CXLUSA Clinical Trial Results S. Lance Forstot , MD, FACS Corneal Consultants of Colorado

1. CXLUSA Clinical Trial Results S. Lance Forstot, MD, FACS Corneal Consultants of Colorado Founding Partner Clinical Professor of Ophthalmology University of Colorado School of Medicine

2. Dr. Rubinfeld has intellectual property in corneal strengthening technology and financial interests in CXLO and CXLUSA CXLUSA Clinical Trial Results Roy S. Rubinfeld, MA, MD Georgetown University Medical Center, Washington Hospital Center, Washington, DC

3. What’s What? • Non-commercial, physician-sponsored UV research studies approved by IRBs since 2009. No IP, no investors Limited number of centers • Commercial start up with IP, investors, BOD, Novel Technology, Commercial Drug, Advisors

4. CXLUSA Study Group Centers • Rubinfeld: Rockville MD, Fairfax VA • Miami FL : Center for Excellence in Eye Care • Chicago IL: Chicago Cornea Consultants, Ltd • Denver, CO: Corneal Consultants of Colorado • Los Angeles CA: LA Sight • West Hills, CA: Davidorf Eye Group • San Diego, CA: Clear View Eye and Laser Center • San Francisco, CA: Goodman Eye Center • Orange County, CA: Harvard Eye Associates • Boston, MA: Talamo Laser Eye Consultants

5. CXLUSA Study Group Centers • St. Louis, MO: Ophth Assoc- Corneal & Laser • Long Island, NY: South Shore Eye Care • Scottsdale, AZ: Schwartz Laser Eye Center • Dallas, TX: Cornea Associates of Texas • Cleveland, OH: Clear Choice Custom LASIK Center • Seattle, WA: Northwest Eye Surgeons • Spokane, WA: Empire Eye Physicians • Bloomington, MN: Minnesota Eye Consultants • Atlanta, GA: Woolfson Eye Institute

6. CXLUSA Study Group Centers • Arizona: Scottsdale • California: Los Angeles Orange County San Diego San Francisco West Hills • Colorado: Denver • Florida: Miami • Georgia: Atlanta • Illinois: Chicago

7. CXLUSA Study Group Centers • Maryland: Rockville • Massachusetts: Boston • Minnesota: Bloomington • Missouri: St. Louis • New York: Long Island • Ohio: Cleveland • Texas: Dallas • Virginia: Fairfax • Washington: Seattle Spokane

8. CXL Mythology

10. Transepithelial Riboflavin Loading @12 min

11. 15 Min Epi-On CXLO (~20 y/o pt)Cobalt Blue Light SL Pix

12. Epi-on Flare

14. 15 Min Epi-On CXLO White Light SL Pix (18 y/o Pt)

16. Haze after Epi-Off CXL

17. Delayed Epithelial Healing and Infiltrate after Epi-Off CXL Courtesy of W. Trattler, MD Postop Day 2

18. Postop Day 5

19. Perforation after Epi-Off CXL

20. Epi-off Complications • Microbial keratitis after corneal collagen crosslinking. Perez-Santonja JCRS 2009;35(6):1138-40 • Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. Sharma. JCRS 2010;36(3):517-20 • Complication and failure rates after corneal crosslinking. Koller, Seiler, et. al.JCRS 2010;36(1):185 • Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. Raiskup, Spoerl,  JRS2009 Sep;25(9):S824-8. • Corneal melting in both eyes after simultaneous corneal cross-linking in a patient with keratoconus and Down syndrome. Ophthalmologe. 2010 Oct; 107(10):951-5 • Corneal melting corneal collagen cross-linking for keratoconus: A case report. Labiris. Journal of Medical Case Reports 5:15 2012 • Early ocular surface-related complications after CXL. Gutman. Modern Medicine Sept, 2012.

21. Critical Balance of 3 Reactants is Essential Oxygen UV light Riboflavin

22. Clear Cornea- Epi-On CXL POD 1

23. Epi-On Advantages • Safety • Treat thinner, steeper, younger corneas, • Return to preop vision, function POD 1 • Return to CLs in days • 1 day of discomfort • KCN as indication for PKP

24. But Epi-on is not “better” if it doesn’t work

25. Clinical Experience - Keratoconus Vision Improvement (>= 1 line of vision) CXLUSA vs. Hersh/Avedro N = 177 N = 48 N = 49 N = 177 N = 48 N = 49 c/o William Trattler, MD

26. 1 Year Results (Advanced KCN) Formulation 1 (36 eyes) UCVA: Improved ≥1 Lines: 56% Worsened: 3% No Change: 40% BSCVA: Improved 1 ≥ Lines: 41% Worsened: 32% No Change: 24% K Max: Avg Flattening vs. Pre Op=1.55D Formulation 2 (31 eyes) UCVA: Improved ≥1 Lines: 64% Worsened: 8% No Change: 28% BSCVA: Improved 1≥ Lines: 56% Worsened: 8% No Change: 35% K Max: Avg Flattening vs. Pre Op= 1.41D

27. Epi- On CXLUSA Results •  UCVA, BSCVA by ≥ 1 line ~50% • Kmax by ~0.7 to 1.55 D • Tx failures <1%, 0 Adverse Events • Comparable to Epi-Off with reduced risk, discomfort, visual recovery time • KCN as indication for PKP

28. Limitations of CXL Alone • Stops Progression • Mild improvement in ~50% • Can we do better for advanced cases?

29. Limitations of CXL Alone • Terrific for early KCN before vision is lost • CXL stops progression of vision loss and corneal steepening • For those who have lost vision from KCN or ectasia, CXL usually yields only mild improvement in vision and topo/tomos • Can we do better for more adv cases?

30. What if we Could Do This Consistently With Two Non-invasive Procedures? 1 Day Postop Preop

31. Observant keratoconus patients sometimes point out, “Pressing on my eye right here, my vision gets much sharper.” c/o Anita Nevyas Wallace, MD Finger Pressure at 6 o’clock Finger Pressure at 7 o’clock No Finger Pressure 20/200 20/40 20/30+

32. CK Plus CXL Technique

33. Immediately Postop CK vsPreop Postop Diff map Preop

34. 27 y/o F Caucasian w KCN @ 1 Mo VAsc PREOP: 20/80 VAsc 1 MO PO: 20/20- Preop RFx: -2.00 +5.50 X 170 20/25 1 MO PO RFx: pl +0.75 X 150 20/25+

35. 27 y/o F Caucasian w KCN @ 6 Mo VAsc PREOP : 20/80 VAsc 6 MO PO : 20/25- Preop RFx: -2.00+5.50 X 170 20/25 6 MO PO RFx: pl + 1.25 X 155 20/25

38. Ongoing Data Collection

39. There are known knowns; there are things we know that we know. There are known unknowns; that is to say there are things that, we now know we don't know. But there are also unknown unknowns – there are things we do not know, we don't know. 2/12/02

40. Epi-On is safer, as effective and likely to supplant Epi-Off Known unknown: Epi-On CXL may “lock in” CK and become important procedure “Known Known”

41. Thank You