NIH-Sponsored Trial Finds Eylea Reduced Vision-Threatening Complications by 68% After 2 Years in DR Patients

Regeneron Pharmaceuticals announced that JAMA Ophthalmology has published initial results from the National Institutes of Health-sponsored Protocol W trial assessing Eylea (aflibercept) injection in patients with moderate to severe non-proliferative diabetic retinopathy (NPDR), without center-involved diabetic macular edema (CI-DME). At 2 years, the primary outcome of the trial showed a 68% reduced risk of developing vision-threatening complications (either proliferative diabetic retinopathy [PDR] or CI-DME with vision loss) in patients who received the Eylea every-16-weeks dosing regimen. In comparison, patients receiving sham injections were almost five times more likely to experience disease progression requiring Eylea rescue therapy.

Although at the 2-year time point of Protocol W, preventive Eylea treatment did not confer a significant difference in visual acuity versus delayed Eylea treatment following vision-threatening complications (i.e., sham), a recent Regeneron follow-up analysis in the similarly designed PANORAMA trial found that delaying Eylea treatment resulted in three times as many patients suffering prolonged vision loss, compared to those receiving preventive Eylea treatment, during a 2-year period. A similar analysis has not yet been conducted for Protocol W.

“Blindness is one of the most feared consequences of diabetic retinopathy, and we thank the National Eye Institute and the DRCR Retina Network for conducting a well-controlled trial that provides useful information to guide treatment in these patients,” George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer at Regeneron, said in a company news release. “Protocol W confirms the landmark results of the similarly-designed PANORAMA trial, underscoring the importance of early and regular diabetic retinopathy treatment and the ability of Eylea to substantially reduce vision-threatening complications and improve disease severity. Importantly, these results were obtained with an every-16-weeks Eylea dosing regimen, confirming the efficacy with Eylea seen in the PANORAMA trial.”

In Protocol W, patients were randomly assigned to receive either Eylea (2 mg, n=200 eyes) every 16 weeks, after receiving four initial doses at weeks 0, 4, 8 and 16, or sham (n=199 eyes). Patients had excellent vision when they entered the trial, with more than three-quarters of eyes having 20/20 visual acuity or better (78% Eylea, 81% sham). Rescue therapy (primarily Eylea) was administered to patients if they developed either PDR or CI-DME.

Compared to sham, Eylea-treated patients were:

• 68% less likely to develop CI-DME with vision loss or PDR, the primary outcome measure at 2 years (P<0.001).
  • The cumulative probability of developing PDR or CI-DME with vision loss was 16% with Eylea versus 44% with sham. Eylea patients were 66% less likely to develop PDR (P<0.001) and 64% less likely to develop CI-DME with vision loss (P=0.002).
• Three times more likely to experience at least a two-step improvement in their DR severity score (DRSS). In total, 69 (45%) Eylea patients experienced at least a two-step improvement, versus 22 (14%) of those in the sham group (adjusted odds ratio [OR]: 5.91; P<0.001).
• Five times less likely to require rescue therapy with Eylea due to PDR or DME (4% Eylea, 19% sham). Other rescue treatments were panretinal photocoagulation (PRP) (<1% Eylea, 2% sham), vitrectomy for PDR (<1% Eylea, <1% sham) and focal/grid laser treatment for DME (0% Eylea, 2% sham).

In the retrospective PANORAMA analysis of vision outcomes over 2 years, three times more patients in the sham group suffered from prolonged vision loss (range: 6 weeks to 6 months), compared to the Eylea every-16-weeks dosing group (12 of 135 EYLEA, 38 of 133 sham). Results by loss of letters were as follows (as measured by the Early Treatment Diabetic Retinopathy Study [ETDRS] chart):

• ≥5 letter loss: 9% Eylea versus 29% sham, nominal p<0.0001.
• ≥10 letter loss: 5% Eylea versus 14% sham, nominal p=0.0212.
• ≥15 letter loss: 3% Eylea versus 8% sham, nominal p=0.0672.

No new safety signals were identified in Protocol W, consistent with the known safety profile of Eylea. Ocular adverse events (AEs) included endophthalmitis (n=3 Eylea, n=0 sham). The rate of any cardiovascular/cerebrovascular AEs was not significantly different among the treatment groups (9% of patients treated with Eylea in one eye, 9% of patients treated with sham in one eye, and 8% of patients treated with both Eylea [one eye] and sham [other eye]).

“Diabetic retinopathy is the leading cause of blindness among working adults. However, vision loss is often preventable if proactive measures are taken by patients and their doctors,” Allen C. Ho, MD, Attending Surgeon and Director of Retina Research at Wills Eye Hospital in Philadelphia, said in the news release. “Past trials have shown that early systemic and ocular intervention in diabetic eye disease can lead to sustained improvements in visual acuity over the long term, while undertreatment can put patients’ vision at risk. The latest data from Protocol W and PANORAMA support this treatment philosophy by showing that an every-16-week Eylea regimen helped patients avoid vision-threatening complications and prolonged periods of vision loss over 2 years. I look forward to seeing additional Protocol W vision outcomes at 4 years.”

Eylea is the only vascular endothelial growth factor (VEGF) inhibitor that is FDA approved with two dosing intervals for DR, allowing doctors to customize treatment. In DR, Eylea may be dosed every 8 weeks following five initial monthly injections, or every 4 weeks. Eylea is not approved for 16-week dosing as was studied in Protocol W.

About Protocol W

Protocol W is a 4-year, randomized, multicenter, controlled phase 3 trial (n=399 eyes) designed to determine the efficacy of Eylea compared to sham in preventing vision-threatening complications in high risk patients. The primary outcome at 2 years was time to development of CI-DME with vision loss or PDR. Key secondary outcomes included development of any PDR or DME criteria based on reading center assessment, as well as development of CI-DME with a ≥10% and ≥25 micron increase in center subfield thickness. Per the trial protocol, Protocol W will continue for another 2 years, when the second primary outcome will assess visual acuity outcomes between the two groups at 4 years.

The Clinicaltrials.gov identifier for this trial is NCT02634333. The trial was supported by the National Eye Institute (NEI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), with funding through the Special Diabetes Program, through a cooperative agreement (EY14231).