Evaluation of Intravitreal Aflibercept for the Treatment of Severe Nonproliferative Diabetic Retinopathy: Results From the PANORAMA Randomized Clinical Trial

Abstract

Importance: Proactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications.

Objective: To evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME).

Design, setting, and participants: The Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better.

Interventions: Intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group).

Main outcomes and measures: Proportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100.

Results: Among 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P < .001). At 52 weeks, 88 of 135 eyes (65.2%) in the aflibercept 2q16 group (adjusted difference, 50.1%; 95% CI, 40.1%-60.1%) and 107 of 134 eyes (79.9%) in the aflibercept 2q8/PRN group (adjusted difference, 64.8%; 95% CI, 55.8%-73.9%) compared with 20 of 133 eyes (15.0%) in the control group (P < .001 for both comparisons) showed a 2-step or greater improvement in DRSS level. Fewer eyes treated with aflibercept vs sham injections developed vision-threatening complications and/or center-involved DME through week 100 (22 of 135 eyes [16.3%] in the 2q16 group [adjusted difference, -34.2%; 95% CI, -44.6 to -23.8] and 25 of 134 eyes [18.7%] in the 2q8/PRN group [adjusted difference, -31.7%; 95% CI, -42.5 to -20.9] compared with 67 of 133 eyes [50.4%] in the control group; P < .001 for both comparisons). No new safety signals were identified.

Conclusions and relevance: In this study, significantly more eyes with moderately severe to severe NPDR that were treated with aflibercept showed a 2-step or greater improvement in DRSS level at 24, 52, and 100 weeks, and significantly fewer eyes treated with aflibercept vs sham developed vision-threatening complications and center-involved DME. Outcomes on the DRSS between year 1 and 2 emphasize the need for ongoing vascular endothelial growth factor suppression and adherence.

Trial registration: ClinicalTrials.gov Identifier: NCT02718326.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Brown reported receiving grants from Regeneron Pharmaceuticals during the conduct of the study and grants from Adverum Biotechnologies, Genentech, Heidelberg Pharma, Kodiak Sciences, Novartis, Regeneron Pharmaceuticals, and REGENXBIO; personal fees from Adverum Biotechnologies, Allergan, Chengdu Kanghong Biotech, Clearside Biomedical, Genentech, Kodiak Sciences, Novartis, Ohr Pharmaceutical, Regeneron Pharmaceuticals, REGENXBIO, Samsung Bioepis, and Santen Pharmaceutical; and consultancy work for Bayer, BioTime, Kodiak Sciences, Optos, and Senju Pharmaceutical outside the submitted work. Dr Wykoff reported receiving grants from Adverum Biotechnologies, Aerie Pharmaceuticals, Aldeyra Therapeutics, Alimera Sciences, Allergan, Apellis Pharmaceuticals, Bayer, Boehringer Ingelheim, Chengdu Kanghong Biotech, Clearside Biomedical, Gemini Therapeutics, Genentech, Graybug Vision, Gyroscope Therapeutics, Ionis Pharmaceuticals, Iveric Bio, Kodiak Sciences, Lowy Medical Research Institute, Mylan Pharmaceuticals, Neurotech Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Opthea, Outlook Therapeutics, Oxurion, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Roche, Samchundang Pharm, Samsung Bioepis, Santen Pharmaceutical, Senju Pharmaceutical, Taiwan Liposome Company, and Xbrane Biopharma; personal fees from Acucela, Adverum Biotechnologies, Aerie Pharmaceuticals, Aerpio Pharmaceuticals, Alcon, Alimera Sciences, Allegro Pharmaceuticals, Allergan, Alnylam Pharmaceuticals, Apellis Pharmaceuticals, Arctic Vision, Arrowhead Pharmaceuticals, Bausch + Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong Biotech, Clearside Biomedical, Corcept Therapeutics, Dutch Ophthalmic Research Center, EyePoint Pharmaceuticals, Genentech, Gyroscope Therapeutics, Iveric Bio, Kato Pharmaceuticals, Kodiak Sciences, Merck & Co, NGM Biopharmaceuticals, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea, Oxurion, Palatin Technologies, PentaVision, PolyPhotonix, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Roche, SAI MedPartners, Santen Pharmaceutical, Takeda Pharmaceutical, Thea Open Innovation, and Verana Health; and other support from ONL Therapeutics, PolyPhotonix, RecensMedical, Regeneron Pharmaceuticals (speaking fees), and Visgenx outside the submitted work. Dr Boyer reported receiving grants from Adverum Biotechnologies, Allergan, Boehringer Ingelheim, Genentech, Graybug Vision, Kodiak Sciences, Novartis, Ophthea, Regeneron Pharmaceuticals, REGENXBIO, and Roche; personal fees from Adverum Biotechnologies, Allegro Pharmaceuticals, Boeringer Ingelheim, Genentech, Regeneron Pharmaceuticals, REGENXBIO, Roche, Santen Pharmaceutical, and Unity Biotechnology; and consulting work for Adverum Biotechnologies, Allergan, Bayer, Boehringer Ingelheim, Genentech, Graybug Vision, Kodiak Sciences, Novartis, Ophthea, Regeneron Pharmaceuticals, and REGENXBIO outside the submitted work. Dr Heier reported receiving grants from Optovue and Regeneron Pharmaceuticals during the conduct of the study and grants from Aerpio Pharmaceuticals, Aldeyra Therapeutics, Apellis Pharmaceuticals, AsclepiX Therapeutics, Bayer, Genentech, Graybug Vision, Gyroscope Therapeutics, Hemera Biosciences, Iveric Bio, Janssen Pharmaceuticals, Chengdu Kanghong Biotech, Kodiak Sciences, NGM Biopharmaceuticals, Notal Vision, Novartis, Regeneron Pharmaceuticals, REGENXBIO, and Stealth BioTherapeutics; personal fees from 4D Molecular Therapeutics, Adverum Biotechnologies, Aerie Pharmaceuticals, Aerpio Pharmaceuticals, Aldeyra Therapeutics, Allegro Pharmaceuticals, Alzheon, Annexon Biosciences, Apellis Pharmaceuticals, Aprea Therapeutics, AsclepiX Therapeutics, Aviceda Therapeutics, Bionic Vision Technologies, Dark Horse Pharmaceuticals, DTx Pharma, Eloxx Pharmaceuticals, Galimedix Therapeutics, Genentech, Graybug Vision, Gyroscope Therapeutics, Iveric Bio, jCyte, Chengdu Kanghong Biotech, LensGen, NGM Biopharmaceuticals, Novartis, Ocular Therapeutix, OcuTerra Therapeutics, Oxurion, Palatin Technologies, Regeneron Pharmaceuticals, REGENXBIO, Stealth BioTherapeutics, Thea Open Innovation, Verseon, Vinci Pharmaceuticals, and Voyant Beauty; and consultancy work for 4D Molecular Therapeutics, Adverum Biotechnologies, Aerie Pharmaceuticals, Aerpio Pharmaceuticals, Aldeyra Therapeutics, Allegro Pharmaceuticals, Alzheon, Annexon Biosciences, Apellis Pharmaceuticals, Aprea Therapeutics, AsclepiX Therapeutics, Aviceda Therapeutics, Beaver-Visitec International, Bionic Vision Technologies, DTx Pharma, Eloxx Pharmaceuticals, Galimedix Therapeutics, Genentech, Graybug Vision, Gyroscope Therapeutics, Horizon Therapeutics, iRenix Medical, Iveric Bio, jCyte, Chengdu Kanghong Biotech, LensGen, NGM Biopharmaceuticals, Notal Vision, Novartis, Ocular Therapeutix, OcuTerra Therapeutics, Oxurion, Palatin Technologies, Regeneron Pharmaceuticals, REGENXBIO, Stealth BioTherapeutics, Thea Open Innovation, Verseon, Vinci Pharmaceuticals, and Voyant Beauty outside the submitted work. Dr Clark reported receiving grants and personal fees from Bayer, Genentech, Kodiak Sciences, and Regeneron Pharmaceuticals during the conduct of the study and grants from Genentech and personal fees from Bayer, Genentech, Cardinal Health, and Regeneron Pharmaceuticals outside the submitted work. Dr Emanuelli reported receiving grants from Aerie Pharmaceuticals, Allegro Pharmaceuticals, Allergan, Diabetic Retinopathy Clinical Research Network, Genentech, ICON, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Kodiak Sciences, Novartis, Opthea, Optos, Regeneron Pharmaceuticals, Santen Pharmaceutical, Senju Pharmaceutical, Sydnexis, and Ribomic during the conduct of the study and personal fees from Aerie Pharmaceuticals, Allegro Pharmaceuticals, Aviceda Therapeutics, Genentech, Kodiak Sciences, Novartis, Regeneron Pharmaceuticals, Santen Pharmaceutical, and EyePoint Pharmaceuticals and participation in a clinical trial funded by Novartis outside the submitted work. Dr Higgins reported serving on the advisory board of Regeneron Pharmaceuticals and participating in clinical trials for Aerpio Pharmaceuticals, Allergan, Apellis Pharmaceuticals, Chengdu Kanghong Biotech, Chiltern, Gemini Therapeutics, Genentech, Graybug Vision, GreenLight Clinical, F. Hoffman-La Roche, Iconic Therapeutics, Ionis Pharmaceuticals, Iveric Bio, Kodiak Sciences, National Institutes of Health, Neurotech Pharmaceuticals, Novartis, Ohr Pharmaceutical, Opthea, OraPharma, Outlook Therapeutics, PanOptica, Regeneron Pharmaceuticals, Samsung Bioepis, Stealth BioTherapeutics, ThromboGenics, Tyrogenex, Xcovery, and XOMA outside the submitted work. Dr Singer reported receiving grants from Aerpio Pharmaceuticals, Allegro Pharmaceuticals, Allergan, Apellis Pharmaceuticals, Genentech, Graybug Vision, Inflammosome Therapeutics, Ionis Pharmaceuticals, Kodiak Sciences, Nanoscope Therapeutics, Novartis, Optos, Regeneron Pharmaceuticals, and Santen Pharmaceutical; serving as a consultant for Aerie Pharmaceuticals, Allergan, Genentech, Guidepoint Global, Novartis, Regeneron Pharmaceuticals, Santen Pharmaceutical, and Spark Therapeutics; and owning equity in Avecida Therapeutics, Inflammosome Therapeutics, and Nanoscope Therapeutics outside the submitted work. Dr Weinreich reported having a patent pending that is licensed to Regeneron Pharmaceuticals and having equity in Regeneron Pharmaceuticals outside the submitted work. Dr Yancopoulos reported having equity in Regeneron Pharmaceuticals outside the submitted work. Dr Berliner reported having a patent pending that is licensed to Regeneron Pharmaceuticals and having equity in Regeneron Pharmaceuticals outside the submitted work. Ms Chu reported having a patent pending that is licensed to Regeneron Pharmaceuticals and having equity in Regeneron Pharmaceuticals outside the submitted work. Dr Reed reported having equity in Regeneron Pharmaceuticals outside the submitted work. Dr Cheng reported having equity in Regeneron Pharmaceuticals outside the submitted work. Dr Vitti reported having equity in Regeneron Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Design

One eye was assessed per participant. Aflibercept 2q16 group: intravitreal injection of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval. Aflibercept 2q8/PRN group: intravitreal injection of aflibercept, 2 mg every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56. DRSS indicates Diabetic Retinopathy Severity Scale; NPDR, nonproliferative diabetic retinopathy; and PRN, pro re nata.

Figure 2.. Proportion of Eyes With a 2-Step or Greater Improvement on Diabetic Retinopathy Severity Scale From Baseline Through Week 100

Eyes in the aflibercept 2q16 group (n = 135) received intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval; eyes in the aflibercept 2q8/PRN group (n = 134) received intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56; and eyes in the control group (n = 133) received sham injections. The full analysis set was analyzed using the last observation carried forward method. At week 52, P < .001 for aflibercept 2q16 vs sham (65.2% vs 15.0%) and aflibercept 2q8/PRN vs sham. At week 100, P values for aflibercept 2q16 vs sham and aflibercept 2q8/PRN vs sham were nominal.

Figure 3.. Analysis of Events Indicative of Diabetic Retinopathy Progression

Eyes in the aflibercept 2q16 group (n = 135) received intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval; eyes in the aflibercept 2q8/PRN group (n = 134) received intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56; and eyes in the control group (n = 133) received sham injections. A, Proportion of eyes that developed VTCs and/or CI-DME through weeks 52 and 100. At week 52, P < .001 for aflibercept 2q16 vs sham (9.6% vs 40.6%) and aflibercept 2q8/PRN vs sham (11.2% vs 40.6%) in eyes that developed VTCs and/or CI-DME, aflibercept 2q16 vs sham (3.7% vs 20.3%) and aflibercept 2q8/PRN vs sham (3.0% vs 20.3%) in eyes that developed VTCs, and aflibercept 2q16 vs sham (6.7% vs 25.6%) and aflibercept 2q8/PRN vs sham (8.2% vs 25.6%) in eyes that developed CI-DME. At week 100, nominal P < .001 for aflibercept 2q16 vs sham (16.3% vs 50.4%) and aflibercept 2q8/PRN vs sham (18.7% vs 50.4%) in eyes that developed VTCs and/or CI-DME, aflibercept 2q16 vs sham (8.1% vs 27.1%) and aflibercept 2q8/PRN vs sham (6.0% vs 27.1%) in eyes that developed VTCs, and aflibercept 2q16 vs sham (10.4% vs 33.1%) and aflibercept 2q8/PRN vs sham (13.4% vs 33.1%) in eyes that developed CI-DME. B, Event rates among eyes that developed VTCs and/or CI-DME through weeks 52 and 100. At week 52, P < .001 for aflibercept 2q16 vs sham (10.1% vs 41.8%) and aflibercept 2q8/PRN vs sham (10.8% vs 41.8%) in eyes that developed VTCs and/or CI-DME, aflibercept 2q16 vs sham (4.0% vs 20.1%) and aflibercept 2q8/PRN vs sham (2.4% vs 20.1%) in eyes that developed VTCs, and aflibercept 2q16 vs sham (7.0% vs 27.6%) and aflibercept 2q8/PRN vs sham (8.5% vs 27.6%) in eyes that developed CI-DME. At week 100, nominal P < .001 for aflibercept 2q16 vs sham (17.9% vs 57.7%) and aflibercept 2q8/PRN vs sham (20.5% vs 57.7%) in eyes that developed VTCs and/or CI-DME, aflibercept 2q16 vs sham (9.1% vs 30.6%) and aflibercept 2q8/PRN vs sham (6.9% vs 30.6%) in eyes that developed VTCs, and aflibercept 2q16 vs sham (11.3% vs 38.4%) and aflibercept 2q8/PRN vs sham (14.4% vs 38.4%) in eyes that developed CI-DME. CI-DME indicates center-involved diabetic macular edema (diagnosed by the investigator); NA, not applicable; and VTC, vision-threatening complication (including proliferative diabetic retinopathy and/or anterior segment neovascularization diagnosed by the investigator and/or the reading center).

Figure 4.. Cumulative Incidence of Events Indicative of Diabetic Retinopathy Progression

Eyes in the aflibercept 2q16 group (n = 135) received intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval; eyes in the aflibercept 2q8/PRN group (n = 134) received intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56; and eyes in the control group (n = 133) received sham injections. A, VTCs through week 100. The cumulative event rate at week 100 was 9.1% in the aflibercept 2q16 group (hazard ratio [HR], 0.23; P < .001) and 6.9% in the aflibercept 2q8/PRN group (HR, 0.17; P < .001) compared with 30.6% in the control group. B, CI-DME through week 100. The cumulative event rate at week 100 was 11.3% in the aflibercept 2q16 group (HR, 0.24; P < .001) and 14.4% in the aflibercept 2q8/PRN group (HR, 0.32; P < .001) compared with 38.4% in the control group. CI-DME indicates center-involved diabetic macular edema (diagnosed by the investigator); VTC, vision-threatening complication (including proliferative diabetic retinopathy and/or anterior segment neovascularization diagnosed by the investigator and/or the reading center).