18th Annual Rodman & Renshaw Global Investment Conference New York, September 12-13, 2016 Gavin Spencer, EVP Corporate Development
(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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At a glance: Nicox the Ophthalmic Specialist •
Founded in 1996 around its proprietary nitric oxide (NO)-donating research platform
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Ophthalmic company focused on drug development: •
Latanoprostene bunod, partnered with Bausch + Lomb • CRL received July 21, 2016 • No safety or efficacy concerns or additional clinical trials identified for approval of latanoprostene bunod. FDA letter relates to CGMP at a Bausch + Lomb facility
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AC-170 (cetirizine eye drops), PDUFA date of October 18, 2016 (contingent upon the information and data to be provided by Nicox during the review period)
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NCX 4251 (fluticasone propionate nanocrystals), Phase 2 planned
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NCX 470 (NO-bimatoprost), Phase 2 planned
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Nicox transferred European & International commercial infrastructure to a new company led by GHO Capital in a transaction worth up to €26 million
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Headquartered in Sophia Antipolis (Nice, France) •
Research Center in Milan, Italy and US offices in Fort Worth, TX
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Listed on Euronext (COX)
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Market Cap ca. 250-260M€
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Recent Developments
November 10, 2015 Naproxcinod out-licensed to Fera Pharma in the U.S.
2015
2016
January 29, 2016 OTC asset AC-120 outlicensed to Ora Inc. for morning eyelid swelling
1.
July – August 2016 Signature & Closing of the transfer of the European and international commercial business to GHO Capital up to €26M
May 9, 2016 Pre-clinical data on pipeline candidates including new standalone NO-donors presented at ARVO 2016 in the US
June 21, 2016 AC-170 NDA Priority Review granted by FDA; PDUFA date October, 18 20161
July 21, 2016 Latanoprostene bunod Complete Response Letter received by Bausch + Lomb
Contingent upon the information and data to be provided by Nicox during the review period
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Building a leading Ophthalmic Company
2 NDAs under review • 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)
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Potential net regulatory / commercial milestones up to $132.5 million plus 6%-11% net royalties
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Complete response letter received by Bausch + Lomb on July 21, 2016 relating to CGMP at a Bausch + Lomb facility
• AC-170: Patented cetirizine eye drop formulation for allergic conjunctivitis •
NDA Priority Review granted by FDA – PDUFA date October 18, 2016 (contingent upon the information and data to be provided by Nicox during the review period)
• Further advanced proprietary pipeline •
NCX 4251: patented nanocrystalline fluticasone for blepharitis; Nicox expects NCX4251 to enter US phase 2 trials post IND filing
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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
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Next generation stand-alone nitric oxide (NO)-donors targeting glaucoma and reduction of IOP
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R&D Pipeline in Ophthalmology Product
Rights
Preclinical
Development
Regulatory/Marketing
Status
Core worldwide pipeline Latanoprostene bunod ophthalmic solution (0.024%) IOP lowering in patients with openangle glaucoma or ocular hypertension
Licensed to Bausch + Lomb (Valeant) worldwide
Complete Response Letter received from the US FDA on July 21, 2016
AC-170 (cetirizine) Ocular itching associated with allergic conjunctivitis
Worldwide
NDA Priority Review granted by US FDA PDUFA date: October 18, 2016
AC-120 Morning eyelid swelling
Licensed to Ora, Inc worldwide
Phase 2
NCX 4251 (fluticasone propionate nanocrystals) Blepharitis
Worldwide
Expected to enter phase 2 post IND filing
NCX 470 (NO-bimatoprost) Glaucoma
Worldwide
Expected to enter phase 2 post IND filing
Next generation stand-alone NO donors Glaucoma and other ophthalmic indications
Worldwide
Lead optimization
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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 - Overview •
If approved, latanoprostene bunod ophthalmic solution (0.024%) is believed to be the first and only once daily nitric oxide-donating prostaglandin analog
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Discovered and synthesized in Nicox Research Laboratories in Milan, Italy
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Licensed exclusively by Nicox to Bausch + Lomb worldwide
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Nicox may receive up to $132.5 million in net milestones and a net royalty of 6% to 11% on sales of latanoprostene bunod
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Latanoprostene bunod was the subject of a Complete Response Letter from the US FDA on July 21, 2016 due to the CGMP deficiencies of B+L plant
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Latanoprostene bunod – Complete Response Letter •
Complete Response Letter was received on July 21, 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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Valeant intends to meet with the FDA as soon as possible to work on a resolution and address these concerns
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Latanoprostene bunod A breakthrough in glaucoma and IOP-lowering 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 nitric oxide-donating prostaglandin analog to provide consistent and sustained efficacy through two distinct modes of action. A single agent therapy eye drop, latanoprostene bunod is thought to reduce IOP by increasing aqueous outflow through both the trabecular meshwork/Schlemm's canal (conventional pathway) and uveoscleral (non-conventional) pathways. In glaucoma patients, damage to the trabecular meshwork, through which the majority of the aqueous humor passes, can lead to reduced drainage and thus elevated IOP.
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Nitric oxide plays a key role in numerous functions throughout the body including many well documented functions in the healthy eye1
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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 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, 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.
1.
The Glaucoma Drugs Market: Opportunities, Challenges, Strategies & Forecasts, SNS Research; Market Intelligence & Consultancy Solutions, 2016.
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Latanoprostene bunod Clinical Program •
Comprehensive clinical program including: o
Latanoprostene bunod vs. timolol, APOLLO and LUNAR Phase 3 Studies: 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.
o
Latanoprostene bunod vs. latanoprost, VOYAGER Phase 2 Study: Mean IOP Reduction Superior to latanoprost • 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
o
52-Week JUPITER Phase 3 Safety Study, open-angle glaucoma patients, conducted in Japan • Mean baseline IOP 19.6 mm Hg resulted in a reduced mean IOP to 14.4mmHg
o
24-hour IOP Lowering CONSTELLATION Phase 2 Study • Latanoprostene bunod demonstrated better 24-hour IOP control vs. timolol
•
No significant safety issues noted in results of Phase 2 and Phase 3 studies 12
APOLLO & LUNAR Phase 3 studies Latanoprostene bunod demonstrated significantly greater IOP lowering than timolol •
Latanoprostene bunod (QD) met primary endpoint of non-inferiority to timolol 0.5% (BID) for mean IOP lowering over 3 months of treatment
•
Latanoprostene bunod also demonstrated significantly greater IOP lowering than timolol 0.5% throughout the day after 3 months of treatment with a 30.4%-32.3% reduction at Month 3.
Weinreb RN, Scassellati Sforzolini B, Vittitow J, Liebmann J. Latanoprostene bunod 0.024% versus Timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the APOLLO study. Ophthalmology. 2016;123(5):965-973. Medeiros FA, Martin KR, Peace J, et al. Comparison of latanoprostene bunod 0.024% and Timolol Maleate 0.5% in Open-Angle Glaucoma or Ocular Hypertension: the LUNAR study. Am J Ophthalmol. 2016;168:250-259. Data on File. Bausch & Lomb, Incorporated. Kaufman PL, Liebmann JM, Vittitow JL, Weinreb RN. Integrated Efficacy of Latanoprostene Bunod 0.024% vs. Timolol Maleate 0.5% for Intraocular Pressure Lowering in Patients with Open-Angle Glaucoma or Ocular Hypertension: APOLLO and LUNAR Studies. 2016 ARVO Poster #3035-A0385.
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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
Sources: For Rescula, Zioptan, Lumigan, Travatan , Xalatan: U.S. labels, available on www.accessdata.fda.gov. 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 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 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 U.S. Single-Agent Prostaglandin Market $1.2 Billion Market (2014 Annual Sales Data)1
$24.3 (-14%)
$18.7 (+1%)
$462.5 (+4%)
$11.9 (+127%)
$102.1 (-12%)
$578.9 (+18%)
LUMIGAN TRAVATAN Z XALATAN ZIOPTAN LATANOPROST TRAVOPROST
•
1.
Major brands represent approximately 40% of the single-agent prostaglandin market Rx volume, but contribute to nearly 90% of the sales dollars o Brand sales volume has remained relatively steady, even with generic entry of latanoprost
IMS National Sales Perspectives, January 2012 – December 2014 MAT U.S. Dollars in MM, 2014 vs. 2013 year over year growth
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AC-170: Allergic conjunctivitis Major market opportunity with established antihistamine, cetirizine (API found in systemic brand Zyrtec®1) •
Novel formulation of cetirizine 0.24%, a widely-used antihistamine developed for topical application in the eye for the first time o Developed for treatment of ocular itching associated with allergic conjunctivitis
NDA Priority Review granted by FDA – PDUFA date October 18, 20162 (contingent upon the information and data to be provided by Nicox during the review period)
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o 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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Two U.S. patents – protection through 2030 and 2032
1. 2.
Zyrtec® is a trademark of UCB Pharma SA or GlaxoSmithKline Approval of the AC-170 NDA in the US triggers a payment in Nicox shares to the previous shareholders of Aciex as follows: $35 million for the US approval of AC 170 on or before the earlier of 18 months after the date of filing of an NDA with the FDA or December 1, 2016; or $10 million if the approval is granted after this date, but on or before the earlier of 30 months after the date of filing of an NDA with the FDA or December 1, 2017.
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AC-170: U.S. 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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NCX 4251: 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 • Fluticasone’s affinity for glucocorticoid receptor is approximately 10x greater than dexamethasone1,2 • 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 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 1. 2. 3.
Nanocrystallized formulation of fluticasone proprionate developed for topical application at the lid margin
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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Our Proprietary Nitric Oxide Donating Platform
N
O
Nobel Prize 1998 RF Furchgott LJ Ignarro F Murad
Nitric Oxide (NO) in ophthalmology NO and other molecules involved in NO-mediated signaling are present in ocular tissues. NO notably plays a role in the regulation of intraocular pressure (IOP). This is of particular interest in glaucoma, which is often associated with increased IOP.
Endogenous cell-signaling molecule
•
•
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 H2 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 shows promising results in three models of ocular hypertension and glaucoma 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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Financial highlights •
Cash1:
- €20.8 million at end of Q1 2016 (not including approximately € 27 M between the EU commercial transaction with GHO Capital and the July PIPE)
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Shares outstanding2:
24.9 million up to $35 million worth of shares issuable to Aciex ex-shareholders upon AC-170 approval if before Dec 1, 2016 ( up to $10 million after Dec 1, 2016)
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Market cap:
•
No bank indebtedness
ca. 250-260M€
Publication of half-year financial results on September 22, 2016
1. 2.
Cash, cash equivalents and financial instruments of €20.8 million as of March 31, 2016. As of June 30, 2016. Does not include $55 million in potential CVRs related to Aciex transaction.
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Key upcoming milestones Bausch + Lomb working with the FDA to resolve and address the concerns associated with the CGMP deficiencies noted in the Complete Response Letter received on July 21, 2016 AC-170 – PDUFA date October 18, 2016 (contingent upon the information and data to be provided by Nicox during the review period) 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 2017
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Nicox Helping people to enhance their sight www.nicox.com
Nicox S.A.
Nicox Ophthalmics, 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 1292 Fort Worth | Texas 76102 | USA
Via Ariosto 21 20091 Bresso | Milano | Italy
T: +1 817 529 9300 F: +1 817 612 6766
T: +39 02 61 03 61 F: +39 02 61 03 64 30
T: +33 (0)4 97 24 53 00 F: +33 (0)4 97 24 53 99
