Anti-VEGF Therapy vs Gold Standard in Preterm Babies With ROP: Dr Darius Moshfeghi

The BUTTERFLEYE trial sought to determine if aflibercept, an anti–vascular endothelial growth factor (anti-VEGF) therapy, was equivalent to laser photocoagulation, the gold standard to treat retinopathy of prematurity (ROP) in preterm babies.

Laser photocoagulation is the current gold standard to treat preterm babies with retinopathy of prematurity (ROP), but anti–vascular endothelial growth factor (anti-VEGF) therapy is as effective, safer, and much faster to perform, explained Darius M. Moshfeghi, MD, chief, Retina Division, and professor at the Horngren Family Vitreoretinal Center, Byers Eye Institute, Department of Ophthalmology, Stanford University School of Medicine.

During an interview with The American Journal of Managed Care® (AJMC®), Moshfeghi discussed the results of the BUTTERFLEYE trial and early identification of progressive disease that requires treatment.

Editor’s note: after this interview, the FDA approved aflibercept injection as the first pharmacologic treatment for preterm infants with ROP.1

AJMC®: You presented results on the phase 3 BUTTERFLEYE trial—can you just explain what the study was evaluating and the primary results of it?

Moshfeghi: In the BUTTERFLEYE trial, we were comparing to 0.4 milligrams of intravitreal aflibercept, which is an anti-VEGF agent, to laser photocoagulation for the outcome of noninferiority when compared to laser at the number of patients that would go on to adverse anatomic outcomes and active ROP. Basically, we're trying to say: is aflibercept at least the equivalent of laser, which is the gold standard therapy when treating ROP in small babies?

The outcome was active disease after the primary end point, which was at 52 weeks chronologic age and active bad outcomes, such as retinal detachment or retrolental mass or something like that.

AJMC®: Is aflibercept less invasive than laser, which is the gold standard? Is it safer than the laser option?

Moshfeghi: It's an interesting question. Laser requires some infrastructure investment. The laser may run you anywhere from $20,000 to $50,000. It's typically done in the operating room; typically done under general anesthesia. These are small babies with short gestation. They're very sick. The baby that requires treatment for ROP typically has much more morbidity and higher risk for mortality than an infant that doesn't require treatment for ROP. They're a higher risk infant for going to the operating room and placing them under general anesthesia. On top of which the laser procedure itself is a procedure that requires a lot of skill, and typically requires years of training to get good at.

When we compare that to intravitreal injections, they require very minimal infrastructure. You can have the syringe and needle, some topical antibiotics and topical antiseptic solution. Typically, they're done with topical anesthesia at the bedside: no sedation, no general anesthesia. You're basically limited by access to the drug. They do require a little bit of training; it's not easy to do on a small, awake infant that is very understandably concerned that you're going to stick them in the eye with a needle.

AJMC®: There are cases of ROP that are mild and can get better without treatment and then there are cases that are progressive and definitely need treatment. How easy is it to distinguish one from the other and to distinguish that early on so that you start intervening early?

Moshfeghi: That's a fundamental question of screening. The joint statement screening guidelines, which are promulgated by the American Academy of Pediatrics and the American Academy of Ophthalmology, have looked at natural history studies of treatments going back 40 years and 30 years now. We can no longer ethically do natural history arms because we have efficacious treatments. But we know that babies at highest risk are those born prior to 30 weeks’ gestation and those at 1500 grams and below at birth. We know when they are going to start developing disease at 31 weeks postmenstrual age or 3 weeks chronological age, whichever is later. We know the type of disease that is going to require treatment.

Currently, we're going off of the early treatment, retinopathy of prematurity type 1, which is zone I with stage 3 ROP or zone I with plus disease or zone I or II with stage 2 or 3 with plus disease. And then finally, there's a fourth category called aggressive retinopathy of prematurity. During our study BUTTERFLEYE and its sister study, FIREFLEYE,2 we were using aggressive posterior ROP, but it's basically a disease characterized by lack of linear progression, or longitudinal progression through stage 1, stage 2, stage 3. It can go from no disease, and it's characterized by very posterior locations—zone I or posterior zone II—and a lot of vascular activity—squiggly blood vessels, fat blood vessels, that we call dilated and torturous blood vessels. Those are the hallmarks: posterior disease and vascular activity.

Those are the 4 treatment indications today. We typically know when they occur. There's a couple of peaks right around 34 weeks for aggressive ROP; right around 37 weeks for type 1 disease. When we're looking at these children, if we see an orderly progression, we know it's more of a traditional type of ROP, so it's going to be more of a type 1 disease. If we see kind of an amorphous posterior disease characterized by highly vascular appearing changes in the eye we know it's going be more of an aggressive ROP. Aggressive ROP is a poor candidate for laser. Anything in zone I is a poor candidate for laser. Historically. as retinal specialists over the last decade, and pediatric retinal specialists in particular, we've been gravitating towards anti-VEGF therapy for those groups.

In order to answer that question, the studies came out—RAINBOW,3 BEAT-ROP,4 and the FIREFLEYE and BUTTERFLEYE trials—to answer the question: is anti-VEGF therapy essentially noninferior to laser?

In this study here, we showed that laser had a smaller success rate—77.8% compared to anti-VEGF therapy with 79.6%. However, the anti-VEGF therapy did not meet its statistical level of noninferiority. That doesn't mean that it wasn't successful from a clinical viewpoint. It absolutely was. When we look at safety: the safety profile was in favor of the anti-VEGF versus the laser group. When we look at the primary outcome of anatomic outcome, which is retinal detachment, there were fewer retinal detachments—6.4% vs 7.6% in the laser group.

When we look at the amount of treatment time, the treatment was 10.7 minutes in the anti-VEGF group for both eyes versus 129 minutes in the laser group. On all the metrics, the anti-VEGF group showed a clinically equivalent response, even though it didn't meet, it's statistically prespecified noninferiority outcome. And on safety it was safer.


1. Eylea (aflibercept) injection approved as the first pharmacologic treatment for preterm infants with retinopathy of prematurity (ROP) by the FDA. Regeneron. New release. February 9, 2023.

2. Stahl A, Sukgen EA, Wu W-C, et al. Effect of intravitreal aflibercept vs laser photocoagulation on treatment success of retinopathy of prematurity: the FIREFLEYE randomized clinical trial. JAMA. 2022;328(4):348-359. doi:10.1001/jama.2022.10564

3. Cohen S-Y, Dominguez M, Coscas F, et al; RAINBOW study investigators. Final 4-year results of the RAINBOW real-world study: intravitreal aflibercept dosing regimens in France in treatment-naïve patients with neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. Published online November 18, 2022. doi:10.1007/s00417-022-05900-6

4. Mintz-Hittner HA, Kennedy KA, Zhuang AZ; for the BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615. doi:10.1056/NEJMoa1007374

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