1. ®Copyright Rubinfeld 2013 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. ®Copyright Rubinfeld 2013 CXLUSA Clinical Trial Results Roy S. Rubinfeld, MA, MD Georgetown University Medical Center, Washington Hospital Center, Washington, DC Dr. Rubinfeld has intellectual property in corneal strengthening technology and financial interests in CXLO and CXLUSA Dr. Rubinfeld has intellectual property in corneal strengthening technology and financial interests in CXLO and CXLUSA

3. ®Copyright Rubinfeld 2013 o o Non-commercial, physician-sponsored UV research studies approved by IRBs since 2009. No IP, no investors Limited number of centers o o Commercial start up with IP, investors, BOD, Novel Technology, Commercial Drug, Advisors What’s What?

4. ®Copyright Rubinfeld 2013  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 CXLUSA Study Group Centers

5. ®Copyright Rubinfeld 2013  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 CXLUSA Study Group Centers

6. ®Copyright Rubinfeld 2013  Arizona: Scottsdale  California: Los Angeles Orange County Orange County San Diego San Diego San Francisco San Francisco West Hills West Hills  Colorado: Denver  Florida: Miami  Georgia: Atlanta  Illinois: Chicago CXLUSA Study Group Centers

7. ®Copyright Rubinfeld 2013  Maryland: Rockville  Massachusetts: Boston  Minnesota: Bloomington  Missouri: St. Louis  New York: Long Island  Ohio: Cleveland  Texas: Dallas  Virginia: Fairfax  Washington: Seattle Spokane Spokane CXLUSA Study Group Centers

8. ®Copyright Rubinfeld 2013 CXL Mythology

9. Epi-Off is BetterEpi-On is Better Epithelium removal is needed to load the stroma with riboflavin See pictures

10. Transepithelial Riboflavin Loading @12 min

11. ®Copyright Rubinfeld 2013 15 Min Epi-On CXLO (~20 y/o pt) Cobalt Blue Light SL Pix

12. ®Copyright Rubinfeld 2013 Epi-on Flare

13. Epi-Off is BetterEpi-On is Better With Epi-On CXL, the riboflavin only loads epithelium which blocks the UVA and limits CXL See picture

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

15. Epi-Off is BetterEpi-On is Better Epithelium off CXL is safer than epi-on See pictures

16. ®Copyright Rubinfeld 2013 Haze after Epi-Off CXL

17. ®Copyright Rubinfeld 2013 Delayed Epithelial Healing and Infiltrate after Epi-Off CXL Postop Day 2 Courtesy of W. Trattler, MD

18. ®Copyright Rubinfeld 2013 Postop Day 5

19. Perforation after Epi-Off CXL

21. ®Copyright Rubinfeld 2013 Epi-off Complications o Microbial keratitis after corneal collagen crosslinking. Perez-Santonja JCRS 2009;35(6):1138-40 o Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. Sharma. JCRS 2010;36(3):517-20 o Complication and failure rates after corneal crosslinking. Koller, Seiler, et. al. JCRS 2010;36(1):185 o Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. Raiskup, Spoerl, JRS2009 Sep;25(9):S824-8. o 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 o Corneal melting corneal collagen cross-linking for keratoconus: A case report. Labiris. Journal of Medical Case Reports 5:15 2012 o Early ocular surface-related complications after CXL. Gutman. Modern Medicine Sept, 2012.

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

23. ®Copyright Rubinfeld 2013 Clear Cornea- Epi-On CXL POD 1

24. ®Copyright Rubinfeld 2013  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 Epi-On Advantages

25. ®Copyright Rubinfeld 2013 Epi-on is not “better” if it doesn’t work But

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

27. 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

28. ®Copyright Rubinfeld 2013  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 Epi- On CXLUSA Results

29. ®Copyright Rubinfeld 2013  Stops Progression  Mild improvement in ~50%  Can we do better for advanced cases? Limitations of CXL Alone

30. ®Copyright Rubinfeld 2013  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? Limitations of CXL Alone

31. ®Copyright Rubinfeld 2013 What if we Could Do This Consistently With Two Non-invasive Procedures?

32. ®Copyright Rubinfeld 2013 No Finger Pressure Finger Pressure at 6 o’clock 20/20020/40 Finger Pressure at 7 o’clock 20/30 + Observant keratoconus patients sometimes point out, “ Pressing on my eye right here, my vision gets much sharper.” c/o Anita Nevyas Wallace, MD

33. ®Copyright Rubinfeld 2013 CK Plus CXL Technique

34. ®Copyright Rubinfeld 2013 Immediately Postop CK vs Preop

35. ®Copyright Rubinfeld 2013 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+

36. ®Copyright Rubinfeld 2013 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

37. ®Copyright Rubinfeld 2013

39. Ongoing Data Collection

40. ®Copyright Rubinfeld 2013 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

41. ®Copyright Rubinfeld 2013 “Known Known”  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

42. ®Copyright Rubinfeld 2013 Thank You