CXL - Amazon S3 · CXL Derek N. Cunningham, O.D., FAAO Disclosure ! ¥ In the last 12 month I have...

transcript

Derek N. Cunningham, O.D., FAAO

Disclosure

• In the last 12 month I have had relations with the following companies:

• Abbott • Alcon • Allergan • B+L • Reichert • Arctic Dx • Tearlab

• Avedro

• Innovision

• TearScience

• Lumenis

background

Keratoconus basics

• Collagen fibers are highly uniform in

diameter (25-35 nm)

• The distance between two corneal fibers is also highly uniform (41.5nm)

Keratoconus and Post-LASIK ectasia

Keratoconus:

• Non-inflammatory, degenerative disorder of the cornea characterized by progressive ectasia and stromal thinning.

• Reported prevalence of 1 in 2000 in the general population.[1]

Post-LASIK corneal ectasia:

• Corneal weakening after a LASIK procedure, creating

progressive steepening and thinning of the cornea and loss of BSCVA.

• Incidence of post-LASIK ectasia estimated to be 1 in 1000

cases of LASIK surgery.

[1] Feder RS, Kshettry P. Non-inflammatory ectatic disorders. [book auth.] Mannis MJ, Holland EJ, eds Krachmer JH. Cornea. Philadelphia : Elsevier Mosby, 2005:956, Vol. Chapter 78.

Typical Cone

Cone? 28 y/o female – 10 year dx of KC

28 y/o female – 10 year dx of KC

41 y/o female – 20 year dx KC

Newly Diagnose Keratoconic

25 y/o white female

• Upset with the sudden diagnosis

• Very upset with the contact lens cost

• Went on line and did DAYS of research

• Came to us for crosslinking (was not told

about crosslinking)

Referring Docs Scans

Other Options?

A.Try a different less expensive lens

C. Corneal Transplant

• B. Crosslink

• D. Monitor

One week later

Lotemax QID Restasis BID Omega 3 supplements

1 week later

6 Months later

First, Fix the Surface…

• Better pre-op data, better quality post-op

– Artificial Tears. All pts.

– O-3 FA. Almost all pts.

– Topical Cyclosporin.

– Topical Azithromycin

– Topical steroids

– Plugs.

Ectasia

CXL - Basics

Basics

• Soaking the cornea with riboflavin (vitamin B2) and then exposing the cornea

to ultraviolet (UV) light with a 370-nm

wavelength at 15 - 45 mW/cm2.

Riboflavin (vitamin B2)

• Water soluble, not stored

• Helps metabolism of carbs, fat and

protein

• Important for skin, hair, eyes, and liver

• RDA = 1.5mg/day

UV absorbtion

Cross-linking

Corneal collagen cross-linking

The figures above show the parallel corneal layers (white) and the collagen cross-linking (red) which are increased after Corneal Cross-Linking treatment.

Cross-Linking:

• Improves the biomechanical properties of the cornea by strengthening the corneal tissue in the anterior stroma.

• The only procedure available to specifically stop the progression of keratoconus and strengthen the individual collagen fibers in the cornea.

• Corneal cross-linking (also know as CXL) is a procedure that has been in global clinical use since 1997.

Cross-linking – First Procedures

Standard CXL, developed by Eberhard Spoerl and Theo Seiler in 1997.[2]

CXL procedure includes:

• Removal of corneal epithelium and then pre-treating with riboflavin 0.1% ophthalmic solution (0.1% diluted in 20% Dextran) for 30 minutes.

• Cornea then irradiated with 3 mW/cm2 of UVA (365 nm) for 30 minutes delivering a total radiant exposure of 5.4 J/cm2.

Exposure of cornea to the combination of UVA light with riboflavin photosensitizer induces cross-linking of the corneal collagen fibrils with a resultant increase in tensile strength and diameter of the collagen fibrils.

[2] Conservative therapy of keratoconus by enhancement of collagen cross-links. Seiler T, Spoerl E, Huhle M, Kamouna A. s.l. : Invest. Ophthalmol. Vis. Sci., Vol. 37. S1017.

Result

• STIFF OLD

• Pain

• Blurred vision

• Delayed healing

• Infection

• Inflammation

• Corneal haze

• Dry eye

Method

• Remove cornea

Avedro’s Cross-Linking Products

The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C

• FDA Approved • FDA Orphan Drug Designation

RFID Card & Riboflavin

KXLTM System

Avedro’s KXL System

Post op

• Handle like a surface ablation patient

• Steroid, antibiotic, NSAID

• Bandage lens for 1 week

Clinical Course

• Gets worse initially

Method

• Epithelium on?

5 minutes post “disruption”

1 day p/o

ACOS-KXL-001:

Cross-linking Trial in Patients with Keratoconus or Corneal Ectasia following

Refractive Surgery

Overall Study Design

Sponsor: ACOS

Title: A Multi-Center, Randomized, Controlled Evaluation of the Safety and Efficacy of the KXL System with VibeX (Riboflavin Ophthalmic Solution) for Corneal Collagen Cross-Linking in Eyes with Keratoconus or Corneal Ectasia after Refractive Surgery

Phase: III

Planned Sample Size: up to 2000 primary eyes with keratoconus and up to 2000 primary eyes with corneal ectasia at 100 sites randomized in 1:1:1 ratio between 3 active treatment groups.

Primary Efficacy Criteria: Mean change in maximum corneal curvature (Kmax) from baseline to 6 months or from baseline to 12 months (within subject comparison). Each treatment condition (keratoconus and corneal ectasia) and treatment group will be evaluated independently.

Schedule of Assessments: Screening/baseline, Day 0 (randomization/treatment day), 1 day, 1 week, and 1, 3, 6 and 12 months after treatment.

Inclusion Criteria

Presence of central or inferior steepening on the topographic map

BSCVA better than 1 and worse than 80 letters on the Early Treatment of Diabetic Retinopathy Study [ETDRS] chart

At least 12 years of age

For corneal ectasia patients only: • Diagnosis of corneal ectasia after refractive surgery • Axial topography consistent with corneal ectasia

For keratoconus patients only:

• Topographic evidence of keratoconus with a diagnosis of mild, moderate or severe keratoconus

• Maximum corneal curvature as measured by steepest keratometry (Kmax) value ≥ 47.00 D

Contact lens wearers only: manifest refraction must be stable between two visits which occur at least 7 days apart

Exclusion Criteria

Eyes classified as either normal, atypical normal (except corneal ectasia),

or keratoconus suspect on the severity grading scheme

A history of previous corneal surgery (other than LASIK or PRK for subjects with corneal ectasia) or the insertion of Intacs in the eye(s) to be treated

Corneal pachymetry that is < 375 microns prior to epithelial debridement at the thinnest point in the eye to be treated

Eyes which are aphakic or pseudophakic and do not have a UV blocking lens implanted

A history of delayed epithelial healing in the eye(s) to be treated

Patients with nystagmus or any other condition that would have prevented

a steady gaze during the CXL treatment or other diagnostic tests

Treatment Groups

15mW/cm2 for 8 minutes

Epithelial removal

0.12% riboflavin 1 gtt/2 mins for 20 mins

Irradiated at 15 mW/cm2 for 8 minutes (7.2 J/cm2)

30mW/cm2

for 4 minutes

Epithelial removal

Irradiated at 30 mW/cm2 for 4 minutes (7.2 J/cm2)

45mW/cm2

for 2 minutes and 40 seconds

Epithelial removal

Irradiated at 45 mW/cm2 for 2 min 40 sec (7.2 J/cm2

Goals and Key Benefits

• Provide patients access to treatment for current unmet medical need in an orphan population

• Greatly increase patient comfort during treatment due to

shorter UVA irradiation time

• Allow qualified contralateral eyes to be treated

• Gain deeper understanding of safety and efficacy of higher powers of UVA irradiation for corneal collagen cross-linking

FDA STUDY

• 2 year follow-up

General success

Great Success!!! Consensus of literature

• CXL prevents further vision loss in over 95% of patients

• 60-70% of patients having improved vision

Complications

13 y/o white male – 5 days p/0 – lost bcl 2 days ago

Father brought son in because eye

seemed red

Child reports no pain – F/U BCL for 2 days

No improvement with BCL for 2 days, 1

days post pressure patch

29 year old black male

• Very poor bcva

• OS worse than OD

Initial presentation

Tough case 1

Do We Dare?

2 months post cxl

3.5 Diopters of flattening

2.5 Diopters of corneal flattening

15 year old Hispanic Male

1 day post op

1 week p/o

Studies

• Being investigated for a treatment of

infectious keratitis

• Effective treatment depth of 300 microns may limit effectiveness

Studies

• Treating corneal edema

• How long will the effect last

Studies

• Combining CXL with thermal or microwave procedures that transiently modify

corneal shape

Studies

• CXL for post-RK ectasia and vision

fluctuations

ARVO 2013

• Topographically Guided Corneal Cross-Linking • David B. Usher

– Uses eye tracker and mirror system to control corneal illumination

• Patterned collagen crosslinking had an effect on corneal astigmatism.

• Finite Element Analysis of Treatment of Corneal Astigmatism with Collagen Crosslinking IBRAHIM SEVEN1

• Photorefrative Intrasromal Crosslinking

The Future of

Corneal Cross-Linking for Refractive Correction

• Potential applications reach beyond the single goal of stabilizing corneas with keratoconus

• The ability to change the biomechanical properties of the cornea presents opportunities for refractive indications

• To apply CXL to refractive surgery, the procedure must be predictable and customizable

The Mosaic System is not approved for sale in the United States

Redistribution of Corneal Stress

• Recent biomechanical studies strengthen the theory that corneal ectasia develops from

focal weakening of the cornea1

• Finite element analysis modeling demonstrates the potential for

optimization of cross-linking through focal stiffening of the cornea2

• Preferentially stiffening the weakest zone of the cornea = Redistribution of corneal stress 1. Roberts, C., Dupps, WJ. Biomechanics of corneal ectasia and biomechanical treatments. J

Cataract Refract Surg 2014: 40:991-998

2. Roy, AS., Dupps, WJ. Patient specific computational modeling of keratoconus progression

and differential responses to collagen cross-linking. Invest Ophthal Vis Sci 2011: 52: 9174-87

What is Photorefractive Intrastromal

Cross-Linking (PiXL)?

• Corneal cross-linking (CXL) was first introduced in 1998 as a treatment for progressive

keratoconus1

• Laboratory2 and clinical studies

3 have demonstrated that CXL stiffens the cornea

(alters corneal biomechanics)

• PiXL is the application of zonal CXL using spatial application of UVA

• The goal of PiXL is to introduce controlled corneal shape change using patterned UVA

CXL, without ablation

1. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal

tissue. Exp. Eye Res. 1998;66(1):97–103. 2. Spoerl E, Seiler T. Techniques for Stiffening the Cornea. J.

Refract. Surg. 1999;15:711–713 3. Goldich Y, et al. Clinical and corneal biomechanical changes

after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up. Cornea. 2012;31(6):609–14.

Sharply defined edges

✓ Eye Tracking to compensate for

patient eye movement

Complex patterning

✓ Digitial Micromirror Device

(DMD) to project UVA pattern of

any design

More stiffening than standard

technology

✓ Pulsed Illumination

✓ Higher Energy Doses

✓ Supplemental Oxygen

Requirements for PiXL derived from the FEA Model: Solutions

Riboflavin is applied to the corneal

surface

The patient is

positioned under the

Mosaic device, and an iris tracker

precisely aligns the

device with the patient’s eye

A customized

treatment pattern is applied using the

Mosaic system

Refractive correction with customized cross-linking

PiXL: Photorefractive Intrastromal

Cross-linking

PiXL for Myopia: Basic Principle

! Specific UVA patterning is applied to the center

(myopia) of the riboflavin-soaked cornea

! Focal stiffening is achieved in the treatment zone

! Redistribution of biomechanical stresses occurs

in response to normal intraocular pressure

! “Bulging” of the cornea in untreated regions

results in central flattening: reduction of myopia

Images Adapted From: Professor John Marshall, MBE, PhD

Post-OP Pre-Op Difference

Epithelium-Off PiXL Case Example– 38 year old

Pre-OP: -1.75-0.75x175 UCVA: 20/50 BCVA: 20/20

1 Month Post-Op: -0.00-1.00x156 UCVA: 20/25 BCVA: 20/20

6 Months Post-OP: -0.25-0.50x160 UCVA: 20/25 BCVA: 20/20

12 Months Post-OP: -0.25 -0.50x180 UCVA: 20/20 BCVA: 20/20

Professor H. Burkhard Dick Dr. Matthias Elling

Ruhr University Bochum, Germany

Ongoing Clinical Studies

Transepi PiXL in Healthy Myopic Eyes

• Intended correction: -0.75 to -2.0D

sphere • No prior corneal surgery

Principal Investigators: • Prof. H. Burkhard Dick, Ruhr

University, Bochum, Germany • Prof. François Malecaze, Hôpital

Purpan, Toulouse, France

• Prof. Anders Behndig, Umea

University, Umea, Sweden

University-Based European Clinical Trials of

Transepithelial PiXL with Oxygen

for Treatment of Low Myopia

Enhanced Crosslinking

• Breathing new life into CXL

• Pulse light therapy

Is this a surgery?

CXL - Amazon S3 · CXL Derek N. Cunningham, O.D., FAAO Disclosure ! ¥ In the last 12 month I have...

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