vision is our mission

Transcription

1 vision is our mission NASDAQ: OPHT December 2018

2 Forward-looking Statements Any statements in this presentation about Ophthotech s future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of Forward-looking statements include any statements about Ophthotech s strategy, future operations and future expectations and plans and prospects for Ophthotech, and any other statements containing the words anticipate, believe, estimate, expect, intend, goal, may, might, plan, predict, project, target, potential, will, would, could, should, continue, and similar expressions. In this presentation, Ophthotech s forward-looking statements include statements about the implementation of its strategic plan, Ophthotech s projected use of cash and cash balances, the timing, progress and results of clinical trials and other research and development activities, the potential utility of its product candidates, its expectations with respect to the financial impacts and benefits to Ophthotech of the acquisition of Inception 4, and the potential for its business development strategy, including its collaborative gene therapy research programs and any potential in-license or acquisition opportunities. Such forward-looking statements involve substantial risks and uncertainties that could cause Ophthotech s clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, those related to the initiation and the conduct and design of research programs and clinical trials, availability of data from these programs, expectations for regulatory matters, need for additional financing and negotiation and consummation of in-license and/or acquisition transactions and other factors discussed in the Risk Factors section contained in the quarterly and annual reports that Ophthotech files with the Securities and Exchange Commission. Any forward-looking statements represent Ophthotech s views only as of the date of this presentation. Ophthotech anticipates that subsequent events and developments will cause its views to change. While Ophthotech may elect to update these forward-looking statements at some point in the future, Ophthotech specifically disclaims any obligation to do so except as required by law. 2 2

3 Value Creation: Building a Leading Retina Company Developing Transformative Gene Therapies and Novel Therapeutics for Retinal Diseases Market: Large and orphan indications Pipeline: Expansion through business development activities Execution: Unique in-house expertise in clinical development Strong Cash Position: Drive future growth 3 3

4 Focus on Potential Treatments for Retinal Diseases Market Opportunity for Age-Related Indications Multibillion dollar opportunities with remaining unmet medical need Growing market size as population ages longer Significant value to patients, caregivers and society Market Opportunity for Orphan Indications Large number of diseases Mostly without any approved treatment options Many have potential for cure with gene therapy 4 4

5 Multi-Modality Approach: Maximize Probability of Success Therapeutics Deep understanding and expertise in ophthalmic drug development Multiple retina specialists in management Highly experienced clinical development team Strong global network Well known KOLs Experienced clinical investigators Gene Therapy Novel and cutting edge AAV gene therapy: Dual function (knockdown + replace) single AAV vector strategy: RHO-adRP Minigene strategy: LCA10 (CEP290) and Stargardt disease (ABCA4) * AAV gene delivery methods * *Sponsored research with UMASS Medical School; option to in-license resulting IP 5 5

6 Gene Therapy Therapeutics Pipeline Strategy: Build Sustainable Long-term Growth Indication Research Pre-clin. Phase 1 Phase 2 Phase 3 Status GA secondary to Dry AMD Zimura monotherapy Phase 2b ongoing Top-line data expected 4Q 2019 Stargardt Disease (STGD1) Zimura monotherapy GA secondary to Dry AMD HtrA1 Inhibitor RHO-adRP AAV vector BEST1 AAV vector LCA10 minicep290 AAV vector STGD1 miniabc4 AAV vector Gene Delivery Methods Phase 2b ongoing Top-line data expected 2020 IND filing planned for late 2020 Phase 1/2: initiate in 2020 UPenn sponsored research Phase 1/2: initiate by 2021 UPenn sponsored research* Ongoing UMMS sponsored research* Ongoing UMMS sponsored research* Ongoing UMMS sponsored research* 6 + Option to in-license resulting IP 6

7 Gene Therapy for Retinal Diseases 7 7

8 Key Rationale for Ocular Gene Therapy Strategy Many ocular orphan indications are due to genetic defects Potential to cure diseases with significant unmet medical need Eye is an ideal target for gene therapy: Localized delivery, minimizing systemic exposure Immune privileged Depth of monogenic disease characterization Relatively easy access to pathology for gene therapy delivery Positive implications for patients and health care providers 8 8

9 Strategic Scientific Collaboration Leading Academic Gene Therapy Centers 9 9

10 Gene Therapy Gene Therapy Programs RHO-adRP AAV vector BEST1 AAV vector Indication LCA10 minicep290 AAV vector STGD1 miniabca4 AAV vector Orphan Disease Estimated Population Status ~11K US/EU Phase 1/2: initiate in 2020 ~10K US/EU Phase 1/2: initiate by 2021 * 2.7K 4.1K US/EU Ongoing * ~62K 77K US/EU Ongoing * AAV Gene Delivery Technology Ongoing * 10 * Sponsored research ongoing; option to in-license resulting IP 10

11 Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa 11 11

12 RHO-adRP: Phase 1/2 Clinical Trial Planned to Initiate in 2020 Mutation independent strategy with single AAV vector Silences / knocks out mutated toxic rhodopsin protein Produces healthy wildtype rhodopsin protein Proof-of-concept in animal models (canine and mouse) Preservation of retinal anatomy and function Clear path to IND submission IND enabling and natural history studies Proc Natl Acad Sci U S A Aug 20. doi: /pnas [Epub ahead of print]. HUMAN GENE THERAPY 23: (April 2012)

13 University of Pennsylvania: Canine Model Vector: AAV2/5 Construct: scaav2/5-h1p-shrna820-hop-rho820, human opsin promoter Delivery: Single subretinal injection of ~150 microliters Canine model: RHO mutant dogs heterozygous for T4R mutant allele (RHO T4R/+ ) AAV2/5 Capsid Produces healthy wildtype rhodopsin protein Source: Proc Natl Acad Sci U S A Aug 20. doi: /pnas [Epub ahead of print].. Silences / knocks out mutated toxic rhodopsin protein 13 13

14 Preservation of Retinal Anatomy: 2 Weeks Post Single Light Exposure * scaav2/5-h1p-shrna820 -hop-rho820: Rescued Outer Retina OCT GFP RS301 White Line: Outer Retinal Thickness Outer retina *13 weeks post-injection Source: Proc Natl Acad Sci U S A Aug 20. doi: /pnas [Epub ahead of print]

15 Preservation of Retinal Function (ERG): 37 Weeks RHO Mutant Dogs Green: scaav2/5- RHO820 -shrna820 RED: Balanced Salt Solution (BSS) Source: Proc Natl Acad Sci U S A Aug 20. doi: /pnas [Epub ahead of print]

16 Best Vitelliform Macular Dystrophy BVMD/Best Disease 16 16

17 BEST1: Phase 1/2 Clinical trial in 2021 Proof-of-concept in naturally occurring canine animal models IND enabling studies planned Natural history studies planned 17 17

18 Best Disease Best Vitelliform Macular Dystrophy (Best disease) is an orphan inherited retinal disease caused by mutations in the BEST1 gene The BEST1 helps regulate chloride ion traffic in retinal cells Patients with Best disease develop an egg yolk-like vitelliform lesion in their macular region, which over time leads to macular atrophy and permanent loss of central vision Best disease generally affects individuals in both eyes Approximately 10,000 individuals in the United States and the five major European markets have Best disease Source: Proceedings of the National Academy of Sciences Mar 2018, 115 (12) E2839-E2848; DOI: /pnas

19 Best Disease Normal Fovea Best: Subclinical Best: Pre-vitelliform Microdetachment Ca 2+ = Cl - Ca2+ Cl - Ca 2+ Cl - Source: Progress in Retinal and Eye Research 58 (2017)

20 AAV2-hBest1 Gene Therapy Vector: AAV2/2 (serotype 2 capsid and type 2 terminal repeats (TRs)) Construct: raav2/2-hvmd2-hbest1 vector, human VMD2 promoter Delivery: Single subretinal injection of ~ microliters, 5E11 vg/ml Canine model: Homozygote cbest-mutant dog Schematic Diagram of Plasmid Construct Source: PLoS ONE 2013; 8(10): e Proc Natl Acad Sci U S A. Retinal and Eye Research 58 (2017) 45e

21 AAV2-hBest1 Gene Therapy: Resolution of Retinal Microdetachment Before Injection BSS: 87 Wks post Inj Before Injection AAV: 103 Wks post Inj BSS: 103 Wks post Inj AAV: 103 Wks post Inj Source: Proc Natl Acad Sci U S A Mar 20;115(12):E2839-E

22 Minigene Strategy Leber Congenital Amaurosis (LCA10): minicep290 Autosomal Ressive Stargardt Disease: miniabca

23 AAV Vectors are Appealing for Ocular Gene Therapy Extensive experience with intraocular application Well documented safety profile Tropism for retinal tissue Limited packaging capacity of < 5kb Minigene Strategy Engineer AAV-amenable genes that encode functionally optimized proteins 23 23

24 Leber Congenital Amaurosis (CEP290) CEP290 mutations: one of the most common causes of LCA Early onset vision loss Extinguished Electroretinogram Preserved outer retinal structure in the foveal area Preservation of foveal outer retinal architecture Source: Ophthalmology 2018 Feb 2. pii: S (17) doi: /j.ophtha

25 Scotopic LCA10: MiniCEP Improves Anatomy and Function MiniCEP Rescued Photoreceptor MiniCEP GFP (Control) 8 x 10 9 vg/µl into the subretinal space of Cep290 rd16 mouse pups (P0/P1), Week 3 Source: Hum Gene Ther Jan;29(1):

26 Therapeutics Program for Retinal Diseases 26 26

27 Zimura, C5 Complement Inhibitor Geographic Atrophy (GA) Secondary to Dry Age-Related Macular Degeneration 27 27

28 Geographic Atrophy Secondary to Dry AMD Major market opportunity Unmet medical need No FDA/EMA approved treatment options Role of complement in dry AMD Genetic link between complement and AMD With aging, complement deposition increases and leads to the formation of inflammasomes and accumulation of Membrane Attack Complex (MAC) Inflammasome and MAC accumulation lead to retinal pigment epithelial (RPE) cell death and loss of vision Sources: The Journal of Biological Chemistry Vol. 290, NO. 52, pp , December 25, Invest Ophthalmol Vis Sci. 2013;54: J Immunol. 2015; 195: Med Sci Monit, 2010; 16(1): BR Am J Ophthalmol 2002;134: Proc Natl Acad Sci USA. 2005, 102(20), Science Apr 15;308(5720): ; ;

29 C8 C9 C9 Zimura Blocks C5 Cleavage: Potential to Block Inflammasome Formation & MAC Accumulation Lectin Classical Alternative X Cell Death Pathogen CD46 C4 C4b C2 C1r C1s C1q Pathogen CD46 Factor H C3 C3b Bb Bb C3b Factor D Microbial Cell Surface Factor B C3 C3b C3 C4b C2a C3b C3b C3b Bb Source: OPHT internal Zimura C5a X X X Cell Death X Inflammasome C5 X C5b X X X C5b C6 C7 Cell Death C6-C9 Membrane Attack Complex (MAC) 29 29

30 Dry AMD (GA): Zimura Phase 1/2a Completed Study Design Intravitreal Zimura was administered for a maximum of 5 injections at one of two dose levels (0.3 mg/eye or 1mg/eye) Week Zimura Dosed 47 Patients Enrolled 0.3 mg dose group (n=24) 1 mg dose group (n=23) *Uncontrolled safety trial; small sample size 30 30

31 Dry AMD (GA): Zimura Phase 1/2a Completed * Safety - No Zimura related adverse events - Zero incidence of wet AMD in eyes treated with Zimura Potential efficacy signal(s) - Presence of a dose-response trend with on-off effect (n=24) (n=23) *Uncontrolled safety trial; small sample size 31 31

32 Geographic Atrophy: Zimura Phase 2b - Ongoing Phase 2b, randomized, double-masked, sham-controlled clinical trial Cohorts: Zimura: 3 dose levels Sham 286 subjects enrolled; monthly study treatment (Zimura or Sham) for 18 months Primary Efficacy Endpoint Mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at three time points Top-line data expected in 4Q

33 Zimura, C5 Complement Inhibitor Autosomal Recessive Stargardt Disease (Orphan Indication) 33 33

34 Autosomal Recessive Stargardt Disease (STDG1) Orphan disease High unmet medical need No FDA or EMA approved treatment available Progressive damage to the macula and retina caused by mutations in the ABCA4 gene ABCA4 gene makes a protein that normally helps clear away visual cycle byproducts inside retinal cells Lack of this protein leads to the accumulation of waste and complement activation leading to retinal cell death and loss of vision Sources: The Journal of Biological Chemistry. 2011; 286(21): Proc Natl Acad Sci U S A. 2017; 114(15): Invest Ophthalmol Vis Sci. 2013;54:

35 Complement Inhibition Rescues Photoreceptors AAV-Null Abca4 -/- AAV-CRRY BALB/c Uninjected Control 30% Photoreceptor Rescue Representative retinal images from 1 Year old Albino Abca4 -/- or BALB/c Mice Source: Proc Natl Acad Sci U S A. 2017; 114(15):

36 Stargardt Disease : Zimura Phase 2b Ongoing Phase 2b Clinical Trial Randomized, double masked, sham controlled clinical trial Two arms: Zimura Sham Duration of treatment: 18 months Primary Endpoint: Mean rate of change in the area of ellipsoid zone defect measured by en face SD-OCT Top-line data expected in 2020 Foundation Fighting Blindness Access to FFB s publicly available ProgStar natural history study Patient registry access to facilitate recruitment 36 36

37 HtrA1 Inhibitor Therapeutic Program (Through Acquisition of Inception 4 from Versant Ventures) 37 37

38 HtrA1 Inhibitor Program Strong genetic link between HtrA1 (high temperature requirement A serine peptidase 1 protein) & AMD: Highest identified odds ratio to develop AMD, homozygotes have ~8.2 fold increased risk AMD patients overexpress HtrA1: Increased HtrA1 protein level in aqueous humor of wet AMD patients Increased intracellular expression of HtrA1 inside the RPE cells of AMD patients Increased HtrA1 staining in a majority of drusen of AMD patients donor eyes HtrA1 protein overexpression may contribute to AMD: Damages the extracellular matrix and Bruch s membrane Alters and disrupts RPE cells Upregulates complement Leads to drusen Interferes with RPE cell function and secondarily impacting photoreceptors Small molecule inhibitors of HtrA1 with high affinity and specificity for HtrA1 Sources: Human Molecular Genetics, 2005: 14, Arch Ophthalmol. 2007;125: Aging Cell May 5:e doi: /acel [Epub ahead of print]. Investigative Ophthalmology & Visual Science January 2017, Vol.58, EBioMedicine 27 (2018) Science 2006; 314 (5801), Cell Cycle 6:9, , 1 May 2007]. Scientific Reports 7: DOI: Invest Ophthalmol Vis Sci. 2010;51: PLoS One. 2011;6(8):e doi: /journal.pone Invest Ophthalmol Vis Sci. 2010;51:

39 Value Creation: Building a Leading Retina Company Focused on Advancing Gene Therapy and Therapeutics RHO-adRP, BEST1, LCA10 and STGD1 HtrA1 Inhibitor in GA secondary to Dry AMD Upcoming Zimura Data Points Dry AMD (GA) in 2019 Stargardt in 2020 Continue Business Development Activities to Expand Portfolio Completed three gene therapy deals in inherited retinal diseases in 2018 Strong Cash Position to Drive Growth $135 million in cash and cash equivalents * * As of September 30,