Presentation on theme: "AMD Trials and Treatments:"— Presentation transcript:
1 AMD Trials and Treatments: AAO Media BriefingAMD Trials and Treatments:An Evolving LandscapeABDHISH R. BHAVSAR, M.D.Chair
2 Financial Disclosures Abdhish R. Bhavsar, MDResearch support - clinical trials: DRCR, Regeneron, Genentech
3 Agenda Abdhish R. Bhavsar, MD: Welcome/Introductions Pravin Dugel, MD: Fovista 2b clinical trial resultsQ/AAbdhish R. Bhavsar, MD: Update CATT and EyleaSusan Bressler, MD: Cataract sugery/AMD - no inc riskPaul Mitchell, MD: Cataract surgery/AMD – inc riskEdwin Stone, MD: Update on genetic testing for AMDMedia Q & A
4 Study DisclosuresThis study does include research conducted on human subjectsIRB 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 1IntegratedVIEW 2Abdhish R. Bhavsar, MD
6 PurposeThe 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 dataThe 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 ACCMEThis presentation may not be duplicated or distributedIntravitreal 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 DesignMulti-center, active controlled, double masked trial VIEW 1 N=1217; VIEW 2 N=1240Patients randomized 1:1:1:1Intravitreal AfliberceptRanibizumab2 mg q4 wks0.5 mg q4 wks2 mg q8 wks0.5 mg q4 wksPrimary endpoint: Maintenance of VisionDosing through Week 52 Modified quarterly dosing through Week 96Secondary endpoint: Mean change in BCVA*After 3 initial monthly doses
10 KEY SECONDARY ENDPOINTS Study EndpointsProportion of patients who maintained BCVA (%) (losing <15 ETDRS letters from baseline)PRIMARY ENDPOINTMean change in BCVA as measured by ETDRS letter score from baselineProportion of patients who gained at least 15 letters of BCVA from baselineCentral Retinal ThicknessKEY SECONDARY ENDPOINTSBCVA: Best-Corrected Visual AcuityETDRS: Early Treatment Diabetic Retinopathy Study1010
24 Treatment Schedule Re-treatment Criteria – 12 weeks since previous injectionNew or persistent fluid on OCTIncrease in CRT of ≥100 μm compared to the lowest previous valueLoss of ≥5 ETDRS letters from the best previous score in conjunction with recurrent fluid on OCTNew onset classic neovascularizationNew or persistent leak on FANew macular hemorrhageSolid = InjectionOutline = ShamHatched = Modified Quarterly Dosing24
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, MDfor the Comparison of AMD Treatments Trials (CATT) Research GroupSupported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS
47 ObjectivesTo determine the relative efficacy and safety of intravitreal ranibizumab and bevacizumab for treatment of neovascular AMDTo 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 Sites1185 patients with neovascular AMD enrolled at 43 sites in the United States48
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 CNVAllowed eyes with VA 20/25-20/320No 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 1Year 2123456789101112131415161718192021222324ranibizumab MonthlybevacizumabMonthlyranibizumab PRNbevacizumabPRN}Retreat if fluid on OCT orother signs of active CNVPrimary EndpointFinal visit
52 Treatment in PRN ArmsTreat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid.May also treat if there is other evidence of CNV activityNew subretinal or intraretinal hemorrhageLeakage or increased lesion size on FAUnexplained 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 studyBevacizumab supplied by CATT repackaged in glass vials under INDMultiple Lines of Evidence Support a Role for VEGF in Choroidal NeovascularizationSurgical 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.1Increased 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.2Compared with healthy controls, VEGF is overexpressed in the retinal pigmented epithelium and choroidal blood vessels of early and neovascular AMD lesions.3In animal studies, overexpression of VEGF165 in retinal pigment epithelial cells led to choroidal neovascularization.4,5Anti-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.
58 Year 1 Adverse EventsNo difference between drugs in rates of death, stroke, or myocardial infarctionImbalance 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?
61 DesignCATT 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 yearsTo 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 2Masking remained robust in Year 2 with identity of assigned drug known to ophthalmologist in only 66 of 12,645 evaluations (11 patients)
63 Statistical FeaturesLittle 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 regimenData analysis2-way ANOVA & linear regression - continuous variablesΧ2 tests & logistic regression - categorical variablesCox 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 yearsThis 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 colorMove 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
70 Mean Change in Total Retinal Thickness Same Regimen for 2 YearsMake Legend just a little smallerAdd 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 YearsTry 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
73 Percent with Geographic Atrophy Same Regimen for 2 YearsSame comment on colorRetain the two shades for foveal and non-fovealRemove 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 YearsAdd the notations “Drug” and “Regimen” for the p valuesChange 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 PRNChange y-axis scale to -100 to +100You may need to move the legend to above the lines
80 15-Letter Change from Baseline at 2 Years Monthly Always and Switched to PRNSame comment on colorsChange the size of the legend (4 color patterns) to the size on Slide 15Move the number of the % in the bottom segment up from the x-axisMake 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 colorRetain the two shades for foveal and non-fovealRemove 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 valuesChange 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 1Monthly 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
90 Death and APTC Events ranibizumab bevacizumab (N=599) (N=586) Difference 95% CI PDeath (5.3%) 36 (6.1%) % (-1.9%, 3.5%) 0.62APTC* 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 PUnadjusted 2-year ratesranibizumab /599 (31.7%)bevacizumab /586 (39.9%) % (2.8%, 13.6%)Adjusted Risk Ratio (1.07, 1.57)RegimenUnadjusted 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 modelAfter adjustment for demographic featuresand coexisting illnesses at baseline, the risk ratio for all systemicserious adverse events within 2 years for bevacizumabwas 1.30 (95% CI, ; P ). Patients treated asneeded had higher rates than patients treated monthly (riskratio, 1.20; 95% CI, ; P 0.08).
97 SummaryRanibizumab 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 SummaryPRN 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 TrialDaniel 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, PhDSacramento, CARetinal Consultants Medical GroupJoel A. Pearlman, MD, PhDSan Francisco, CAWest Coast Retina Medical GroupRichard McDonald, MDSanta Barbara, CACalifornia Retina ConsultantsRobert L. Avery, MDDenver, COColorado RetinaJohn D. Zilis, MDFort Meyers, FLNational Ophthalmic Research InstJoseph 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, MDLexington, KYRetina Associates of KentuckyThomas W. Stone, MDLouisville, KYUniv of Louisville – Lions Eye CtrCharles C. Barr, MDBoston, MAMassachusetts Eye & Ear InfirmaryIvana Kim, MDOphthalmic Consultants of BostonTrexler M. Topping, MDBaltimore, MDElman Retina Group, P.A.Michael Elman, MD
102 Participating CATT Centers St. Louis, MOBarnes Retina InstituteDaniel P. Joseph, MD, PhDChapel Hill, NCUniversity of North CarolinaChapel HillTravis A. Meredith, MDCharlotte, NCCharlotte, Eye, ENT AssociatesAndrew N. Antoszyk, MDDurham, NCDuke University Eye CenterSrilaxmi Bearelly, MDNew Brunswick, NJRetina Vitreous CenterDaniel B. Roth, MDChevy 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, MDPortland, ORCasey Eye InstituteChristina J. Flaxel, MDPhiladelphia, PAWills Eye Hospital Retina AssocRichard Kaiser, MDPittsburgh, PARetina Vitreous ConsultantsBernard H. Doft, MDWest Columbia, SCPalmetto Retina CenterJohn A. Wells, MDKnoxville, TNSoutheastern Retina AssociatesStephen 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, MDHouston, TXRetina and Vitreous of TexasMichael Lambert, MDMadison, WIUniv of Wisconsin – Visual SciSuresh R. Chandra, MD
105 CommitteesExecutive 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, MDData 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 CommitteesClinic 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.