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Reliable technology or programed
failure ?
Anne-Sophie Berteloot
Marie Crétal
Julienne Gombet
Marion Stylemans
1
Safe Harbor
This is an independent study
performed by students from the
Faculté des Sciences
Pharmaceutiques de Lille
The opinions expressed are our own
and not necessarily those of NicOx
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I)
II)
III)
IV)
V)
NicOx company overview
Successes and failures
Naproxcinod: the last hope?
What about the financial health of NicOx?
Do we want to work at NicOx?
3
4
NicOx in brief …
 French Biotechnology Business company (Private
placements: 8,3 M€)
 Location :
Italian
subsidiary
US Headquarters
Head office :
Sofia Antipolis
Core expertise : nitric oxide-donating technology
Application : Drug discovery in the cardiometabolic and
inflammatory domain
 NicOx’s products don’t target a « niche » but compete with
drugs existing in huge markets.
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NicOx in brief …
 Corporate statut :
 Founded in 1996 in France by Piero Del Soldato,
Elizabeth Robinson and Michele Garufi
 Chief Executive Officer : Michele Garufi
 Public company
IPO date : November 3, 1999; 33 million euros
Listed on Euronext
 117 employees
 Aim : « build itself into a fully integrated
bio-pharmaceutical company »
 Strategy of development :
Partnerships and co-development agreements with
pharmaceutical companies
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An idea …
.N
« NO-donating technology can bring clear
medical and market benefits »
« NO-donating drugs are more effective and
tolerable than existing compounds »
O
…A technology concept
Established drug + linker + -ONO2 =
Novel Chemical Entity
Ester linkage
7
Protects from Gastrointestinal injury
 Maintains mucosal blood flow
 Inhibits platelet adhesion
Autoimmune system
Anti-inflammatory
Cardiovascular system
 Reduces blood pressure
 Vasodilatation
Protects against
oxidative
damage
Neurotransmitter
8
Endogenous production

NO synthase (NOS)
enzymes
3 isoforms:
•
•
Inductible form
(iNOS)
“Constitutive” forms
- Endothelium (eNOS)
- Neurons (nNOS)
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NO= key relaxing factor
10

When production of NO is impaired, or its
bioavailability reduced, the following can result:
• vasoconstriction
inflammation
• vascular hypertrophy and
thrombosis
stenosis
These effects can lead to diseases and conditions
such as:
 hypertension
 heart failure
 obesity
 atherosclerosis
 dyslipidemias
 diabetes (I+II)
 Commercial interest
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Discovery
of NO
1772
NO is nominated
« Molecule of the
Year »
1987
1996
1992
NO is identified as
endotheliumderived relaxing
factor (EDFR)
Nobel Prize in
Medicine for « NO
as a signaling
molecule in the CV
system »
2005
1998
Naproxcinod
Phase III
Translation of basic
knowledge of NO
into new medicines
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INDUSTRIAL STRATEGY OF
NICOX AND PARTNERSHIP
13
Strong
intellectual
property
Strong
scientific
« idea »
License and
codevelopment
agreements
with Pharma
companies
Development
through CROs
and contract
scale-up /
manufacturing
The company :
• minimal structure
• high outsourcing
level
Research collaboration
with world leading
experts
Strong
management
team
“Focussed” and
“lean” internal
research
structure
14
Industrial strategy of NicOx
…
…To a fully integrated biopharmaceutical
company
In-house R&D
programmes
Fully integrated
biopharmaceutical
company
Selective
acquisitions
In-licensing
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Great and attractive
communication
Lien Nitric Oxid Knowledge Center
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1996
1998
2002
2003
2004
2005
2006
1st agreement
License
agreement with
Pfizer and Merck
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18
Phase I
HCT1026
(Alzheimer)
2002
2005
2003
Phase II
AZD3582
NicOx
Astra-Zeneca
Phase III ongoing
by NicOx
Phase II
NCX100
(Portal hypertension)
NicOx
Axcan
Phase II NCX4016 (AOMI)
NicOx
Bayer
Phase II ongoing by
NicOx (Type 2 diabetes)
Phase IIa NCX1020 (COPD)
NicOx
Topigen
2008
2007
Phase IIa
PF-03187207
NicOx
Pfizer
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NICOX PARTNERSHIPS
Overview of the clinical studies
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Collaborations with Pfizer in
ophthalmology
PF-03187207 a nitric oxide-donating prostaglandin analog
Glaucoma - Phase 2
Partnered with Pfizer Inc
First agreement signed in August 2004 for glaucoma
New agreement signed on March 2, 2006
21
Elevated intraocular pressure is a risk
factor for glaucoma which can lead to
vision loss
Xalatan® Latanoprost vs PF-03187207
(Pfizer, 2011)
(NicOx)
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NicOx/Pfizer sign Research, Development
and Licensing Agreement 2004
Financial terms 24 august, 2004
NicOx will receive:
 €1 million in upfront
+
 €1 million six month later
+
 €32 million in future
milestones
+
 royalties
Pfizer should reveive:
 A worldwide license on
NO-Donating
compounds
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2006 agreement in ophtamology
Exclusive rights to NO-donating technology in ophthalmology
in multiple compound classes and indications
NicOx
€5 million upfront technology license fee
€23 million in 2006
€15 million as equity investment
€3 million as research funding
€3 million in 2007 & 2008
Pfizer
as research funding
Option of a worldwilde exclusive licence
“Total potential milestones >€300 million”
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PF-03187207 in phase 2 clinical
development
March’07: First phase 2 PoC study initiated in the U.S
NAME
PF-03187207
NO-donating prostaglandin F2α analogs for glaucoma
OBJECTIVES
Compare the safety and efficacy of PF’7207 versus
Xalatan 0,005%
PRIMARY
END-POINTS
change in diurnal intraocular pressure (IOP) at
day 28
In 215 patients with primary open angle glaucoma
or ocular hypertension
28day
randomized
Dose-finding
double-masked trial
Parallel group
STRUCTURE
RESULTS
highest dose of PF-03187207 showed ↘ 12% (1 mmHg)
… BUT non significant results!!
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PF-03187207 in phase 2 clinical
development
January’08: Second phase 2 PoC study initiated in Japan
CODE
PF-03187207
NAME
NO-donating prostaglandin F2α analogs for glaucoma
OBJECTIVES
Compare the safety and efficacy of PF’7207
versus Xalatan
change in diurnal intraocular pressure (IOP) at
day 28
120 Japanese patients to be enrolled
Primary
End-points
Structure
Similar design to U.S. study
August 2008 Pfizer won’t continue PF-03187207
development to phaseIII
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Collaboration with Topigen in
COPD
TPI-1020
novel anti-inflammatory respiratory drug candidate
Respiratory disorders - Phase 2
Partnered with TOPIGEN Pharmaceuticals Inc.
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COPD Chronic Obstructive
Pulmonary Disease
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Agreements details
Canadian-based TOPIGEN
•
•
the North American rights
develop and market NCX 1020
NicOx would receive
- a 2 million Euros upfront payment
+
- Up to 52.9 million Euros in milestones
+
- Commercial success fees in addition to a share in future revenues
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Safety, Tolerability and PD Activity of Inhaled TPI
1020 Versus Inhaled Budesonide in COPD Patients
CODE
TPI 1020 NO-donating anti-inflammatory
STRUCTURE
61 patients with Chronic Obstructive Pulmonary Disease
Primary
Outcome
Measures:
To determine general safety and the tolerability of
inhaled TPI 1020 administered via Aerolizer™ in COPD
patients.
Secondary
Outcomes
Measures:
To assess the effects of TPI 1020 versus those of
budesonide on sputum neutrophil counts on
Days 0 and 42
Results
Reduction of neutrophils in patients expectorations
Primary outcome on Safety and torerability is achieved
No additional efficacity effects observed!!
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Major license, development and co-promotion
agreement with Merck
in the antihypertensive field
Agreement signed on March 21, 2006
Nitric oxide-donating antihypertensives
Hypertension - phase 1b
Partnered with Merck & Co., Inc.
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Prototype compound NCX 899 - Significantly
better Blood Pressure lowering in a validated
model of hypertension
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Merck agreement details
€9.2 million in up front
€279 million potential milestone
In 2006
•
January 2007:
€5 million milestone
•
Initiation of toxicology studies
development candidate selected
•
July 2007:
€5 million milestone
•
A series trials on the first drug candidate
which is a phase 1
•
dose escalating study in healthy volunteers
on
first
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NicOx pipeline
??
34
NicOx future blockbuster?
Will it come in the market without a hitch?
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Code
Derived from
AZD 3582 / HCT 3012
Naproxen
Non-steroidal anti-inflammatory drug (NSAID)
Mechanism: COX-1 and COX-2 inhibitor
Indications: To moderate pain, inflammation and
fever in Osteoarthritis, rheumatoid arthritis,
ankylosing spondylitis, tendinitis, bursitis…
Side effects:
- Raise blood pressure in hypertensive patients
- Gastroduodenal ulcers
now generics, market = 13,3 billion $
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Code
AZD 3582 / HCT 3012
Derived from
Naproxen
Structure:
NO-Naproxen
NO-donating
group
Naproxen
Class
Indication
Ester linkage
Leading drug of a new class: CINOD
(COX Inhibiting Nitric Oxid Donators)


Phase III clinical trials completed
Treatment of the signs and symptoms of
osteoarthritis
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Expected
benefits
- At least as effective as Naproxen
- No negative effects on blood pressure
different from all NSAIDs
- Better gastrointestinal safety
Commercial - Future blockbuster: potential sales > $ 1 billion
- Opportunity of the market in osteoarthitis
benefits
treatment …
expected
38
 Osteoarthritis: > 70 M Patients in the US and in Europe
 NSAIDs market > $ 12 billion / year
 40 % of people suffering from osteoarthritis are hypertensive
 Significant opportunity for Naproxcinod since the
withdrawal of Cox-2 inhibitor Vioxx® (Rofecoxib) from the
market in 2004.
Celebrex is now the only one NSAIDs promoted in the US
 Most of NSAIDs raise blood pressure
 End of patents for most NSAIDs: generics
A need of an effective NSAID without negative
effects on blood pressure
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Naproxcinod’s history
Positive results
from phase III
annonced by
NicOx
Co-development
with Astra-Zeneca
$ 37 M
2003
mid2009
2005
2010
Different
partnerships
1998
Naproxcinod
Phase III
Naproxcinod phase II:
Disappointing results
Astra-Zeneca cancels the deal
NicOx wants to pursue a phase III
study
2007
2008
Planned filling
in Europe
Planned NDA
filling in the US
Search for Partnering activities
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Pharmacokinetics datas
Esterases
Ester linkage
The lenght and chemical nature of the ester linkage can influence the rate of
release of NO from the molecule
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Intracellular Release of NO
from NO-aspirin
Method: Confocal microscopy
1)Human endothelial cells were loaded with a dye that becomes
fluorescent on reaction with NO
2)Cells were exposed to NO-aspirin
Results:
POTENTIAL CARDIOPROTECTIVE ACTIONS OF NO-RELEASING ASPIRIN
NATURE REVIEWS/DRUG DISCOVERY, volume 1, May 2002
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Phase 2 study: AZD3582 vs
naproxen in osteoarthritis
Objective
Primary
endpoints
To evaluate the gastrointestinal safety and efficacy
of AZD3582 in patients with hip or knee
osteoarthritis.
The six week incidence of endoscopic
gastroduodenal ulcers (diameter >3 mm)
Design
AZD3582 750 mg
n=970
Naproxen 500mg
a six week
double blind
randomised trial
Placebo
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Gastrointestinal safety



Placebo: 0
AZD3582: 9,7%
Naproxen: 13,7%
But the results
didn’t achieve
statistical
significance (p=0,07)
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


02/2003: Disappointing phase II results for
Naproxcinod
NicOx’s action is incotable for 2 days
NicOx’s action collapse:
- 85 %



NicOx is convinced of the efficacy and safety of
naproxcinod and critizes the methodology used
09/2003: Astra-Zeneca ends the partnership
NicOx wants to pursue a phase III study (2005)
45
Objective
To evaluate safety and efficacy of Naproxcinod
Primary
endpoints
- WOMAC* pain and WOMAC function subscales and
patient’s global assessment
- Safety focused on adverse effects and blood pressure
*WOMAC = index assessing pain, disability and joint stiffness using
a battery of 24 questions
Design
In patients with OA of the knee
Naproxcinod 375 mg
Naproxcinod 750 mg
n = 918
Naproxen 500 mg
13-week
double-blind
randomized trial
Placebo
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§ High statistical significance for superiority to placebo (p<0.001)
Naproxcinod > Placebo
But…
Naproxcinod ≡ Naproxen
Yes but….
For gastrointestinal safety:
Naproxcinod ≡ Naproxen
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Objective
To evaluate the profile of Naproxcinod on blood pressure,
compared to placebo and naproxen (13 weeks)
Primary
endpoints
OBPMs = Office blood pressure measurements collected at
each visit to the treatment centers from the 3 studies
48

Yes but…

A significantly proportion of patients on
Naproxcinod experienced an increase in SBP of
5mmHg or more, compared to Naproxen

Interesting for hypertensive patients but the others
???
Is reduction of blood pressure sufficient to be a
good commercial argument?
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STRENGHTS
• Reduces blood
pressure
OPPORTUNITIES
• Interesting for
hypertensive patients
WEAKNESSES
• Not more effective than Naproxen
• No scientific communication on study results: credibility?
• No direct confrontation Naproxen/Naproxcinod
• Decrease in blood pressure not really convincing
• Nicox cannot cope with commercialisation fees
• Time of development
• SMR evaluation: weak
• No Economic interest compare to generics
THREATS
•FDA is reluctant to approve NSAID since CV problems
with Vioxx, COX inhibitor as well
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
Market revenues:




Initial Public Offering on Euronext Paris: € 33,2 M((November 1999)
Follow-on public offerings: September 2004( € 26 M), May 2006 (€
45,5 M), February 2007 (€ 130 M).
Increase of capital € 15 M reserved to its partner Pfizer (June 2006)
Private placements (€ 8,3 M)
% of shares
2006
Co-funders
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Operational revenues

Payments received under collaboration agreements
with pharmaceutical partners ( € 52,1 M)
Agreements with
Pfizer and Merck
End of the
collaboration
agreements
54
86,4
Increase +++ in R&D expenses results
mainly from the cost related to the phase 3
development of Naproxcinod
61,3
24,2
20,9
16,6
21,4
36,3
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AstraZeneca deal
Pfizer and
Merck deals
Naproxcinod
results and
share offer
Termination of
AstraZeneca deal
58
Historic chart : 1 year
+ 70%: agreement signed
with Archimica for the
production of
naproxcinod
Positive treasury
New positive
results for
naproxcinod
Financial crisis
Less attraction for
investors
59
In thousand euros
In 2010
???
« We currently believe that we have sufficient cash to finance the
activities of the commpany until the end of 2010 »
Eric Castaldi, Chief Financial Officer of NicOx
60

Positive approbation for naproxcinod
Takeover bid
Partnership
Is it realistic?

Setback of naproxcinod
Failure
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If I were a pharmacist, I would / would not like to work
in NicOx and why ?
Strenghts
•Biotech = opportunity of quick
progression
•One product well-advanced in the
clinical trials
•No liabilities
Opportunities
• positive approbation for the
naproxcinod  reflation of
partnerships and takeover bid
Weaknesses
• credibility of NO technology?
• loss of €74 million in 2008
•A lot of failures in NicOx pipeline
Threats
• no scientific support
• cessation of the partnerships
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CONCLUSION
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Special thanks
We especially want to thank Guy
Dausque, Ms Gras, Mr Tartar and
Julien Samier for their help and the
time they gave us
Any questions?
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