1. AMD Trials and Treatments:
AAO Media Briefing
AMD Trials and Treatments:
An Evolving Landscape
ABDHISH R. BHAVSAR, M.D.
Chair

2. Financial Disclosures
Abdhish R. Bhavsar, MD
Research support - clinical trials: DRCR, Regeneron, Genentech

3. Agenda Abdhish R. Bhavsar, MD: Welcome/Introductions
Pravin Dugel, MD: Fovista 2b clinical trial results
Q/A
Abdhish R. Bhavsar, MD: Update CATT and Eylea
Susan Bressler, MD: Cataract sugery/AMD - no inc risk
Paul Mitchell, MD: Cataract surgery/AMD – inc risk
Edwin Stone, MD: Update on genetic testing for AMD
Media Q & A

4. Study Disclosures
This study does include research conducted on human subjects
IRB approval has been obtained for each of the studies discussed.

5. Investigation of Efficacy and Safety of Intravitreal Aflibercept Injection in Wet Age-Related Macular Degeneration (AMD)
VIEW 1
Integrated
VIEW 2
Abdhish R. Bhavsar, MD

6. Purpose
The following has been developed in response to an unsolicited request for slides on the intravitreal aflibercept injection (IAI)* VIEW 1 and VIEW 2 Year 1 and 2 data
The slides may be used by the requesting physician for scientific presentation at a medical meeting. NOTE: The slides may not be used for any program supported by Regeneron Pharmaceuticals, Inc. through an educational grant and accredited by the ACCME
This presentation may not be duplicated or distributed
Intravitreal aflibercept injection has been approved by the FDA for the treatment of patients with neovascular (Wet) Age-related Macular Degeneration and Macular Edema following Central Retinal Vein Occlusion under the trade name EYLEA® (aflibercept) Injection. Please see the Important Product Information at the end of this deck, and the full Prescribing Information for EYLEA accompanying this presentation
*also known as VEGF-Trap Eye in the scientific literature

9. Study Design
Multi-center, active controlled, double masked trial VIEW 1 N=1217; VIEW 2 N=1240
Patients randomized 1:1:1:1
Intravitreal Aflibercept
Ranibizumab
2 mg q4 wks
0.5 mg q4 wks
2 mg q8 wks
0.5 mg q4 wks
Primary endpoint: Maintenance of Vision
Dosing through Week 52 Modified quarterly dosing through Week 96
Secondary endpoint: Mean change in BCVA
*After 3 initial monthly doses

10. KEY SECONDARY ENDPOINTS
Study Endpoints
Proportion of patients who maintained BCVA (%) (losing <15 ETDRS letters from baseline)
PRIMARY ENDPOINT
Mean change in BCVA as measured by ETDRS letter score from baseline
Proportion of patients who gained at least 15 letters of BCVA from baseline
Central Retinal Thickness
KEY SECONDARY ENDPOINTS
BCVA: Best-Corrected Visual Acuity
ETDRS: Early Treatment Diabetic Retinopathy Study 10 10

13. VIEW 1
Integrated
VIEW 2
Results Week 52

23. VIEW 1
Integrated
VIEW 2
Results Week 52 – Week 96

24. Treatment Schedule Re-treatment Criteria –
12 weeks since previous injection
New or persistent fluid on OCT
Increase in CRT of ≥100 μm compared to the lowest previous value
Loss of ≥5 ETDRS letters from the best previous score in conjunction with recurrent fluid on OCT
New onset classic neovascularization
New or persistent leak on FA
New macular hemorrhage
Solid = Injection
Outline = Sham
Hatched = Modified Quarterly Dosing 24

37. VIEW 1
Integrated
VIEW 2
Safety

41. Summary Aflibercept noninferior to ranibizumab
Safety and efficacy was similar amongst the treatment groups

42. Important Product Information42 42

43. EYLEA® (aflibercept) Injection Important Prescribing Information
EYLEA® (aflibercept) Injection is indicated for the treatment of patients with neovascular (Wet) Age-related Macular Degeneration (AMD). The recommended dose for EYLEA is 2 mg administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks.
EYLEA is indicated for the treatment of patients with Macular Edema following Central Retinal Vein Occlusion (CRVO). The recommended dose for EYLEA is 2 mg administered by intravitreal injection every 4 weeks (monthly).

44. EYLEA® (aflibercept) Injection Important Safety Information
EYLEA® (aflibercept) Injection is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to aflibercept or to any of the excipients in EYLEA.
Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately. Intraocular inflammation has been reported during the post approval use of EYLEA.
Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.

45. EYLEA® (aflibercept) Injection Important Safety Information (Continued)
There is a potential risk of arterial thromboembolic events (ATEs) following use of intravitreal VEGF inhibitors, including EYLEA, defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of ATEs in the VIEW 1 and VIEW 2 wet AMD studies in patients treated with EYLEA was 1.8% during the first year. The incidence of ATEs in the COPERNICUS and GALILEO CRVO studies was 0% in patients treated with EYLEA compared with 1.4% in patients receiving sham control during the first six months.
The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous detachment, vitreous floaters, and increased intraocular pressure.
Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis, traumatic cataract, increased intraocular pressure, and vitreous detachment. 

46. Comparison of AMD Treatments Trials (CATT): Two Year Results
Abdhish R. Bhavsar, MD
for the Comparison of AMD Treatments Trials (CATT) Research Group
Supported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS

47. Objectives
To determine the relative efficacy and safety of intravitreal ranibizumab and bevacizumab for treatment of neovascular AMD
To determine if less than monthly dosing of either drug compromises long term visual outcomes
- Designed as two-year study with primary outcome at one year

48. CATT Clinical Sites
1185 patients with neovascular AMD enrolled at 43 sites in the United States 48

49. Enrollment Criteria More Inclusive than Previous AMD Trials
CNV not required to be subfoveal as long as center involved by some component such as SRF, PED, or blood.
Allowed RAP lesions, juxtafoveal, and extrafoveal CNV
Allowed eyes with VA 20/25-20/320
No limit on size of lesion

50. Enrollment Criteria More Inclusive than Previous AMD Trials
Allowed eyes with >50% blood. All other entry criteria had to be met (VA 20/320 or better and can identify CNV on FA and fluid on OCT) 50

51. } CATT Treatment Year 1 Year 2 Retreat if fluid on OCT or
(Months)
Year 1
Year 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
ranibizumab Monthly
bevacizumab
Monthly
ranibizumab PRN
bevacizumab
PRN }
Retreat if fluid on OCT or
other signs of active CNV
Primary Endpoint
Final visit

52. Treatment in PRN Arms
Treat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid.
May also treat if there is other evidence of CNV activity
New subretinal or intraretinal hemorrhage
Leakage or increased lesion size on FA
Unexplained decrease in visual acuity with no obvious atrophy or subretinal fibrosis.
No retinal thickness threshold (100 microns) as used in many neovascular AMD treatment studies.

53. CATT Study Drugs Ranibizumab supplied locally
similar to patients outside of the study
Bevacizumab supplied by CATT repackaged in glass vials under IND
Multiple Lines of Evidence Support a Role for VEGF in Choroidal Neovascularization
Surgical removal and staining of subfoveal fibrovascular membranes from patients with AMD reveal the increased expression of VEGF protein and mRNA. VEGF mRNA expression was highest in membranes with an inflammatory response. VEGF expression was concentrated in areas containing fibroblasts and inflammatory cells.1
Increased VEGF levels are present in the vitreous of eyes with subfoveal neovascularization. Vitreous samples obtained from patients undergoing vitrectomy were compared with vitreous samples from patients who did not display subfoveal neovascularization.2
Compared with healthy controls, VEGF is overexpressed in the retinal pigmented epithelium and choroidal blood vessels of early and neovascular AMD lesions.3
In animal studies, overexpression of VEGF165 in retinal pigment epithelial cells led to choroidal neovascularization.4,5
Anti-VEGF drugs may improve vision in patients with CNV and lead to resolution of fluorescein leakage.
1. Kvanta et al. Invest Ophthalmol Vis Sci. 1996;37:1929.
2. Wells et al. Br J Ophthalmol. 1996;80:363.
3. Kliffen et al. Br J Ophthalmol. 1997;81:154.
4. Baffi et al. Invest Ophthalmol Vis Sci. 2000;41:3582.
5. Spilsbury et al. Am J Path. 2000;157:135.

54. Mean Change in Visual Acuity
All Groups

55. Distribution of Visual Acuity at 1 Year

56. Mean Change in Total Retinal Thickness Over Time
All Groups

57. Percent with No Fluid at 1 Year

58. Year 1 Adverse Events
No difference between drugs in rates of death, stroke, or myocardial infarction
Imbalance in total SAE’s (mostly hospitalizations): 24% bevacizumab vs 19% ranibizumab (p=0.04)
SAEs broadly distributed across all organ systems with differences present in areas not previously identified as areas of concern in systemic bevacizumab trials.

59. Questions at End of Year 1
Would ranibizumab and bevacizumab remain equivalent for visual acuity in Year 2?
Would wider visual acuity differences emerge between monthly and PRN dosing in Year 2?
Would the fluid differences between treatments noted in year 1 impact visual acuity with longer follow-up?
Would switching to PRN dosing after one year of monthly treatment maintain or adversely effect vision?
Would important safety differences emerge with longer follow-up?

60. Two Year Results

61. Design
CATT is non-inferiority trial with its primary outcome at 1 year.
Objectives of Year 2:
To evaluate outcomes in patients who maintain the same regimen for two years
To determine the effects of switching to as-needed treatment after 1 year of monthly dosing.

62. Patients 1107 patients alive who continued in Year 2
All available monthly treated patients in Year 1 (n=549) were successfully randomized to monthly or PRN treatment in Year 2
Masking remained robust in Year 2 with identity of assigned drug known to ophthalmologist in only 66 of 12,645 evaluations (11 patients)

63. Statistical Features
Little evidence that dosing regimen affects drug effects in Year 1 (no interaction)
Because no interaction and 6 groups in Year 2, we report results by drug and by dosing regimen
Data analysis
2-way ANOVA & linear regression - continuous variables
Χ2 tests & logistic regression - categorical variables
Cox model - incidence of serious adverse events

64. Visual Acuity Results Same Regimen for Two Years

65. Mean Change in Visual Acuity
Same Regimen for Two years
This is what the second click of the animation should look like (with black font for the 4 ending average VAs

66. Patients Without 15 Letter Decrease Same Regimen for 2 Years
The colors here are not as saturated or intense as the colors (blue and red) on other slides so far – is there a way for the colors to match exactly across all slides?
Is there a fill pattern that is denser or larger dots so there is not so much white space in the PRN Always bars? This applies to a number of bar graphs, not just this one.
Decrease the size of the legend at the top to the size used on the slide 15

67. 15 Letter Change from Baseline Same Regimen for 2 Years
Same note about color
Move the percentages in the bottom segment up so that they are farther from the x axis.
Decrease the size of the legend at the top to the size used on the next slide (slide 15)

68. Distribution of Visual Acuity
Same Regimen for 2 Years

69. Anatomical Results Same Regimen for Two Years

70. Mean Change in Total Retinal Thickness
Same Regimen for 2 Years
Make Legend just a little smaller
Add p-values for drug and regimen over to the right “P=0.xx Drug”

71. Percent with No Fluid on OCT
Same Regimen for 2 Years
Try moving p-values to the right of the last bar (bevacizumab PRN)
Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y- axis

72. Typical Amount of Residual Fluid

73. Percent with Geographic Atrophy
Same Regimen for 2 Years
Same comment on color
Retain the two shades for foveal and non-foveal
Remove the current percentages like 4.7% and 21.1%
Add the total percentage on top of the bar – like 25.8%

74. Percent with No Leakage on FA
Same Regimen for 2 Years
Add the notations “Drug” and “Regimen” for the p values
Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y-axis

75. Mean Change in Lesion Area
Same Regimen for 2 Years

76. Mean Number of Injections
Same Regimen for 2 Years

77. Effect of Switching to PRN after One Year of Monthly Dosing

78. Mean Change in Visual Acuity after Week 52
Monthly Always and Switched to PRN

79. Mean Change in Total Retinal Thickness from Week 52
Monthly Always and Switched to PRN
Change y-axis scale to -100 to +100
You may need to move the legend to above the lines

80. 15-Letter Change from Baseline at 2 Years
Monthly Always and Switched to PRN
Same comment on colors
Change the size of the legend (4 color patterns) to the size on Slide 15
Move the number of the % in the bottom segment up from the x-axis
Make N numbers (134, 129 etc) a little smaller

81. Percent with No Fluid on OCT Monthly Always and Switched to PRN
Try moving p-values to the right of the last bar (bevacizumab PRN)
Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y- axis

82. Percent with Geographic Atrophy Monthly Always and Switched to PRN
Same comment on color
Retain the two shades for foveal and non-foveal
Remove the current percentages like 4.7% and 21.1%
Add the total percentage on top of the bar – like 25.8%

83. Percent with No Leakage on FA Monthly Always and Switched to PRN
Add the notations “Drug” and “Regimen” for the p values
Change label on y-axis to “% of Patients” and drop the “%” from the labels on the y-axis

84. Monthly Always and Switched to PRN
Mean Change in Lesion Area from Year 1
Monthly Always and Switched to PRN

85. Mean Number of Injections in Year 2 Monthly Always and Switched to PRN

86. Mean Change in Visual Acuity
By Regimen within Drug

87. Mean Change in Total Retinal Thickness
By Regimen within Drug

88. Distribution of Visual Acuity at 2 Years

89. Adverse Events

90. Death and APTC Events ranibizumab bevacizumab
(N=599) (N=586) Difference 95% CI P
Death (5.3%) 36 (6.1%) % (-1.9%, 3.5%) 0.62
APTC* 28 (4.7%) 29 (5.0%) % (-2.2%, 2.8%) 0.89
*Includes nonfatal myocardial infarction, nonfatal stroke, and vascular deaths

91. Cumulative Proportion with a Systemic Serious Adverse Event

92. Any Systemic Serious Adverse Event
Drug Difference % CI P
Unadjusted 2-year rates
ranibizumab /599 (31.7%)
bevacizumab /586 (39.9%) % (2.8%, 13.6%)
Adjusted Risk Ratio (1.07, 1.57)
Regimen
Unadjusted 2-year rates*
Monthly /587 (33.9%)
PRN /598 (37.6%) % (-1.7%, 9.1%)
Adjusted Risk Ratio§ (0.98, 1.47)
*Regimen as originally assigned
§PRN a time dependent covariate in Cox model
After adjustment for demographic features
and coexisting illnesses at baseline, the risk ratio for all systemic
serious adverse events within 2 years for bevacizumab
was 1.30 (95% CI, ; P ). Patients treated as
needed had higher rates than patients treated monthly (risk
ratio, 1.20; 95% CI, ; P 0.08).

93. Systemic Serious Adverse Events
ranibizumab bevacizumab
(N=599) (N=586) Difference (95% CI) P
Associated
w/ Anti-VEGF*
Yes ( 7.5%) ( 10.6%) % (-0.2%, 6.4%)
No (28.4%) (34.5%) % (0.8%,11.3%)
* Arteriothrombotic events (myocardial infarction, stroke), systemic hemorrhage, congestive heart failure, venous thrombotic events, hypertension, vascular death.

94. Ocular Adverse Events Endophthalmitis – 0.06% (11 /18,509 injections)
- 11 cases (4 ranibizumab, 7 bevacizumab)
- 10 of 11 cases in monthly treatment group; PRN case had received 22 injections
Pseudo-endophthalmitis
Ocular HTN or Glaucoma
ranibizumab 1
bevacizumab - 1
ranibizumab - 15
bevacizumab - 14

95. 2-Year Drug Cost Per Patient95

96. Distribution of Visual Acuity at 2 Years

97. Summary
Ranibizumab and bevacizumab were equivalent for visual acuity at all time points over a 2-year period.
PRN treatment resulted in less gain in visual acuity (-2.4 letters) at 2 years but vision for all groups was similar at end of 2 years.
PRN dosing resulted in mean of 10 fewer injections over 2 years than monthly dosing. Bevacizumab patients received mean 1.5 more injections than ranibizumab.
More eyes were completely dry on OCT with monthly dosing with the highest rate in eyes receiving ranibizumab monthly.
More eyes developed geographic atrophy with monthly dosing with the highest rate in eyes receiving ranibizumab monthly.

98. Summary
PRN groups had more leakage on FA and more lesion growth than monthly groups.
Switching to PRN after one year of monthly treatment produced visual and anatomical results that were similar to PRN-always.
There were no differences between drugs in rates of death or arteriothrombotic events.
Bevacizumab treated patients had higher rates of systemic SAEs than ranibizumab treated patients.
The reason for this difference remains unclear given the lack of specificity to conditions associated with inhibition of VEGF.

99. Organization Daniel F. Martin MD - Study Chair (Cleveland Clinic)
CATT: ranibizumab-bevacizumab Trial
Daniel F. Martin MD - Study Chair (Cleveland Clinic)
Stuart L. Fine MD - Study Vice-Chair (U Colorado)
Maureen G. Maguire PhD - Coordinating Center (Penn)
Glenn J. Jaffe MD - OCT Reading Center (Duke)
Juan E. Grunwald MD - Photo Reading Center (Penn)
Maryann Redford DDS, MPH – NEI Project Officer

100. Participating CATT Centers
Phoenix, AZ Retinal Consultants of AZ Pravin V. Dugel, MD Tucson, AZ Retina Associates Southwest April E. Harris, MD Beverly Hills, CA Retina-Vitreous Associates Firas Rahhal, MD Sacramento, CA University of CA – Davis Susanna S. Park, MD, PhD
Sacramento, CA
Retinal Consultants Medical Group
Joel A. Pearlman, MD, PhD
San Francisco, CA
West Coast Retina Medical Group
Richard McDonald, MD
Santa Barbara, CA
California Retina Consultants
Robert L. Avery, MD
Denver, CO
Colorado Retina
John D. Zilis, MD
Fort Meyers, FL
National Ophthalmic Research Inst
Joseph P. Walker, MD

101. Participating CATT Centers
Fort Lauderdale, FL Retina Group of Florida Larry Halperin, MD Atlanta, GA Emory Eye Center Baker Hubbard, MD Iowa City, IA University of Iowa Hospitals/Clinics James C. Folk, MD Harvey, IL Ingalls Memorial – IL Retina Assoc. David H. Orth, MD and Sohail Hasan MD Indianapolis, IN Midwest Eye Institute Thomas A. Ciulla, MD
Lexington, KY
Retina Associates of Kentucky
Thomas W. Stone, MD
Louisville, KY
Univ of Louisville – Lions Eye Ctr
Charles C. Barr, MD
Boston, MA
Massachusetts Eye & Ear Infirmary
Ivana Kim, MD
Ophthalmic Consultants of Boston
Trexler M. Topping, MD
Baltimore, MD
Elman Retina Group, P.A.
Michael Elman, MD

102. Participating CATT Centers
St. Louis, MO
Barnes Retina Institute
Daniel P. Joseph, MD, PhD
Chapel Hill, NC
University of North Carolina
Chapel Hill
Travis A. Meredith, MD
Charlotte, NC
Charlotte, Eye, ENT Associates
Andrew N. Antoszyk, MD
Durham, NC
Duke University Eye Center
Srilaxmi Bearelly, MD
New Brunswick, NJ
Retina Vitreous Center
Daniel B. Roth, MD
Chevy Chase, MD Retina Group of Washington Daniel M. Berinstein, MD Towson, MD Retina Specialists John T. Thompson, MD Royal Oak, MI Associated Retinal Consultants Michael T. Trese, MD Edina, MN VitreoRetinal Surgery David F. Williams, MD Rochester, MN Mayo Clinic Sophie J. Bakri, MD

103. Participating CATT Centers
Great Neck, NY Long Island Vitreoretinal Consult Philip J. Ferrone, MD Beachwood, OH Retina Associates of Cleveland Lawrence J. Singerman, MD Dublin, OH Ohio State – Retina Division Frederick H. Davidorf, MD Oklahoma City, OK Dean A. McGee Eye Institute Reagan H. Bradford, MD Portland, OR Retina Northwest Richard F. Dreyer, MD
Portland, OR
Casey Eye Institute
Christina J. Flaxel, MD
Philadelphia, PA
Wills Eye Hospital Retina Assoc
Richard Kaiser, MD
Pittsburgh, PA
Retina Vitreous Consultants
Bernard H. Doft, MD
West Columbia, SC
Palmetto Retina Center
John A. Wells, MD
Knoxville, TN
Southeastern Retina Associates
Stephen L. Perkins, MD

104. Participating CATT Centers
Nashville, TN Tennessee Retina, P.C. Carl C. Awh, MD Dallas, TX Texas Retina Associates Gary Edd Fish, MD Houston, TX Retinal Consultants of Houston David M. Brown, MD
Houston, TX
Retina and Vitreous of Texas
Michael Lambert, MD
Madison, WI
Univ of Wisconsin – Visual Sci
Suresh R. Chandra, MD

105. Committees
Executive Committee: Daniel F. Martin, MD (chair); Robert L. Avery, MD; Sophie J. Bakri, MD; Ebenezer Daniel, MBBS, MS, MPH; Stuart L. Fine, MD; Juan E. Grunwald, MD; Glenn Jaffe, MD, Marcia R. Kopfer, BS, COT; Maureen G. Maguire, PhD; Travis A. Meredith, MD; Ellen Peskin, MA, CCRP; Maryann Redford, DDS, MPH; David F. Williams, MD
Data and Safety Monitoring Committee: Lawrence M. Friedman, MD (chair); Susan B. Bressler, MD; David L. DeMets, PhD; Martin Friedlander, MD, PhD; Mark W. Johnson, MD; Anne Lindblad, PhD; Douglas W. Losordo, MD, FACC; Franklin G. Miller, PhD.

106. Committees
Clinic Monitoring Committee: Ellen Peskin, MA, CCRP (chair); Mary Brightwell-Arnold, SCP; Joan DuPont; Maureen G. Maguire, PhD; Kathy McWilliams, CCRP; Susan K. Nolte.
Operations Committee: Daniel F. Martin, MD (chair); Ebenezer Daniel, MBBS, MS, MPH; Frederick L. Ferris III, MD; Stuart L. Fine, MD; Juan E. Grunwald, MD; Glenn Jaffe, MD; Katie Hall; Maureen G. Maguire, PhD; Ellen Peskin, MA, CCRP; Maryann Redford, DDS, MPH; Cynthia Toth, MD.

108. VIEW 1 & 2 Mean Change in Visual Acuity to 1 year Compared to Baseline
10.9* 2q4 (n=304)
Rq4 (n=304)
7.9† q8 (n=301)
6.9† q4 (n=301)
VIEW 2
9.7† q4 (n=296)
Rq4 (n=291)
8.9† q8 (n=306)
7.6† q4 (n=309)
*P =
†P = NS
vs. Rq4
Week
108

109. Distribution of number of injections PRN Always and Switched to PRN

110. Future Improved drug delivery systems Treatments for non-exudative AMD
Targeted treatments with combinations of drugs
Better prevention strategies

111. Additional Questions
Mary Wade, Academy Science and International PR Manager
Cell:

112. Thank You!