UPDATE ON AVEDRO CROSSLINKING STUDIES

UPDATE ON AVEDRO

CROSSLINKING STUDIES

Peter S. Hersh, M.D.

Director, Cornea & Laser Eye Institute CLEI Center for Keratoconus

Clinical Professor of Ophthalmology, Rutgers Medical School

Visiting Researcher, Princeton University

Dept Mechanical and Aerospace Engineering Avedro, Inc: Medical Monitor

U.S. MULTICENTER CXL

TRIAL

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Treatment Groups

Total KC treated = 293

Total Ectasia treated = 219



U.S. multicenter

trial of CXL

started February

2008

Hersh Vision Group

COLLAGEN CROSSLINKING

Procedure: 30 Min, 3mW Protocol

 9 mm epithelium removal

 Riboflavin drops every 2 minutes X 30 minutes

— 0.1% in 20% dextran

 30 minutes UV exposure (365 nm UVA, 3mW/cm2)

Hersh Vision Group

AVEDRO CLINICAL TRIALS

U.S. Multicenter CXL Trial



Primary Efficacy Criteria

 Mean change in Kmax of ≥1 diopter (D) between the CXL treatment group and the control group from baseline

K_max

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Multicenter Trial: 1 Yr K

Change

 Last observation carried forward (LOCF) used for control group 1.0 -2 -1.5 -1 -0.5 0 0.5 1 1.5 D iopt er C hange KC CXL KC Control

Ectasia CXL Ectasia Control* -0.7 0.7 -1.6 KC (n=205) Ectasia (n=175) Preop 1 Year

Average Change Kmax = -1.6D

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Topography Indices (Pentacam): 1 Yr

 3 out of 6 KC indices significantly improved 1 year after CXL

Preop 1 Yr

Hersh PS, Greenstein SA, Fry KL. Corneal Topography Indices after Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia J Cat Refract Surg 2011;37:1282-91

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Higher Order Aberrations: 1 Yr

2.8 0.9 2.6 1.0 2.6* 0.8* 2.4* 0.9* 0.0 1.0 2.0 3.0

Total HOA Spherical Aberration Coma Trefoil

Hi ghe r O rde r A be rr a ti ons ( RM S W a v e fro n t E rro r in µ m ) Preoperatively 1 Year

Greenstein SA, Fry KL, Hersh MJ, Hersh PS. Higher Order Aberrations after Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia J Cat Refract Surg 2012;38: 292-302

Hersh Vision Group

CXL RESULTS

Visual Acuity: 1 Year (n=85)

0.83 0.87 0.82 _0.81 0.76 0.60 0.70 0.80 0.90

Baseline 1 Month 3 Months 6 Months 12 Months

UCV A (l ogM A R ) 20/137 20/117 20/34 20/450.34 0.38 0.30 0.26 0.24 0.16 0.21 0.26 0.31 0.36 0.41

Baseline 1 month 3 Months 6 Months 12 Months

BS CV A ( logM A R )

ACCELERATED

CROSSLINKING

Hersh Vision Group

AVEDRO CROSSLINKING

Accelerated Crosslinking

•

Avedro platform with higher

irradiance

• Standard CXL treatment is 3 mW UV for

30 minutes

• Accelerated crosslinking increases

irradiance and decreases time

• Up to 45 mW

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Accelerated Crosslinking

 U.S. multicenter study

 190 study eyes with keratoconus

 2 concurrent studies for submission to FDA (KXL 001 & 002)

 30 mW for 4 minutes

 Randomized to treatment vs placebo

 Inclusion criteria

 >12 yo

 Pachymetry >375 um

 Efficacy criterion

 Decrease in K_maxbetween treatment and control at 6 mo

Peter Hersh – Teaneck, NJ

Daniel Durrie – Overland Park, KS Leejee Suh – New York, NY

Sam Garg – Irvine, CA

Michael Gordon – San Diego, CA Vance Thompson – Sioux Falls, SD Michael Raizman – Boston, MA Francis Price – Indianapolis, IN Deepinder Dhaliwal – Pittsburgh, PA Jose de la Cruz – Chicago, IL

Kraig Scot Bower – Baltimore, MD J. Bradley Randleman – Atlanta, GA Rajesh Rajpal – McLean, VA

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Accelerated Crosslinking

Milestone KXL-001 KXL-002

First Patient Enrolled August 2012 September ₂₀₁₂

No. of sites 5 6

Number of subjects

enrolled 118 133

Anticipate completion of enrollment Summer, 2014 Preliminary analysis of patients at 6 mo f/u

1.03 D greater flattenning in treatment group

ACCELERATED

CROSSLINKING

Hersh Vision Group 15 mW/cm2 for 8 minutes 30 mW/cm2 for 4 minutes 45 mW/cm2

for 2 minutes 40 seconds

AVEDRO CLINICAL TRIALS

ACOS



ACOS

— Society sponsored study

— Up to 4000 subjects (2000 KC, 2000 ectasia) at 100 sites

Milestone Number

First Subject Enrolled July 2012 Active Sites 83

Subjects Enrolled 990 Eyes Treated 1204

Hersh Vision Group

AVEDRO CLINICAL TRIALS

ACOS: KC Preliminary Data

PULSED CROSSLINKING

KXL-005

Hersh Vision Group

AVEDRO CLINICAL TRIALS

Accelerated CXL: Pulsing

• Laboratory studies indicate 2

pathways of crosslinking

• Type 2: O₂ dependent • Type 1: Ribo*

• Clinical goal: Increase efficacy

crosslinking by enhancing O₂

availability

• Pulsed 1 sec on: 1 sec off UV light • Allows O₂ replenishment

• Early patients in U.S. trial treated

365 nm 1_O 2 Ribo* Pulsed + O2Crosslinking CW Crosslinking Control with no dose

LASIK WITH ACCELERATED

CROSSLINKING

Hersh Vision Group

AVEDRO CROSSLINKING

Accelerated Crosslinking/LASIK Xtra

LASIK Soak 90 sec 0.25% ribo, rinse ribo

Replace flap UV 30 mW x 3 min

- Avoid corneal biomechanical weakening and ectasia - Improve refractive accuracy and stability

Hersh Vision Group

AVEDRO CROSSLINKING

International Experience

 Faruk Yilmaz, Turkey

— Results Published in JCRS

 A. John Kanellopoulos, Greece

— >5 Year Follow Up, Lower Enhancement Rate, Greater Stability in Hyperopes

 Howard Gimbel, Canada

— 1010 cases (542 LASIK Xtra, 468 PRK Xtra) Being Followed

 Minoru Tomita, Japan

— >24,000 Patients Treated

 Rohit Shetty, India

— 6 Month Follow Up with Demarcation Line Visible on OCT

 Robert Pinelli, Italy

Hersh Vision Group

AVEDRO CROSSLINKING

Accelerated Crosslinking/LASIK Xtra

•

International studies underway

U.S. clinical trial for high myopia

PHOTOREFRACTIVE

INTRASTROMAL

CROSSLINKING

Hersh Vision Group

AVEDRO CROSSLINKING

KXL II: PiXL

• Utilizes topo-guided KXLII system (Avedro) • International studies underway

• U.S. clinical trial for topo guided crosslinking planned for early 2015