Aflibercept to treat ROP in extremely-low-birth-weight children

A new study¹ from Poland published in the Journal of Clinical Medicine found that following treatment with aflibercept (Eylea, Regeneron Pharmaceuticals), the retinopathy of prematurity (ROP) initially regressed in all cases. After treatment over the course of 2 to 7 weeks, the ROP reactivated in 45% of cases as ROP type 2.

The authors, led by first author Maria Szwajkowska, MD, theorized that the extremely low birth weights and the complications arising from the low birth weights may have influenced the ROP reactivation and complications. She is from the Department of Head and Neck Surgery for Children and Adolescents, University of Warmia and Mazury, and Prof. Stanislaw Popowski Regional Specialized Children’s Hospital, both in Olsztyn, Poland.

She was joined in this study by Beata Jaroszewska-Świątek, MD, PhD, from Prof. Stanislaw Popowski Regional Specialized Children’s Hospital and the Department of Clinical Pathology and Birth Defects in Newborns and Infants, University of Warmia and Mazury, both in Olsztyn, Poland; and Małgorzata Woś, MD, from the Ophthalmology Department with a Children’s Unit, S. Żeromski Specialist Hospital, Krakow, Poland.

While laser applied to the avascular peripheral retina remains the gold standard treatment for ROP worldwide, anti-vascular endothelial growth factor (VEGF) drugs have been receiving more attention for ROP treatment in Poland and worldwide. Bevacizumab (Avastin, Genentech and Roche) and ranibizumab (Lucentis, Genentech and Roche) have been used the most, the authors explained, but aflibercept is being used more and more.

“Unlike bevacizumab (full-length antibody) and ranibizumab (fragment of an antibody (Fab)), aflibercept is a recombinant fusion protein composed of the human VEGFR-1 and VEGFR-2 domains fused to the Fc part of human IgG. After intravitreal administration, aflibercept is slowly absorbed from the vitreous into the circulatory system and is present in the systemic circulation, mainly in the form of an inactive, stable complex with VEGF, while only “free aflibercept” can bind to endogenous VEGF. Within 1 to 3 days after intravitreal injection of 2 mg of the drug (adult dose), free aflibercept plasma concentrations decrease to the limit of quantification. The elimination time from the vitreous body is approximately 7 days, and the maximum plasma concentration occurs 1–3 days after injection. Free aflibercept is detected in peripheral blood up to 4 weeks after intravitreal injection,^2,3” Szwajkowska and colleagues explained.

A caveat regarding the use of aflibercept in children is consideration of the drug’s effects on organ development in these children in that VEGF is involved in the normal development of the kidney, lungs, and brain.

Methodology of the aflibercept study

The study included both eyes of 11 children with extremely low birth weights (average 677 grams; range, 460-940 grams) and type 1 ROP and A-ROP (aggressive ROP). Children were treated between 32 and 38 weeks of postconceptional age (on average at 33.3 weeks). The investigators administered 1 mg (0.025 mL) of aflibercept intravitreally to each eye of the babies under local anesthesia.

What effect did aflibercept have on ROP?

The authors reported, “In all cases, there was complete regression of ROP, and retinal vascularization was observed up to the end of zone III or up to the border of laser therapy. Between 2 and 7 weeks after treatment, the disease reactivated in five children (45%) in the form of ROP type 2, and these children underwent retinal laser photocoagulation.”

A cataract developed in 1 child, and no complications developed in the other 10 children after the injections and laser. The child with the cataract underwent a lensectomy.

The authors discussed their findings. “In this study, the treated children were characterized by extremely low birth weight, and, as a result, numerous complications related to prematurity occurred, such as bronchopulmonary dysplasia, sepsis, anemia, heart defects, and others. Many of them were in the intensive care unit. These factors may influence ROP reactivation and complications.”

They mentioned previous studies in which the same dose of 1 mg was used; of seven studies listed, 5 had very high rates of ROP regression.^4-8 However, the birth weights of the children in these studies varied. The ROP regression rates in the 5 studies were low.

Currently, a 0.4-mg dose is being studied.

They concluded, “Studies on aflibercept obviously require further observations, so all reports, even from small groups, are important.”

References

1. Szwajkowska M, Jaroszewska-Świątek B, Woś M. Use of aflibercept to treat retinopathy of prematurity in children with extremely low birth weight. J Clin Med. 2026;15:1912; https://doi.org/10.3390/jcm15051912

2. Hartnett ME, Stahl A. Laser versus anti-VEGF: a paradigm shift for treatment-warranted retinopathy of prematurity. Ophthalmol Ther. 2023;12:2241–52.

3. Stahl A, Sukgen EA, Wu WC, et al. Effect of intravitreal aflibercept vs laser photocoagulation on treatment success of retinopathy of prematurity: the FIREFLEYE Randomized Clinical Trial. JAMA. 2022;26:348–59.

4. Salman AG, Said AM. Structural, visual and refractive outcomes of intravitreal aflibercept injection in high-risk prethreshold type 1 retinopathy of prematurity. Ophthalmic Res. 2015;53:15–20.

5. Sukgen EA, Söker G, Koçluk Y, Gulek B. Effect of intravitreal aflibercept on central retinal arterial blood flow in type 1 retinopathy of prematurity. Eur J. Ophthalmol. 2017;8: 751–5.

6. Huang CY, Lien R, Wang NK, et al. Changes in systemic vascular andothelial growth factor levels after intravitreal injection of aflibercept in infants with retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2018;256:479–87.

7. Vural A, Perente I, Onur I, et al. Efficacy of intravitreal aflibercept monotherapy in retinopathy of prematurity evaluated by periodic fluorescence angiography and optical coherence tomography. Int Ophthalmol. 2019;39: 2161–9.

8. Sukgen EA, Koçluk Y. Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity. Comparative study. Graefes Arch Clin Exp Ophothalmol. 2019;257: 49–55.