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

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Presentation on theme: "AAO Media Briefing ABDHISH R. BHAVSAR, M.D. Chair 1 AMD Trials and Treatments: An Evolving Landscape."— Presentation transcript:

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

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

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 3

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

5 V 2.0; Oct 2012 VIEW 1 Integrated Investigation of Efficacy and Safety of Intravitreal Aflibercept Injection in Wet Age-Related Macular Degeneration (AMD)

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

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

10 Study Endpoints Proportion of patients who maintained BCVA (%) (losing <15 ETDRS letters from baseline) 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 PRIMARY ENDPOINT KEY SECONDARY ENDPOINTS BCVA: Best-Corrected Visual Acuity ETDRS: Early Treatment Diabetic Retinopathy Study

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13 V 2.0; Oct 2012 Results Week 52 VIEW 1 Integrated

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23 V 2.0; Oct 2012 Results Week 52 – Week 96 VIEW 1 Integrated

24 Treatment Schedule Solid = Injection Outline = Sham Hatched = Modified Quarterly Dosing 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

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37 V 2.0; Oct 2012 Safety VIEW 1 Integrated

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

42 V 2.0; Oct 2012 Important Product Information

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

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 47

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

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 49

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 51 (Months ) ranibizumab Monthly bevacizumab Monthly ranibizumab PRN bevacizumab PRN Final visit Primary Endpoint Retreat if fluid on OCT or other signs of active CNV Year 1 Year 2 }

52 Treatment in PRN Arms 52 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. 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

54 Mean Change in Visual Acuity 54 All Groups

55 55 Distribution of Visual Acuity at 1 Year

56 All Groups Mean Change in Total Retinal Thickness Over Time

57 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. 58

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? 59

60 Two Year Results 60

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. 61

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) 62

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  Χ 2 tests & logistic regression - categorical variables  Cox model - incidence of serious adverse events 63

64 Visual Acuity Results Same Regimen for Two Years 64

65 Mean Change in Visual Acuity Same Regimen for Two years

66 Patients Without 15 Letter Decrease Same Regimen for 2 Years 66

67 15 Letter Change from Baseline Same Regimen for 2 Years 67

68 68 Distribution of Visual Acuity Same Regimen for 2 Years

69 Anatomical Results Same Regimen for Two Years 69

70 Mean Change in Total Retinal Thickness Same Regimen for 2 Years

71 71 Percent with No Fluid on OCT Same Regimen for 2 Years

72 Typical Amount of Residual Fluid 72

73 73 Percent with Geographic Atrophy Same Regimen for 2 Years

74 74 Percent with No Leakage on FA Same Regimen for 2 Years

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

76 76 Mean Number of Injections Same Regimen for 2 Years

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

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

80 15-Letter Change from Baseline at 2 Years 80 Monthly Always and Switched to PRN

81 81 Percent with No Fluid on OCT Monthly Always and Switched to PRN

82 82 Percent with Geographic Atrophy Monthly Always and Switched to PRN

83 83 Percent with No Leakage on FA Monthly Always and Switched to PRN

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

85 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

88 88 Distribution of Visual Acuity at 2 Years

89 Adverse Events 89

90 Death and APTC Events 90 ranibizumab bevacizumab (N=599) (N=586) Difference 95% CI P Death 32 (5.3%) 36 (6.1%) 0.8% (-1.9%, 3.5%) 0.62 APTC* 28 (4.7%) 29 (5.0%) 0.3% (-2.2%, 2.8%) 0.89 * Includes nonfatal myocardial infarction, nonfatal stroke, and vascular deaths ranibizumab bevacizumab (N=599) (N=586) Difference 95% CI P Death 32 (5.3%) 36 (6.1%) 0.8% (-1.9%, 3.5%) 0.62 APTC* 28 (4.7%) 29 (5.0%) 0.3% (-2.2%, 2.8%) 0.89 * Includes nonfatal myocardial infarction, nonfatal stroke, and vascular deaths

91 Cumulative Proportion with a Systemic Serious Adverse Event 91

92 Any Systemic Serious Adverse Event 92 Drug Difference 95% CI P Unadjusted 2-year rates ranibizumab 190 /599 (31.7%) bevacizumab 234 /586 (39.9%) 8.2% (2.8%, 13.6%) Adjusted Risk Ratio 1.30 (1.07, 1.57) Regimen Unadjusted 2-year rates* Monthly 199 /587 (33.9%) PRN 225 /598 (37.6%) 3.7% (-1.7%, 9.1%) 0.18 Adjusted Risk Ratio § 1.20 (0.98, 1.47) 0.08 *Regimen as originally assigned § PRN a time dependent covariate in Cox model Drug Difference 95% CI P Unadjusted 2-year rates ranibizumab 190 /599 (31.7%) bevacizumab 234 /586 (39.9%) 8.2% (2.8%, 13.6%) Adjusted Risk Ratio 1.30 (1.07, 1.57) Regimen Unadjusted 2-year rates* Monthly 199 /587 (33.9%) PRN 225 /598 (37.6%) 3.7% (-1.7%, 9.1%) 0.18 Adjusted Risk Ratio § 1.20 (0.98, 1.47) 0.08 *Regimen as originally assigned § PRN a time dependent covariate in Cox model

93 Systemic Serious Adverse Events 93 ranibizumab bevacizumab (N=599) (N=586) Difference (95% CI) P Associated w/ Anti-VEGF* Yes 45 ( 7.5%) 62 ( 10.6%) 3.1% (-0.2%, 6.4%) 0.07 No 170 (28.4%) 202 (34.5%) 6.1% (0.8%,11.3%) 0.02 * Arteriothrombotic events (myocardial infarction, stroke), systemic hemorrhage, congestive heart failure, venous thrombotic events, hypertension, vascular death. ranibizumab bevacizumab (N=599) (N=586) Difference (95% CI) P Associated w/ Anti-VEGF* Yes 45 ( 7.5%) 62 ( 10.6%) 3.1% (-0.2%, 6.4%) 0.07 No 170 (28.4%) 202 (34.5%) 6.1% (0.8%,11.3%) 0.02 * 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 94  ranibizumab 1  bevacizumab - 1  ranibizumab - 15  bevacizumab - 14

95 2-Year Drug Cost Per Patient 95

96 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. 97

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. 98

99 Organization 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 99 CATT: ranibizumab-bevacizumab Trial

100 Participating CATT Centers 100 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 101 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 Boston, MA Ophthalmic Consultants of Boston Trexler M. Topping, MD Baltimore, MD Elman Retina Group, P.A. Elman Retina Group, P.A. Michael Elman, MD Michael Elman, MD

102 Participating CATT Centers 102 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 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

103 Participating CATT Centers 103 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 104 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 105 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 106 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.

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108 VIEW 1 & 2 Mean Change in Visual Acuity to 1 year Compared to Baseline *P = † P = NS vs. Rq4 VIEW Rq4 (n=291) 7.6 † 2q4 (n=309) 9.7 † 0.5q4 (n=296) 8.9 † 2q8 (n=306) VIEW Rq4 (n=304) 10.9* 2q4 (n=304) 6.9 † 0.5q4 (n=301) 7.9 † 2q8 (n=301) Week

109 109 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 110

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

112 Thank You! 112


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