NEJM Study: Aflibercept Offers Benefits Over Rivals for DME if Vision Loss Is Worse at Outset

August 5, 2015
Mary K. Caffrey

Evidence-Based Diabetes Management, July 2015, Volume 21, Issue SP11

The study evaluated the 3 new anti-VEGF agents for treatment of a condition that frequently occurs in patients who suffer from diabetes mellitus.

About 750,000 people in the United States are affected by diabetic macular edema (DME).1 This results from diabetic retinopathy (DR), in which damage to the blood vessels in the retina progresses to the point where fluid leaks from the macula, the central area of the retina. Vision is clouded and it becomes impossible to focus.2

Until recently, laser treatments were the only available standard of care, and they are still part of the care regimen. Starting in 2012, however, the FDA approved injections of vascular endothelial growth factor (VEGF) inhibitors,3 which were first approved in 2006 for age-related macular degeneration.4 This new class of therapy proved more effective than laser treatments, and by 2013 a survey of US retina specialists found that 90% were using anti-VEGF agents for the initial treatment of vision loss from DME.5

Within weeks of the first approval of a VEGF inhibitor for treatment of DME, the Diabetic Retinopathy Clinical Research Network began a randomized clinical trial, sponsored by the National Institutes of Health, to compare 3 commonly used intravitreous VEGF inhibitors: aflibercept, marketed as Eylea; ranibizumab, marketed as Lucentis; and bevacizumab, marketed as Avastin. Only aflibercept and ranibizumab have FDA approval for treatment of DME. The trial ran from August 22, 2012, to August 28, 2013, and results were published online March 26, 2015, in the New England Journal of Medicine.1

Researchers, studying 660 adult patients at 89 sites, found that all 3 VEGF inhibitors improved vision in eyes with center-involved DME, but the relative effect depended on visual acuity at base-line. When vision loss was mild at the outset, there were no apparent differences among the 3 drugs. However, for those patients with more impaired vision at the start of the study, aflibercept was more effective at improving vision, the study found.


Study participants had either type 1 or type 2 diabetes mellitus (T2DM), with 90% having T2DM. The mean duration of their diabetes was 17 years ±11 years. The mean age of the participants was 61 years ±10 years, 47% were women, and 65% were white. Each had at least 1 eye affected by DME, with the mean baseline visual acuity letter score of 64.8 ±11.3 at baseline on a scale of 0 to 100, with higher scores indicating better acuity. This would translate to an equivalent of 20/50. Baseline characteristics were similar in the 3 groups.

Patients were randomly assigned to 1 of the 3 groups: 224 received aflibercept at a dose of 2.0 mg, 218 received a dose of bevacizumab at 1.25 mg, and 218 received a dose of ranibizumab at 0.3 mg. Doses were administered according to individual protocols, as often as every 4 weeks. A subset of patients required laser photocoagulation at 24 or 48 weeks, based on measurements of visual acuity and central subfield thickness. The primary end point was measurement of the mean visual acuity letter score at 1 year. With deaths excluded, the overall completion rate to the 1-year visit was 96%.


During the year, laser treatments were necessary at least once between 24 and 48 weeks for 76 of the 208 aflibercept-treated eyes (37%), 115 of the 206 bevacizumab-treated eyes (56%), and 95 of the 206 ranibizumab-treated eyes (46%).

When initial visual acuity was 20/32 to 20/40, the median number of injections was 9 in each group, with 36% in the aflibercept-treated eyes, 47% in the bevacizumab-treated eyes, and 43% in the ranibizumab-treated eyes receiving photocoagulation therapy. When initial visual acuity was 20/50 or worse, median injections were 10 for those treated with aflibercept, 11 for the bevacizumab group, and 10 for the ranibizumab group. Photocoagulation therapy was necessary for 37%, 65%, and 50% of the treated eyes, respectively.

Vision improved more after a year for those treated with aflibercept than with the other 2 therapies. Those treated with aflibercept improved their scores by 13.3 on average, compared with 9.7 for bevacizumab and 11.2 for ranibizumab. However, when initial visual acuity scores were higher, equivalent to 20/40 vision or better, the mean improvement scores were within a point for all 3 drugs (8.0, 7.5, and 8.3). When initial visual acuity scores were below 69, or the equivalent of 20/50, the mean improvement scores grew farther apart:

• 18.9 ±11.5 for aflibercept

• 11.8 ±12.0 for bevacizumab

• 14.2 ±10.6 for ranibizumab

Results showed all 3 therapies produced improvement by 4 weeks; for those with the worst initial vision, the benefits of aflibercept became apparent early on. The 1-year visit also showed that all 3 therapies reduced central subfield thickness, with the benefits varying based on initial thickness.

All 3 groups had similar rates of adverse events (AEs). The rate of death from any cause was 1% in the aflibercept group, 2% in the bevacizumab group, and 2% in the ranibizumab group. Vascular event rates were 3%, 4%, and 5%, respectively; an analysis found more participants in the ranibizumab group reported AEs when the Medical Dictionary for Regulatory Activities system of organ classes of cardiac and vascular disorders were combined. Researchers wrote that this may be due to chance.


The price of VEGF inhibitors used in the treatment of ocular conditions has raised eyebrows for years. Ranibizumab’s full price listed at $1950 when it hit the market in 2006,6 which is the price researchers list for aflibercept in their study.1 A recent cost and safety analysis by Adverse Events, Inc, listed the per prescription price of aflibercept at $1471.56 and ranibizumab at $1408.71 for several indications, including diabetic retinopathy.7 In an interview with Evidence-Based Diabetes Management, Robert Kyle, chief product officer for Adverse Events, said the pricing information is based on averages from 2014.

Bevacizumab, approved as a cancer drug, is not indicated for any eye condition but has been widely used off-label in repackaged doses, which are a fraction of the size used in cancer care. At $50 per dose, it’s also a fraction of the cost of the FDA-approved rivals.6,8 Because bevacizumab and ranibizumab are both made by Genentech—the Washington Post called them “biological cousins”—there has been controversy dating back to 2006 regarding why eye patients are being sold a much more expensive drug, with much of the tab going to Medicare.6,8

However, the results of the NEJM study indicate that while the off-label formulation produced some vision improvement for DME patients, it was not as effective for patients who began treatment at greater levels of vision loss.


On April 21, 2015, Adverse Events, Inc, which evaluates safety data of new drugs for payers, issued a report to clients, “Cost Comparison and Safety Analysis of Eylea vs Lucentis for Diabetic Retinopathy.”7 The report actually covered multiple indications, including DR, DME, retinal vein occlusion, and wet macular degeneration. The report concluded, “Eylea (aflibercept) appears to be a safer alternative to [the] existing DR drug Lucentis (ranibizumab).”

Adverse Events based its assessment on a number of factors, including the fact that ranibizumab was associated with a higher downstream cost per prescription of $25.19 versus $8.87 for aflibercept. The report noted that aflibercept was less likely to be associated with AEs, based on the firm’s analysis of records to the FDA’s Adverse Event Reporting System.7 In the interview with EBDM, Kyle said ranibizumab was more frequently associated with cardiovascular events and hospitalizations.

While aflibercept may have a higher cost per prescription, Kyle explained, its treatment course differs from ranibizumab’s. Both drugs require injections every 4 weeks for the first 5 cycles, but then aflibercept requires injections every 8 weeks. Adverse Events’ report listed the annual cost of aflibercept at $7,694,584, compared with $26,739,226 for ranibizumab.7 References

1. The Diabetic Retinopathy Clinical Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema [published online March 26, 2015]. N Engl J Med. doi:10.1056/NEJMoa1414264.

2. Facts about diabetic eye disease. National Eye Institute website. health/diabetic/retinopathy. Updated June 2012. Accessed April 20, 2015.

3. FDA approves Lucentis to treat diabetic macular edema [press release]. Silver Spring, MD: FDA Newsroom; April 10, 2012.

4. FDA approves new biologic treatment for wet age-related macular degeneration [press release]. PressAnnouncements/2006/ucm108685.htm. Silver Spring, MD: FDA Newsroom; June 30, 2006.

5. American Society of Retina Specialists Preference and Trends (PAT) Survey 2013. Accessed April 23, 2015.

6.Steinbrook R. The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006;355:1409-1412.

7. Adverse Events, Inc. Cost comparison and safety analysis of Eylea vs Lucentis for diabetic retinopathy. Published and accessed April 21, 2015.

8. Whoriskey P, Keating D. An effective eye drug is available for $50, but many doctors choose a $2000 alternative. Washington Post website. economy/an-effective-eye-drug-is-available-for-50-but-many-doctors-choose-a-2000-alternative/2013/12/07/1a96628e-55e7-11e3-8304-caf30787c0a9_story.html. Published December 7, 2013. Accessed April 20, 2015.