R&D Day 1: Santen's Contribution to Ophthalmology

Ophthalmology Is Our Singular Focus

R&D Day 1 Santen’s Contribution to Ophthalmology

Global R&D Santen Pharmaceutical Co., Ltd. July 12th, 2019

Day 1

Santen's Contribution to Ophthalmology Introduction of Ophthalmology and Santen’s Contribution Santen’s Research and Development

Day 2

Santen’s Future R&D Long-term Perspective of Ophthalmology Santen’s R&D approach

Values

1 “Exploring the secrets and mechanisms of nature in order to contribute to people’s health” Santen’s original interpretation of a passage from chapter 22 of Zhongyong (The Doctrine of the Mean) by Confucius. We think carefully about what is essential, decide clearly what we should do, and act quickly.

Mission By focusing on ophthalmology, Santen develops unique scientific Statement knowledge and organizational capabilities that contribute to the well- being of patients, their loved ones and consequently to society.

Congenital disorder Ocular Infection Refractive disorders (Myopia, Hyperopia, Astigmatism) Allergic conjunctivitis Dry Eye

Age-related diseases（Retina, Glaucoma, Cataract, Presbyopia)

Establishment of Maximization & Supporting Products Guidelines Penetration of Product Doctors, Medical

Congresses in each country value (PhⅣ etc) personnel General

companies PAP/ Program for continuation Activities by by Activities Raising disease awareness Pharmaceutical Pharmaceutical of treatment Patients and their families

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 3 Our original activities in Asia led Santen to No.1 in important markets -Up to and From today- Huge economic area at the moment and in the future with over 3 billion population

Ocular Infection: Blindness both parents and children Main treatment

Dry Eye：Rapid penetration of mobile phones and PCs at the moment （low coverage in Allergic conjunctivitis：Aggravation by pollutions （by decades） medical examine）

Congenital disorder Mega shift In some countries, the items below are progressing Refractive disorders (Myopia, Hyperopia, Astigmatism) (Presbyopia) -Acceleration of aging, -Preventive treatment for Age-related（Glaucoma, Retina, Cataract) children as important future Medical Infrastructure under way Samples of Low disease Low quality Lack of Level-up of problems awareness in patients products Ophthalmologists Ophthalmologist Establishment of Treatment guideline Santen’s Raising BFS/PF products/ Medical Caravan to EGC/ACS Santen remote areas in Strength Disease awareness Dimple bottle China Grant/… Efforts to Myopia BFS; Blow Fill Seal, PF: Preservative Free, EGC: English Glaucoma Camp, ACS : Asia Cornea Society

Treatment Continuation Affected Diagnosis Treatment initiation period of treatment

Raising disease Improvement of Differentiated Improvement of awareness diagnosis rate products compliance Global ・Improvement of usability Supports for stakeholders in Stable supply ophthalmology ・Minimally invasive

Advanced Recurrence Prevention New technology for diagnosis and treatment Countries prevention

・Initiatives to age-related chronic disease

Developing Raising disease High quality Eco system Raising and Supporting Countries of ophthalmologists awareness products

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 6 Protect the Sight of People Around the World Ophthalmic market (2018) and number of patients Dry Eye Low Vision Cataract Approx. Approx. Glaucoma 217million Approx. 340M patients 560M patients Blindness 120M patients 36million 8B yen 550B yen 730B yen Vision impairment estimated Myopia impacting 1 in 30 of world Ocular Allergic Approx. population Infection Conjunctivitis Retinal 2600M patients 230B yen 200B yen Diseases Anti- Approx. Education Employment Inflammatory 270M patients Source: WHO World Sight Day Poster 190B yen 860B yen

Number of Glaucoma patients

90.6M patients 80.4M patients (Forecast) 79.1M patients

Data Source: United Nations, World Population Prospects: 2015 Revision Data Source: Market Scope; Santen analysis

FUNDAMENTAL • To become a “Specialized Pharmaceutical Company with a Global Presence” POLICY • Construct a path for sustainable growth beyond FY2020

Increase customer Increase Increase satisfaction organizational profitability strength

STRATEGIC GOALS Raise strength / efficiency of Grow faster than the market Enhance the product pipeline and business framework; boost human through progress in global business 1 2 develop new treatment options 3 resource and organizational strategy capabilities Responding to the needs of patients and medical professionals worldwide, Santen will achieve reliable growth while sustainably contributing to ophthalmic treatment worldwide

Network

Bring out joy Collaboration with SERI “to be able to see” Develop new therapies for eye disease that are prevalent in Asia by fulfilling UMNs Gene therapy using iPS cell related technology Aiming to develop Japan’s first gene therapy in collaboration with New industry, academia and government Products New drug discovery technology using macrocyclic/constrained peptides New approach for drug discovery

Intraocular lens for cataract surgery LENTIS® Comfort Aiming to provide treatment that will not be Glaucoma and Ocular Hypertension Treatment Patient a burden to patients Eybelis Support Preservative free solution/container Assistive device for eye drop administration Devise for Glaucoma Improved distinguishability US submission for DE-128 scheduled to be Drip prevention completed in 2019CY Easy to squeeze bottle

Application of Therapies specific New modality systemic drug to ophthalmology Gene therapy Eye infection Retinal disease Cell therapy Anti inflammatory Glaucoma Regenerative medicine Allergic Conjunctivitis Dry eye etc. Refractive disorder

Treatment for vision impairment QOL improvement

Formulation Administration New Dosage form change Intravitreal Injection Long lasting formulation Low preservative Drug Delivery System Combination drug Medical device Dosage form change Container

*Unmet Medical Needs

in Japan & Europe to Asia Registration Status in China

South Korea 11/25

China 3/18 Pakistan September October 1/4 Taiwan 2015 2017 15/33 2015 2016 2017 Hong Kong 13/29 India Macau 5/5 6/22 Philippines Myanmar Vietnam 18/29 Only 27 new products have been approved 12/12 10/22 by China FDA Thailand Sri Lanka 9/17 Brunei 2/4 Cambodia 4/4 8/8 Malaysia 4,400 pharmaceutical companies, 15/21 including 200 foreign companies Singapore Indonesia Subsidiary or Rep Office 15/26 0/8 Business through Distributors Only Santen for

No. of approved products in recent 5 years: 147 Products ophthalmic agent / Total No. of products: 287 Products

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 13 Conducting R&D Specific to Ophthalmology to Contribute to Improving QOL* in Patients Around the World Glaucoma / Ocular Surface Optic Nerve Disorder Back of the Eye Dry Eye Glaucoma  Macular Diseases Allergic Conjunctivitis • wetAMD Eye infection • DME Cataract  Diabetic retinopathy Myopia etc.  Retinal vein occlusion  Posterior Uveitis etc.

Sclera Ciliary body Choroid Anterior chamber Retina Cornea Macula Fovea Pupil Optic disk Lens Optic nerve *Quality of Life Iris Vitreous

Optic nerve damage Visual field loss due to high intraocular pressure

Initial stage Late stage Inhibiting progressive visual field loss Inter Ocular IOP lowering Pressure (Start/Continuation)

Optic nerve Image (Right eye only)

Keep and recovery of visual field

Neuroprotection

*1: WHO Global Data on Visual Impairments 2010 *2: Morizane et al, Japanese Journal of Ophthalmology, January 2019, Volume 63, 26–33

●IOP lowering agents Efficacy Stronger IOP lowering agents (start) Supporting to non responders Instillation to lower intraocular Timoptol XE Detantol Tapros Eybelis pressure 0.5% 0.01% 0.0015％ 0.002% ●IOP lowering agents (Continuation) Continue treatment for a lifetime. Change or add the treatment Safety depending on severity Reduction and avoidance of adverse reactions Trusopt Tapcom Reduction of invasiveness and 1％ ●Laser complications of surgery The laser is applied to the part where the aqueous humor is discharged (trabecular meshwork) to promote the drainage.

● Usability Surgery Improve compliance Removes a part of trabecular Reduce Patients’ burden meshwork and creates the （Easy to drop） drainage route for aqueous humor. e.g. Trabeculectomy

Mechanism Normalization of Improvement of A disease that can decrease productivity and tear film objective signs worsen the QOL over time. （by normalization of tear film）

Decreased Tear film tear volume instability Decreased tear secretion Changed composition of tear Increased fluid Lipid evaporation of tears layer Aqueous layer Tears

Mucous Ocular surface layer Epithelial damage inflammation

Epithelium Improvement of

Bowman’s membrane subjective symptoms

Corneal nerve Corneal storoma Asthenopia, Dryness, Discomfort, Eye-pain, etc. Abnormalities of visual function

Diquas 3％

Hyalein Soft Santear Cationorm® MD / 0.1% （OTC） Cationorm® SD

Ikervis®

●Improvement of main symptoms Anti-histamine ophthalmic solution Itching Chemical mediator release inhibitors Alegysal Alesion Lecrolyn® SD Hyperemia / edema 0.1％ 0.05％ ●Improvement of main symptoms Anti-inflammatory ophthalmic solution

Flumetholon 0.1% Verkazia® Papilock Mini Cogan Collection, NEI/NIH 0.1%

＊For vernal conjunctivitis ●Improvement of safety and usability BAK free Reduce dose frequency Reduce dose frequency

4times/day 2t imes / day

●Antibacterial

Basic treatment with antibacterial Ecolicin ophthalmic agent ointment Depending on the type of bacteria, using ophthalmic ointment and oral medicine Tarivid Cravit Cravit Eye mucus, Hyperemia, 0.3% 0.5% 1.5% Edema, Foreign body Tarivid Mass（Sty, etc.） ophthalmic ointment ●Antiviral Antiviral ophthalmic solution Antiviral ophthalmic ointment Zovirax ophthalmic ointment

Glare, Tears, Eye pain Ulcer, Suppuration ●Improvement of main symptoms Anti-inflammatory Flumetholon Proranon Santeson ophthalmic solution 0.1% 0.1% ophthalmic ointment

●Suppression of lens opacity Ophthalmic agent to suppress lens opacity by stopping degeneration of lens protein

Opacity of the Lens

Kary Uni 0.005％ Light

●Cataract surgery The lens that has become cloudy is removed and replaced with an intraocular lens

Eternity Lentis Comfort® National Eye Institute

*1: WHO Global Data on Visual Impairments 2010 *2: 科学的根拠 (evidence) に基づく白内障診療ガイドラインの策定に関する研究 2002

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 21 Myopia: Aim to Develop and Provide the World’s First Treatment 27% of the world population is Retina estimated to have myopia*. Forecast to increase in the future.

Suppression of the axial length elongation Treatment of the Low dose atropine cause of vision loss light rays form a focus point in front of the retina Regression of neovascularization （Anti-VEGF therapy) Axial length growth Vision Correction Eye glasses, Contact lenses, LASIK Pathologic myopia

Vision loss

*: IMPACT OF INCREASING PREVALENCEOF MYOPIA, Report of the Joint World Health Organization

Retinal pigment epithelial cells Retina Bruch's membrane Choroid Macula Macula Sclera

wet Age-related Macular Diabetic Retinapathy (DR) Central Retinal Vein Occlusion (CRVO) Posterior Uveitis Degeneration (wetAMD) Diabetic Macular Edema (DME) Branch Retinal Vein Occlusion (BRVO) Inflammation occurs in the uvea (choroid) Abnormal blood vessels begin to grow The retina is damaged due to diabetes. If Retinal hemorrhage and edema caused due to various causes, resulting blurred toward the macula. Then, the macula is edema develops in macula (DME), it by the retinal vein occlusion. If this extends to vision, ocular floater, photophobia and impaired and can result in a severe loss directly linked to vision loss. the macula, vision loss occurs rapidly. vision loss. of central vision.

Anti-VEGF therapy Anti-TNFα therapy Regression of the neovascular vessels and inhibition of neovascularization

Laser photocoagulation Steroid Laser cauterize the lesion or related tissue.

Photodynamic therapy Steroid (PDT) Anticoagulant (Oral)

Santen Oy (Finland) Headquarters （Japan）

Santen INC. （U.S.）

Santen SAS （France) R&D Nara R&D Center Manufacturing （Japan） Sales Office

Network Unmet Improving Treatments Reducing Patient Burden Medical Needs Santen’s Product Development Santen’s Industry Internal Partner Expertise

Open Research Innovation Retinal and Kerato- Institute Refractive Glaucoma Uveal conjunctival disorders disorders disorders

Digital Academia

Expanding Partnerships globally

Academia Research Institute

Industry Partner

Enhancement of clinical evaluation technology Banking of clinical samples

Clinical Research Clinical Research (Individual) Higher PTS & (Cohort) Productivity Clinical epidemiology, Translational research in the Pharmacoepidemiology, narrow sense Proteomics, Genomics

Validation of MOA in human Basic Clinical data analysis Analysis of pathology research Analysis of biospecimen

*Probability of Technical Success

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 28 Clinical Development that are Fast and Have Higher Clinical Success Rates Operation Speed of clinical trials DE-117 clinical trials (Glaucoma)

Phase 2a Phase 2b Phase 3 (AYAME study) Development region: U.S. Development region: U.S. Development region: Japan No. of patients: 91 No. of patients: 184 No. of patients: 253

5 months 8 months 14 months Phase 3 success rates in ophthalmology

Santen1 Industry Average 58% in Ophthalmology2 92%

1. Internal analysis in 2006-2018 2. Clinical Development Success Rates 2006-2015, Bio, Biomedtracker, Amplion, 2016

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 30 Innovative Pharmaceutical Development to Meet Formulation/ Customer Needs CMC Improve usability Continuous treatment by improving adherence and compliance

Less frequency Ophthalmic Solution Reduce frequency of instillation with High Safety Reduce complexity by using Reduce the effect on ocular surface by many of combination preservatives.

Easy-to-use bottle Develop easy-to-use bottle for everyone including elderly

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 31 Formulation/ Less frequency: Reduce Patient Burden CMC COREAL CONCENTRATION 60,000 (Results of animal model) ciclosporin (0.1%) 3.6 x HIGHER 50,000 1.0mg/mL Ciclosporin in cationic

40,000 formulation

hr/g of tissue) of hr/g . 30,000

, ng 1.9 x HIGHER 72hr

- Tapros Timoptol 0 0.5mg/mL 0.0015％ 0.5%

20,000 Ciclosporin (AUC

150 nm in cationic Corneal ConcentrationCorneal emulsion 0.5mg/mL 10,000 Ciclosporin Combination Drug in anionic 0 AUC = Area under curve Rabbit corneal Cornea, 2013;32:345-354

Cornea

Tapcom

® Cationorm SD Cationorm® PFMD Kary Uni 0.005％

Lecrolyn® SD Lecrolyn® PFMD Source: Santen analysis

Low BAK BAK Free Preservative Free

Low Other Preservative Conventional Preservative Preservative Free preservative in new in new in new formulation formulation formulation

Benzalkonium Benzalkonium Chlorhexidine N/A Chloride Chloride gluconate (Low Concentration) solution

Sales Share Trend of Diquas in Japan Sales Share Trend of Alesion in Japan

Launched BAK free formulation

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 35 “Dimple Bottle” was Developed Formulation/ by Bringing in Voice of Patients CMC 2019~ Assist tool for instillation 2002~ Just In Dimple bottle 1992~ Chip & Cap Instillation success rate 1977~ 84％ Bottle pack Instillation success rate 52％ Easy to see residual Easy to drop Easy-to-see display volume

Concentration display on the top of the cap Product name labeling on top of the shrink label Slits on both sides With the design of holding position With the line ofキャップと the same cap’s同色のライン color

Front Back Sentence-enlarging labels

Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 36 Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 37 Copyright© 2019 Santen Pharmaceutical Co., Ltd. All rights reserved. 38 R&D Leadership Members

Naveed Shams

Senior Corporate Officer & CSO, Head of R&D Division

Reza Haque Kenji Morishima Peter Sallstig Takeshi Matsugi Corporate Officer, Senior Vice President, Head of R&D Strategic Senior Vice President, Head of Pharmaceutics & Head of Biomedical Pharmacology Head of Product Operations Strategy & Research Representative, Asia R&D Development