Topo-Guided Crosslinking for Keratoconus Rajesh K. Rajpal, M.D. Medical Director and Founder See Clearly Vision Group Mclean, Virginia, USA Clinical Associate Professor Georgetown University Washington, DC, USA Chief Medical Officer Avedro, Inc. Waltham, MA, USA

Financial Disclosure Abbott Omeros Alcon Polyactiva Allergan RPS Avedro Bausch & Lomb Calhoun Mimetogen Ocular Therapeutix Omeros Polyactiva RPS Santen Shire Stemnion Tear Solutions Valeant

Introduction Combination Procedures CXL + IOL CXL + Intacs Cross-linking is an established procedure, proven effective in halting progression of keratoconus Stabilization alone is not beneficial if the patient can not see: to the patient, success is defined by good, functional vision Combination procedures may aid in visual rehabilitation, including enabling patient return to successful contact lens wear Combination Procedures CXL + IOL CXL + Intacs CXL + TG-PRK Customized cross-linking (PiXL) is an alternative to combination procedures, with the aim to stabilize progression and normalize corneal shape

Image from A. John Kanellopoulos TG-PRK plus CXL: The Athens Protocol Image from A. John Kanellopoulos

TG-PRK plus CXL: The Athens Protocol 50um PTK + minimal (50um) topoguided PRK aims to regularize the corneal shape Same day CXL applied to stabilize against progression Clinical results suggest good safety and effiacy, however technique requires tissue removal in ectatic corneas

Corneal Cross-Linking Progressive Keratoconus- Distribution of Change (Observed Eyes) N= 89 (Month 12) Mean Change= -1.8D 73% While the goal of conventional cross-linking for treatment of keratoconus is to stabilize progression, mean flattening of steepest keratometry is observed in a large percentage of patients. Pooled data from Avedro Sponsored US Clinical Trials

Patient Characteristics Predictive of Corneal Flattening After Cross-linking Koller T, Pajic B, Vinciguerra P, et al. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg. 2011;37(8):1488–92. Significant corneal flattening observed in 40% of cases. The only factor that was independently predictive of flattening was baseline Kmax of greater than 54.00 D. Greenstein S a, Hersh PS. Characteristics influencing outcomes of corneal collagen crosslinking for keratoconus and ectasia: Implications for patient selection. J Cataract Refract Surg. 2013;39(8):1133–40. The only evaluated factors independently predictive of improvement after CXL were CDVA of 20/40 or worse, or KMax of 55.00 D or greater. Wisse RPL, Godefrooij D a, Soeters N, et al. A Multivariate Analysis and Statistical Model for Predicting Visual Acuity and Keratometry One Year After Cross-linking for Keratoconus. Am J Ophthalmol. 2014;157(3):519–525.e2. Baseline KMax was not predictive of cross-linking outcome in this study. However, a more eccentric cone was associated with steeper keratometry at 1 year follow-up. For the same cross-linking parameters, variability in the change in Kmax predicted by: Initial Kmax Cone Location

Localized Treatment for Normalization Standard 9mm Cone-localized Computational finite element analysis predicts greater flattening effect with regional increases in elastic modulus, vs. conventional treatment. If we selectively induce stiffening in the weak zone, can we flatten the cone and improve visual function? Computer simulated difference maps Modeling showed greatest effect of simulated cross-linking when it was applied over the cone, rather than across the whole cornea Images at bottom are simulated difference maps William J. Dupps, Jr., MD, PhD Ophthalmology, Biomedical Eng. & Transplant Cole Eye Institute & Lerner Research Institute ESCRS, 2013

In the absence of direct clinical measures of corneal biomechanics, Targeting Weak Cornea Recent biomechanical studies demonstrate underlying stromal weakness localized on the keratoconus cone. In the absence of direct clinical measures of corneal biomechanics, tomographic measures (anterior steepening & posterior elevation) can serve as indirect indicators of the “weak zone”

Customized CXL for treatment of Keratoconus Professor Anders Behndig, MD Umeå University Hospital, Sweden Randomized controlled trial of regional vs. conventional CXL for treatment of keratoconus 30mW/cm2 pulsed illumination used in both treatment groups All PiXL eyes received stacked/concentric patterns Arcuate shapes used for inferiorly located cones Circular shapes used for centrally located cones Dose determined by K readings on Pentacam Axial Map

Example Treatment Plan Greatest energy dose applied over area of steepest anterior curvature, encompassing area of posterior elevation 15 J, 10 J and 5.4 J treatment zones 30 mW/cm2 pulsed [1,1] illumination

Customized CXL for treatment of Keratoconus: Case Example Professor Anders Behndig, MD Umeå University Hospital, Sweden 3 Months Pre-OP

Inferior flattening @ 2mm Customized CXL for treatment of Keratoconus Professor Anders Behndig, MD Umeå University Hospital, Sweden Inferior flattening @ 2mm Change in Kmax Superior Normalization of the Cornea: flattening steep zones, steepening flat zones Greater flattening of KMax relative to conventional cross-linking

Customized CXL for treatment of Keratoconus Professor Anders Behndig, MD Umeå University Hospital, Sweden Change in BCVA Change in UCVA Change in LogMAR UCVA from Baseline: Significantly greater improvement in custom group Change in LogMAR BCVA from Baseline: Significantly greater improvement in custom group

Customized CXL for treatment of Keratoconus Cosimo Mazzotta, Antonio Moramarco, Claudio Traversi, Stefano Baiocchi, Alfonso Iovieno, and Luigi Fontana Italian Multicenter Study of Customized CXL for Treatment of Keratoconus 10 minute VibeX Rapid Soak 30mW/cm2 pulsed illumination [1,1] Cone areas with corneal curvature under 48 diopters were treated with 7.2 J/cm2 Cone areas with corneal curvature 48 D to 52 D were treated with 10 J/cm2 Cone areas with corneal curvature over 52 D were with 15 J/cm2

Customized CXL for treatment of Keratoconus Italian Multicenter Study

Customized CXL for treatment of Keratoconus Italian Multicenter Study Mazzotta C, Moramarco A, Traversi C, Baiocchi S, Iovieno A, Fontana L. Accelerated Corneal Collagen Cross-Linking Using Topography-Guided UV-A Energy Emission: Preliminary Clinical and Morphological Outcomes. J Ophthalmol. 2016;2016:2031031

Customized CXL for treatment of Keratoconus Prof. Theo Seiler Prospective evaluation of customized CXL versus conventional cross-linking 10 minute VibeX Rapid Soak 10mW/cm2 continuous illumination in custom group Concentric superimposed circular zones applied Treatment zone centered on posterior float Treatment doses ranging from 5.4 to 10 J Dresden CXL in conventional group

Customized CXL for treatment of Keratoconus Prof. Theo Seiler Prospective evaluation of customized CXL versus conventional cross-linking inner circle: total energy applied 10J/cm2 – shortest diameter of PF – 0.5mm intermediate circle: total energy applied 7.2J/cm2 – average diameter of outer/inner circle outer circle: total energy applied 5.4J/cm2 - maximal diameter of PF + 1.0 mm

Customized CXL for treatment of Keratoconus Prof. Theo Seiler Case Example demonstrating typical evolution regularization index = 5.3D

regularization index [D] epithelial healing time [days] Customized CXL for treatment of Keratoconus Prof. Theo Seiler significant differences in 1 year changes between groups customized CXL standard CXL p-value Δ Kmax [D] -1.7 ± 2.0 -0.9 ± 1.3 0.03 regularization index [D] 5.2 ± 2.7 4.1 ± 3.1 epithelial healing time [days] 2.56 ± 0.5 3.19 ± 0.73 0.02 Δ -logMAR -0.07 ± 0.20 -0.04 ± 0.14 0.22 Theo G. Seiler

distribution of flattening in Kmax Customized CXL for treatment of Keratoconus Prof. Theo Seiler distribution of flattening in Kmax change in Kmax customized CXL standard CXL >+2 D 1 (5.3%) 0 (0%) >+1 D +1D to -1D 8 (42.1%) 12 (63.2%) <-1 D 10 (52.6%) <-2 D 7 (36.8%) 2 (10.5%) <-3 D 4 (21.0%) Theo G. Seiler

Conclusions Keratoconus is a heterogeneous disease; a single treatment protocol for corneal cross-linking may not be optimal for all patients Topographic guided treatments may assist in improving outcomes Current therapeutic customized (PiXL) treatment patterns apply greater UVA energy doses on the areas of greatest maximum curvature and/or posterior elevation Clinical studies show the promise of these techniques to improve corneal regularity and visual rehabilitation after corneal cross-linking The introduction of in-vivo techniques to measure regional corneal biomechanics have the potential to further optimize the technique for individual patient variability