nICOX

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

2. 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

3. Contents • NicOx company overview • Successes and failures • Naproxcinod: the last hope? • What about the financial health of NicOx? • Do we want to work at NicOx?

4. NICOX COMPANYOVERVIEW

5. NicOx in brief … • French Biotechnology Businesscompany(Private placements: 8,3 M€) • Location : Italian subsidiary US Headquarters Head office : Sofia Antipolis • Core expertise : nitricoxide-donatingtechnology • Application : Drug discovery in the cardiometabolic and inflammatorydomain • NicOx’sproductsdon’ttarget a « niche » but competewithdrugsexisting in hugemarkets.

6. NicOx in brief … Corporate statut : • Founded in 1996 in France by Piero Del Soldato, Elizabeth Robinson and Michele Garufi • ChiefExecutiveOfficer : MicheleGarufi • Public company • IPO date : November 3, 1999; 33 million euros • Listed on Euronext • 117 employees • Aim : « builditselfinto a fullyintegratedbio-pharmaceuticalcompany » Strategy of development : Partnerships and co-developmentagreementswithpharmaceuticalcompanies

7. .N O An idea … « NO-donatingtechnologycanbringclearmedical and marketbenefits » « NO-donatingdrugs are more effective and tolerablethanexisting compounds » …A technology concept Establisheddrug + linker + -ONO2 = NovelChemicalEntity Ester linkage

8. NO regulatesbiologicalfunctions • ProtectsfromGastrointestinalinjury • Maintainsmucosalblood flow • Inhibitsplateletadhesion • Cardiovascular system • Reducesbloodpressure • Vasodilatation Autoimmune system Protectsagainstoxidative damage Anti-inflammatory Neurotransmitter

9. Endogenous production • NO synthase (NOS) enzymes • 3 isoforms: • Inductibleform (iNOS) • “Constitutive” forms • - Endothelium (eNOS) • - Neurons (nNOS)

10. NO= key relaxing factor Vascularmechanism of NO

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

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

13. Industrialstrategy of nicox and partnership

14. Industrialstrategy of NicOx: From a specializedbiotech… Strongintellectualproperty Strongscientific « idea » License and co-developmentagreementswithPharmacompanies Strong management team • The company : • minimal structure • high outsourcing level DevelopmentthroughCROs and contract scale-up / manufacturing “Focussed” and “lean” internalresearchstructure Researchcollaborationwith world leadingexperts

15. Industrialstrategy of NicOx… …To a fullyintegratedbiopharmaceuticalcompany In-house R&D programmes Fully integrated biopharmaceutical company Selective acquisitions In-licensing

16. Great and attractive communication Lien NitricOxidKnowledge Center

17. NicOxPartnership 1996 1998 2002 2003 2004 2005 2006 License agreement with Pfizer and Merck 1st agreement

18. NicOx: a large Pipeline

19. NicOxclinicalstudiesfailures Phase I HCT1026 (Alzheimer) Phase II NCX100 (Portal hypertension) NicOx Axcan 2002 2005 2008 2003 2007 Phase II NCX4016 (AOMI) NicOx Bayer Phase II ongoing by NicOx (Type 2 diabetes) Phase IIa NCX1020 (COPD) NicOx Topigen Phase II AZD3582 NicOxAstra-Zeneca Phase IIa PF-03187207 NicOx Pfizer Phase III ongoing by NicOx

20. Nicoxpartnerships Overview of the clinicalstudies

21. Collaborations with Pfizer in ophthalmology PF-03187207a nitricoxide-donatingprostaglandinanalogGlaucoma - Phase 2Partnered with Pfizer Inc First agreement signed in August 2004 for glaucoma New agreement signed on March 2, 2006

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

23. NicOx/Pfizer sign Research, Developmentand 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

24. 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 • €15 million as equity investment €23 million in 2006 €3 million as research funding €3 million in 2007 & 2008 as research funding Pfizer Option of a worldwilde exclusive licence “Total potential milestones >€300 million”

25. PF-03187207 in phase 2 clinical development March’07: First phase 2 PoC study initiated in the U.S

26. PF-03187207 in phase 2 clinical development January’08:Second phase 2 PoC study initiated in Japan August 2008 Pfizer won’t continue PF-03187207 development to phaseIII

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

28. COPD Chronic Obstructive PulmonaryDisease

29. Agreementsdetails • Canadian-based TOPIGEN • the North American rights • develop and market NCX 1020 • NicOxwould 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

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

31. 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.

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

33. 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 ? ?

34. NicOxpipeline ? ?

35. Naproxcinod:The last hope ? NicOx future blockbuster? Will it come in the market without a hitch?

36. Naproxcinod: A new anti-inflammatory agent

37. Naproxcinod’s profile NO-donating group Naproxen Ester linkage

38. Naproxcinod’s profile

39. Opportunity of the market • Osteoarthritis: > 70 M Patients in the US and in Europe • NSAIDsmarket > $ 12 billion / year • 40 % of people sufferingfromosteoarthritis are hypertensive • Significantopportunity for Naproxcinodsince the withdrawal of Cox-2 inhibitorVioxx® (Rofecoxib) from the market in 2004. • Celebrexisnow the only one NSAIDspromoted in the US • Most of NSAIDsraiseblood pressure • End of patents for mostNSAIDs: generics A need of an effective NSAID withoutnegativeeffects on blood pressure

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

41. 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

42. Intracellular Release of NO fromNO-aspirin • Method: Confocal microscopy • Human endothelial cells were loaded with a dye that becomes fluorescent on reaction with NO • Cells were exposed to NO-aspirin • Results: POTENTIAL CARDIOPROTECTIVE ACTIONS OF NO-RELEASING ASPIRIN NATURE REVIEWS/DRUG DISCOVERY, volume 1, May 2002

43. Phase 2 study: AZD3582 vsnaproxen in osteoarthritis AZD3582 750 mg a six week double blind randomised trial n=970 Naproxen 500mg Placebo

44. Gastrointestinal safety • Placebo: 0 • AZD3582: 9,7% • Naproxen: 13,7% • But the resultsdidn’tachievestatisticalsignificance (p=0,07)

45. The AstraZeneca « Affair » 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)

46. 301 study (October 2006) Naproxcinod 375 mg Naproxcinod 750 mg 13-week double-blind randomized trial n = 918 Naproxen 500 mg Placebo

47. Results of the 301 study § High statistical significance for superiority to placebo (p<0.001) Yes but…. For gastrointestinalsafety: Naproxcinod≡ Naproxen Naproxcinod > Placebo But… Naproxcinod≡ Naproxen

48. Pooledanalysis

49. Pooledanalysis Is reduction of blood pressure sufficient to be a good commercial argument? • Yes but… • A significantly proportion of patients on Naproxcinodexperienced an increase in SBP of 5mmHg or more, compared to Naproxen • Interesting for hypertensive patients but the others ???

50. Naproxcinod’sdifferenciated profile