Inherited Retinal Disease Milestones: Reasons to be Excited

1. Inherited Retinal Disease Milestones: Reasons to be Excited Brian Mansfield, PhD Senior Vice President, Research

2. 1971

3. Affected Families Drive Research Eliot Berson, MD, Mass. Eye and Ear Gordon and Llura Gund Ben and Beverley Berman Berman-Gund Laboratory for the Study of Retinal Degenerations • 1968 National Eye Institute • 1971 Foundation Fighting Blindness • >55 Organizations in US alone Founded in 1971, the Foundation Fighting Blindness has raised more than $725MM toward R&D and public health education

4. Understanding the Genetic Basis of Disease Rhodopsin gene isolated Rhodopsin Identified as genetic cause of RP Rpe65 Gene Therapy Approved First human IRD gene therapy We can dentify the gene in 65% of retinal disease Gene detection rate of LCA >80% >260 genes now identified

5. 2018 - Approved Products • United States: • Argus II Prosthesis 55 electrodes, epiretinal Second Sight • Luxturna RPE65 Gene Therapy Spark Therapeutics • Europe: • IRIS II 150 electrodes, subretinal Pixium Vision • Alpha IMS 1,600 electrodes, subretinal, no camera Retina Implant • Compassionate Use – UK • LCA - AIPL1 - MeiraGTx

6. Gene Augmentation Clinical Trials 23 gene-based clinical trials - 13 different genes

7. Optogenetic Gene Therapy Clinical Trials • Photoreceptors lost • Bacterial light-sensitive gene • Insert into healthy retinal cells – bipolar, ganglion cells There is a pipeline of >16 similar therapies in preclinical development

8. Gene Patch Clinical Trials • Gene itself does not encode a bad protein • The instructions that drive the gene fool it to act wrongly • “Deep Intronic” mutations • A small DNA molecule is injected to cover up the faulty instruction • Not virus – repeat injections every few months • 3 month interim data – well tolerated, improved VA, mobility course • Planning a pivotal Phase 2/3 trial A similar approach for a group of mutations in USH2A is near clinic

9. Other Genetic Technologies • Gene editing – CRISPR/Cas9 • “Cut and Paste” • Enzyme seeks out and repairs the defective gene in retinal cells • LCA due to CEP290 c.2991+1655A>G (p.Cys998X) • Editas – close to clinic • Base Editing • “Backspace and Retype” • Autosomal recessive RP - IMPG2 There is a pipeline of very precise, innovative, genetic technologies

10. Cell Therapy Clinical Trials • J-Cyte 12 month, 28 patients Phase I/II result: • Appears safe • Trends in improvement in best corrected visual acuity (BCVA) in the treated eyes compared to untreated eyes Over 20 cell therapy trials – RPE cells and AMD

11. Small Molecule Drugs Promising pipeline – pan-disease Antioxidants – Mitochem Gene-independent therapies – OptiKira; PhotoSwitch Biosciences Over 8 new pharmaceutical drugs in clinic Rich pan-disease pipeline

12. Career Development Awards Founded 1968 Attract and retain young researchers into our field Establish a career – enable them to attract funding – NIH and beyond

13. Bright Minds - Cutting Edge Innovation David Gamm, PhD University of Wisconsin Photoreceptor transplantation iPSC and microengineering Shannon Boye, PhD University of Florida Dual AAV vector-mediated therapy for Myosin7a Usher syndrome (USH1B) The Foundation continues to fund ground breaking translational research in the area of cell and gene therapy

14. Focus on Translational Research Providing 16 years of preclinical research support ($10M) FFB helped, with others, to catalyze the first commercial gene therapy

15. Industry Expertise Guiding Development Konstantin Petrukhin, PhD Columbia University Optimization of Small molecule RBP4 antagonists for treatment of Stargardt’s disease The Foundation collaborates with the Harrington Discovery Institute to speed translation of new therapies

16. Strategic Funding of Companies • Clinical Gene Therapy Pipeline • X-linked retinoschisis – RS1 • Achromatopsia – CNGA3 • Achromatopsia – CNGB3 • X-linked retinitis pigmentosa RPGR AGTC leveraged an early FFB investment to garner $265M to Develop Gene Therapies

17. Co-Funding Commercialization • Start up company founded in 2017 • Based on FFB supported research in • Dr. Campochiaro’s lab • NACA – N-acetyl cysteine amide • Independent of the genetic cause of disease • Reduces oxidative stress on cells • Novel aqueous humor clinical biomarkers Oral NACA has just completed Phase 1 clinical testing in Australia

18. Equity Investments - Startups • Start up founded in 2016 • Rod-derived cone viability factor (RdCVF) • Pan-disease gene therapy • Technology seeded by FFB grants at several universities – international collaboration • Scientific founders: • Jose Sahel, MD • Thierry Leveillard, PhD Sparing Vision is dedicated to developing RdCVF as a novel therapeutic target for treating IRDs

19. Supporting Pipeline Expansion QRX-421 Ushers2A exon 13 splice correction QRX-421 • Single stranded 21-mer RNA oligonucleotide • Targets USH2A exon 13 mutations • Injected into the eye every few months ProQR plans to be in the clinic for with QRX-421 by the end of 2018

20. Natural History Study of Stargardt disease Understanding Disease Progression • How variable is disease? • How does the disease progress? • How do we know if a therapy has changed the course of disease? 11 publications to date Identified and endpoint that is acceptable to the FDA

21. International Clinical Consortium Tubingen Milwaukee Jersey City Ann Arbor Baltimore Bethesda • First study ongoing: RUSH2A (Rate of Progression of USH2A Related Retinal Degeneration) 20 Clinical centers of excellence with experience in IRDs and with standardized assessment protocols Gainesville

22. Attracting Industry - Registries • What is the best disease to test my technology or drug on? • How many people are affected? • Where are they? • How do we contact them? • What is the age of onset? • How does that disease progress? • What impacts does the disease have on patient lives? • What is a meaningful treatment for patients? • i.e. is there an accessible, comprehensive • patient registry? A comprehensive registry is a key resource for rare disease drug development

23. Your Knowledge is a Key Resource • Sharing what you know is critical • Your understanding of the disease • How it impacts you and your family in daily life • What would you do for a treatment – injection every week? • What would mean the most to you in a treatment or cure • What would not be acceptable to you in a therapy – your fears • What don’t clinicians, researchers, regulatory agencies really understand • Focus groups • Patient journey • Testing new endpoints - maze Patient input is a critical part of the drug development pathway

24. Constituent Portal Clinician Portal Researcher Portal My Retina Tracker www.MyRetinaTracker.org Professional, Secure, Privacy

25. My Retina Tracker Genetic Testing Study • Eligibility – member, My Retina Tracker • Enrich the value of the registry • No cost comprehensive gene panel test • Includes genetic counseling Participants to date 2,300 Clinicians participating >190

26. BEAM Over 40 biotechs and companies developing novel therapies Most in contact with the Foundation MitoChem Therapeutics, Inc.

27. Collaboration • Sofia Sees Hope – Foundation Fighting Blindness: • Jointly promote awareness of: • Retinal disease research and resources – quarterly newsletters • Importance of patient registries • Importance of genetic testing • Jointly authored LCA Information and Resource page • National Organization for Rare Disorders • Co-fund: • My Retina Tracker Genetic Testing Study • Key research especially related to LCA • Communicate and collaborate closely to accelerate treatments and cures