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1January 2010
NicOx- Evoluzione di una start-up nella ricerca
farmaceutica -
Ennio Ongini Nicox
Sophia Antipolis (France) and Milano (Italy)
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
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
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
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.
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
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
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
56
January 2010
Thank you
Corporate site:www.nicox.com
Nitric Oxide Knowledge Center:www.nitricoxideonline.net
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