IR Conference Call on EYLEA (aflibercept) Injection in Diabetic Macular Edema September 28, 2013
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Intravitreal Aflibercept Injection for Diabetic Macular Edema Primary Results David M. Brown, M.D. Houston Methodist Hospital Houston, TX For the -DME/-DME Study Investigators
Diabetes: An Epidemic Ø 25.8 million people in the United States (~8.3% of the population) Ø After 15 years of diabetes, prevalence is approximately Ø 20% in patients with Type 1 diabetes. Ø 14% to 25% in patients with Type 2 diabetes Ø Leading cause of blindness in workingage Americans www.cdc.gov. Accessed Sept 2013 Data from the 2011 National Diabetes Fact Sheet (released Jan. 26, 2011) Klein R, Klein B, Moss S, Davis M, DeMets D. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, IV: diabetic macular edema. Ophthalmology 1984;91:1464-1474
TEXAS: Diabetes Statistics Over 2 million Texans affected.
Early Treatment Diabetic Retinopathy Study Vision Gain Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. - Arch Ophthalmol - 01-DEC-1985; 103(12): 1796-806
ETDRS: Vision Loss Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. - Arch Ophthalmol - 01-DEC-1985; 103(12): 1796-806
RIDE and RISE: Ranibizumab for Diabetic Macular Edema
Intravitreal Aflibercept Injection Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgGFc Pre-clinical studies showed that aflibercept Traps multiple VEGF-A isoforms and placental growth factor (PlGF) Binds to VEGF-A and PlGF with higher affinity than native receptors Binds VEGF between its arms without risk of complex formation Purified and formulated preparation of aflibercept specifically for intravitreal injection Iso-osmotic solution compatible with intraocular environment Purified form to reduce unnecessary ingredients in the eye
Intravitreal Aflibercept Injection for Diabetic Macular Edema Primary Results
Study Sites Japan Europe Austria, Czech Republic, Denmark, France, Germany, Hungary, Italy, Poland, Spain USA 73 Centers 404 Patients Australia 54 Centers 461 Patients
Study Design Randomized, multicenter, double-masked trials in patients with clinically significant DME with central involvement and ETDRS BCVA 20/40 to 20/320 N=406 () N=466 () Patients randomized 1:1:1 IVT Aflibercept 2 mg q4 wks IVT Aflibercept 2 mg q8 wks* Laser Photocoagulation Primary endpoint: Mean change in BCVA Primary Endpoint: Week 52 Key Secondary endpoint: Change in DRSS *After 5 initial monthly doses Continued treatment through Year 3
Treatment Schedule IAI 2q4 Week 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 92 96 100 104 108 144 148 IAI 2q8 Laser Laser (no more often than every 12 weeks) Sham laser (if re-treatment criteria met) Laser (as needed based on pre-specified criteria) Primary Endpoint IAI 2mg Year 2 Year 3 Sham injection IAI 2 mg (as needed based on pre-specified criteria) or sham Starting at Week 24 : Additional (rescue) treatment available to all patients Patients with BCVA below BSL and loss from previous best BCVA score of 15 letters at 1 visit or 10 letters on 2 consecutive visits
Key Eligibility Criteria Inclusion Criteria: Adults 18 years with Type 1 or 2 diabetes with DME involving central subfield ETDRS BCVA 20/40 to 20/320 Exclusion Criteria: No previous treatment for DME in last 3 months Active PDR IOP 25 mm Hg No previous vitreoretinal surgery Uncontrolled diabetes or blood pressure History of CVA or MI within 6 months
Patient Disposition Laser IAI 2q4 IAI 2q8 ALL IAI Randomized, n 135 136 135 406 Received Study Medication, n 133 136 135 404 Completed Week 52, n (%) 115 (85.2%) 125 (91.9%) 120 (88.9%) 360 (88.7%) Randomized, n 156 156 154 466 Received Study Medication, n 154 155 152 461 Completed Week 52, n (%) 145 (92.9%) 146 (93.6%) 144 (93.5%) 435 (93.3%)
Baseline Demographics Laser IAI 2q4 IAI 2q8 Laser IAI 2q4 IAI 2q8 N 132 136 135 154 154 151 Age, years (SD) 63.9 (8.6) 62.6 (8.6) 64.2 (7.8) 61.7 (8.7) 62.0 (11.2) 63.1 (9.4) Gender (Women), n (%) 54 (40.9%) 53 (39.0%) 47 (34.8%) 69 (44.8%) 67 (43.5%) 73 (48.3%) Race, n (%) White 106 (80.3%) 109 (80.1%) 106 (78.5%) 131 (85.1%) 128 (83.1%) 125 (82.8%) Black 1 (0.8%) 0 1 (0.7%) 16 (10.4%) 16 (10.4%) 19 (12.6%) Asian 25 (18.9%) 27 (19.9%) 27 (20.0%) 3 (1.9%) 5 (3.2%) 2 (1.3%) Other 0 0 1 4 5 5 HbA1c, mean % (SD) 7.7 (1.26) 7.8 (1.46) 7.7 (1.43) 7.6 (1.68) 7.9 (1.65) 7.9 (1.56) Proportion w/ >8%, n (%) 42 (31.8%) 55 (40.4%) 44 (32.6%) 45 (29.2%) 57 (37.0%) 57 (37.7%) Duration of Diabetes, years (SD) Full analysis set 14.5 (9.8) 14.3 (9.2) 14.1 (8.9) 17.2 (9.55) 16.5 (9.94) 17.6 (11.46)
Baseline Disease Characteristics Laser IAI 2q4 IAI 2q8 Laser IAI 2q4 IAI 2q8 N 132 136 135 154 154 151 BCVA, ETDRS Letter score (SD) 60.8 (10.6) 60.8 (10.7) 58.8 (11.2) 59.7 (10.9) 58.9 (10.8) 59.4 (10.9) CRT, µm (SD) 540 (152) 502 (144) 518 (147) 483 (153) 485 (157) 479 (154) Prior Anti-VEGF Treatment, n (%) 11 (8.3%) 7 (5.1%) 14 (10.4%) 63 (40.9%) 66 (42.9%) 68 (45.0%) BCVA: Best-Corrected Visual Acuity CRT: Central Retinal Thickness (Central Subfield) Full analysis set
Baseline Disease Characteristics N 132 136 135 154 154 151 DRSS, n (%) 43 36 (27.3%) 31 (22.8%) 28 (20.7%) 60 (39.0%) 49 (31.8%) 52 (34.4%) 47 24 (18.2%) 18 (13.2%) 27 (20.0%) 26 (16.9%) 26 (16.9%) 32 (21.2%) 53 35 (26.5%) 44 (32.4%) 42 (31.1%) 42 (27.3%) 52 (33.8%) 40 (26.5%) Cannot grade 33 (25.0%) 39 (28.7%) 34 (25.2%) 4 (2.6%) 2 (1.3%) 3 (2.0%) 40 Laser IAI 2q4 IAI 2q8 Laser IAI 2q4 IAI 2q8 40 Proportion of Patients 30 20 10 30 20 10 0 10 20 35 43 47 53 61 65 71 75 Level About 74% of patients in, and 98% of patients in could be graded DRSS: Diabetic Retinopathy Severity Score; Full analysis set 0 10 20 35 43 47 53 61 65 71 75 Level
Exposure and Rescue Treatment
Treatment Experience Mean # of Active Injections* Mean # of Active Injections* 12 12.2 11.8 Number of Treatments 10 8 6 4 2 Mean # of Active Lasers* 2.1 8.7 8.4 Mean # of Active Lasers* 2.7 Laser 2q4 2q8 0 SAF: Laser: n=133; 2q4: n=136; 2q8: n=135; SAF: Laser: n=154; 2q4: n=155; 2q8: n=152 *Not considering Rescue Treatment; 13 Injections possible; Minimum # of lasers = 1, maximum = 4/5
Additional (Rescue) Treatment Experience SAF Laser: n=133; 2q4: n=136; 2q8: n=135 SAF Laser: n=154; 2q4: n=155; 2q8: n=151 *Patients in IAI arms received laser and patients in the laser arm received IAI if Rescue Treatment Criteria were met. Proportion of Patients Receiving Rescue Treatment Proportion of Patients 100% 80% 60% 40% 20% 0% 24.1% 31.2% 4.4% 8.1% 2.6% 0.7% Laser 2q4 2q8
Fellow Eye Treatment Proportion of Patients Receiving anti-vegf Treatment Proportion of Patients 100% 80% 60% 40% 20% 24.1% 26.5% 25.2% 59.1% 59.1% 70.9% Laser 2q4 2q8 0% Laser: n=132; 2q4: n=136; 2q8: n=135 SAF Laser: n=154; 2q4: n=154; 2q8: n=151
Efficacy
Mean Change in Best-Corrected Visual Acuity ETDRS letters 14 Laser 2q4 2q8 12 10 8 6 4 2 1.2 Laser 0 14 12 10 8 6 4 2 0 0.2 Laser 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week ETDRS; Compared to baseline; FAS; LOCF Laser: n=154; 2q4: n=154; 2q8: n=151 - Laser: n=132; 2q4: n=136; 2q8; n=135
Mean Change in Best-Corrected Visual Acuity ETDRS letters 14 12 10 8 6 4 2 0 14 12 10 8 6 4 Week ETDRS; Compared to baseline; FAS; LOCF Laser: n=154; 2q4: n=154; 2q8: n=151 - Laser: n=132; 2q4: n=136; 2q8; n=135 *P < 0.0001 vs. laser *P < 0.0001 vs. laser Laser 2q4 2q8 10.7 2q8 10.5 2q4 1.2 Laser 12.5 2q4 10.7 2q8 2 0 0.2 Laser 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Proportion of Patients Gaining 10 Letters 100% Proportion of Patients 80% 60% 40% 20% 25.8% 54.4%* 53.3%* 19.5% 64.9%* 58.3%* Laser 2q4 2q8 0% FAS- Laser: n=132; 2q4: n=136; 2q8: n=135 FAS- Laser: n=154; 2q4: n=154; 2q8: n=151 Compared to baseline; LOCF *P < 0.0001 vs. laser *P < 0.0001 vs. laser
Proportion of Patients Gaining 15 Letters 100% Proportion of Patients 80% 60% 40% 20% 32.4%* 41.6%* 33.3%* 31.1%* 9.1% 7.8% Laser 2q4 2q8 0% FAS- Laser: n=132; 2q4: n=136; 2q8: n=135 FAS- Laser: n=154; 2q4: n=154; 2q8: n=151 Compared to baseline; LOCF *P < 0.0001 vs. laser *P < 0.0001 vs. laser
Proportion of Patients Losing 15 Letters 50% Proportion of Patients 40% 30% 20% 10% 0% 10.6% 9.1% 0.7% 0.0% 0.6% 0.7% Laser 2q4 2q8 FAS- Laser: n=132; 2q4: n=136; 2q8: n=135 FAS- Laser: n=154; 2q4: n=154; 2q8: n=151 Compared to baseline; LOCF
0 Mean Change in Central Retinal Thickness Week Laser 2q4 2q8 0 4 8 12 16 20 24 28 32 36 40 44 48 52 *P < 0.0001 vs. laser -50-100 -150-66 Laser µm -200 0-195 2q4-192 2q8-50 -100-150 -200-73 Laser -186 2q4-183 2q8 - Laser: n=132; 2q4: n=136; 2q8: n=135 Laser: n=154; 2q4: n=154; 2q8: n=151 Central Sub-field; Compared to baseline; FAS; LOCF; SD-OCT *P < 0.0001 vs. laser
DRSS: Diabetic Retinopathy Severity Score Compared to baseline; LOCF Proportion of Patients with 2 Step Improvement in DRSS 100% Proportion of Patients 80% 60% 40% 20% 7.5% 33.3% 33.8% 27.7% 29.1% 14.3% Laser 2q4 2q8 0% n=80 n=81 n=83 P < 0.0001 2q4 vs. laser P = 0.0006 2q8 vs. laser n=154 n=151 n=154 P < 0.0001 2q4 vs. laser P = 0.0017 2q8 vs. laser
Safety
Safety Overview Laser IAI 2q4 IAI 2q8 ALL IAI Laser IAI 2q4 IAI 2q8 ALL IAI N 133 136 135 271 154 155 152 307 Ocular AEs (study eye), n (%) Systemic AEs, n (%) Ocular SAEs (study eye), n (%) Systemic SAEs, n (%) 82 (61.7%) 76 (55.9%) 80 (59.3%) 156 (57.6%) 103 (66.9%) 96 (61.9%) 87 (57.2%) 183 (59.6%) 81 (60.9%) 92 (67.6%) 98 (72.6%) 190 (70.1%) 132 (85.7%) 125 (80.6%) 119 (78.3%) 244 (79.5%) 6 (4.5%) 2 (1.5%) 3 (2.2%) 5 (1.8%) 6 (3.9%) 3 (1.9%) 2 (1.3%) 5 (1.6%) 18 (13.5%) 19 (14.0%) 25 (18.5%) 44 (16.2%) 47 (30.5%) 48 (31.0%) 39 (25.7%) 87 (28.3%) (S)AE = (Serious) Adverse Event Safety analyses set
Intraocular Inflammation Study Eye Laser IAI 2q4 IAI 2q8 Laser IAI 2q4 IAI 2q8 Number of Injections 283 1656 1168 418 1832 1284 Number of events, n (%) 1 (0.4%)* 4 (0.2%) 5 (0.4%) 1 (0.2%)* 4 (0.2%) 1 (0.1%) Endophthalmitis, n (%) 0 0 0 0 0 0 *Patient did not receive an IVT injections in study eye Safety analyses set
APTC Events* N 133 136 135 271 Any APTC event, n (%) 2 (1.5%) 2 (1.5%) 4 (3.0%) 6 (2.2%) Non-fatal MI 1 (0.8%) 1 (0.7%) 0 1 (0.4%) Non-fatal stroke 0 1 (0.7%) 2 (1.5%) 3 (1.1%) Vascular deaths 1 (0.8%) 0 2 (1.5%) 2 (0.7%) Laser IAI 2q4 IAI 2q8 ALL IAI N 154 155 152 307 Any APTC event, n (%) 6 (3.9%) 7 (4.5%) 6 (3.9%) 13 (4.2%) Non-fatal MI 4 (2.6%) 3 (1.9%) 3 (2.0%) 6 (2.0%) Non-fatal stroke 2 (1.3%) 2 (1.3%) 3 (2.0%) 5 (1.6%) Vascular deaths 1 (0.6%) 2 (1.3%) 0 2 (0.7%) *As adjudicated by a masked committee; Only treatment emergent events included; APTC=Anti-platelet thromboembolic Collaboration Safety analyses set
Deaths Through Week 52 N 133 136 135 271 Death, n (%) 1 (0.8%) 0 4 (3.0%)* 4 (1.5%) Acute MI 1 (0.8%) 0 0 0 Cardiac failure 0 0 1 (0.7%) 1 (0.4%) Hypertensive heart disease 0 0 1 (0.7%) 1 (0.4%) Lung neoplasm 0 0 1 (0.7%) 1 (0.4%) B-cell lymphoma 0 0 1 (0.7%) 1 (0.4%) Laser N 154 155 152 307 Death, n (%) 1 (0.6%) 2 (1.3%) 0 2 (0.7%) Death 0 1 (0.6%) 0 1 (0.3%) Myocardial infarction 0 1 (0.6%) 0 1 (0.3%) Sudden cardiac death 1 (0.6%) 0 0 0 *Note: One additional death (MI) occurred in the 2q8 group in in year 2 (406 and 77 days after the first and last active injections, respectively), but due to data conventions it was included in the Year 1 clinical database Safety analyses set IAI 2q4 IAI 2q8 ALL IAI
Deaths Through Week 52 Kaplan Meier Plot of Time to Death Note: One additional death (MI) occurred in the 2q8 group in -DME in year 2 (406 and 77 days after the first and last active injections, respectively), but due to data conventions it was included in the Year 1 clinical database. Safety analyses set
Conclusions ETDRS letters 14 12 10 8 6 4 10.7 2q8 10.5 2q4 14 12 10 8 6 4 12.5 2q4 10.7 2q8 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 1.2 Laser 2 0 0.2 Laser 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Superiority of IAI over laser treatment seen through Week 52 On average, IAI 2q8 group performed similarly to the IAI 2q4 group No systemic safety signal in both IAI treatment groups evident through Week 52
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