2. Reliable technology or programed failure ? 1 Anne-Sophie Berteloot Marie Crétal Julienne Gombet Marion Stylemans

3. 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 2

4. I) NicOx company overview II) Successes and failures III) Naproxcinod: the last hope? IV) What about the financial health of NicOx? V) Do we want to work at NicOx? 3

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6.  French Biotechnology Business company (Private placements: 8,3 M€)  Location : Head office : Sofia Antipolis Italian subsidiary US Headquarters NicOx in brief …  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. 5

7. 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 6

8. « NO-donating technology can bring clear medical and market benefits » « NO-donating drugs are more effective and tolerable than existing compounds ». N O …A technology concept Established drug + linker + -ONO2 = Novel Chemical Entity An idea … Ester linkage 7

9. Cardiovascular system Reduces blood pressure Vasodilatation Anti-inflammatory Protects from Gastrointestinal injury Maintains mucosal blood flow Inhibits platelet adhesion Autoimmune system Neurotransmitter Protects against oxidative damage 8

10. 9  NO synthase (NOS) enzymes 3 isoforms: Inductible form (iNOS) “Constitutive” forms - Endothelium (eNOS) - Neurons (nNOS) Endogenous production

11. NO= key relaxing factor 10

12. 11  When production of NO is impaired, or its bioavailability reduced, the following can result: vasoconstrictioninflammation vasoconstrictioninflammation vascular hypertrophy andthrombosis vascular hypertrophy andthrombosisstenosis These effects can lead to diseases and conditions such as: These effects can lead to diseases and conditions such as:  hypertension  obesity  dyslipidemias  heart failure  atherosclerosis  diabetes (I+II)  Commercial interest

13. Discovery of NO NO is identified as endothelium- derived relaxing factor (EDFR) NO is nominated « Molecule of the Year » Translation of basic knowledge of NO into new medicines Nobel Prize in Medicine for « NO as a signaling molecule in the CV system » 1772 1987 1992 1996 1998 2005 Naproxcinod Phase III 12

14. INDUSTRIAL STRATEGY OF NICOX AND PARTNERSHIP 13

15. The company : minimal structure high outsourcing level Strong scientific « idea » Strong intellectual property License and co- development agreements with Pharma companies Development through CRO s and contract scale-up / manufacturing Strong management team “Focussed” and “lean” internal research structure Research collaboration with world leading experts 14

16. Industrial strategy of NicOx … …To a fully integrated biopharmaceutical company 15 In-house R&D programmes In-licensing Selective acquisitions Fully integrated biopharmaceutical company

17. Great and attractive communication Lien Nitric Oxid Knowledge Center 16

18. 1st agreement 1996200320042005 2006 19982002 License agreement with Pfizer and Merck 17

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20. 20022005 2007 2008 Phase II AZD3582 NicOx Astra-Zeneca Phase II NCX4016 (AOMI) NicOx Bayer Phase II ongoing by NicOx (Type 2 diabetes) Phase IIa NCX1020 (COPD) NicOx Topigen Phase IIa PF-03187207 NicOx Pfizer 2003 Phase I HCT1026 (Alzheimer) Phase II NCX100 (Portal hypertension) NicOx Axcan Phase III ongoing by NicOx 19

21. Overview of the clinical studies NICOX PARTNERSHIPS 20

22. First agreement signed in August 2004 for glaucoma New agreement signed on March 2, 2006 Collaborations with Pfizer in ophthalmology PF-03187207 a nitric oxide-donating prostaglandin analog Glaucoma - Phase 2 Partnered with Pfizer Inc 21

23. Elevated intraocular pressure is a risk factor for glaucoma which can lead to vision loss Xalatan® Latanoprost vs PF-03187207 (Pfizer, 2011) (NicOx) 22

24. 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 23 NicOx/Pfizer sign Research, Development and Licensing Agreement 2004 Financial terms 24 august, 2004

25. 2006 agreement in ophtamology €23 million in 2006 €5 million upfront technology license fee €15 million as equity investment €3 million as research funding Exclusive rights to NO-donating technology in ophthalmology in multiple compound classes and indications €3 million in 2007 & 2008 as research funding “Total potential milestones >€300 million” 24 NicOx Pfizer Option of a worldwilde exclusive licence

26. PF-03187207 in phase 2 clinical development NAMEPF-03187207 NO-donating prostaglandin F2 α analogs for glaucoma OBJECTIVESCompare 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 STRUCTURE 28day randomized Dose-finding double-masked trial Parallel group RESULTS highest dose of PF-03187207 showed ↘ 12% (1 mmHg) … BUT non significant results!! March’07: First phase 2 PoC study initiated in the U.S 25

27. PF-03187207 in phase 2 clinical development CODEPF-03187207 NAMENO-donating prostaglandin F2 α analogs for glaucoma OBJECTIVES Compare the safety and efficacy of PF’7207 versus Xalatan Primary End-points change in diurnal intraocular pressure (IOP) at day 28 120 Japanese patients to be enrolled Structure Similar design to U.S. study January’08: Second phase 2 PoC study initiated in Japan August 2008 Pfizer won’t continue PF-03187207 development to phaseIII 26

28. Collaboration with Topigen in COPD TPI-1020 novel anti-inflammatory respiratory drug candidate Respiratory disorders - Phase 2 Partnered with TOPIGEN Pharmaceuticals Inc. 27

29. COPD Chronic Obstructive Pulmonary Disease 28

30. 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 Agreements details 29

31. CODETPI 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!! Safety, Tolerability and PD Activity of Inhaled TPI 1020 Versus Inhaled Budesonide in COPD Patients 30

32. Nitric oxide-donating antihypertensives Hypertension - phase 1b Partnered with Merck & Co., Inc. Agreement signed on March 21, 2006 Major license, development and co-promotion agreement with Merck in the antihypertensive field 31

33. Prototype compound NCX 899 - Significantly better Blood Pressure lowering in a validated model of hypertension 32

34. Merck agreement details €9.2 million in up front €279 million potential milestone In 2006 - January 2007: €5 million milestone Initiation of toxicology studies on first 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 33 ? ?

35. NicOx pipeline 34 ? ?

36. NicOx future blockbuster? Will it come in the market without a hitch? 35

37. CodeAZD 3582 / HCT 3012 Derived fromNaproxen 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 $ 36

38. CodeAZD 3582 / HCT 3012 Derived fromNaproxen Structure: NO-Naproxen Class Leading drug of a new class: CINOD (COX Inhibiting Nitric Oxid Donators) Indication  Phase III clinical trials completed  Treatment of the signs and symptoms of osteoarthritis Naproxen Ester linkage NO-donating group 37

39. Expected benefits - At least as effective as Naproxen - No negative effects on blood pressure different from all NSAIDs - Better gastrointestinal safety Commercial benefits expected - Future blockbuster: potential sales > $ 1 billion - Opportunity of the market in osteoarthitis treatment … 38

40. A need of an effective NSAID without negative effects on blood pressure  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 39

41. Naproxcinod’s history Co-development with Astra-Zeneca $ 37 M Naproxcinod phase II : Disappointing results Astra-Zeneca cancels the deal NicOx wants to pursue a phase III study 1998 2003 mid- 2009 Naproxcinod Phase III 2007 2008 Positive results from phase III annonced by NicOx Different partnerships 2005 Planned NDA filling in the US 2010 Planned filling in Europe Search for Partnering activities 40

42. Pharmacokinetics datas Ester linkage The lenght and chemical nature of the ester linkage can influence the rate of release of NO from the molecule Esterases 41

43. 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 42

44. Phase 2 study: AZD3582 vs naproxen in osteoarthritis Objective To evaluate the gastrointestinal safety and efficacy of AZD3582 in patients with hip or knee osteoarthritis. Primary endpoints The six week incidence of endoscopic gastroduodenal ulcers (diameter >3 mm) Design n=970 AZD3582 750 mg Naproxen 500mg Placebo a six week double blind randomised trial 43

45. Gastrointestinal safety  Placebo: 0  AZD3582: 9,7%  Naproxen: 13,7% 44 But the results didn’t achieve statistical significance (p=0,07)

46.  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

47. n = 918 Naproxcinod 375 mg Naproxcinod 750 mg Naproxen 500 mg Placebo ObjectiveTo 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 DesignIn patients with OA of the knee 13-week double-blind randomized trial 46

48. § High statistical significance for superiority to placebo (p<0.001) Naproxcinod > Placebo But… Naproxcinod ≡ Naproxen Yes but…. For gastrointestinal safety: Naproxcinod ≡ Naproxen 47

49. ObjectiveTo 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

50.  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? 49

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52. 51 STRENGHTS Reduces blood pressure 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 OPPORTUNITIES Interesting for hypertensive patients THREATS FDA is reluctant to approve NSAID since CV problems with Vioxx, COX inhibitor as well

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54.  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 Co-funders 2006 53

55. Operational revenues  Payments received under collaboration agreements with pharmaceutical partners ( € 52,1 M) Agreements with Pfizer and Merck End of the collaboration agreements 54

56. 55 86,4 61,3 36,321,4 16,620,9 24,2 Increase +++ in R&D expenses results mainly from the cost related to the phase 3 development of Naproxcinod

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59. 58 AstraZeneca deal Termination of AstraZeneca deal Pfizer and Merck deals Naproxcinod results and share offer

60. Historic chart : 1 year New positive results for naproxcinod + 70%: agreement signed with Archimica for the production of naproxcinod Positive treasury Financial crisis Less attraction for investors 59

61. 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

62.  Positive approbation for naproxcinod  Setback of naproxcinod Takeover bid Partnership Failure Is it realistic? 61

63. If I were a pharmacist, I would / would not like to work in NicOx and why ? 62 Biotech = opportunity of quick progression One product well-advanced in the clinical trials No liabilities StrenghtsWeaknesses credibility of NO technology? loss of €74 million in 2008 A lot of failures in NicOx pipeline Opportunities positive approbation for the naproxcinod  reflation of partnerships and takeover bid Threats no scientific support cessation of the partnerships

64. CONCLUSION 63

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66. 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 65 Any questions?