STIFEL 2016 Healthcare Conference New York – November 15-16, 2016 Michele Garufi, Chairman & Chief Executive Officer
(Euronext Paris: COX)
Disclaimer This document has been prepared by Nicox S.A. and may not be reproduced or distributed, in whole or in part. The information contained in this document has not been independently verified and no representation, warranty or undertaking, expressed or implied, is made as to, and no reliance should be placed on, the fairness, accuracy, completeness or correctness of the information or opinions contained herein. The information contained in this document may be modified without former notice. This information includes forward-looking statements. Such forward-looking statements are not guarantees of future performance. These statements are based on current expectations or beliefs of the management of Nicox S.A. and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Nicox S.A. and its affiliates, directors, officers, employees, advisers or agents, do not undertake, nor do they have any obligation, to provide updates or to revise any forward-looking statements. None of Nicox S.A. nor any of its affiliates, directors, officers, employees, advisers or agents, shall have any liability whatsoever (in negligence or otherwise) for the use of these materials by any person or for any loss arising from any use of this document or its contents or otherwise arising in connection with this document. It is not the purpose of this document to provide, and you may not rely on this document as providing, a complete or comprehensive analysis of the Company’s financial or commercial position or prospects. This document is not intended for potential investors and does not constitute or form part of, and should not be construed as an offer or the solicitation of an offer to subscribe for or purchase securities of the Company, and nothing contained herein shall form the basis of or be relied on in connection with any contract or commitment whatsoever. Risk factors which are likely to have a material effect on Nicox S.A.’s business are presented in the 4th chapter of the “Document de référence, rapport financier annuel et rapport de gestion 2015” filed with the French Autorité des marchés financiers (AMF) on April 15, 2016 under number D. 16-0351 and available on Nicox S.A.’s website (www.nicox.com).
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2016 - an Year of Transformation
May 9, 2016 Pre-clinical data on pipeline candidates including new standalone NO-donors presented at ARVO 2016 in the US
July – August 2016 Signature & Closing of the transfer of the European and international commercial business to GHO Capital up to €26M
October 7, 2016 AC-170 Complete Response Letter received
2016
January 29, 2016 OTC asset AC-120 out-licensed to Ora Inc. for morning eyelid swelling
June 21, 2016 AC-170 NDA Priority Review granted by FDA; PDUFA date October 18, 2016
July 21, 2016 Latanoprostene bunod Complete Response Letter received by Bausch + Lomb
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A Late-Stage leading Ophthalmic R&D Company
2 Pre-Approval Products • Latanoprostene bunod - Potential to become an important product in the IOP-lowering space •
Partnered worldwide with Bausch+Lomb (a wholly-owned subsidiary of Valeant Pharmaceuticals International)
•
Potential net regulatory/commercial milestones up to $132.5 million plus 6%-11% net royalties
•
Complete Response Letter received by Bausch+Lomb on July 21, 2016 relating to CGMP at one of its facilities; Bausch + Lomb anticipates launch mid-20171
• AC-170: Patented cetirizine eye drop formulation for allergic conjunctivitis •
Complete Response Letter received on October 7, 2016 relating to GMP at API manufacturer
•
FDA meeting during 4Q16
• Further advanced proprietary pipeline
1
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NCX 4251: patented nanocrystalline fluticasone for blepharitis; Nicox expects NCX4251 to enter US phase 2 trials post IND filing in 2H17
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NCX 470: NO-donating bimatoprost targeting glaucoma and reduction of IOP; Nicox expects NCX 470 to enter phase 2 studies post-IND filing in 2 H17
•
Next generation stand-alone nitric oxide (NO)-donors targeting glaucoma and reduction of IOP
subject to regulatory approval
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Latanoprostene bunod ophthalmic solution (0.024%) If approved, the first and only once daily nitric oxide-donating prostaglandin analog
Latanoprostene bunod A breakthrough in glaucoma and IOP-lowering therapy Latanoprostene bunod ophthalmic solution (0.024%) is being developed for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. If approved, latanoprostene bunod is believed to be the first and only once daily single IOP lowering drug to provide consistent and sustained efficacy through two distinct modes of action : by increasing aqueous outflow through both the trabecular meshwork/Schlemm's canal (conventional pathway) and uveoscleral (non-conventional) pathways.
Glaucoma patients have lower levels of ocular nitric oxide than those observed in normal eye 2,3
1. 2. 3.
Culotta E, et al. Science. 1992;258:1862-5 Nathanson JA, et al. Invest Ophthalmol Vis Sci. 1995;36:1774-84 Galassi F, et al. Br J Ophthalmol. 2004;88:757-760
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Latanoprostene bunod Primary endpoint met in Phase 2b dose ranging study Primary endpoint met on Day 28
Secondary endpoint met
Reduction in mean diurnal IOP, change from baseline (mmHg)
Responder rate: % of subjects with mean diurnal IOP18mmHg latanoprostene bunod 0.024%
*
latanoprost 0.005%
*
* *
*
* *
*p<0.05 VOYAGER: Randomized, investigator-masked dose-ranging Phase 2b study; 413 patients randomized, received latanoprostene bunod (various concentrations) or latanoprost 0.005% once a day in the evening for 28 days. Weinreb RN, Ong T, Scassellati Sforzolini B, Vittitow JL, Singh K, Kaufman PL. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015, 99(6):738-45.
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Latanoprostene bunod Clinical Program •
Comprehensive clinical program including: o
o
Latanoprostene bunod vs. timolol, APOLLO and LUNAR Phase 3 Studies (with 840 patients overall in U.S. and Europe): Mean IOP Reduction Non-Inferior & Superior to timolol 0.5% •
Studies met their primary endpoint and showed positive results on a number of secondary endpoints
•
Latanoprostene bunod also demonstrated significantly greater IOP lowering than timolol 0.5% throughout the day at 3 months of treatment resulting in a 30.4%-32.3% reduction from baseline with a range of 7.5-9.1 mmHg.
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Latanoprostene bunod was safe and well tolerated with no significant adverse events. Rates for hyperemia were comparable to latanoprost
Latanoprostene bunod vs. latanoprost, VOYAGER Phase 2 Study: Mean IOP Reduction Superior to latanoprost •
o
52-Week JUPITER Phase 3 Safety Study, open-angle glaucoma patients, conducted in Japan •
o
Mean baseline IOP 19.6 mm Hg resulted in a reduced mean IOP to 14.4mmHg
24-hour IOP Lowering CONSTELLATION Phase 2 Study •
•
Two of the four doses tested, including the FDA approved dose for latanoprostene bunod, 0.024%, showed greater IOP reduction compared with Xalatan (latanoprost ophthalmic solution 0.005%), with differences reaching more than 1mm Hg
Latanoprostene bunod demonstrated better 24-hour IOP control vs. timolol
No significant safety issues noted in results of Phase 2 and Phase 3 studies 8
IOP lowering range of selected prostaglandins Mean Reduction in Intraocular Pressure (mmHg)
0
-1.0
-2.0
-3.0
-4.0
-5.0
-6.0
-7.0
-8.0
-9.0
Rescula® 3–4 Zioptan® 5 – 8 Lumigan® 7–8 Travatan® 7–8 Xalatan® 6–8 Latanoprostene bunod 7.5 – 9.1 Sources: For Rescula, Zioptan, Lumigan, Travatan , Xalatan: U.S. labels, available on www.accessdata.fda.gov. For latanoprostene bunod, results of Phase 3 studies APOLLO and LUNAR Note: Numbers in FDA labels have been rounded. *Baseline IOP was 23 mmHg for RESCULA, 23 to 26 mmHg for ZIOPTAN, 23,5 mmHg for LUMIGAN 24 to 25 mmHg for XALATAN, 25 to 27 mmHg for TRAVATAN. and 26.7 mmHg for latanoprostene bunod
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The importance of each mmHg in the progression of glaucoma Results from the Early Manifest Glaucoma Trial (EMGT) evaluating the effect of immediately lowering IOP on the progression of newly detected open-angle glaucoma1
“In these analyses, each millimeter of mercury of decreased IOP was related to an approximately 10% lowering of risk, and the results showed no significant treatment effects beyond those related to IOP reduction.” Pr. Anders Heijl, 2002
Results from the United Kingdom Glaucoma Treatment Study (UKGTS) assessing the effect of IOP lowering treatment by latanoprost on vision preservation2,3
“[…] the risk reduction could be about 19% per mm Hg, confirming results from the EMGT and Canadian Glaucoma Study, and showing that intraocular pressure reduction is highly effective, and that every mm of pressure counts.” Pr. Anders Heijl, 2015
1. 2. 3.
Heijl et al. Arch Ophthalmol. 2002; 120: 1268-1279 Garway Heath et al. The Lancet 2015; 385: 1295-1304 Heijl; The Lancet 2015; 385: 1264-1266
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Latanoprostene bunod – FDA Regulatory Status •
Complete Response Letter was received on 21 July 2016 (the PDUFA date for latanoprostene bunod)
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The concerns raised by the FDA pertained to a Current Good Manufacturing Practice (CGMP) inspection at Bausch + Lomb’s manufacturing facility in Tampa, Florida where some deficiencies were identified by the FDA
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The FDA’s letter did not identify any efficacy or safety concerns with respect to the NDA or additional clinical trials needed for the approval of the NDA for latanoprostene bunod ophthalmic solution, 0.024%
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Bausch + Lomb is currently addressing the issues identified by the U.S. Food and Drug Administration (FDA) and anticipates being ready for inspection by the end of the year.
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Bausch + Lomb anticipates launch mid-20171
1
subject to regulatory approval
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Latanoprostene bunod Significant revenue potential for Nicox •
U.S. glaucoma market represents nearly $2.3 billion annually1
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In March 2010, Nicox signed a worldwide licensing agreement which granted Bausch + Lomb exclusive worldwide rights to develop and commercialize latanoprostene bunod
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Potential Nicox revenues from worldwide licensing agreement with Bausch + Lomb: o Bausch + Lomb made an initial license payment to Nicox of $10 million o Bausch + Lomb made an additional $10 million milestone payment in April 2012 following its decision to pursue further development of latanoprostene bunod o Nicox may receive future milestone payments of up to $132.5 million in net milestones, relating to regulatory approvals, achievement of sales targets and future development steps, net of up to $30 million in payments due to Pfizer (from the approval and first sales milestone), per the terms of the contract Nicox signed with Pfizer in August 2009 by which Nicox recovered the rights to latanoprostene bunod. o Net royalty of 6% to 11% on sales of latanoprostene bunod
1.
The Glaucoma Drugs Market: Opportunities, Challenges, Strategies & Forecasts, SNS Research; Market Intelligence & Consultancy Solutions, 2016.
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AC-170 The first ocular formulation of Cetirizine
AC-170 - The first ocular formulation of Cetirizine Major market opportunity with established antihistamine, cetirizine (API of the systemic brand Zyrtec®1)
1.
•
Novel formulation of cetirizine 0.24%, a widely-used antihistamine for ocular topical application for treatment of ocular itching associated with allergic conjunctivitis
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Two Phase 3 safety and efficacy studies completed with statistically significant results over vehicle control for primary endpoint of ocular itching
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NDA Priority Review granted by FDA – Complete Response Letter received October 7, 2016 focused solely on GMP issues of the API producer – FDA meeting during 4Q16
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Two U.S. granted patents – protection through 2030 and 2032
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Partnering discussions underway for commercialisation in the U.S.
Zyrtec® is a trademark of UCB Pharma SA or GlaxoSmithKline
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AC-170 - Two Phase 3 studies successfully completed Two Phase 3 safety and efficacy studies have demonstrated statistically significant results for AC-170 over vehicle control for primary endpoint of ocular itching Study NCT01881113 – Itching scores by visit – all subjects
-0.92 -1.53
-1.34
-0.90
-0.87
-1.07
1
1
Ora-CAC® (Conjunctival Allergen Challenge) model of allergic conjunctivitis. Ora-CAC® is a registered trademark of Ora, Inc.
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.
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AC-170 - Entering a growing ocular anti-allergy market In million $
•
1. 2. 3.
U.S. ocular anti-allergy market: >$800 million annually1 o
Branded Rx products represent 80%+ market share growing almost 9% a year
o
>74 million U.S. adults suffer from allergic conjunctivitis2
o
20% of people estimated to suffer from allergic conjunctivitis in developed countries3
IMS: December 2011 – November 2014 MAT U.S. Dollars in MM Source: Kantar Group 2009 National Survey Williams DC et al. Recognition of allergic conjunctivitis in patients with allergic rhinitis. World Allergy Organization Journal 2013
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AC-170 - FDA Regulatory Status •
Complete Response Letter was received from FDA on 7 October 2016
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The concerns raised by the FDA pertain solely to a Good Manufacturing Practice (GMP) inspection at a third party facility producing the active pharmaceutical ingredient (API) cetirizine and supplying it to the manufacturer of the finished product
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The safety and efficacy data submitted by Nicox in the AC-170 NDA have not resulted in the FDA requesting any further clinical or non-clinical testing for the approval of the AC-170 NDA
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Furthermore, the CRL did not include any concerns related to the finished product manufacturing facility
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In close contact with the relevant suppliers to address the FDA’s concerns.
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Nicox to meet with the FDA during 4Q16 regarding the next steps for the resubmission of the AC-170 NDA and expects to receive feedback from the FDA by early 2017.
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Early Clinical and Preclinical Pipeline
NCX 4251- A new Potential Treatment of Blepharitis Nanocrystalline fluticasone propionate (formerly known as AC-155) to target blepharitis, an unmet medical need • Novel formulation of fluticasone propionate developed for first time for topical treatment via an applicator swab at the eyelid margin • Nicox expects a pre-IND meeting to be held by the end of Q1 2017 and also expects to start clinical studies directly at Phase 2 in 2H 2017 • Recently issued U.S. formulation and use patent – protection through January 2033 • Blepharitis is one of the most common conditions encountered in clinical practice3 • 37% and 47% of patients seen by ophthalmologists and optometrists, respectively, present with signs of the disease • Currently no approved treatment by FDA
1. 2. 3.
Hogger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 59: 597-602, 1994 Johnson M. The anti-inflammatory profile of fluticasone propionate. Allergy 1995; 50 {Suppl 23):11-14 Lemp MA, Nichols KK. Ocul Surf. 2009 Apr;7(2 Suppl):S1-S14.
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Nicox Proprietary Nitric Oxide Research Platform
N
O
Nobel Prize 1998 RF Furchgott LJ Ignarro F Murad
Nitric Oxide (NO) in ophthalmology NO and other messengers involved in NOmediated signaling are present in ocular tissues. NO notably plays a role in the regulation of intraocular pressure (IOP) and thus of potential interest in glaucoma
Endogenous cell-signaling molecule
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First generation NO-donors •
Designed to release both NO and a well-established drug
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Potential to provide enhanced efficacy compared to the well-established drug
Second generation stand-alone NO-donors •
Enable optimization of NO dosing
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Target ophthalmic diseases which have a major component modulated by NO
Latanoprostene bunod NCX 470
NCX 667
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NCX 470 - NO-donating bimatoprost for glaucoma •
Dual mode of action targeting conventional (trabecular meshwork/Schlemm’s canal via nitric oxide) and non-conventional (uveoscleral route via bimatoprost) outflow pathway
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Superior IOP-lowering effect vs bimatoprost in three models of ocular hypertension and glaucoma in different species (ARVO 20151)
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Potential of reduced dose resulting in lower side-effect liability
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Currently in pre-IND studies
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Nicox expects a pre-IND meeting to be held by the end of Q1 2017 and also expects to start clinical studies directly at Phase 2 in 2H 2017 Transient saline-induced ocular hypertensive rabbits
Ocular normotensive dogs
Ocular hypertensive non-human primates
P<0.5 vs
* p<0.05 vs bimatoprost at the respective time point
1.
Impagnatiello F, Bastia E, Toris CB, Krauss AH, Prasanna G, Ongini E, ARVO 2015 Annual Congress, Abstract No. 5809.
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Next generation stand-alone NO-donors for glaucoma •
Competitive Advantages •
Designed for optimized nitric oxide dosing
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Unique mode of action involving conventional (trabecular meshwork / Schlemm’s canal) outflow pathway
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Potential low side-effect liability vs. existing products
Current stage: Lead optimization of NCX 667 •
NCX 667 promising results in three models of ocular hypertension in different species1
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Planned development in collaboration with an ocular drug delivery technology company
Ocular normotensive rabbits
Transient saline-induced ocular hypertensive rabbits
Ocular hypertensive non-human primates
P<0.5 vs
* p<0.05 vs vehicle at the respective time point
1.
Bastia E, Impagnatiello F, Almirante N, Lanzi C, Masini E, Toris C, Ongini E. ARVO 2015 Annual Congress, Abstract No. 1999-D0242.
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Further licensing collaborations and partnerships
AC-120 - an OTC asset licensed to Ora
Exclusive worldwide licensing agreement for AC-120 signed with Ora, Inc. in January 2016 •
AC-120 is an eye drop targeting morning eyelid swelling, a common complaint of aging individuals, particularly women • •
• •
AC-120 initially developed by Aciex Therapeutics, Inc., acquired by Nicox in October 2014 Phase 2 clinical program conducted by Aciex and Ora showed a statistically significant reduction in morning eyelid swelling. AC-120 was also well tolerated, with no adverse effects noted
Ora is responsible for all development activities Potential revenues for Nicox, pending approval and launch • • •
$10 million upon NDA approval Percentage of any proceeds received by Ora under sub-license Nicox could pay up to $10 million in Nicox shares to Aciex’s former shareholders upon approval 24
Naproxcinod licensed to Fera for the US Market
Exclusive licensing agreement for naproxcinod in the U.S. signed with Fera Pharmaceuticals in November 2015 •
Naproxcinod is a CINOD (Cyclooxygenase-Inhibiting Nitric Oxide Donating) anti-inflammatory drug-candidate discovered by Nicox • •
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Fera plans to seek advice from U.S. FDA on additional clinical work required prior to submitting a new NDA •
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Robust clinical package in OA, including three phase 3 studies in 2,700 patients Confirms value of Nicox’s proprietary NO-donating research platform
Fera responsible for all clinical, manufacturing and commercialization activities & costs
Potential revenues for Nicox, pending approval and launch • •
Up to $35 million in sales-based milestones 7% royalties 25
Participation in a new pan-European Ophthalmic Specialty Pharmaceutical Company
In August 2016, Nicox completed the transfer of its European and International commercial operations and related late-stage development programs to VISUfarma BV, led by GHO Capital, a newly-founded private company focused on the commercialisation of ophthalmic products in Europe. Under the terms of the transaction, Nicox received: • €9 million cash • €12 million stake in the parent company of VISUfarma BV in combination of ordinary shares and interest-bearing loan notes • In addition, Nicox has the right to receive up to €5 million in additional loan notes on the achievement by the new company of agreed business and commercial milestones. Note : Nicox will be responsible for completing, at its own cost, the development and regulatory approval in Europe of product candidates transferred to the new company and is eligible to receive reimbursement of some costs upon achievement of regulatory and commercial milestones associated with these product candidates. As a minority shareholder, Nicox has one seat on the Board of the parent company of VISUfarma BV
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Financial highlights •
Cash1: €32 million as of September 30, 2016
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Shares outstanding2-3: 25 million
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Market cap: ca. €185 million
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No bank indebtedness
1.
Non – audited figures
2.
As of September 13, 2016. Does not include $55 million in potential CVRs related to Aciex transaction
3.
Up to $10 million worth of shares issuable to Aciex ex-shareholders upon AC-170 approval if after Dec 1,’16 or up to $35 million if before Dec 1,’16. The monetary amount of the payments due will be reduced by the costs incurred by Nicox in running the additional clinical safety study on AC-170. Nicox estimates that this reduction will be $3.2 million, the maximum allowable under the terms governing the warrants associated with the share payments.
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Key upcoming milestones • Latanoprostene bunod: Bausch + Lomb working with the FDA to address the concerns associated with the CGMP deficiencies noted in the Complete Response Letter received on July 21, 2016 and anticipates launch mid-20171 •
AC-170: API manufacturer to address the GMP concerns noted in the Complete Response Letter received on October 7, 2016. Nicox to meet with the FDA during 4Q 2016 for next steps of an NDA resubmission and FDA feedback expected early 2017
• Initiation of phase 2 study for NCX 4251 and NCX 470 post IND filing • Pre-IND meetings for each product expected to be held by the end of Q1 2017 • POC clinical studies expected to start in 2H 2017
1
subject to regulatory approval
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Experienced leadership team Michele Garufi, PharmD
Elizabeth Robinson, Ph.D.
Co‐Founder, Chairman and Chief Executive Officer 30+ years in international pharma Co‐founder of other Research and Pharma start‐ups
Co‐Founder, President, Nicox Research Institute 20+ years in pharma development Recordati Italy, Techint Engineering & Genzyme
Gavin Spencer, Ph.D. EVP, Corporate Development 20+ years in life sciences Novartis Consumer Health & Boots Healthcare International
Michael Bergamini, Ph.D. EVP, Chief Scientific Officer 30+ years in drug development and registration Alcon Research Ltd., Laboratorios Cusí, Allergan Pharmaceuticals, Inc.
Sandrine Gestin
Stéphane Nicolas
Ennio Ongini, Ph.D.
Senior Director Human Resources 20+ years in HR Scubapro, American Express
VP Research 30+ years in drug discovery Schering Plough
Finance Director 25+ years in finance Nicox, IBM
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Board of Directors
Michele Garufi
Adrienne Graves
Chairman and CEO, Nicox Co-Founder
Former President and CEO, Santen Inc.
Les Kaplan Former Executive Chairman, Aciex Therapeutics, Inc. Former Executive VP of Allergan, Inc.
Jean-François Labbé Former CEO, SpePharm Holding BV
Luzi von Bidder Former Chairman, Acino Holding AG Former Chairman and CEO, Novartis Ophthalmics AG
Birgit Agneta Stattin Norinder Former Chairman and CEO, Prolifix Ltd
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