Developing first in class cardiovascular drugs JUNE 2016 - PowerPoint PPT Presentation

Developing first in class cardiovascular drugs JUNE 2016

Highlights Lead drug candidate, QGC001, currently in 30-patient phase IIa in hypertension - data expected in Q3 2016 Novel therapeutic class - brain aminopeptidase A inhibitors (BAPAIs) - provides antihypertensive effects and cardioprotection Program QGC101 received approval in France to initiate a pan-european phase IIa in congestive heart failure in mid 2016 3 patent families granted, 3 patent families filed and starting to be granted Experienced management team and Scientific/Clinical Advisory Board Willing to target subgroups of patients in large indications with strong unmet medical need (hypertension and heart failure) 2

Do you know that ? 9.4 million 1/3 Deaths worlwide every year due 1/3 of humans is dying due to to complications of high blood cardiovascular diseases. 1st cause of pressure (1) death with 17 million deaths in the world each year (1) Of adults ar more, depending on countriy has high “Hyper -pressure contributes to nearly 9.4 million deaths due blood pressure. to heart disease and stroke every year and, together, With the these two diseases are the number one cause of death worldwide. proportion going And, hyper-pressure also increases the risk of kidney failure, up to one in two blindness and several other conditions. It often occurs together for people aged with other risk factors like obesity, diabetes and high cholesterol – 50 and above (1) increasing the health risk even further .” WHO Chief Dr Margaret Chan – World Health Day April 07, 2013 $ 40 billion $ 39 billion Global anti-hypertensive Global heart failure drugs market estimate for 2015 (3) drugs market in 2013 (2) Sources : (1) WHO (World Health Organization) - A global brief on hypertension, Silent killer, global public health crisis (2013), (2) the pharmaletter (June 2014), (3) Heidenreich et al, Circulation Heart Failure (2013) 3 3

Blockbuster patent expiration creates opportunity Blockbuster (I.N.N.) Company Main Patent expiration date Diovan Sept. 2012 (valsartan) Micardis Top-selling Jan. 2014 (telmisartan) antihypertensive Benicar, Olmetec Oct. 2016 drugs (olmesartan) Avapro, Aprovel Mar. 2014 (irbesartan) Blopress Jun. 2012 (candesartan) Antihypertensive drugs account for 5 of 10 top-selling cardiovascular products, Pipeline lacks innovation; each with annual sales >$1 billion majority of late stage programs focused on combination Increasing generic threat creates significant therapies using existing drugs need for innovative antihypertensive therapeutics candidates 4

1 BAPAI : novel therapeutic class

BAPAI : a new therapeutic approach to treat hypertension and associated cardiovascular diseases Hypertension Heart failure Brain Aminopeptidase Other diseases A Inhibitors (BAPAIs) Quantum Genomics, the BAPAI company, is developing first in class treatment targeting a new pharmacological pathway in the brain Benefiting from more than 20 years of the highest standard academic research in Europe Catherine Llorens-Cortes , PhD in Neurobiology, Director of the Central 2014 Category Neuropeptides and cardio-vascular hydro- « Research team » regulation research team – College de France CIRB-CNRS UMR U1050 7241/INSERM 6

A triple mechanism of action with a single drug Inhibition of Aminopeptidase A Angiotensin II Angiotensin III Vasopressin release Sympathetic nerve activity Baroreflex BAPAI Increase of the diuresis Lowering vascular Controlling (urinary elimination) resistance heart rate BAPAIs are innovative drugs that target a new central pharmacological Mechanism of action described in several peer reviewed pathway leading to both academic publications: antihypertensive effects and Bodineau & al – Hypertension – 2008 cardioprotection Marc & al – ProgNeuroscience – 2011 7 Marc & al – Hypertension - 2012

Our goal is to target a specific population of patients : LRHV Low Renin High Vasopressin patients Mostly uncontrolled or poorly controlled : LRHV patients LRHV is overexpressed in elderly, Asian, African American and Hispanic populations ACEs and ARBs drugs are not effective for those patients 8

2 Robust pipeline of new drug candidates

A robust pipeline of new drug candidates Quantum Genomics Partner Identification of Preclinical Clinical studies Clinical studies Clinical studies Clinical studies New drug Commercia- active studies Phase I Phase IIa Phase IIb Phase III approval lization compounds (NDA) QGC001 First-in-class Tolerance, safety and efficacy Treatment of In hypertensive patients hypertension as monotherapy HYPERTENSION QGC011 Combination Regulatory Preclinical results Treatment of Pharmacokinetics and toxicology hypertension (rats and dogs) in combination QGC006 Best-in-class Proof of efficacy single dose Optimized treatment in hypertensive rats of hypertension as monotherapy QGC101 HEART FAILURE CONGESTIVE Proof of efficacy repeated doses First-in-class (post infarction rats and dogs models) Prevention and and start of phase II treatment of congestive heart failure 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. 10

QGC001, phase I trials Identification of Clinical studies Clinical studies Target discovery Preclinical studies active compounds Phase I Phase II QGC001 First-in-class Stand alone treatment of Hypertension Phase Ia • 2012 Positive : overall safety and tolerability Randomized, double blind, placebo controlled study of single ascending doses in 80 healthy volunteers of QGC001 up to 2g Phase Ib • 2013 Positive : overall safety and tolerability of QGC001 up to 750mg twice a day Randomized, double blind, placebo controlled study of multiple ascending doses in 44 healthy volunteers and no food interaction Michel Azizi, MD, Phase IIa • Q1 2015 Medical Doctor, University Professor – Hospital Initiation of a phase IIa Practitioner Director of CIC 9201 (Cardiovascular, in 30 hypertensive patients renal, endocrine pathology and physiology) 11

QGC001, summary of the clinical findings in healthy normotensive subjects Safety & Tolerability : Clinically and biologically well-tolerated in healthy male subjects after a single oral dose up to 2000 mg and after multiple oral doses up to 750 mg b.i.d. Pharmacokinetics Rapidly absorbed with a Tmax of 1.5 hours QGC001 is partly converted in its active metabolite EC33 at the gastrointestinal tractus level Mild accumulation of QGC001 and EC33 and increase in half-life with time after repeated administrations over 7 days No food influence on the pharmacokinetics profile of QGC001 Pharmacodynamics : No effect on blood pressure, heart rate, and the systemic Renin-Angiotensin System activity. QGC001 is not a hypotensive drug in healthy normotensive subjects 12

QGC001, preclinical pharmacology in DOCA-Salt rats Single oral administrations of RB150/QGC001 decrease mean blood pressure (MBP) in alert hypertensive rats (DOCA-salt rats) without affecting significantly heart rate (HR) Single oral administrations of RB150/QGC001 have no effect in normotensive rats (WKY and Sham rats) RB150 = QGC001 Bodineau et al, Hypertension, 2008 13

QGC001, preclinical pharmacology in SHR rats Single oral administrations of RB150/QGC001 decrease mean blood pressure (MBP) in alert spontaneously hypertensive rats (SHRs) Brain APA activity Blood pressure ** 10 *** ** 100 0 Saline ∆MABP (mmHg) 80 ∆ 2 -10 * QGC001 ∆ 1 * (15 mg/kg) 60 -20 QGC001 ** * (100 mg/kg) 40 * * * ** Enalapril -30 ** ** (3 mg/kg) 20 QGC001 -40 ** 0 (150 mg/kg) ED50 : 30 mg/kg QGC001 ** ** Saline Saline -50 100mg/kg 0 1 2 3 4 5 6 24 SHR Temps (h) Adapted from Marc et al, Hypertension, 2012 14

QGC001, preclinical pharmacology in SHR rats Inhibiting both the brain and the systemic RAS by combining QGC001 with an ACE inhibitor or an AT1 receptor antagonist results in synergy of action and should improve the control of BP in hypertensive patients Saline QGC001 (100 mg/kg) 10 10,0 Valsartan (0.3 mg/kg) * Enalapril (1 mg/kg) * 0 0,0 * -10 -10,0 ∆MABP (mmHg) QGC001 (100 mg/kg) ** ‡ * -20,0 -20 ‡ * ‡ * -30 -30,0 * QGC001 (100 mg/kg + Valsartan (0.3 mg/kg) QGC001(100 mg/kg) -40 -40,0 ‡ ** +Enalapril (1mg/kg) ** -50 -50,0 0 1 2 3 4 5 6 24 0 1h 2h 3h 4h 5h 6h 24h Time (h) Time (h) 15 Adapted from Marc et al, Hypertension, 2012

Phase IIa for QGC001: trial completed Randomization 1:1 Period P1 Washout Period P2 Tapering and discontinuation of Run-in current HTA Period A QGC001 Placebo Placebo therapy No drug Placebo treatment Period P1 Washout Period P2 B Placebo Placebo QGC001 2 weeks 2 weeks 4 weeks 2 weeks 4 weeks 4 Centers in France all labelled as “ Centers of Excellence” by the European Society of Hypertension. Principal Investigator: Pr. Michel Azizi - Hôpital Européen Georges Pompidou - Paris Safety endpoints : Evaluated from signs, symptoms and laboratory tests at each visit Pharmacokinetics endpoints : Measured twice during each of the two treatments periods Efficacy endpoints include : 24 hours ambulatory blood pressure measurement (ABPM) Home blood pressure measurement (HBPM) Office blood pressure measurement (OBPM) 16 Hormonal measurement of several biomarkers