Corneal Collagen Cross-linking with Photrexa Viscous (riboflavin ophthalmic solution) 20% dextran, Photrexa (riboflavin ophthalmic solution)/kxl System NDA 203324 Joint Meeting of the Dermatologic and Ophthalmic Drugs Advisory Committee and Ophthalmic Device Panel of the Medical Devices Advisory Committee February 24, 2015 Silver Spring, MD Avedro, Inc.
Opening Remarks David Muller, Ph.D. President and Chief Executive Officer Avedro, Inc.
Company Overview Avedro is a medical device and pharmaceutical company founded in 2007 Comprised of approximately 100 employees (headquarters in Waltham, MA) Mission: Advance the science of corneal collagen cross-linking to help patients with corneal disorders CC-3
Product Overview History of Corneal Collagen Crosslinking Developed in Europe by researchers at the University of Dresden in the late 1990s Riboflavin and UVA irradiation are applied to the cornea Goal: Strengthen the cornea Approved in over 60 countries worldwide Performed internationally for over a decade and has become an accepted modality worldwide for treatment of keratoconus and corneal ectasia Over 75,000 patients CC-4
Clinical Study History 2007 - Three clinical studies started under different sponsorship 2010 - Avedro acquired rights to UVX-001 data and sponsorship of IND 77,882 (UVX-002 and UVX-003) All patients treated CC-5
Clinical Study History Dec 2011/Jan 2012 Avedro finalized Statistical Analysis Plans Extended primary endpoint analysis to Month 12 FDA recommended 12 Month endpoint to original sponsor Review of published literature Supports efficacy analysis at later time-points CC-6
Proposed Indication NDA 203324 for corneal collagen cross-linking with Photrexa Viscous (riboflavin ophthalmic solution) 20% dextran, Photrexa (riboflavin ophthalmic solution)/kxl System is indicated for the treatment of progressive keratoconus or corneal ectasia following refractive surgery. Both are orphan drug indications CC-7
Presentation Agenda Disease Background, Mechanism of Action and Unmet Medical Need Device and Drug Description Phase III Clinical Study Design Efficacy and Safety of Corneal Collagen Cross-linking Benefits and Risks Summary Rajesh Rajpal, M.D. Founder, See Clearly Vision Group Medical Director and Founder See Clearly Vision Group McLean, Virginia Clinical Associate Profsor of Ophthalmology Georgetown University Medical Center Washington, D.C. David Muller, Ph.D. President and CEO, Avedro, Inc. Peter Hersh, M.D. Medical Monitor, Avedro, Inc. Director, Cornea & Laser Eye Institute Clinical Professor of Ophthalmology Director, Cornea Division, Rutgers Medical School Visiting Researcher, Princeton University Dept. Aerospace and Mechanical Engineering David Muller, Ph.D. President and CEO, Avedro, Inc. CC-8
Responders Pamela Nelson Vice President, Regulatory Affairs Avedro, Inc. Vineeta Belanger, Ph.D. Vice President, Clinical Affairs Avedro, Inc. Evan Sherr Vice President, Advanced Product Development Avedro Inc. Robert Gibbons, Ph.D. Statistical Consultant Professor, University of Chicago Maureen O Connell Regulatory Device Consultant O Connell Regulatory Consultants, Inc. Christopher Peterson, Ph.D. Engineering Consultant. CC-9
Disease Background and Unmet Medical Need in the U.S. Rajesh Rajpal, M.D. Medical Director and Founder See Clearly Vision Group McLean, Virginia Clinical Associate Professor of Ophthalmology Georgetown University Medical Center Washington, D.C.
Background Cornea responsible for 70% of refractive power of the eye Collagen microarchitecture allows cornea to maintain rigid shape and curvature Orderly structure of collagen fibrils transmits light with minimal distortion CC-11
Etiology Keratoconus and Corneal Ectasia Eyes with ectatic conditions develop irregular corneas Keratoconus naturally occurring Corneal Ectasia - Keratoconus after refractive surgery Cornea is structurally weak Progressive deformation leads to architectural and optical distortion CC-12
Visual Loss Distortion of cornea optics Aberrations in eye s optical system Leads to diminished visual function Abnormal Corneal Curve CC-13
Visual Loss (Cont d) Common symptoms are ghosting, multiple images, glare, halos, starbursts around lights and blurred vision. CC-14
Patient Impact Keratoconus is a disease of the young Average onset 15 years of age Life long impacts Visual decline continuing for two decades or longer interfering with education and career Corneal ectasia affects older population Both are progressive diseases Increased corneal distortion and scarring May lead to loss of functional vision and need for corneal transplantation Keratoconus references: Wagner 2007, Olivares 1997, Kymes 2004, Rabinowitz 1998 Ectasia progression references: Pallikaris 2001, Binder 2005 CC-15
Current Disease Management Options and Limitations Options Limitations Rigid or Specialty Contact Lens Provide temporary visual rehabilitation Difficult to fit Does not influence disease progression Disease progression limits contact lens tolerance over time CC-16
Current Disease Management Options and Limitations Options Limitations Intra-corneal ring segments Not applicable for all patients Does not influence disease progression CC-17
Current Disease Management Options and Limitations (Cont d) Option Corneal Transplant Limitations* KC comprises 30% total penetrating keratoplasty in U.S. Required in over 6000 patients/yr 73% of grafts fail within 20 years Potential for multiple transplants Long visual rehabilitation Potential complications Rejection Infection *2013 Eye Banking Statistical Report, Borderie 2009, Wietharn 2004, Geerards 2006, Mohammadpour 2007 CC-18
Rationale for Cross-linking Keratoconus and corneal ectasia inherently biomechanical problems causing weak cornea Goal of collagen crosslinking is to strengthen the cornea Increase corneal rigidity Stop progression of disease Improve disease prognosis CC-19
Mechanism of Action Interaction of UV light at ~365 nm with riboflavin produces activated riboflavin and reactive oxygen species ( 1 O 2 ) Interact with collagen and GAG s in corneal stroma to form crosslinks ~365 nm 1 O 2 CC-20
Mechanism of Action (Cont d) Improves the biomechanical properties of the cornea by strengthening tissue in the anterior corneal stroma Control CXL Tissue Young s modulus increased 4.5X (Wollensack 2003) CC-21
Epithelial and Stromal Remodeling after Cross-linking Re-epithelialization process approximately 5 days Epithelial and stromal remodeling several months Irregular epi in KC masks cone CC-22
Persistence of Effect Crosslinking trial literature suggest corneal crosslinking has persistence of effect 3-year results: Wittig-Silva 2014 CXL treated eyes and control eyes utilizing same treatment utilized in UVX studies Treated eyes had improvement of -1.03D at 36 months; controls had deterioration of 1.75D» p<0.0001 10-year results: Raiskup et al (2014) 34 treated eyes Preop mean 61.5D 10 year post op mean 55.3D BSCVA improved mean 0.14 logmar over 10 years CC-23
Challenges to U.S. Patients and Clinicians No FDA approved drug therapy in these orphan populations to treat disease Patients traveling overseas to seek treatment Procedures performed in the U.S. with products that are not approved for collagen crosslinking Device (Non FDA approved international sources) Drug Non cgmp (compounded) Needs appropriate labeling CC-24
Unmet Patient Need in U.S. Crosslinking treats underlying problem of compromised corneal biomechanical integrity By slowing or halting progression Avoid risks associated with corneal transplantation Long rehabilitation Rejection, infection Potential for multiple transplants over lifetime Retain sufficient visual function to lead normal lives Patients able to better utilize spectacle correction and contact lens Minimize public health impact and financial burden Leading cause for penetrating keratoplasty CC-25
Device and Drug Description David Muller, Ph.D. President and CEO, Avedro, Inc.
Riboflavin Ophthalmic Solutions Drug Substance Riboflavin 5 -phosphate sodium (vitamin B2) Manufactured in U.S. under cgmps in FDA registered and inspected facility Drug Products Photrexa (0% dextran) Photrexa Viscous (20% dextran) Manufactured in U.S. under cgmps in FDA registered and inspected facility CC-27
UVA Illumination UVX clinical trial device KXL System proposed commercial device Manufactured in U.S. under QSR s in FDA registered and inspected facility Testing demonstrates equivalence to clinical system Our plan to submit NDA with KXL device was discussed with FDA in 2011 Pre-NDA Meeting Comparability plan reviewed by FDA FDA acknowledged the comparative information appeared to support commercial product (12SEP2011) FDA recommended spectral output comparison & electromagnetic interference testing Information provided by Avedro CC-28
KXL System UVX System User Interface Articulating Arm UV Indicator UV Output Both are LED based illumination systems that deliver a spectral output of 365 nm with an illumination intensity of 3.0 mw/cm 2 CC-29
Device Comparison-Spectral Output The spectral output of the KXL and UVX Systems is equivalent CC-30
Device Equivalence Summary Critical Device Specifications for Crosslinking: Specification UVX System KXL System Spectral output 365 nm 365 nm UV Irradiance 3.0 mw/cm 2 3.0 mw/cm 2 UV exposure time 30 minutes 30 minutes Total UV dose 5.4J/cm 2 5.4J/cm 2 Critical Specifications Identical Critical CC-31
Comparative Device Specifications Treatment Alignment KXL Device Alignment UVX Device Alignment CC-32
Device Comparison UV Focal Plane KKXL System KXL System IRUVX System C UV-X Greater distance improves physician access to treatment area, visualization of treatment area, and ease of use No impact on treatment safety or efficacy The majority of study subjects (91%) were treated at 9.5 mm. CC-33
Treatment Diameter Comparison KXL Treatment Area UV-X Treatment Area Min. Limbus Diameter CC-34
Phase III Clinical Studies Peter Hersh, M.D. Medical Monitor, Avedro, Inc. Director, Cornea & Laser Eye Institute Clinical Professor of Ophthalmology Director, Cornea Division, Rutgers Medical School Visiting Researcher, Princeton University Dept. Aerospace and Mechanical Engineering
Treatment Rationale Rationale of collagen crosslinking: Strengthen cornea Clinical Benefit: Slow the natural, progressive time course of keratoconus and corneal ectasia CC-36
Phase III Study Design Prospective, randomized, open-label, controlled, 12-month, parallel-group clinical trials Study eye randomized into one of two groups CXL treatment Control Planned study size 160 eyes 80 eyes per treatment group At Month 3 or later: Non-randomized fellow eyes could receive CXL treatment Control eye could receive CXL treatment CC-37
Phase III Clinical Study Sites UVX-001 (KC and Ectasia) Site No. Principal Investigator Site 01 R. Doyle Stulting, M.D., Ph.D. Emory Vision UVX-002 (KC) & 003 (Ectasia) Site No. Principal Investigator Site 01 Perry S. Binder, M.D. Gordon, Binder & Weiss Vision Institute 02 Eric D. Donnenfeld, M.D. Ophthalmic Consultants of Long Island 03 Peter Hersh, M.D. Cornea and Laser Eye Institute 04 Francis Price, Jr. M.D. Price Vision Group and Cornea Research 05 David Schanzlin, M.D. UCSD, Shiley Eye Center 07 Steven Trokel, M.D. Columbia University, Harkness Eye Institute 08 Daniel Durrie, M.D. Overland Park, KS 09 William Trattler, M.D. Center for Excellence in Eye Care 10 David Hardten, M.D., FACS Minnesota Eye Consultants, P.A. 11 Walter Stark, M.D. Wilmer Eye Institute, Johns Hopkins Hospital CC-38
Clinical CXL Procedure Consistent in all three studies Standard Dresden protocol Epithelium removal Riboflavin with dextran drops Every 2 minutes for 30 minutes Check riboflavin uptake at slit lamp Cornea saturation Anterior chamber flare CC-39
Clinical Procedure (Cont d) Check corneal thickness If >400 um, proceed with UV If <400, administer riboflavin without dextran drops every 10 seconds for 2 minutes until cornea swells >400 um 30 minutes UV exposure ~ 365 nm UVA, 3mW/cm 2 = total dose 5.4 J/cm 2 Riboflavin with dextran drops continued every 2 minutes CC-40
Study Design CXL Group Control Group Epithelial Removal No Epithelial Removal 0.1% Riboflavin 1 gtt/2 min for 30 Confirm Saturation Irradiated at 3 mw/cm 2 for 30 min <400 um 0.1% Hypotonic Riboflavin 1 gtt/10 sec for 2 min >400 um 0.1% Riboflavin 1 gtt/2 mins for 30 min No Irradiation, Gaze at Instrument for 30 CC-41
Inclusion Criteria 14 years of age Diagnosis of progressive keratoconus or corneal ectasia after refractive surgery Axial topography consistent with KC or ectasia K > 47 D I:S ratio >1.5 BSCVA worse than 20/20 on ETDRS chart Corneal thickness >300 um S I CC-42
Inclusion Criteria (Cont d) Demonstration of disease progression over previous 2 years (keratoconus study) An increase of 1.00 diopter (D) in the steepest keratometry value (or simulated keratometry) An increase of 1.00 D in manifest astigmatism A myopic shift of 0.50 D on subjective manifest refraction A decrease 0.1 mm in the back optical zone radius in rigid contact lens wearers CC-43
Exclusion Criteria History of corneal surgery or intra-corneal ring segments History of corneal disease that would interfere with healing after procedure Chemical injury Herpes simplex, herpes zoster keratitis, recurrent erosion syndrome, corneal dystrophy CC-44
Primary Efficacy Measurement (K max ) For quantification of corneal curvature, maximum keratometry (K max ) was chosen Derived from computerized corneal topography analysis Measures salient feature of ectatic corneal disease Steepness and height of topography irregularity Objective, quantitative endpoint Consistent equipment and software amongst study sites Pentacam HR Scheimpflug imaging device K max CC-45
Primary Efficacy Endpoint The primary efficacy parameter evaluated over time was corneal curvature, as measured by maximum keratometry (K max ) Study success was defined as a difference of at least 1 diopter in the mean change in Kmax from baseline comparing the CXL treatment group and the control group K max CC-46
Primary Efficacy Endpoint Extension from Month 3 to Month 12 Extension in timing of efficacy endpoint analysis from Month 3 to Month 12 Better understanding of the timeframe of epithelial healing* 3 months too early to assess the efficacy of the CXL procedure Criteria for study success remain the same No change in endpoint criteria of >1D difference between groups *Mazzotta 2008, Caporossi 2010, Wittig-Silva 2014 CC-47
Progressive Keratoconus Results Disposition and Demographics (Pooled UVX-001 & UVX-002) Peter Hersh, M.D. Medical Monitor, Avedro, Inc. Director, Cornea & Laser Eye Institute Clinical Professor of Ophthalmology Director, Cornea Division, Rutgers Medical School Visiting Researcher, Princeton University Dept. Aerospace and Mechanical Engineering
Progressive Keratoconus Subject Disposition Pooled Studies Category CXL Group Control Group Total Received Randomized Treatment (CXL or Sham) (N) 102 103 205 Completed*: n (%) 92 (90.2) 85 (82.5) 177 (86.3) Discontinued: n (%) 10 (9.8) 18 (17.5) 28 (13.7) * Completers defined as those subjects who remained in the study for at least the start of the Month 12 visit window CC-49
Progressive Keratoconus Demographics Pooled Studies Parameter Statistic CXL Group Control Group Total N 102 103 205 Age (yrs) Mean 31.1 35.0 33.0 Gender Female - n (%) 27 (26.5) 35 (34.0) 62 (30.2%) Male - n (%) 75 (73.5) 68 (66.0) 143 (69.8%) Kmax Mean (SD) 60.9 D (+/- 9.14) 60.4 D (+/- 8.94) CC-50
Progressive Keratoconus Timing of Cross-over KC Group Enrolled 3 month 6 month 12 month Control Control Control Control UVX-001 Control Crossover 29 29 18 (9) 0 (14) UVX-002 Control Crossover 74 72 21 (48) 2 (19) Pooled Control Crossover 103 101 39 (57) 2 (33) Control subjects allowed to cross-over to treatment after 3 month follow-up examination CC-51
Primary Efficacy Analysis Last observation carried forward (LOCF) method was used to impute missing data for 12 month analysis Control group eligible to receive treatment after month 3 visit For control subjects that crossed over to treatment, efficacy data prior to cross-over carried forward to month 12 LOCF valid for imputation Progressive conditions No spontaneous remission or improvement Presumes no further progression in control group Control group would be expected to worsen CC-52
Progressive Keratoconus Results Efficacy (Pooled UVX-001 & UVX-002)
Primary Endpoint Met Mean Change K max (D) Month 12 n=103* +1.0D steepening n=102* -1.6D flattening Mean Difference Kmax Change = 2.6 D Meets definition of success, p<0.0001 *Includes LOCF CC-54
Progressive Keratoconus Mean Change K max (D) Randomized Eyes -0.5D -1.0D -1.6D CC-55
Progressive Keratoconus Mean Change K max (D) Randomized Eyes Diff = 1.1D Diff = 2.0D Diff = 2.6D Month 3 Month 6 Month 12 p-value 0.0867 0.0032 <0.0001 Includes LOCF CC-56
Progressive Keratoconus Mean Change K max (D) Observed Eyes n=96 n=39 n=2 n=96 n=95 Diff = 1.2D Diff = 2.3D Diff = 2.6D n=89 Month 3 Month 6 Month 12 p-value 0.0798 0.0067* 0.4048 CC-57
Progressive Keratoconus Mean K max All CXL Eyes Preoperative progression required for inclusion Change Kmax 1.0D -0.4D -0.9D -1.6D CC-58
Progressive Keratoconus Distribution of Change Observed Eyes 73% Mean Change = -1.8D N=89 (Month 12) CC-59
Pediatric Population UVX-001* UVX-002 CXL Group Control Group CXL Group Control Group Pooled Age < 16 -- 1 4 2 7 Age 16 21 2 3 13 8 26 Total 2 4 17 10 33 *Progressive Keratoconus Subjects CC-60
Pediatric Efficacy Progressive Keratoconus (Pooled) CC-61
Progressive Keratoconus Efficacy Conclusions Results meet primary endpoint Pooled (difference = 2.6 D, p=0.0001) Individual study results meet endpoint UVX-001 (Difference 1.9 D p=0.0175) UVX-002 (Difference 2.9 D p=0.0010) CXL was effective in stopping disease progression over one year Improvements in corneal topography compared to control Keratoconus patients improved by 1.6 D Patient population that had been worsening CC-62
Corneal Ectasia Following Refractive Surgery Efficacy Results Disposition and Demographics (Pooled UVX-001 & UVX-003)
Corneal Ectasia Subject Disposition Pooled Studies Category CXL Group Control Group Total Received Randomized Treatment (CXL or Sham) (N) 91 88 179 Completed*: n (%) 78 (85.7) 72 (81.8) 150 (83.8) Discontinued: n (%) 13 (14.3) 16 (18.2) 29 (16.2) * Completers defined as those subjects who remained in the study for at least the start of the Month 12 visit window CC-64
Corneal Ectasia Demographics Parameter Statistic Pooled Studies CXL Group Control Group Total N 91 88 179 Age (yrs) Mean 43.5 41.8 42.7 Female - n (%) 33 (36.3) 24 (27.3) 57 (31.8) Gender Male - n (%) 58 (63.7) 64 (72.7) 122 (68.2) Kmax Mean (SD) 55.4 D (+/- 6.86) 54.8 D (+/- 6.40) CC-65
Corneal Ectasia Timing of Crossover Ectasia Group Enrolled 3 month 6 month 12 month UVX-001 UVX-003 Pooled Control Crossover Control Crossover Control Crossover Control Control Control Control 25 25 13 (10) 63 62 19 (38) 88 87 32 (48) 0 (12) 2 (17) 2 (29) Control subjects allowed to cross-over to treatment after 3 month follow up examination CC-66
Corneal Ectasia Following Refractive Surgery Efficacy Results Pooled Studies (UVX-001 & UVX-003)
Primary Endpoint Met Mean Change K max (D) Month 12 n=88* +0.7D steepening n=87* -0.7D flattening Mean Difference Kmax Change = 1.4 D Meets definition of success, p<0.0001 *Includes LOCF CC-68
Corneal Ectasia Mean Change K max (D) Randomized CXL Eyes -0.1D -0.5D -0.7D CC-69
Corneal Ectasia Mean Changes K max (D) Randomized Eyes Diff = 0.8D Diff = 1.1D Diff = 1.4D Month 3 Month 6 Month 12 p-value 0.0061 0.0001 <0.0001 Includes LOCF CC-70
Corneal Ectasia Mean Changes K max (D) Observed Eyes Diff = 0.8D Diff = 1.3D Diff = 1.2D Month 3 Month 6 Month 12 p-value 0.0073 0.0021 0.4388 CC-71
Corneal Ectasia Mean K max (D) - All CXL Treated Eyes Change Kmax +1.2D +0.2D -0.4D -0.7D CC-72
Corneal Ectasia Distribution of Change 65% Mean Change = -0.8D N=74, Month 12, Observed CC-73
Corneal Ectasia Efficacy Conclusion Results meet primary endpoint Pooled (difference =1.4D, p=<0.0001) Individual study results meet endpoint UVX-001 (Difference 2.0 D, p=0.0001) UVX-003 (Difference 1.0 D, p=0.0080) CXL was effective in stopping disease progression over one year Improvements in corneal topography compared to control CC-74
Safety of Corneal Collagen Cross-linking Progressive Keratoconus Pooled Studies: UVX-001 & 002 Corneal Ectasia Pooled Studies: UVX-001 & 003
Safety Database Safety data pooled across Phase III studies Evaluation of CXL group compared to control (Baseline to Month 3) Progressive keratoconus = 205 eyes Corneal ectasia = 179 eyes Evaluation in all CXL eyes (Baseline to Month 12) Progressive keratoconus = 293 eyes Corneal Ectasia = 219 eyes CC-76
Treatment Emergent Adverse Events (TEAEs) No subjects discontinued due to an AE Most common ocular TEAEs observed in the CXL group from baseline to Month 3 were: Expected sequelae following debridement of the cornea and subsequent epithelial healing Occurred at higher incidence in treatment than in control subjects who did not undergo debridement CC-77
Ocular AEs in 10% Randomized Study Eyes (Baseline to Month 3) Progressive Keratoconus CXL Group (N=102) n (%) Control Group (N=103) n (%) CXL Group (N=91) n (%) Corneal Ectasia Control Group (N=88) n (%) Corneal Opacity (haze) 58 (56.9) 4 (3.9) 62 (68.1) 7 (8.0) Punctate keratitis 25 (24.5) 8 (7.8) 18 (19.8) 3 (3.4) Corneal Striae 24 (23.5) 12 (11.7) 8 (8.8) 6 (6.8) Corneal epithelium defect (post Week 1 visit) 23 (22.5) 1 (1.0) 24 (26.4) 3 (3.4) Eye pain 17 (16.7) 3 (2.9) 24 (26.4) 0 Vision blurred 16 (15.7) 2 (1.9) 15 (16.5) 4 (4.5) Photophobia 11 (10.8) 0 17 (18.7) 0 Conjunctival hyperaemia 10 (9.8) 1 (1.0) 4 (4.4) 3 (3.4) Eye Irritation 10 (9.8) 1 (1.0) 8 (8.8) 1 (1.1) Visual acuity reduced 10 (9.8) 9 (8.7) 10 (11.0) 1 (1.1) Dry Eye 6 (5.9) 2 (1.9) 13 (14.3) 4 (4.5) Lacrimation increased 5 (4.9) 0 9 (9.9) 1 (1.1) CC-78
Ocular AEs at Month 12 ( 2%) Progressive Keratoconus Corneal haze in 4 subjects Punctate keratitis in 2 subjects Corneal scar in 2 subjects Corneal Ectasia Visual acuity reduced in 4 subjects Corneal scar in 2 subjects CC-79
Corneal Haze Preferred Term CXL Group Control Group Seen postoperatively (N=102) in preponderance (N=103) of crosslinked corneas Corneal opacity (KC) Corneal opacity (ectasia) Preop All CXL Eyes (N=293) 58 (56.9) 4 (3.9) 178 (60.8) 62 (68.1) 7 (8.0) 148 (67.6) General Haze Scheimpflug 1 mo 3 mo 6 mo 12 mo Greenstein SA, Fry KL, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia. J Cat Refract Surg 2010;37:2105-2114 CC-80
Serious Adverse Events (SAEs) No deaths Total of seven (7) SAE s across all studies 5 non-ocular SAE s UVX-001: Two suicide attempts (progressive keratoconus subject 00211, control group) UVX-001: Head injury (ectasia subject 03203, control group) UVX-002: Appendicitis (subject 08201, control group) UVX-002: Infectious cat bite (subject 10211, control group) CC-81
Serious Adverse Events: Ocular 2 Ocular SAE s Corneal Ulcer UVX-002: (subject 02206, following CXL in the sham eye) 19-year-old Developed ulcerative keratitis 3 days after crosslinking Treated with Zymar, fortified vancomycin, Pred Forte, bacitracin, and doxycycline Ulcer resolved Epithelial ingrowth beneath LASIK flap UVX-003: (subject 04308, CXL group) 47-year-old Reported on Day 35 after crosslinking LASIK flap was lifted to remove epithelial ingrowth SAE resolved CC-82
Endothelial Cell Count Consistent Cohort Keratoconus (Pooled) Baseline (ECD) 3mo (ECD) Change from Baseline 3mo 12 mo (ECD) Change from Baseline 12 mo Treatment (n=66) 2622 +/- 370 2551 +/- 343-72 (-2.7%) 2653 +/- 348 +31 (+1.2%) Control (n=86) 2575 +/- 410 2598 +/- 424 +24 (+0.9%) na Ectasia (Pooled) Baseline (ECD) 3mo (ECD) Change from Baseline 3mo 12 mo (ECD) Change from Baseline 12 mo Treatment (n=62) 2469 +/- 437 2418 +/- 340-51 (-2.1%) 2357 +/- 364-112 (-4.5%) Control (n=71) 2594 +/- 431 2541 +/- 395-53 (-2.1%) na *Safety population, observed data CC-83
Endothelial Cell Count Endothelial Cell Count (KC Group) 80.00% 60.00% 40.00% 20.00% 0.00% >-20% -10 to - 20% No change (within 10%) +10 to +20% >+20% Endothelial Cell Count (Ectasia Group) Note scatter in data likely secondary to difficulty obtaining specular microscopy in population 80.00% 60.00% 40.00% 20.00% 0.00% >-20% -10 to - 20% No change (within 10%) +10 to +20% >20% CC-84
Vision Outcomes Progressive Keratoconus Pooled Studies: UVX-001 & 002 Corneal Ectasia Pooled Studies: UVX-001 & 003
Progressive Keratoconus BSCVA - #ETDRS Letters Read* 1 ETDRS LINE Improvement * * *Observed subjects CC-86
Progressive Keratoconus UCVA - #ETDRS Letters Read* 1 ETDRS LINE *Observed CC-87
Progressive Keratoconus BSCVA Categorical Change Month 12* Mean Change = +5.9 Letters *Observed Subjects (n=83) CC-88
Corneal Ectasia BSCVA - #ETDRS Letters Read* 1 ETDRS LINE Improvement *Observed subjects CC-89
Corneal Ectasia UCVA - #ETDRS Letters Read* 1 ETDRS LINE *Observed subjects CC-90
Corneal Ectasia BSCVA Categorical Change Month 12* Mean Change = +5.8 Letters *Observed Subjects (n=72) CC-91
Loss of BSCVA Transient reduction in BSCVA 15 letters at Week 1 visit observed in higher proportion of treatment subjects for both indications Consistent with corneal debridement and expected time course of corneal healing Improved at Month 1 Month 12 4 CXL subjects lost 15 letters BSCVA 1/83 Keratoconus 3/72 Ectasia No predictive preoperative characteristics 26% 1% 31% 6% 15 Letters Loss in BSCVA CC-92
Subjective Vision Questionnaire Keratoconus 5 Subjective Visual Questionnaire Randomized CXL Group (Pooled) 4.5 4 3.5 3 2.5 2 1.5 2.6 2.3 3.3 2.9 3.6 3.1 2.5 2 2.7 2.3 3 2.5 2.8 2.4 2.2 2.2 2.2 2.1 1.5 1.4 Baseline CXL Month 12 CXL 1.9 1.6 1.3 1.2 1 0.5 0 observed data CC-93
Subjective Vision Questionnaire Corneal Ectasia 5 Subjective Visual Function Randomized CXL Group (Pooled) 4.5 4 3.5 3 2.5 2 1.5 1 2.3 2.2 3.5 3.5 3.4 3.1 2.4 2.2 2.8 2.5 2.9 2.7 2.7 2.5 2.4 2.4 2.1 2 Baseline CXL Month 12 CXL 1.4 1.3 1.4 1.3 1.2 1.1 0.5 0 observed data CC-94
Safety Conclusions Robust safety database for these orphan indications 293 eyes with progressive keratoconus 219 eyes with corneal ectasia Corneal collagen cross-linking was safe and well tolerated over the 12-month study period Two ocular SAEs - resolved Most common ocular adverse events Expected sequelae related to debridement of cornea Corneal haze Most mild or moderate in intensity and resolved over time CC-95
Benefit/Risk Conclusions Positive benefit-risk profile of corneal collagen cross-linking Provided clinically meaningful and statistically significant improvements in corneal curvature Cross-linking effective in stopping disease progression Cross-linking was safe and well tolerated Treatment group improved in patient population which would have progressed if left untreated CC-96
Conclusions Slows or prevents disease progression Helps keep patients in contact lenses Delays or prevents corneal transplantation CXL would be the first drug-device combination product in the US for the treatment of patients with progressive keratoconus or corneal ectasia Both indications are orphan indications for which there is an unmet medical need in the US CC-97
Summary David Muller, Ph.D. President and Chief Executive Officer Avedro, Inc.
Phase IV Study UVX-001, -002 and -003 have established safety and efficacy through 12 months Crosslinking trial literature suggest corneal crosslinking has persistence of effect (Wittig 3 yrs) Prospective, Observational, Single Arm Study Approximately 500 study eyes to be enrolled to yield at least 250 evaluable eyes at 36 months Efficacy will be determined by change from baseline in Kmax at 12, 24, and 36 months Safety will include AEs, slit lamp, BSCVA, pachymetry, tonometry, and endothelial cell counts CC-99
Conclusion Progressive keratoconus and corneal ectasia are progressive diseases leading to visual loss Crosslinking performed internationally for over a decade Avedro s KXL System approved internationally performed in over 75,000 patients Drug substance and drug product manufactured under cgmp Device is manufactured under QSR U.S. Orphan populations Need approved labeling to guide physicians and patients CC-100
Conclusion The totality of the safety and efficacy data from UVX-001, UVX-002 and UVX-003 supports approval of corneal collagen crosslinking in the treatment of progressive keratoconus and corneal ectasia following refractive surgery CC-101
Thank You
Backup Slides Shown
Table 14: Progressive Keratoconus: Best Spectacle- Corrected Visual Acuity (ETDRS Letters Read) in the Randomized Eye (Observed Values) CXL Group (N=29) UVX-001* UVX-002 Pooled Studies Control CXL Control CXL Group Group Group Group (N=29) (N=73) (N=74) (N=102) Control Group (N=103) Visit Statistic Baseline N 29 29 73 73 102 102 Mean 32.4 31.7 33.5 33.2 33.2 32.8 SD 11.64 13.03 14.06 13.99 13.37 13.68 Month 1 N 29 28 72 70 101 98 Mean Change 1.0 3.5 0.3 1.6 0.1 2.1 from Baseline SD 9.87 10.24 9.04 7.35 9.25 8.26 Month 3 N 29 29 69 68 98 97 Mean Change 6.5 3.8 4.1 1.2 4.8 1.9 from Baseline SD 10.56 9.43 8.72 8.21 9.31 8.62 Month 6 N 28 18 68 20 96 38 Mean Change 6.1 4.4 5.7 2.0 5.8 1.1 from Baseline SD 10.84 10.61 10.70 10.89 10.68 11.09 Month 12 N 20 0 66 2 86 2 Mean Change 9.6 ---- 4.8 0.0 5.9 0.0 from Baseline SD 8.80 ---- 10.55 8.49 10.32 8.49 *Progressive keratoconus subjects only X-19 BT-19
Summary of Adverse Events Reported by 2% of Subjects: Age 14-18 (UVX-001 and UVX-002, Pooled) CXL Group (N=7) Control Group (N=4) CXL Group (N=7) Control Group (N=4) MedDRA System Organ Class/ Preferred Term Month 3 Month 12 Corneal opacity 3:2(28.6%) 0 -- -- Anterior chamber flare 1:1(14.3%) 0 -- -- Corneal epithelium defect 1:1(14.3%) 0 -- -- Corneal striae 1:1(14.3%) 0 -- -- Corneal Thinning 1:1(14.3%) 0 -- -- Eye Pain 1:1(14.3%) 0 -- -- Glare -- -- 1:1(14.3%) 0 Halo Vision 1:1(14.3%) 0 -- -- Lacrimation increased 1:1(14.3%) 0 -- -- Photophobia 1:1(14.3%) 0 -- -- Visual Impairment 1:1(14.3%) 0 -- -- Statistics displayed are number of events: number of subjects (percent of subjects at risk). At each level of summarization, subjects reporting more than 1 event are only counted once. Note: Ocular events in the fellow eye are excluded X-1 RR-1
Summary of Adverse Events Reported by 2% of Subjects: Age 18-21 (UVX-001 and UVX-002, Pooled) CXL Group (N=12) Control Group (N=10) CXL Group (N=12) Control Group (N=10) MedDRA System Organ Class/ Preferred Term Month 3 Month 12 Corneal Opacity 9:8(66.7%) 1:1(10.0%) -- -- Eye Pain 3:3(25.0%) 0 -- -- Punctate Keratitis 3:3(25.0%) 0 -- -- Conjunctival Hyperaemia 2:2(16.7%) 0 -- -- Corneal striae 2:2(16.7%) 3:3(30.0%) -- -- Foreign Body Sensation in Eyes 2:2(16.7%) 0 -- -- Corneal Epithelium Defect 1:1(8.3%) 0 -- -- Conjunctivitis -- -- -- -- Dry Eye 1:1(8.3%) 0 -- -- Eyelid Oedema 1:1(8.3%) 0 -- -- Ocular Hyperaemia 1:1(8.3%) 0 -- -- Photophobia 1:1(8.3%) 0 -- -- Vision Blurred 1:1(8.3%) 0 -- -- Visual Acuity Reduced 1:1(8.3%) 0 1:1(8.3%) 0 Ingrowing Nail 1:1(8.3%) 0 -- -- Statistics displayed are number of events: number of subjects (percent of subjects at risk). At each level of summarization, subjects reporting more than 1 event are only counted once. Note: Ocular events in the fellow eye are excluded X-2 RR-2
Protocol Deviations List includes deviations for all eyes randomized study eyes and secondary eyes All but 2 deviations were minor (not treated per randomization) No patients excluded from primary efficacy analysis due to PDs 95% of minor deviations related to study procedure(s) not performed IOP not performed constitute the majority 2% deviations related to minor inclusion/exclusion; sites received waivers from prior sponsor 2.7% deviations related to patient consent all patients consented prior to study specific procedures and prior to treatment majority of consent deviations related to standard of care screening procedures LO-5
Results of Sensitivity Analyses Log-Linear Mixed-effects Regression Models Progressive Keratoconus Random effects BIC 52 Weeks Δ SE p Between-subject int(2, 3) 3770.88-2.73 0.65 <.0001 CXL vs Control * int + slope(2) 3765.98-2.68 0.64 <.0001 int + slope(2, 3) 3770.60-2.68 0.64 <.0001 Within-subject int(2, 3) 3770.88-2.73 0.65 <.0001 Controls - Primary Eye (before/after) * int + slope(2) 3765.98-2.68 0.64 <.0001 int + slope(2, 3) 3770.60-2.68 0.64 <.0001 Within-subject * int(2, 3) 2597.15-2.91 1.23 0.018 Controls - Primary vs. Fellow Eyes int + slope(2) 2601.62-2.91 1.31 0.026 int + slope(2, 3) 2606.31-2.91 1.31 0.026 Ectasia Random effects BIC 52 Weeks Δ SE p Between-subject * int(2, 3) 2643.74-1.66 0.34 <.0001 CXL vs Sham int + slope(2) 2645.92-1.65 0.34 <.0001 int + slope(2, 3) 2650.55-1.65 0.34 <.0001 Within-subject int(2, 3) 2381.79-1.10 0.47 0.0194 Controls - Primary Eye (before/after) * int + slope(2) 2381.02-1.10 0.45 0.0159 int + slope(2, 3) 2385.27-1.08 0.46 0.0178 Within-subject * int(2, 3) 1639.45-2.34 0.91 0.010 Controls - Primary vs. Fellow Eyes int + slope(2) 1643.53-2.35 0.92 0.011 int + slope(2, 3) 1648.06-2.35 0.92 0.010 X-1 ST-1
Table 47: Summary of Ocular Adverse Events in Any CXL Eye Reported for 2% of Eyes Summarized by Outcome (Safety Population: Keratoconus) MedDRA Preferred Term a) Outcome Any CXL Eyes (N=293) All TEAEs 249 (85.0%) Eye disorders Resolved 165 (56.3%) Ongoing 83 (28.3%) Corneal opacity Resolved 147 (50.2%) Ongoing 31 (10.6%) Corneal striae Resolved 52 (17.7%) Ongoing 18 (6.1%) Corneal epithelium defect Resolved 64 (21.8%) Ongoing 5 (1.7%) Punctate keratitis Resolved 56 (19.1%) Ongoing 6 (2.0%) Eye pain Resolved 58 (19.8%) Visual acuity reduced Resolved 33 (11.3%) Ongoing 15 (5.1%) Vision blurred Resolved 41 (14.0%) Ongoing 1 (0.3%) Photophobia Resolved 22 (7.5%) Ongoing 6 (2.0%) Conjunctival hyperaemia Resolved 18 (6.1%) Ongoing 1 (0.3%) Dry eye Resolved 15 (5.1%) Ongoing 3 (1.0%) Eye irritation Resolved 14 (4.8%) Ongoing 4 (1.4%) Lacrimation increased Resolved 18 (6.1%) Eyelid oedema Resolved 10 (3.4%) Foreign body sensation in eyes Resolved 10 (3.4%) Anterior chamber flare Resolved 9 (3.1%) Eye oedema Resolved 9 (3.1%) Corneal thinning Resolved 6 (2.0%) Ongoing 2 (0.7%) X-62 BT-62