Building an international ophthalmic company Shareholder information meeting Michele Garufi, CEO Gavin Spencer, EVP Corporate Development Philippe Masquida, EVP Managing Director of European & International Operations Oct 10, 2014 – Palais Brongniart, Paris Disclaimer This presentation contains certain forward-looking statements. Although the Company believes its expectations are based on reasonable assumptions, these forward-looking statements are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those anticipated in the forward-looking statements. Risks factors which are likely to have a material effect on Nicox’s business are presented in the 4th chapter of the “Document de référence, rapport financier annuel et rapport de gestion 2013” filed with the French Autorité des Marchés Financiers (AMF) on April 2nd, 2014, in the “Rapport semestriel financier et d’activité au 30 juin 2014” and in the 5th chapter of the “Actualisation du Document de Référence 2013” filed on September 30, 2014 (D. 14-0271-A01), available on Nicox’s website (www.nicox.com). 2 An emerging specialty opthalmic company United States Ophthalmology R&D companies e.g. Aerie, Ophthotech, pSivida, Insite Europe Dominated by small national companies Lab. Thea the only pan-EU group Nicox Building an innovative pipeline supported by specialist sales infrastructure and partnerships Major ophthalmology companies Allergan, B+L, Alcon (Novartis), Santen Global pharma companies entering ophthalmology: e.g. Bayer, Shire 3 2014: a year of substantial progress  International sales infrastructure developed • Specialist sales teams built in France, Germany, Italy, Spain, UK and US • Established national businesses acquired in France (Doliage) and Italy (Eupharmed) • International partnerships signed in key markets including Japan  New products launched • Europe: AdenoPlus® and Xailin™ ocular lubricants range • US: Sjö™ and RetnaGene™ diagnostic tests  Product pipeline significantly enhanced • Successful efficacy results in pivotal phase 3 trials for VESNEO by partner B+L • Acquisition of anti-viral eye drop Carragelose® for management of viral conjunctivitis • Proposed acquisition of Aciex Therapeutics to transform therapeutics pipeline 4 Direct commercial presence in 6 major markets United States Commercial team based in Forth Worth and covering US territory Europe Commercial teams in top 5 EU markets Doliage (France) Eupharmed (Italy) ROW Switzerland Turkey Benelux South Africa Poland Japan Australia New Zealand 5 Proposed acquisition of Aciex Therapeutics, Inc. Your vote is essential to help us transform Nicox into a successful ophthalmic business. Aciex: strengthening Nicox’s therapeutic portfolio • Proposed acquisition is a major step in creating an international ophthalmic business • Near-term pipeline of therapeutic candidates includes AC-170 in phase 3 for allergic conjunctivitis and AC-155 for post-operative ocular inflammation and pain • Innovative technologies including SyK / JAK inhibitors through collaboration with Portola Inc • $65 million upfront payment in the form of 20,627,024 newly-issued Nicox shares • Aciex shareholders to own at closing 20,8% of the enlarged group, with no impact from variations in the Nicox share price or €/$ exchange rates. • Additional CVRs1 worth up to $55 million depending on certain US product approvals • Transaction subject to approval by Nicox’s shareholders, EGM2 convened on Oct 22, 2014 1. 2. CVRs: Contingent Value Rights EGM: Extraordinary General Meeting 7 New Nicox shareholders following Aciex acquisition Aciex’s shareholders entering Nicox’s capital following the upfront payment of $65 million in Nicox shares Shareholder Number of shares post-acquisition1 % of Nicox’s capital post-acquisition1 Bay City Capital 4,692,528 4.73% Health Care Venture (HCV) 3,639,103 3.67% New Enterprise Associates (NEA) 3,639,103 3.67% Akorn 4,405,230 4.44% Other shareholders 4,251,060 4.28% Total 20,627,024 20.78% Total number of Nicox shares post-acquisition1: 99,241,648 1. Following upfront payment only 8 Aciex: AC-170 for allergic conjunctivis Addresses major market opportunity with established allergy molecule • AC-170 – novel formulation of cetirizine, widely-used antihistamine developed for topical application in the eye for first time • Allergic conjunctivits is a major opportunity • • US market worth an estimated $816 million1 with 74 million US adults suffering from allergic conjunctivitis2 • 20% of people in developed countries estimated to suffer from allergic conjunctivitis3 Significant revenue potential based on existing products • Patanol® and Pataday® (Alcon); sales ~$550 million1 (>4 million prescriptions) • Bepreve® (Bausch + Lomb); sales ~$35 million1 (>200,000 prescriptions) • Lastacaft® (Allergan); sales ~$32 million1 (>285,000 prescriptions) • Recently issued US patent – patent protection through March 2030 1. IMS April 2014 2. Source: Kantar Group 2009 National Survey 3. Williams DC et al. Recognition of allergic conjunctivitis in patients with allergic rhinitis. World Allergy Organization Journal 2013 9 Aciex: AC-170 – two phase 3 studies completed Two phase 3 safety and efficacy studies have demonstrated statistically significant results for AC-170 over vehicle control for the primary endpoint of ocular itching. -0.92 -1.53 -1.34 -0.90 -0.87 -1.07 Gomes PJ, Raval Y, Schoemmell E, Welch DL.Evaluation of the Onset and Duration of Action of Topical AC-170 (Cetirizine 0.24%) for the Prevention of Allergic Conjunctivitis. Association for Research in Vision and Ophthalmology (ARVO) 2014, Poster number C0010. 10 US Ocular Anti-Allergy Market $1 000,0 $800,0 $600,0 Branded Generic OTC $400,0 $200,0 $2012 • • 2013 2014 The US ocular anti-allergy market is worth over $800 million annually Branded Rx products represent 80%+ market share growing almost 9% year over year Source: IMS National Sales Perspectives, June 2011 – July 2014 MAT US Dollars in MM 11 Aciex: AC-155 for postoperative pain and inflammation • AC-155 – novel form of fluticasone, a leading corticosteroid, developed for the first time as a topical application in eye • • Uses Aciex’s proprietary nanocrystallization manufacturing process US ophthalmic corticosteroid market estimated at $560 million1 • Durezol® (Alcon); sales ~$105 million1 (>945,000 prescriptions) • Lotemax® (Bausch + Lomb); sales ~$175 million1 (>1.3 million prescriptions) • Pred Forte® & prednisolone generics (Allergan & others); sales ~$220 million1 (>5.1 million prescriptions) • Expected to move directly into phase 2 in 2015 following toxicity studies and IND filing (pending FDA approval) • Fluticasone’s affinity for the glucocorticoid receptor is approximately 10x greater than dexamethasone  could enable reduced dosing frequency2,3 • Recently issued US patent – patent protection through January 2033 1. IMS April 2014 2. Hogger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 59: 597-602, 1994. 3. Johnson M. The anti-inflammatory profile of fluticasone propionate. Allergy 1995; 50{Suppl 23):11-14 12 VESNEO® (latanoprostene bunod) Positive phase 3 results to support FDA filing VESNEO® – A major potential long-term growth driver • VESNEO® (latanoprostene bunod) is the first NO-donating PGF2α analog for potential treatment of glaucoma and ocular hypertension • New dual approach mechanism of action, developed in Nicox’s research laboratories in Milan • VESNEO® is the only product to have shown superiority to latanoprost in a solid phase 2b study • VESNEO® showed an IOP effect statistically superior to timolol in two phase 3 studies • There is no prostaglandin with a superiority claim to timolol in their label 14 VESNEO® – Positive phase 3 results to support FDA filing • Primary endpoint met in two phase 3 studies (APOLLO and LUNAR) pivotal for US registration • Non-inferiority to timolol maleate 0.5% in lowering IOP • Randomized, multi-center, double-masked, parallel-group • 840 patients overall in North America and Europe • Positive results on a number of secondary endpoints • No significant safety findings • Reduction in mean IOP from baseline: 7.5-9.1 mmHg in both studies (2-12 wks) • IOP effect statistically superior to timolol in both studies (p<0.05) IOP: Intraocular pressure 15 IOP lowering effect of selected prostaglandins Mean Reduction in Intra Ocular Pressure (mmHg) -2.0 -3.0 -4.0 -5.0 -6.0 -7.0 -8.0 -9.0 -10.0 Rescula® 3– 4 Zioptan® 5 – 8 Lumigan® 7–8 Travatan® 7–8 Xalatan® 6–8 Sources: For Rescula, Zioptan, Lumigan, Travatan and Xalatan: US labels, available on www.accessdata.fda.gov 16 VESNEO® – Innovative mechanism of action VESNEO targets two distinct anatomical compartments each contributing to aqueous humor outflow VESNEO, first NO-donating PGF2α analog for the potential treatment of glaucoma and ocular hypertension Discovered in Nicox’s research laboratories in Milan Heyne GW, Kiland JA, Kaufman PL, Gabelt BT, Effect of Nitric Oxide on Anterior Segment Physiology in Monkeys, Invest. Ophthalmol. Vis. Sci., published online before print June 25, 2013, doi: 10.1167/iovs.12-11491 17 VESNEO® – Significant revenue potential for Nicox • Positive phase 3 data to support FDA filing • FDA filing planned mid-2015 by B+L • US launched planned mid-2016, pending FDA approval • B+L estimate peak sales: US >$500 million, worldwide >$1 billion1 • Potential revenues from worldwide licensing agreement with B+L • $20 million already paid to Nicox in 2010 and 2012 (upfront + 1st milestone) • Remaining net milestones for Nicox up to $132.5 million2 over drug life-time • Potential net tiered royalties on sales from 6% up to 11%3 • Nicox exercised its option to co-promote VESNEO in the US in Aug. 2014 1. Source: Valeant corporate press release 26/09/14 2. Potential miltestones from B+L of up to $162.5 million, which would result in net milestones for Nicox of up to $132.5 million following payments due to Pfizer as part of 2009 agreement 3. Potential net royalties following payments due to Pfizer as part of 2009 agreement 18 US Glaucoma Market – TRx 25 000 000 20 000 000 15 000 000 Other Prostaglandin 10 000 000 5 000 000 2011 • • 2012 2013 2014 The US glaucoma market generates nearly 25 million prescriptions annually, and is consistently growing between 4% and 6% year over year The prostaglandin class of medications contribute nearly 67% of the US glaucoma market with over 16 million prescriptions in 2014 Source: IMS National Prescription Audit, June 2010 – July 2014 MAT US Prescriptions 19 US Glaucoma Market – Dollar Sales $2 000,00 $1 800,00 $1 600,00 $1 400,00 $1 200,00 $1 000,00 $800,00 $600,00 $400,00 $200,00 $- Other Prostaglandin 2011 • • 2012 2013 2014 The US glaucoma market is one of the largest segments in eyecare valued at nearly $2 billion annually Even with recent generic prostaglandins becoming available, the prostaglandin class of agents represent greater than $1 billion annually growing 6% and 8% year over year the past two years Source: IMS National Sales Perspectives, June 2010 – July 2014 MAT US Dollars in MM 20 Recent European acquisitions 3 acquisitions successfully completed in less than 12 months Eupharmed, Italy – Acquired in December 2013 Products Category Cationorm1, Theradrop, Theragel Tear lubricants Eukinoft antibiotic Dropflam non-steroidal anti-inflammatory Eucombidex fixed combination antibiotic steroid Eucortex steroid Eustamyl antiallergics Zared 2, Eukom 1000, Euvision Ofta nutraceuticals Therablef eyelid cleansing wipes Naviblef1 eyelid cleansing foam 2013 sales: €3.9 million 1. under distribution agreement 22 Doliage – Acquisition of an established French company in September 2014 • Acquisition of French ophthalmic specialist Doliage complements Nicox’s commercial infrastructure in France • Growing and profitable ophthalmic product portfolio with 2013 revenues of €2.6 million • Rx pharmaceuticals: Euronac® for corneal healing and Tobrabact® Gé, an ocular antibiotic • Nutraceuticals: e.g. Rétinofta®, Visioprev®, Hydrofta® • Medical devices: e.g. MeiboPatch® 23 Carragelose® – Promising anti-viral eye drop acquired in September 2014 • Acquisition of full rights to Carragelose® anti-viral eye drop from Marinomed Biotechnologie • To be developed for the potential management of adenoviral conjunctivitis • Could be launched in Europe in 2016 pending CE marking • Carragelose®: polymer derived from red seaweed with unique anti-viral properties • Already marketed in nasal sprays against cold and influenza by Marinomed’s commercial partners, including Boehringer Ingelheim 24 Portfolio & Pipeline overview An innovative proprietary diagnostics portfolio Product Therapeutic Area Status Licensor (Territory) Sjö™ Sjögren’s Syndrome US launch Nov 2013 (North America) RetnaGene™ AMD & LR AMD risk US launch June 2014 (North America) AdenoPlus® Differential diagnosis of acute conjunctivitis Launched in EU and ROW (via distributors) (Worldwide except US and Canada) RPS-AP (AAT) Adenoviral and allergic conjunctivitis In development (Worldwide except US and Canada) RPS-OH (OHT) Ocular herpes In development (Worldwide except US and Canada) 26 Compelling, late-stage pro-forma therapeutic pipeline (subject to closure of the acquisition of Aciex) Product Therapeutic Area Carragelose eye drop1 Viral conjunctivitis VESNEO (latanoprostene bunod) AC-170 (cetirizine) AC-155 (fluticasone) Phase 2 Phase 3 Partners EU launch planned 2016 Glaucoma FDA filing planned mid-2015 Allergic conjunctivitis Post-operative ocular pain and inflammation DME, RVO Syk/JAK inhibitors Various ophthalmic indications Next generation NO-donors Glaucoma and others Undisclosed Therapeutics, nutraceuticals and medical devices Medical device Phase 1 To NO-donating steroids 1. Research & Preclinical worldwide Pre-NDA meeting by Q1 2015 Ready to enter phase 2 in 2015 From In development – First launches 2015 27 Early-stage NO-donors programs Next Generation NO-donors NO-steroids Target profile Target profile • • • • • • • Intravitreal administration or eye drops Low liability for increase in IOP Potential of retinal cell protection Reduction of oxidative stress and inflammatory cytokines Competitive Advantages • Competitive advantages • • • Two lead compounds ready for IND-enabling program (NCX 434 and NCX 422) Sustained and potent activity following intravitreal administration Small or no IOP increase in experimental models Topically effective Extended NO donation No tolerance • NO independent effect on IOP lowering Compounds specifically designed to target selected disorders associated with NO deficiency 28 Naproxcinod: re-focused in muscular dystrophies In a long term (9 months of treatment) confirmatory study, naproxcinod improves skeletal and cardiac muscle function and reduces skeletal muscle inflammation in mdx mice(1)(2) Naproxcinod significantly improved skeletal muscle force and cardiomyopathy in mdx mice, showing a safe profile on blood pressure ** 90 80 ## 70 60 50 35 mdx-vehicle # ** 120 ** 30 ## 25 ** 100 80 # 60 40 20 20 Wild type Systolic blood pressure SBP (mmHg) % change in normalized hindlimb 100 Cardiac function Fraction shortening (%) Skeletal muscle force 0 mdx-prednisolone 0.9 mg/kg mdx- naproxcinod 10 mg/kg # p<0.05, ## p<0.01 vs wt mice; ** p<0.01 vs mdx–vehicle Mdx mice are known to develop cardiomyopathy at 9-10 months of age. Long term treatment with prednisolone exacerbates it, whereas naproxcinod improves cardiac function. 1. 2. Collaboration with a leading US center (Children’s National Medical Center, Washington DC) Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy, Uaesoontrachoon K, Quinn JL, Tatem KS, Van der Meulen JH, Yu Q, Phadke A, Miller BK, Gordish-Dressman H, Ongini E, Miglietta D, Nagaraju K. Hum Mol Genet. 2014, Early online publication Jan 23, 2014. 29 Upcoming milestones Revenue growth to continue positive momentum in H2 Aciex – completion of acquisition pending shareholder approval AC-170 – request for pre-NDA meeting with FDA by Q1 2015 VESNEO (latanoprostene bunod) – FDA filing planned Q2 2015 Naproxcinod in DMD: investment decision on POC study by the financial partner Additional European product launches in 4Q 2014 and 2015 Further in-licensing and corporate development opportunities 30 Q&A Session www.nicox.com Nicox S.A. | Nicox Pharma Nicox Inc. Nicox Research Institute S.r.l. Drakkar 2 – Bât D 2405 Route des Dolines CS 10313 Sophia Antipolis 06560 Valbonne | France 777 Main Street | Suite 2160 Fort Worth | Texas 76102 Via Ariosto 21 20091 Bresso | Milano Italy T: +33 (0)4 97 24 53 00 F: +33 (0)4 97 24 53 99 T: +1 817 529 9300 F: +1 817 612 6766 T: +39 02 61 03 61 F: +39 02 61 03 64 30