Aflibercept for Prevention of Diabetic Retinopathy Complications
Explore the efficacy of aflibercept in preventing vision-threatening complications of diabetic retinopathy through a randomized clinical trial. Learn about the study design, outcomes, and implications for high-risk eyes.
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DRCR Retina Network Intravitreous Aflibercept for Prevention of Vision Threatening Complications of Diabetic Retinopathy (Protocol W) 1
Financial Disclosures Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services. Additional Contributions: JDRF provided funds to DRCR Retina Network to defray some of the study s clinical site costs Regeneron provided the aflibercept for the study. In addition, Regeneron provided funds to the DRCR Retina Network to defray some of the study s clinical site costs. 2
Anti-VEGF Treatment Anti-VEGF is effective treatment for center- involved DME and PDR. Can anti-VEGF prevent these vision threatening complications in high-risk eyes? If so, is there visual benefit at 4 years associated with preventing these complications? 3
Background PANORAMA randomized patients with severe NPDR and without CI-DME to aflibercept injection (q8W or q16W) or sham. Primary Outcome: improvement by 2 or more steps in DR severity over 24 weeks. 100% Proportion with 2-Step Improvement 24 Weeks 52 Weeks 100 Weeks Nominal p<0.001 vs. sham *Independent reading center review of investigator PRN decisions suggests under treatment during year 2 80% 60% Wykoff CC, on behalf of the PANORAMA Investigators. A phase 3, double-masked, randomized study of the efficacy and safety of aflibercept in patients with moderately severe to severe NPDR: Week 100 Results. https://investor.regeneron.com/stati c-files/f30ef8ab-2a66-4496-9bc6- c731c481dc70 80% 40% 65% 63% 62% 55% 50% 20% 15% 13% 6% 0% Sham (N= 133) 2q16 (N = 135) 2q8 (PRN*) (N = 134) 4
Background PANORAMA1 Secondary Outcomes: Proportion of Patients Developing VTC or CI-DME through Week 100 (Kaplan-Meier Analysis) VTC, vision threatening complication, PDR, Proliferative diabetic retinopathy, ASNV, Anterior segment neovascularization *Reductions in risk derived from hazard rations from Kaplan-Meier estimates (%) Nominal p<0.001 vs. sham 100% Sham (N = 133) 2q16 (N = 135) 2q8 (N = 134) 80% Proportion of Patients 60% Reduction in likelihood of development over time* 1. Wykoff CC, on behalf of the PANORAMA Investigators. A phase 3, double-masked, randomized study of the efficacy and safety of aflibercept in patients with moderately severe to severe NPDR: Week 100 Results. https://investor.regeneron.com/stati c-files/f30ef8ab-2a66-4496-9bc6- c731c481dc70 40% 79% 75% 58% 76% 68% 20% 77% 83% 38% 31% 21% 18% 14% 9% 11% 7% 0% VTC (PDR/ASNV) or CI-DME VTC CI-DME 5
Protocol W: Study Design Randomized Multicenter Clinical Trial (N = 64 Sites) 18 years old with type 1 or type 2 diabetes Severe NPDR in at least 1 eye* DRSS between 43 and 53 on reading center grading No evidence of NV on FA within the 7 modified ETDRS fields Best-corrected VA letter score 79 (20/25 or better) No hx of DME/DR treatment within 12 months and 4 prior injections No prior PRP Primary Outcome 2 mg Intravitreous Aflibercept Cumulative probability of development of PDR or CI-DME with vision loss Sham Injection *NPDR determined by investigator; eyes with CI-DME or CST greater than machine and gender- specific OCT thresholds were excluded. After 9 months of recruitment the lower cutoff was modified from 47B 6
Follow-Up Visits and Treatment Month 1 Month 2 Month 4 Month 8 Baseline (0) Month 16 Month 20 Month 12 Before 2 Years: Injections given at every visit Month 28 Month 32 Month 24 2 Years: Injections given if worse than mild NPDR (> level 35 on clinical exam) Month 40 Month 44 Month 36 Final Visit (48M) Participants and VA/OCT/Photo technicians masked to treatment 7
Study Design: PDR Outcome Treatment Following Outcome Treatment with aflibercept initiated if: High-risk characteristics develop VH from PDR develops Once initiated, treatment followed Protocol S algorithm Development of NV within the 7 modified ETDRS Fields on fundus photography or FA, confirmed by reading center TRD, VH, or pre-retinal hemorrhage presumed to be from PDR, documented on fundus photos or FA NVI, NVA, or NVG on clinical exam PRP, anti-VEGF or vitrectomy for PDR
Study Design: DME Outcome Treatment Following Outcome Outcome criteria met Treatment initiated with aflibercept Once initiated, treatment followed Protocol T algorithm CI-DME on clinical exam with 10% increase in CST from baseline and VA loss VA loss defined as 10 letter score loss at a single visit or 5 to 9 letter score loss at 2 consecutive visits from DME TX for DME performed without meeting above criteria 9
Randomization 399 Eyes (328 participants; 36% bilateral) Included in the Primary Analyses 104 Weeks N = 160 (80%) Aflibercept N = 200 N = 200 N = 167 (84%) Sham N = 199 N = 199 *Excluding deaths 10
Participant Baseline Characteristics Aflibercept N = 200 57 42% 94% 8.6 46% 15% 31% 5% 2% Sham N = 199 56 43% 88% 8.3 43% 16% 34% 5% 2% Age (y), median Female Type 2 Diabetes HbA1c (%), median White Black/African American Hispanic or Latino Asian Other Race/Ethnicity 11
Ocular Baseline Characteristics Aflibercept N = 200 Sham N = 199 Visual Acuity Median letter score 88 88 Snellen equivalent 84 Letter Score (20/20 or better) Median OCT CST, m (Spectralis equivalent) Prior DME treatment 20/20 20/20 78% 81% 283 283 10% 11% Anti-VEGF 4% 3% Focal/laser 6% 10% 12
Ocular Baseline Characteristics Aflibercept N = 200 Sham N = 199 Diabetic Retinopathy Severity Scale Graded by Reading Center* Moderate NPDR: Level 43 17% 18% Moderately Severe NPDR: Level 47A 33% 31% Moderately Severe NPDR: Levels 47B D 27% 28% Severe NPDR: Level 53 24% 24% 13 * Randomization stratification factor
Time to Development of DME or PDR Follow-up Complete Follow-up Ongoing 100% Adjusted Hazard Ratio Aflibercept vs Sham = 0.32 (97.5% CI = 0.21, 0.50); P <0.001 Aflibercept Sham 80% Aflibercept >2 Years Cumulative Percent Sham >2 Years 60% 44% 40% 16% 20% 0% No. at risk 0 200 1 173 2 133 3 35 Aflibercept Sham 199 153 101 22 15 Years from Randomization
Time to Development PDR Follow-up Complete Follow-up Ongoing 100% Adjusted Hazard Ratio Aflibercept vs Sham = 0.34 (97.5% CI = 0.21, 0.55); P <0.001 80% Cumulative Percent 60% 40% 33% 20% 14% 0% 0 1 2 3 No. at risk Aflibercept 200 175 137 37 Sham 199 157 114 29 Years from Randomization
Time to Development of DME Follow-up Complete Follow-up Ongoing 100% Adjusted Hazard Ratio Aflibercept vs Sham = 0.36 (97.5% CI = 0.17, 0.77); P =0.002 80% Cumulative Percent 60% 40% 15% 20% 4% 0% No. at risk 0 200 1 2 142 3 45 Aflibercept 178 Sham 199 174 137 32 17 Years From Randomization
Development of DME or PDR Aflibercept N = 200 Sham N = 199 First PDR and/or DME criteria met, N N = 35 N = 81 NVA 0 1 NVD/NVE 17 39 NVD/NVE + preretinal hemorrhage 1 5 NVD/NVE + VH 2 3 NVD/NVE + VH + preretinal hemorrhage 0 4 NVI 0 1 VH 4 4 18
Development of DME or PDR Aflibercept N = 200 Sham N = 199 First PDR and/or DME criteria met, Cont., N N = 35 N = 81 VH + preretinal hemorrhage 0 1 CI-DME w/ 5 9 letter VA loss at 2 visits 0 4 CI-DME w/ 10-letter VA loss 6 12 NVD/NVE + CI-DME w/ 10-letter VA loss 2 2 PRP for PDR 0 1 Anti-VEGF for DME 3 3 Focal/grid laser for DME 0 1 19
Development of DME or PDR by Baseline DR Severity Adjusted Hazard Ratio (97.5% CI) 0.13 (0.01, 1.42) 0.29 (0.11, 0.77) 0.36 (0.16, 0.77) 0.36 (0.19, 0.69) N Aflibercept Sham Moderate NPDR (Level 43) Moderately Severe NPDR (level 47A) Moderately Severe NPDR (level 47B D) Severe NPDR (level 53) 68 3% 24% 126 12% 34% 109 11% 46% 96 36% 68% 20
Change in DR Severity at 2 Years 2 Step Worsening 2 Step Improvement 100% 100% Adjusted Odds Ratio Aflibercept vs Sham = 0.37 (97.5% CI = 0.13, 1.01); P =0.03 Adjusted Odds Ratio Aflibercept vs Sham = 5.91 (97.5% CI = 3.19, 10.95); P <0.001 80% 80% 60% 60% 45% 40% 40% 20% 20% 14% 12% 5% 0% 0% Aflibercept N = 154 Sham N = 161 Aflibercept N = 154 Sham N = 161 21
Mean VA Letter Score Change from Baseline 10 Mean Change in VA from Randomization, N = 200 N = 199 N = 160 N = 166 8 6 4 Letter Score -0.9 2 0 -2 -2.0 -4 Adjusted Mean Difference at 2-Years Aflibercept vs. Sham:0.5 (-1.0, 1.9); P =0.47 -6 -8 Figure is not drawn to scale. -10 0 1 2 4 8 12 16 20 24 Month 23 Aflibercept Sham
Mean VA Letter Score AUC 10 Mean Change in VA from Randomization, N = 200 N = 199 N = 160 N = 166 8 -0.3 6 4 Letter Score 2 0 -1.0 -2 -4 AUC Adjusted Mean Difference Over 2-years Aflibercept vs. Sham:0.1 (-0.7, 1.0); P =0.73 -6 -8 Figure is not drawn to scale. -10 0 1 2 4 8 12 16 20 24 Month 24 Aflibercept Sham
VA Letter Score Loss At 2 Years Aflibercept Sham Adjusted Odds Ratio (97.5% CI) 1.05 (0.42, 2.56); P =0.90 EYES (%) 14% 13% 8% 7% 6% 3% 5 10 15 25
Mean OCT CST Change from Baseline 40 N = 159 N = 166 N = 200 N = 199 30 20 CST Mean Change, m 10 -1 m 0 -6 m -10 -20 Adjusted Mean Difference at 2-Years Aflibercept vs. Sham:-4 (-12, 4); P =0.26 -30 Figure is not drawn to scale. -40 0 1 2 4 8 12 16 20 24 Month Aflibercept Sham 27
Treatments for PDR and DME Aflibercept Sham 1 Year N = 180 N = 181 1 PRP tx 1 (<1%) 0 1 aflibercept injection for PDR or DME 3 (2%) 13 (7%) 1 focal/grid tx for DME 0 1 (<1%) aflibercept injections, mean (SD) 4.9 (0.5) 0.3 (1.1) 29
Treatments for PDR and DME Aflibercept Sham 2 Years N = 160 N = 167 1 PRP tx 1 (<1%) 3 (2%) 1 aflibercept injection for PDR or DME 7 (4%) 32 (19%) 3 (2%) 1 focal/grid tx for DME 0 aflibercept injections, mean (SD) 8.0 (1.2) 1.1 (2.7) 30
Safety 31
Ocular Adverse Events P Aflibercept N = 200 Sham N = 199 Value Endophthalmitis 3 (2%) 0 0.10 2 (1%) Any retinal detachment 2 (1%) 1.00 IOP increase 10 mmHg 12 (6%) 13 (7%) 0.90 IOP increase 30 mmHg 3 (2%) 8 (4%) 0.14 Total number of injections: Aflibercept, N = 1888; Sham, N = 399 32
APTC* Systemic Adverse Events Aflibercept N = 129 Sham N = 128 Bilateral N = 71 P Value Any APTC event 6 (8%) 11 (9%) 11 (9%) 1.00 Nonfatal myocardial infarction Nonfatal stroke Death due to potential vascular or unknown cause Hypertension 1 (1%) 2 (2%) 3 (2%) 0 3 (2%) 3 (2%) 5 (7%) 6 (5%) 5 (4%) 13 (10%) 7 (10%) 18 (14%) 33 *APTC = Antiplatelet Trialists Collaboration
Limitations Retention through 2 years was less than 90% in both groups. Two-year visit results may be biased by the loss to follow-up. The primary outcome included components determined by an unmasked investigator; only 3% of outcomes were based on investigator assessment. Results using an anti-VEGF agent or treatment approach other than the one used in this study may be different. 34
Conclusion Among eyes with moderate to severe NPDR, the proportion that developed PDR or CI-DME was lower with periodic aflibercept treatment compared with sham through at least 2 years. Through 2 years, preventative treatment with aflibercept did not confer VA benefit compared with anti-VEGF initiated after PDR or DME development. 4-year results will be important for determining whether preventing PDR and CI-DME improves long-term VA. 35
