1January 2010

NicOx- Evoluzione di una start-up nella ricerca

farmaceutica -

Ennio Ongini Nicox

Sophia Antipolis (France) and Milano (Italy)

2

January 20102

3

January 2010

NicOx: A French Company with an Italian Engine

HeadquartersNon-Clinical and Clinical Development, Finance,

Administration & Corporate Activities

HeadquartersNon-Clinical and Clinical Development, Finance,

Administration & Corporate Activities

Research & PatentsResearch & Patents

Commercial Affairs, Medical Affairs &

Clinical Operations in North America

Commercial Affairs, Medical Affairs &

Clinical Operations in North America

• Founded in 1996 in France• Listed on the NYSE Euronext (Paris) since 1999• 132 employees total

Warren, NJ, USAWarren, NJ, USA

Sophia Antipolis, France

Sophia Antipolis, France

Bresso, ItalyBresso, Italy

4

January 2010

SpinSpin--offoff e Starte Start--up: le tappe piup: le tappe piùù importantiimportanti

• Progetto innovativo (“L’idea”)

• Il risvolto applicativo (Business Plan)

• La gestione (management)

• Il finanziamento

• Il decollo

5

January 2010

SpinSpin--off e Startoff e Start--up: le tappe piup: le tappe piùù importantiimportanti

L’IDEA

6

January 2010

Gas as neurotransmitter

N O

Nitric oxideO

C

Carbon monoxide

S

Hydrogen sulfide

7

January 2010

The EDRF (Endothelium-derived relaxing factor)

The Furchgott experiment

Robert F Furchgott showed that acetylcholine-induced relaxation of blood vessels was dependent on the endothelium(Furchgott and Zawadzki, 1980)

8

January 2010

Milestones in the discovery of NO in biology

19801980Discovery of a potent

biological mediator EDRF (Endothelium-Derived

Relaxing Factor)

EDRF was identified to be NO19871987

19921992NO was named

“Molecule of the Year”

Nobel Prize in Medicine and Physiology awarded

for NO-related discoveries

19981998

9

January 2010

Generation of NO from L-arginine occursthrough the enzyme Nitric Oxide Synthase (NOS)

O2

NADPHNADP +

H2O NH2

NHO

OHNH2 O

+ NO.

L-arginine L-citrulline

NOS

NH2

NHNH

OHNH2 O

Three different isoforms of NOS:

2 constitutive NOS (NOS I = nNOS; NOS III = eNOS)

1 inducible NOS (NOS II = iNOS)

10

January 2010

Key action of low concentrations of NO at the cellular level

NO

Guanylyl cyclasesignaling

Anti-oxidant

? Cyclic GMP formation, ?Ca2+ levels

Scavenge Reactive Oxygen Species (ROS)

NF-kB inhibition, ? proinflamm. cytokines

Anti-inflammatory

11

January 2010

The field of nitric oxide (NO) biology has expanded considerablywith many roles in a variety of cells and organ systems

Defense against pathogens

N O

Hepatic

Gastrointestinal

Cardiovascular

Bone metabolismRenal

Nervous system

Immunology

Respiratory

12

January 2010

Publications on NO in biomedical research

0

600

1200

1800

2400

3000

3600

4200

4800

1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 sept.2009

Source: PubMed

Keywords used: nitric oxide donors, nitric oxide releasing, nitric oxide donating, nitric oxide

N. of publications

13

January 2010

Robert F. Furchgott

postulated that an unknown signaling molecule (EDRF),

produced vasorelaxation

Louis J. Ignarro

concluded that EDRF was identical to NO

Ferid Murad

discovered that vasodilatingcompounds act by releasing NO via activation of soluble

guanylyl cyclase.

1998 Nobel Prize in physiology or medicine

14

January 2010

SpinSpin--offoff e Starte Start--up: le tappe piup: le tappe piùù importantiimportanti

• Progetto innovativo (“L’idea”)

• Il risvolto applicativo (Business Plan)

• La gestione (management)

• Il finanziamento

• Il decollo

15

January 2010

naproxen 30 mg/kg vehicle

Naproxen-induced GI damage in the rat

Male Wistar rats receiving naproxen orallyGastric damage assessed 4 h afterwards

Lesi

on In

dex

0

10

20

30

40

50

naproxen30 mg/kg

vehicle

16

January 2010

NO is a key mediator in gastrointestinal mucosal defence and integrity

N O

Gastric epithelium

? mucus secretion

Neutrophils

? adherence and secretion

Fibroblasts

? wound repair

Vasculature

Vasorelaxation; ? cell adhesion

Macrophages

? cytokine release

Mast cells

? degranulation and mediators release

Adapted from Wallace, Gastroenterology 2000

17

January 2010

Contribution of NO in the pylorus ligation ulcer model

Legend: CF, control fasted; CL, control ligated

Ulcers induced in rats by pylorus ligation. SNP (1 mg/kg) or L-NAME (10 mg/kg) administered intraduodenally right after ligation. Data collected 4 h thereafter.

*P<0.05 vs. CLaP<0.01 vs. L-NAME

Dixit, Pharmacol Res 1999

Ulcer index Total acid content

*P<0.05 vs. CFaP<0.05 vs L-NAME

Ulc

er In

dex

0

1.2

4.8

3.6

2.4

6

*

a

*

CF CL SNP L-NAMETo

tal A

cid

Out

put (

meq

/4hr

)0

200

600

500

300

800

700

400

100

CL SNP L-NAME

a*

*

18

January 2010

Nitrovasodilators decrease risk of upper gastrointestinal bleeding in subjects using NSAIDs

Lanas et al, New Engl J Med, 2000, 343, 834

19

January 2010

Key steps in the discovery of non steroidal anti-inflammatory drugs (NSAIDs)

1893

1899

Acetylsalicylic acid

1963

Indomethacin

1961 1971

1989

1991

Cloning of COX-2

1997

1999

Rofecoxib

Nobel Prize to Samuelsson, Bergström and Vane (1982)

1973

Diclofenac

Acetaminophen IbuprofenCelecoxib

(first COX-2 inhibitor)Naproxen

1982

Discovery that NSAIDs act by inhibiting prostaglandin

synthesis

Cloning of COX-1

20

January 2010

ConventionalConventional drugdrug --OO--NONO22

NicOx technology in a glimpse

21

January 2010

NicOx Technology

22

January 2010

Naproxcinod: molecular structure

Naproxcinod

O

O N+

O

O-

O

CH3O

CH3

naproxen

NO-donating moiety

4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate

23

January 201023

Discovery of Nitric Oxide (NO) and translation of knowledge into new therapies

1980

Discovery of EDRF (Endothelial-Derived

Relaxing Factor)

1987

Nobel Prize in Medicine and Physiology

awarded for NO-related discoveries

1998

EDRF identified as NO

2005

Naproxcinod enters phase 3

2008

Completion Phase 3

2009

Filing in EU

(EMEA)

NDA filing in the US (FDA)

19961996

Translation of basic knowledge into new medicines

24

January 2010

Models of gastrointestinal damage

- Reduces gastric damage, rat

- Reduces intestinal damage, rat

- Improves ulcer healing, rat

Naproxcinod shows superior gastric safety profile to naproxen in animal models

Pharmacology of naproxcinod - Gastrointestinal

25

January 2010

Naproxcinod is better tolerated than naproxen at the gastric level – single oral administration

Female Sprague-Dawley rats (n=10); single oral dose; damage score assessed @ 5h; *, p<0.05; **, p<0.01 vs. vehicle

Seve

rity

gast

ric d

amag

e(a

rbitr

ary

units

)

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Naproxen NaproxcinodVeh. 3 6 18 18 54 70

Severity

His

tolo

gica

l sco

re(a

rbitr

ary

units

)

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Naproxen NaproxcinodVeh. 3 6 18 18 54 70 mg/kg

*

**

**

**

Damage

26

January 2010

Naproxcinod is better tolerated than naproxen at the gastric level – subcutaneous single administration

0

5

10

15

20

25

30

35

40

45Le

sion

inde

x

Naproxen Naproxcinod

0 3 10 30 30 90 mg/kg

*

**

*, p<0.002 vs. vehicle; **, p<0.001 vs. vehicle; †, p<0.001 vs. 30mg/kg naproxen

†

** **

Gastric damage in a model of ischemia-reperfusion in the rat. Drugs administered s.c.

27

January 2010

Il processo di Il processo di DrugDrug DiscoveryDiscovery & & DevelopmentDevelopment

RicercaSviluppo

non-clinico(tossicologia)

Sviluppo non-clinico

(tossicologia, formulazione)

Fase I Fase II Fase IIIFase IV(farmaco-vigilanza)

Richiesta autorizzazione per l’utilizzo del nuovo

farmaco

Richiesta autorizzazione per la sperimentazione

sull’uomo

0 5.5 8.5 12

ANNI

28

January 2010

0

2

4

6

8

10

75

0 m

g o

d

Mea

ner

osio

nsan

d ul

cers

, Day

12

50

0 m

g b

i d

Scand. J. Gastroenterol. (2006) 41: 264-273

Randomised, double blind, crossover study25 healthy volunteers/groups, 12-day treatment

Phase 1 Study: Naproxcinod – Enhanced GI Safety Profile

75

0 m

g b

i d

37

5 m

g b

i d2

50

mg

bi d

**

p < 0.05 vs. naproxen*

NaproxenNaproxcinod 375 mgNaproxcinod 750 mg

29

January 2010

• Design• 6-week, double-blind, parallel-group study

• 970 hip or knee OA patients

• randomised to naproxcinod 750 mg bid, naproxen 500 mg bid or placebo

• Primary variable• The number of subjects with at least one ulcer

=3 mm in the stomach or duodenum after 6 weeks of treatment, as assessed by gastroscopy

• Statistically significant results in secondary endpoints including:

• cumulative rate of stomach and duodenal ulcers and erosions (p<0.01)

• within subject changes in stomach and duodenal ulcers and erosions

• other GI symptoms

Lohmander et al. Ann Rheum Dis 2005 ; 64: 449-456

% o

f Sub

ject

s w

ith G

astr

oduo

dena

lUlc

ers

0%Naproxcinod

750mg bidn=437 (BL)n= 404 (6W)

54/394 (13.7%)

39/404(9.7%)

0

5

10

15

p=0.07

Placebo bid

n=116 (BL) n=100(6W)

Naproxen500mg bidn=415 (BL) n=394(6W)

20

Phase 2 Study: STAR Multinational Study Group

30

January 2010

31

January 2010

NICOX SA Euronext Paris

32

January 2010

News Release_________________________________________________________________Merck Announces Voluntary Worldwide Withdrawal of VIOXX®

WHITEHOUSE STATION, N.J., Sept. 30, 2004 – Merck &. Co., Inc. today announced a voluntary worldwide withdrawal of VIOXX® (rofecoxib), its arthritis and acute pain medication.

The company’s decision, which is effective immediately, is based on new, three-year data from a prospective, randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial. The trial, which is being stopped, was designed to evaluate the efficacy of VIOXX 25 mg in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas.In this study, there was an increased relative risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking VIOXX compared to those taking placebo.…………………………………

http://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf

33

January 2010

Nitric oxide (NO) has several functions in a variety of cells and organ systems

Cardiovascular systemGastrointestinal tract .N O

Protects from gastrointestinal injury by

ØMaintaining mucosal blood flow

ØInhibiting platelet adhesion

Beneficial effects on cardiovascular system

ØProtects from endothelial dysfunction

ØReduces blood pressure

34

January 2010

Vehicle Naproxcinod 13.5 mg/kg Naproxen 10 mg/kg180

190

200

210

220

230

240

basal 1 2 3 4 5 6 7

SBP

(mm

Hg)

Day of treatment

*

*, p<0.05 naproxcinod vs. naproxen, ANOVA for AUC values

Naproxcinod reduces blood pressure in spontaneously hypertensive rats

35

January 2010

Naproxcinod: Clinical Overview

• Three large pivotal OA trials• “301”: 918 patients with knee OA • “302”: 1020 patients with knee OA • “303”: 810 patients with hip OA

• Blood pressure Data• Office Based Blood Pressure Measurements

• Pre-specified secondary endpoints in all Phase 3 trials• « 304 » pooled analysis to generate sufficient BP data

• Ambulatory Blood Pressure Measurements• Two large ABPM trials completed in 417 patients

• GI Data• 3 Upper GI endoscopy studies• General Safety from Phase 3

All phase 3 trials are: •double-blind•placebo & naproxen controlled •3 standard co-primary efficacy endpoints at 13 weeks

36

January 2010

HCT 3012-X-304 Difference in SBP LS Mean changes between treatments at Week 13

First group better Second group better-5 -4 -3 -2 -1 0 1 2 3 4 5

Naproxcinod 750 mg bid vs Naproxen 500 mg bid: LS Mean Diff. (95% CI)At Week 13 662 vs 522 -1.78 [-3.05 , -0.51] 0.0059

HCT 3012-X-304 Difference in SBP LS Mean changes between treatments at Week 13

First group better Second group better-5 -4 -3 -2 -1 0 1 2 3 4 5

Naproxcinod 375 mg bid vs Naproxen 500 mg bid: LS Mean Diff. (95% CI)At Week 13 405 vs 522 -0.74 [-2.20 , 0.72] 0.3176

HCT 3012-X-304 Difference in SBP LS Mean changes between treatments at Week 13

First group better Second group better-5 -4 -3 -2 -1 0 1 2 3 4 5

Naproxcinod 750 mg bid vs Placebo: LS Mean Diff. (95% CI)At Week 13 662 vs 607 -0.37 [ - , 0.64] 0.2753

HCT 3012-X-304 Difference in SBP LS Mean changes between treatments at Week 13

First group better Second group better-5 -4 -3 -2 -1 0 1 2 3 4 5

Naproxcinod 375 mg bid vs Placebo: LS Mean Diff. (95% CI)At Week 13 405 vs 607 0.67 [ - , 1.90] 0.1827

HCT 3012-X-304 Difference in SBP LS Mean changes between treatments at Week 13

First group better Second group better-5 -4 -3 -2 -1 0 1 2 3 4 5

Naproxen 500 mg bid vs Placebo: LS Mean Diff. (95% CI)At Week 13 522 vs 607 1.42 [ - , 2.50] 0.0160

304 Pooled Analysis - Systolic Blood PressureLS Mean Changes from Baseline at Weeks 2, 6, 13 and by Week 13 (Pooled Safety Population)

37

January 2010

Naproxcinod - US NDA and EU MAA in 2009

• NDA to FDA• Submission done Sept. 24, 2009• Action Letter at the end of the Final Phase (July 24th, 2010)• Statistics:

• 4018 subjects exposed to naproxcinod (>3000 with osteo-arthritis)• electronic filing 11.5 GB in size with 360,000 pages in total

• EU MAA• MAA Submission: by Dec. 18, 2009• Validation period completed by Jan. 20, 2010.

38

January 2010

39

January 2010

NicOx global network

NicOx Headquarters, Sophia-Antipolis, FranceNicOx Research Institute Bresso, Italy

Axcan PharmaMont-Saint-Hilaire, Quebec, Canada

Biolipox ABStockholm, Sweden

Grupo Ferrer Int. SABarcelona, Spain

Merck & Co., Inc.Rahway, NJ, USA

Pfizer Inc.La Jolla, CA, USA

Topigen Pharm. Inc.Montreal, Canada

NicOx Inc, Warren, NJ, USA

AstraZeneca Sodertalje, Sweden

40

January 2010

1 - Agreement with Pfizer

2 – Agreement with Merck

3 – FDA feedback

NICOX SA Euronext Paris

41

January 2010

Collaborations with Pfizer in ophthalmology

First agreement signed in August 2004 for glaucoma

New agreement signed on March 2, 2006

42

January 2010

Elevated intraocular pressure is a risk factor for glaucoma leading to vision loss

43

January 2010

NO-releasing derivative of latanoprost

OH

OH

O

O

OH

OH

OH

O

O

OH

L NO donating moiety

Xalatan™(Isopropyl ester of latanoprost acid)

PF-03187207 / NCX 116

44

January 2010

US Phase 2 study: LS Mean (90% CI) Change from Baseline in IOP (mmHg) at Each Timepoint across All Study Visits: statistically significant difference in IOP reduction 20 hours post-dose

-11

-10

-9

-8

-7

-6

-5

-4

Time Across Visits

LS M

ean

(90%

CI)

Cha

nge

from

BSL

in IO

P (m

mH

g)

PF 0.040% PM Latan 0.005% PM

8AM12h post-dose

Statistically significant result (p<0.10):PF-207 PM vs Latanoprost PM:

LS Mean Diff at 4PM: 1.38 (0.26, 2.49) p-value = 0.043

10AM14h post-dose

1PM17h post-dose

4PM20h post-dose

45

January 2010

46

January 2010

Major license, development and co-promotion agreement with Merck in the antihypertensive field

Agreement signed on March 21, 2006

47

January 2010

Enhanced NO availability may deliver multiple CV benefits

Rudd, Trolliet and Loscalzo, 2000

48

January 2010

ACE inhibitoror ARB Nitric Oxide+

Superior BP lowering efficacy and/or

Superior end-organ protection

Nicox-Merck exploratory project

49

January 2010

SpinSpin--offoff e Starte Start--up: le tappe piup: le tappe piùù importantiimportanti

• Progetto innovativo (“L’idea”)

• Il risvolto applicativo (Business Plan)

• La gestione (management)

• Il finanziamento

• Il decollo

50

January 2010

The NicOx Model

THE COMPANYTHE COMPANY• Minimal structure

• High outsourcinglevel

Strong scientific

“idea”

License and

co-developmentagreements with

Pharmacompanies

Developmentthrough CROsand contract

scale-up / manufacturing

Strong intellectual

propertyStrong

management team

“Focussed”and “lean”

internalresearch structure

Research collaborations

with world leading experts

51

January 2010

295- Other countries

17- Priority Applications (USA provisional + EP priority)

36- EP + PCT

27- USA

455Total Pending Patent Applications

177- Other countries

444- European Countries

31- EP

45- USA

666Total granted Patents

86Total Patent families

Jan. 2009NICOX PATENT PORTFOLIO

May 2009: Acquisition of NitroMed Patent Portfolio

52

January 2010

NicOx Executive Management Team

Michele Garufi,Chairman and CEO

Maarten Beekman,Vice President ClinicalDevelopment & Medical Affairs

Eric Castaldi,Chief Financial Officer

Jacques Djian,Vice President Explo.Dev. & Translational Medicine

Ennio Ongini,Vice President, Research

Pascal Pfister, Chief Scientific Officer

Philippe Serrano,Vice PresidentRegulatory Affairs

Sanjiv Sharma,Vice President of Commercial Affairs

Gavin Spencer,Vice-President Business Development

53

January 2010

Scientific Advisory Board (SAB) Members

Bengt Samuelsson Karolinska Inst, Stockholm

Garret FitzGeraldUniversity of Pennsylvania Philadelphia

Salvador MoncadaThe Wolfson Inst. for Biomedical Research, London

Thomas SchnitzerNorthwestern UniversityChicago

Joel MenardDép Santé Publique, Informatique et Statistiques Médicale, Paris

54

January 2010

• Feb 1996 2.5 M$ from funding VCs• Dec 1997 7 M$ from funding VCs• Nov 1999 33 M€ at the IPO (Paris)• May 2001 59 M€ at follow-on equity offering• Sept 2004 26 M€ in a Private Placement• Apr 2006 45 M€ in a Private Placement• Feb 2007 120 M€ in Rights issue• Dec 2009 30 M€ in a Private Placement• Dec 2009 70 M€ in Rights issue

Total ~ 390 M€

Funding of Nicox since 1996

55

January 2010

Laboratory life at NicOx Research Institute

56

January 2010

Thank you

Corporate site:www.nicox.com

Nitric Oxide Knowledge Center:www.nitricoxideonline.net