Anti-VEGFs can improve DRSS in majority of patients


Using a specific anti-vascular endothelial growth factor (VEGF) drug in patients with moderately severe to severe nonproliferative diabetic retinopathy (NPDR) can result in a ≥2-step improvement in diabetic retinopathy severity scores (DRSS) in almost 60% of those treated, according to results of the PANORAMA study presented during this year’s American Society of Retina Specialists meeting.

These study results add to the ever-growing body of evidence that suggest anti-VEGF injections can lead to “robust” improvements in DR, said Charles C. Wykoff, MD, PhD, Houston. In fact, the 2018 PAT Survey 1 found intravitreal anti-VEGF agents are the overwhelming first choice by retinal specialists for treating diabetic eye diseases.

In the early 1990s, the Early Treatment of Diabetic Retinopathy Study standardized how to quantify and qualify NPDR and created a threshold for its treatment, Dr. Wykoff said.

“That standardization allowed different researchers and clinicians to begin to speak the same language about DR but maybe even more importantly, the designation of an eye within this quantitative scale has proven to be predictive of DR progression itself,” he said.

Greater DR scores confer a greater chance of converting to PDR, he added. Higher scores are also associated with decreased vision-related quality of life measures, he said, making earlier intervention a key component to consider in management.

“Patients with center-involved diabetic macular edema (DME) with visual acuity loss warrant intervention,” he told attendees. “Those with high-risk PDR warrant intervention as well.” But other scenarios are not as clear-cut including patients with non-center involved DME and those with center-involved DME but without specific visual acuity loss.

“But what about nonproliferative disease?” he said. “There is little data available to guide discussion on when to treat these patients and how often.”

To that end, Dr. Wykoff and colleagues wanted to evaluate “the efficacy and safety of intravitreal aflibercept injection for treatment of moderately severe to severe NPDR in eyes that had not yet developed DME.”

Study Details

The PANORAMA trial2 is a phase 3, double-masked, randomized study with a primary outcome at week 24 of the proportion of patients who improved by at least 2 steps on the DRSS ( Identifier: NCT02718326).
The study enrolled 402 patients with NPDR without DME and a DRSS score of 47 or 53. Patients were randomized to two dosing schedules of intravitreal aflibercept (2 mg every 8 weeks or every 16 weeks) or to sham injection. The primary endpoint was the proportion of patients with a ≥ 2-step improvement in DRSS score from baseline to 24 weeks. The two aflibercept groups were combined for the primary outcome analysis.

Baseline demographics were similar among the three groups, with a mean age of 56, mean A1c of 8.5%, and mean diabetes duration of 14 years. Baseline vision averaged between 82 and 83 letters, and the mean central retinal thickness was 246-249 µm. At week 24, 61.5% of those in the 8-week aflibercept group (83/135) and 55.2% in the 16-week aflibercept group (74/134) had a ≥ 2-step improvement from baseline in DRSS, compared to 6% in the sham group (8/133).

Almost 10% of the aflibercept-treated eyes had a ≥3-step improvement in DRSS scores compared to <1% of the sham group. Vision improved slightly in the aflibercept groups, with each gaining 1.9 letters compared to the sham group, which gained 0.4 letters. Central retinal thickness improvements also were statistically significant greater for aflibercept, with the pooled group improving by -19.4 µm compared to the sham group, which increased in thickness by 4.7 µm. About 25% of the sham group developed vision-threatening complications, including PDR/anterior segment neovascularization (13.5%) or center-involving DME (14.4%). The pooled aflibercept groups had a cumulative rate of vision-threatening complications of 4.5%.

Otherwise, there were no new safety signals, Dr. Wykoff said.

Other studies

Other anti-VEGFs have also demonstrated efficacy towards DR severity improvement. A post hoc analysis of the RIDE and RISE studies (n=468) found “further support that improvement in DRSS is a clinically important outcome that should be evaluated as a measure of treatment effectiveness in future studies of diabetic eye disease.”3 Similarly, treatment with intravitreal ranibizumab can improve DRSS by 2 steps at year 2 in 37% of patients treated and in up to 39% of patients treated in year 3. 4, 5

Treatment with aflibercept has shown a ≥ 2-step or more improvement in DRSS (29.3%-37.1%) in patients with confirmed DME at 100 weeks in another study.6 While the decision to treat these patients should remain individualized, “the PANORAMA study has provided excellent data to guide the discussion,” Dr. Wykoff said.


Dr. Wykoff is a consultant for Allergan, Alimera, Bayer, Clearside, DORC, Genentech, ONL Therapeutics, and Regeneron.


1. American Society of Retina Specialists, Stone TW. ASRS 2018 Preferences and Trends Membership Survey. Chicago, IL, 2018;  American Society of Retina Specialists.

2. Wykoff C, PANORAMA Investigators. Intravitreal Aflibercept for Moderately Severe to Severe Non-Proliferative Diabetic Retinopathy (NPDR): The Phase 3 PANORAMA Study. Paper presented at: American Society of Retina Specialists. Vancouver, B.C. Paper presented on July 24,, 2018.

3. Ip MS, Zhang J, Ehrlich JS. The Clinical Importance of Changes in Diabetic Retinopathy Severity Score. Ophthalmology 2017;124(5):596-603.

4. Ip MS, Domalpally A, Hopkins JJ, et al. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 2012;130(9):1145-52.

5. Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology 2015;122(2):367-74.

6. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology 2015;122(10):2044-52.

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