continues to increase4

1Calhoun et al. Hypertension 2008;51:1403-1419 2Kaplan NM. J Hypertens. 2005; 23:1441-1444. 3Persell SD. Hypertension. 2011;57:1076-1080. 4Egan et al. Circulation. 2011;124:1046-1058

58

Causes of True Resistant Hypertension ‐ Identifiable (secondary) Causes of Hypertension ‐ Drug-Induced or Other Causes ‐ Volume Overload-high sodium intake, Chronic Kidney Disease, inadequate diuretic therapy ‐ Aldosterone Excess ‐ Associated Conditions ➢ Obesity ➢ Excess alcohol intake ➢ Sleep apnea ‐ Clinical Inertia ‐ Suboptimal antihypertensive drug combinations

Fagard, Robert H. Heart. 2012;98:254-261.

59

Consequences of Unmanaged Hypertension on Organes

Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

BP: Blood pressure CHD: Coronary heart disease CV: Cardiovascular

Peripheral arterial disease Chronic kidney disease LVH, CHD, HF, angina TIAs, stroke, dementia

For every 20mmHg systolic (or 10 mmHg diastolic) increase in BP there is a doubling in mortality for both CHD and stroke Control of systolic hypertension reduces all-causes mortality, CV mortality, stroke and heart failure events Hypertension is responsible for 62% of cerebrovascular diseases and 49% of CHD

HF: heart failure LVH: left ventricular hypertrophy

60

Hypertension in African-American: a major public health concern

G

Hypertension is 1.5 more common in African American as compared to White Hypertension is less often Controlled in African American, Hispanic and Asian

28 41,2 24,9 25,9 5 10 15 20 25 30 35 40 45 Total

Percent

Non-Hispanic white Non-Hispanic black Non-Hispanic Asian Hispanic 55,7 48,5 43,5 47,4 10 20 30 40 50 60 Total

Percent of controled HTN

Non-Hispanic white Non-Hispanic black Non-Hispanic Asian Hispanic

1Significant difference from non-Hispanic Asian. 2Significant difference from non-Hispanic White. 3Significant difference from Hispanic.

Adapted from Yoon SS, et al. NCHS data brief, no 220. Hyattsville, MD: National Center for Health Statistics, 2015. CDC/NCHS, NHANES, 2011-2014.

1 1,2,3 1 1,2,3

61

Hypertension in African American: Potential Physiologic & Hemodynamic Determinants ‐ Obesity (>50% of women ≥40 BMI ≥30 kg/m2)1 ‐ Higher salt sensitivity2 ‐ Low levels of plasma renin2 ‐ Vascular function (sympathetic overactivity)2 ‐ Attenuated nocturnal fall in Blood Pressure3 ‐ Greater comorbidity (especially Diabete Mellitus)2 ‐ Inactivity ‐ Family history

1Nesbitt SD. Curr Hypertens Rep 2005;7:244-248. 2Gadegbeku CA et al. Med Clin North Am. 2005;89:921-933. 3Profant J et al. Hypertension.1999;33:1099-1094

62

200 250 300 350 400 450 2000 2002 2004 2006 2008 2010 2012 2014 Cardio-vascular Mortality Non-Hispanic White Non-Hispanic Black

Higher Cardio-Vascular morbidity and mortality rates in Non- Hispanic Blacks vs. Whites 6-year event rate1

Black Non- Black Relative Risk Stroke 6,5% 5,3% +23% ESRD 2,6% 1,5% +73% All-causes mortality 17,7% 16,8% +5%

1Wright JT, et al. JAMA 2005:293:1595-1608 2Adapted From Sidney, S.et al. JAMA cardiology, 2016,1(5), 594-599.

2

33%

ESRD: End-Stage Renal Dysfunction HTN: Hypertension

63

Adjusted End-Stage Renal Dysfunction incidence rate, by race categories (1996-2013)

Af Am: African American

Special analyses, USRDS ESRD Database. *Adjusted for age and sex. The standard population was the U.S. population in 2011.

64

Initial Medications For The Management of Hypertension Lifestyle Modification – Especially Diet and Exercise

JAMA 2014;311(5): 507-520. Feb 5,2014

Diuretics Calcium Antagonists ACE inhibitors

• r ARBs

Black population

*Β-blockers should be included in the regimen if there is a compelling indication

Β-blockers*

65

Pooled Estimates of Decrement in Blood Pressure With Antihypertensive Treatments

Brewster LM, et al Ann Intern Med 2004; 141:614-627

Drug Category White-Black Difference SBP/DBP (mmHg) Diuretics –3.5/–1.5 Greater response in Blacks CCBs –2.4/–0.6 Greater response in Blacks BBs 6.0/2.9 Greater response in Whites ACE-Is 4.6/3.0 Greater response in Whites

ACE-Is: angiotensin converting enzyme inhibitor BBs: β-Blockers CCBs: calcium channel blockers

66 ACE-Is: angiotensin converting enzyme inhibitor CCB: calcium channel blocker CV: Cardiovascular ESRD: End-stage renal dysfunction HF: Heart failure MI: Myocardial Infarction

ALLHAT TRIAL

Wright JT, et al. JAMA 2005:293:1595-1608

ALLHAT: Randomized double-blind study Lisinopril (ACE-I) vs chlorthalidone (diuretic) vs amlopidine (CCB) 11 792 Blacks and 21 565 Non-Blacks To reduce overall CV disease,including MI, stroke, HF and ESRD Lisinopril and chlorthalidone had: Similar effect in Non-Black But chlorthalidone was more effective in Black Amlodipine and chlorthalidone had same effet in Non-Blacks and in Blacks

67

Angioedema with ACE-Is is twofold frequent in African American Total Blacks Non- blacks Chlorthalidone 8/15,255 0.1% 2/5,369 <0.1% 6/9,886 0.1% Lisinopril 41/9,054 0.5% 23/3,210 0.7% 18/5,844 0.3% p<0.001 p<0.001 p=0.002 There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant)

Wright JT, et al. JAMA 2005:293:1595-1608

68

ALLHAT Trial: Implications

Wright JT, Dunn JK, Cutler JA et al. JAMA 2005:293:1595-1608

In Blacks, ACEI’s should be considered second-line therapy

ACE-Is: angiotensin converting enzyme inhibitor

69

2014 evidence-based guideline (JNC 8)

Adapted from James P, et al. JAMA. 2014;311:507–520.

Non-Black Black All races Initiate thiazide-type diuretic or ACEI or ARB or CCB, alone or in combination. Initiate thiazide-type diuretic or CCB, alone or in combination. Initiate ACEI or ARB, alone or in combination with other drug class.

ACEI: angiotensin converting enzyme inhibitor ARB: angiotensin II receptor blocker;

General population No CKD CKD present

CCB: calcium channel blocker CKD: chronic kidney disease

70

Conclusions

Wright JT, Dunn JK, Cutler JA et al. JAMA 2005:293:1595-1608

Hypertension control is essential especially among African Americans who are at highest risk for CVD/CKD Potentially effective pharmacotherapy includes first-step diuretics/CCB’s and combo in most patients to reduce and eventually eliminate CVD disparities.

CCB: calcium channel blocker CKD: chronic kidney disease CVD: Cardiovascular disease

71

Need for innovation Vigilance and innovation an essential to address the on-going challenge

• f CVD prevention1.

Recent deceleration of the rate of decline in HD mortality warrants expanded innovative efforts1. Hypertension is a major risk factor for CVD2 and under control only in half

• f Americans3 despite exciting therapy, specially in minorities.

True need for new therapeutic classes

1Sidney, S.et al. JAMA cardiology, 2016,1(5), 594-599. 2Chobanian AV, et al. Hypertension. 2003;42:1206-1252. 3National Health and Nutrition Examination Survey 2011-2012.

72

For an Health Equity

QGC001 : PHASE IIA RESULTS AND NEXT STEPS

www.quantum-genomics.com

QGC001, the first orally active aminopeptidase A inhibitor as the prototype of a new class of centrally-acting antihypertensive agents

74

In Rat:

• Decrease in blood pressure in hypertensive

rats (SHR1 and DOCA-salt2)

• No change in blood pressure in

normotensive rats1 In Human :

• No change in blood pressure, heart rate

and renal function (eGFR) in normotensive volunteers Pharmacokinetics Tmax 3-5 h; Half-life >5h; Steady state 4 days

1Marc & al, Hypertension. 2012; 60(2):411-8 2Bodineau & al, Hypertension. 2008;51(5):1318-25

v v v

Vasopressin release Sympathetic nerve activity Baroreflex

Blood pressure

www.quantum-genomics.com

Study QGC001/2QG1

75

A multice center, randomized, double le-bli lind, two-period, placebo controlle led, forced- ti titration proof of

• f concept crossover study to

to compare QGC001, a brain aminopep epti tidase A in inhib ibit itor, with ith pla lace cebo in in patie tients with ith gr grade I or

• r II

II essentia ial hypertension

Professeur Michel Azizi (1), Principal Investigator

(1) Hôpital Européen Georges-Pompidou (Paris) U691/1050 « Central Neuropeptides and Regulations

• f Water Balance and

Cardiovascular Functions » Biomedical Innovation in public- private Research Partnership

www.quantum-genomics.com

QCG001/2QG1 is the first pilot (Phase IIa) study in hypertension with QGC001

76

The aim of this pilot study is: to confirm proof of concept obtained in animals to identify predictors for blood pressure response to help to design further trials Study limitations: Small sample size (n=34) not based on power calculation Short duration of treatment (28 days) Unselected population (all comers hypertensive) fast validation of proof

• f concept in Human

www.quantum-genomics.com

Study design & main selection criteria

77

Study design Selection criteria

• Pilot randomized, double-blind

placebo-controlled, cross-over design

• 2 weeks placebo run-in period
• QGC001 : 250 mg BID one week then

500 mg BID for 3 weeks or matching placebo

• Primary endpoint : Difference between

placebo and QGC001 in change from baseline to D28 in daytime ABPM

• 4 centers in France
• Male & female 18-75 years
• Stage I or II primary hypertension (SBP

140-179 mmHg or DBP 90- 109 mmHg)

• Normal renal function

(eGFR> 60ml/min )

www.quantum-genomics.com

Mainly male caucasian patients with mild hypertension were recruited

78

40 patients screened 6 not included 34 patients randomized (ITT & Safety population) 4 discontinued* 30 patients completed the study 1 protocol deviation 29 patients (per-protocol)

*2 adverse events, one consent withdrawal, one blood pressure>170

N=34 Age (year), mean±SD 57 ± 9 Male N(%) 25 (73.5 %) BMI (kg/m²), mean±SD 27 ± 3 White ethnicity, N (%) 30 (88%) Office systolic blood pressure (mmHg) 148 ± 14 Office diastolic Blood pressure (mmHg) 93± 9

www.quantum-genomics.com

At baseline, blood pressure was similar in both groups

79

Systolic Blood Pressure (mmHg) - QGC001 Systolic Blood Pressure (mmHg) - Placebo

DAY 0

www.quantum-genomics.com

Multivariate analysis demonstrated the effect of initial blood pressure and QGC001 treatment

80

p value Baseline Day-time ABPM 0.01 QGC001 Treatment 0.06 Active renin ns Age ns Gender ns Ethnicity ns eGFR ns Copeptin ns Apelin ns

www.quantum-genomics.com

Primary endpoint: decrease in daytime ambulatory systolic blood pressure (D28)

81

QGC001 Placebo

Day 28

QGC001

Systolic daytime ABPM* Office SBP Difference QGC001 vs Placebo

• 2.7 mmHg
• 4,7 mmHg

P**

0,16 0,15

* Primary endpoint **ANOVA for cross-over (adjusted on sequence period, center)

Daytime

DAY 28

QGC001

www.quantum-genomics.com

Plasma hormones confirmed the original mode of action

82

No change in plasma hormones (Active Renin, Aldosterone, Cortisol, ACTH, Copeptin, Apelin) level occured (either in QGC001 nor in placebo) This confirmed the original mode of action of QGC001 not mediated by Renin or Aldosterone.

www.quantum-genomics.com

Safety profile was similar to what was observed in phases I

83

QGC001 Placebo All Adverse events, n (%) 9 (28,1%) 7 (21,9%) Serious Adverse events, n (%)

Rash Vestibular disorder Arthralgia Severe hypertension

3 (9,4%)

1 1 1

2 (6,2%)

1 1

Change from baseline Potassium (mmol/L) 0,13 ± 0,48

• 0,07 ± 0,46

Sodium (mmol/L) 0,20 ± 1,9

• 0,10 ± 1,5

Creatinine (µmol/L)

• 1,4 ± 8,4

0,6 ± 6,5 No significant changes in Haematological nor other biochemical parameters (neither in QGC001 nor in placebo)

www.quantum-genomics.com

Study limitations

84

Small sample size (n=34) and high inter/intra subjects variability Lack of power (The sample size had thus not been formally determined based on power calculations) Short duration of treatment (28 days) The effect is larger at D28 vs D14, standard duration 2-3 month-treatment in studies

→Fast validation of proof of concept in Human

Population Unselected hypertensive patients (not specifically LRHV; 88% white) Low level of baseline blood pressure while QGC001 effect increased with baseline BP level

www.quantum-genomics.com

Conclusion

85

In multivariate analysis, the predictors of BP response were baseline BP (p=0.01) and treatment (p=0.06) Compared to placebo, four-week administration of QGC001 (250 BID → 500 mg BID)

Decreased day-time Ambulatory systolic BP by 2.7 mmHg (p= 0.16) Decreased Office systolic BP by 4.7 mmHg (p=0.15) Had no effect on hormones (Active renin, Aldosterone, Cortisol, ACTH, Copeptin, Apelin) Was safe

Brain Aminopeptidase A inhibition elicits an antihypertensive response in hypertensive patients, as already been demonstrated in animals which opens the way for this potential new class of drugs to treat CV disease.

Next steps

www.quantum-genomics.com

Consistency between experimental and clinical (human) data

87

• 35
• 30
• 25
• 20
• 15
• 10
• 5

normotensive rat SHR DOCA-Salt

Rat

Placebo QGC001

• 8
• 7
• 6
• 5
• 4
• 3
• 2
• 1

1

normotensive volunteers unselected hypertensive Selected hypertensive (LRHV)

Human

Placebo QGC001

?

Change in blood pressure Change in office blood pressure

www.quantum-genomics.com

Novel Evaluation With QGC001 in Hypertensive Overweight Patients

• f Multiple Ethnic Origins (NEW-HOPE)

Study design

A Phase 2 Open-Label Treatment period: 8 weeks Dose-Titrating : 250 mg BID for 2 weeks followed by 500 mg BID (based on BP response) for 6 weeks, HCT 25 mg may be added depending on blood pressure

BID: twice daily (bis in die) BP: blood pressure HCT: Hydrochlonothiazine

2 weeks 2 weeks 2 weeks 4 weeks

Run-in (no treatment) QGC001 250mg BID QGC001 250mg BID QGC0001 500mg BID 250mg BID 500mg BID 500mg BID + 25mg HCT

D56 End of treatment period D28 D14 Baseline D0 Screening

88

www.quantum-genomics.com

Study objectives Primary endpoint : change from baseline to Week 8 in office SBP Secondary efficacy endpoints:

Change in office DBP from baseline to Week 8; Change in office SBP and DBP from baseline to Week 4; Change in mean 24-hour ambulatory SBP, DBP, and mean OBP from baseline to Week 8; Percentage of responders (defined as subjects with normalized OBP, ie, ≤140/90 mmHg at Week 8) Predictive factors for responders at Week 8.

Safety enpoints

Adverse events Lab tests

SBP: Systolic Blood Pressure DBP: Diastolic Blood Pressure OBP: Office Blood Pressure 89

www.quantum-genomics.com

Study population Targeted population Adults male of female (no age limitation) With primary hypertension SBP at screening 145-170 mmHg if treatment naïve (130-150 mmHg if treated) SBP after 2 week run-in period (no treatment) : 145-170 mmHg Overweight or obese : BMI 25-45 kg/m² At least 50% predominantly self-identified as African American and Hispanic.

BMI: Body Mass Index (weight/height2) DBP: Diastolic Blood Pressure SBP: Systolic Blood Pressure 90

www.quantum-genomics.com

Study metrics

250 patients 25 centers in the US First patient first visit (FPFV) : Q4 2017 Last Patient Last visit (LPLV) : Q1 2019 Results : Q2 2019

91

PANEL DISCUSSION

QUANTUM GENOMICS SA

Tour Montparnasse 33 avenue du Maine 75015 PARIS FRANCE T : + 33 (0)1.85.34.77.70 Contact@quantum-genomics.com