Retinopathy of prematurity (ROP) is a condition that affects premature infants born before the completion of normal retinal vascularization. Exposure to high levels of oxygen, fluctuations in oxygenation, and poor postnatal growth can lead to abnormal completion of retinal vascularization. This can lead to aberrant neovascularization and its consequences. 

In 1986, the CRYO-ROP study demonstrated that cryotherapy was a safe and effective therapy for threshold disease.¹ Today, the current standard for type 1 ROP is laser photocoagulation of the peripheral avascular retina, based on the Early Treatment of Retinopathy of Prematurity Study (ETROP).² Both therapies aim to ablate ischemic retina, therefore inhibiting the release of vascular endothelial growth factor (VEGF), which induces pathologic angiogenesis in ROP.

However, laser therapy for ROP involving zone I and posterior disease can inevitably cause permanent peripheral visual field loss and has been correlated with increased risk of significant myopia. Due to these limitations, anti-VEGF therapy has been increasingly used to treat type 1 ROP. In this article, we summarize the arsenal of anti-VEGF therapy available to treat ROP today (Table 1). 

Bevacizumab

Bevacizumab (Avastin; Genentech) is a recombinant humanized anti-VEGF monoclonal antibody that prevents all VEGF factor A (VEGF-A) isoforms from binding to endothelial cell receptors, thereby inhibiting angiogenesis and vascular permeability.³ Although it is not US Food and Drug Administration (FDA) approved for ocular use, bevacizumab has been shown to be effective as an off-label therapy for type 1 ROP (Figure 1). 

In 2011, the BEAT-ROP clinical trial assessed the efficacy of bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) compared to laser therapy in infants with stage 3+ ROP in zone I or zone II.⁴ The trial showed significant efficacy for stage 3+ zone I disease in terms of absolute difference in the risk of recurrence. No benefit was demonstrated for zone II disease. One safety concern is the effect of anti-VEGF agents in the systemic circulation of infants, as it may reduce circulating serum VEGF levels with unknown effects on neurodevelopment.⁵ However, there is little evidence to support worse neurodevelopmental outcomes in ROP babies treated with intravitreal bevacizumab.^6,7 

A lower effective dose could be considered for ROP therapy. In 2020, a phase 1 clinical trial suggested that 0.004 mg may be the lowest effective dose to treat type 1 ROP (90% success, defined as an improvement by 4 days post-injection without recurrence), though further investigation is needed.⁸

Compared to the recurrence rate of ROP after laser therapy, the recurrence rate after intravitreal bevacizumab monotherapy is not significantly different, but recurrence does occur at later ages.⁹ Ling et al found that the mean age of recurrence for bevacizumab monotherapy was 43.4±3.5 weeks (compared to 39.5±2.8 weeks for laser therapy), with the latest recurrence occurring at 50 weeks of postmenstrual age.⁹ Risk factors of recurrence include early postmenstrual age at initial treatment, zone I disease, low Apgar score, and multiple births. Anti-VEGF monotherapy can also cause persistent avascular retina, which Çömez et al observed in 25.8% of eyes without peripheral laser treatment at the corrected age of 1 year (38.6% in aggressive posterior ROP eyes vs 10.5% in type 1 eyes).¹⁰ Due to the risk of recurrence and persistent avascular retina, frequent follow-up examinations for 80 weeks postmenstrual age or longer must be performed after bevacizumab monotherapy, especially for infants with risk factors for recurrence.

Ranibizumab 

Ranibizumab (Lucentis; Genentech) is also a recombinant humanized anti-VEGF monoclonal antibody that binds and inhibits VEGF-A. Because it lacks an Fc region, it is significantly smaller, allowing for easier penetration of the retina and faster systemic and intravitreal clearance. Its shorter systemic half-life compared to bevacizumab is desirable in ROP therapy, and in 2018, the CARE-ROP trial investigated its efficacy as a monotherapy for infants with bilateral aggressive posterior ROP (APROP).¹¹ The trial demonstrated that intravitreal ranibizumab did not require rescue therapy in 88.9% of infants who were given 0.12 mg (24% of standard adult dose) and 85.7% of infants given 0.20 mg (40% of standard adult dose). Interestingly, physiologic vascularization proceeded faster and was completed more frequently in eyes that received the lower dosage (55% in the 0.12 mg group, vs 16.7% in the 0.20 mg group).

The RAINBOW trial followed shortly after, comparing the safety and efficacy of ranibizumab to the current standard of laser therapy.¹² The study defined treatment success as survival without active retinopathy, unfavorable structural outcomes, or need for a different treatment modality at or before 24 weeks. Among 214 infants assessed, treatment success was achieved in 80% of infants who received 0.2 mg of ranibizumab, 75% of infants who received 0.1 mg, and 66% of infants after laser therapy (odds ratio of treatment success when compared to laser were 2.19 in the 0.2 mg group and 1.57 in the 0.1 mg group). The trial also demonstrated fewer unfavorable outcomes in ranibizumab groups compared to laser therapy, and its systemic safety profile after 24 weeks was consistent with the established safety profile in adults. 

RAINBOW extension studies have now assessed outcomes at age 2 years¹³ and 5 years.¹⁴ Both extension studies for ranibizumab therapy showed no new safety signals and even demonstrated reduced high myopia, possibly improved vision-related quality of life, and no systemic adverse effects. However, much like bevacizumab, ranibizumab monotherapy was observed to have a later age of recurrence compared to laser therapy (42.3±2.0 weeks for ranibizumab, and 39.5±2.8 weeks for laser therapy). Therefore, infants should also receive frequent follow-up examinations for 80 weeks postmenstrual age or longer after ranibizumab monotherapy.⁹ In 2019, ranibizumab received approval from the European Medicines Agency (EMA) for treatment of ROP with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 3+), or aggressive posterior ROP disease.

Aflibercept

Aflibercept (Eylea; Regeneron) is a soluble decoy receptor with a stronger affinity for VEGF-A, VEGF-B, and placental growth factor than the body’s native receptors.¹⁵ Aflibercept also has a unique binding action known as a VEGF trap, because it binds to both sides of the VEGF dimer to form an inert 1:1 complex. 

In 2022, the FIREFLEYE clinical trial assessed if aflibercept 0.4 mg monotherapy was noninferior to the standard laser therapy in infants with severe ROP.¹⁶ Treatment success was defined as the absence of active ROP without unfavorable structural outcomes after 24 weeks post-treatment. The trial resulted in 85.5% treatment success with a 0.4 mg dose of intravitreal aflibercept, compared to 82.1% with laser photocoagulation at week 24. In the 2-year efficacy and safety outcomes follow-up study of the FIREFLEYE trial, disease control and visual function of infants treated with aflibercept were found to be stable and appropriate, respectively.¹⁷ 

Like the FIREFLEYE trial, the BUTTERFLEYE trial evaluated a 0.4 mg dose of aflibercept’s efficacy, safety, and tolerability compared to laser photocoagulation in patients with ROP. Its primary endpoint was the proportion of infants without active ROP and unfavorable structural outcomes by week 52 of chronological age.¹⁸ The study achieved its primary outcome in 79% of patients treated with aflibercept, compared to 77% with laser therapy. Because both studies found that aflibercept had a similar safety profile as laser and was better than no treatment, aflibercept was approved by the FDA for ROP treatment in 2023, making it the first and only anti-VEGF therapy approved in the United States for ROP.

Aflibercept has been found to have a significantly later mean recurrence time compared to ranibizumab (14.2±1.03 weeks post-aflibercept therapy, compared to 8.2±0.92 weeks post-ranibizumab therapy), though with a significantly lower rate of recurrence (13.9% for aflibercept, compared to 48.1% for ranibizumab).¹⁹ Aflibercept’s later mean recurrence time may necessitate an even longer follow-up period for infants compared to bevacizumab or ranibizumab monotherapy.

Biosimilars

With increasing options for anti-VEGF therapy, biosimilars are also being explored. A biosimilar is defined by the FDA as “a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.” Biosimilar products must demonstrate similarity in structure and function to their reference product, as well as have no clinically significant differences. 

Several anti-VEGF biosimilars have now been evaluated in ROP, though mostly retrospectively. One such product is Razumab (Intas Pharmaceuticals), a well-established biosimilar molecule that has been approved in India for the treatment of retinal vascular diseases such as diabetic macular edema, retinal vein occlusion, and macular neovascularization of various etiologies.²⁰ A retrospective, noncomparative study that evaluated its efficacy on ROP outcomes demonstrated retreatment rates at 7 weeks post-injection in 35% of eyes.²⁰ Although this study did not have a comparison group with ranibizumab, its vascularization outcomes matched prior ranibizumab studies. It is important to note that in early batches of Razumab in India, cases of sterile endophthalmitis were reported, raising safety concerns.²¹ 

The bevacizumab biosimilar Bevatas (Intas Pharmaceuticals), which is currently marketed in India for oncologic purposes, demonstrated complete regression of type 1 ROP in 87% of eyes in the BIOS-ROP clinical trial.²² In the United States, a retrospective case series reported safety and clinical outcomes for 7 ROP babies treated with treated with biosimilar bevacizumab-bvzr (Zirabev; Pfizer).²³ The study noted a positive clinical response in all patients, as well as no post-injection inflammation, intraocular pressure abnormalities, or endophthalmitis. More research is required to analyze its efficacy compared to existing anti-VEGF options as well as its long-term safety and durability. 

Biosimilar products have a significant benefit of potentially reducing costs for patients’ families, which is an important consideration for populations with low socioeconomic status or in developing countries. 

Conclusion

Anti-VEGF therapy has increased our options for the treatment of ROP from the days of exclusive cryotherapy or laser therapy. There are no established long-term safety profiles nor clear differences in neurodevelopmental outcomes for most therapies. Although biosimilar use in ROP is less common than in other adult vascular diseases, it is important to tread cautiously with paucity of safety data in premature infants. Nonetheless, intravitreal anti-VEGF agents have made a significant impact and will continue to play an important role in ROP therapy. RP

Vernon S. Volante, BS, is a fourth-year medical student at the University of South Florida Morsani College of Medicine in Tampa, Florida. He reports no disclosures.

Lauren C. Kiryakoza, MD, is a first-year vitreoretinal surgery fellow and rising chief resident at Bascom Palmer Eye Institute, University of Miami, in Miami, Florida. She reports no disclosures.

Hong-Uyen Hua, MD, is an assistant professor of clinical ophthalmology and specializes in adult and pediatric retina at the Bascom Palmer Eye Institute, University of Miami. Dr. Hua has served on advisory boards for Alimera, AbbVie, and Genentech. Reach her at honguyenhua@gmail.com.

References

1. Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. (1988). Pediatrics. 1988;81(5):697-706. 

2. Good WV, Hardy RJ. The multicenter study of Early Treatment for Retinopathy of Prematurity (ETROP). Ophthalmology. 2001;108(6):1013-1014. doi:10.1016/s0161-6420(01)00540-1

3. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391-400. doi:10.1038/nrd1381

4. Mintz-Hittner HA, Kennedy KA, Chuang AZ; 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

5. Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153(2):327-333.e1. doi:10.1016/j.ajo.2011.07.005

6. Webb AR. Neurodevelopmental outcomes associated with intravitreal bevacizumab injections for retinopathy of prematurity. Adv Neonatal Care. 2022;22(2):154-160. doi:10.1097/ANC.0000000000000881

7. Tsai CY, Yeh PT, Tsao PN, Chung YE, Chang YS, Lai TT. Neurodevelopmental outcomes after bevacizumab treatment for retinopathy of prematurity: a meta-analysis. Ophthalmology. 2021;128(6):877-888. doi:10.1016/j.ophtha.2020.11.012

8. Wallace DK, Kraker RT, Freedman SF, et al. Short-term outcomes after very low-dose intravitreous bevacizumab for retinopathy of prematurity. JAMA Ophthalmol. 2020;138(6):698-701. doi:10.1001/jamaophthalmol.2020.0334

9. Ling KP, Liao PJ, Wang NK, et al. Rates and risk factors for recurrence of retinopathy of prematurity after laser or intravitreal anti–vascular endothelial growth factor monotherapy. Retina. 2020;40(9):1793-1803. doi:10.1097/IAE.0000000000002663

10. Çömez A, Karaküçük Y, Özmen MC, Çelemler P, Saygılı O. The results of intravitreal bevacizumab monotherapy for treating aggressive posterior retinopathy of prematurity and Type 1 retinopathy of prematurity. Eye (Lond). 2021;35(12):3302-3310. doi:10.1038/s41433-021-01413-4

11. Stahl A, Krohne TU, Eter N, et al. Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity: a randomized clinical trial. JAMA Pediatr. 2018;172(3):278-286. doi:10.1001/jamapediatrics.2017.4838

12. Stahl A, Lepore D, Fielder A, et al. Ranibizumab vs laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet. 2019;394(10208):1551-1559. doi:10.1016/S0140-6736(19)31344-3

13. Marlow N, Stahl A, Lepore D, et al. 2-year outcomes of ranibizumab vs laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. Lancet Child Adolesc Health. 2021;5(10):698-707. doi:10.1016/S2352-4642(21)00195-4

14. Marlow N, Reynolds JD, Lepore D, et al. Ranibizumab vs laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial. EClinicalMedicine. 2024;71:102567. doi:10.1016/j.eclinm.2024.102567

15. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171-185. doi:10.1007/s10456-011-9249-6

16. 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;328(4):348-359. doi:10.1001/jama.2022.10564

17. Stahl A, Nakanishi H, Lepore D, et al. Intravitreal aflibercept vs laser therapy for retinopathy of prematurity: two-year efficacy and safety outcomes in the nonrandomized controlled trial FIREFLEYE next. JAMA Netw Open. 2024;7(4):e248383. doi:10.1001/jamanetworkopen.2024.8383

18. Moshfeghi DM. Effect of intravitreal aflibercept vs laser photocoagulation for retinopathy of prematurity: results from the phase 3 BUTTERFLEYE trial. Invest Ophthalmol Vis Sci. 2023;64(8):5126.

19. Sukgen EA, Kocluk, Y. Comparison of clinical outcomes of intravitreal ranibizumab and aflibercept treatment for retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. (2019);257(1):49-55. doi:10.1007/s00417-018-4168-5

20. Prajapati V, Choudhary T, Chauhan W, et al. Efficacy of a biosimilar ranibizumab monotherapy for the treatment of retinopathy of prematurity. Indian J Ophthalmol. 2023;71(2):411-415. doi:10.4103/ijo.IJO_973_22

21. Sharma A, Kumar N, Kuppermann BD, Francesco B, Lowenstein A. Ophthalmic biosimilars: lessons from India. Indian J Ophthalmol. 2019;67(8):1384-1385. doi:10.4103/ijo.IJO_430_19

22. Chakraborty S, Sheth JU. Efficacy of an Indian bevacizumab biosimilar (Bevatas) for type 1 and aggressive posterior retinopathy of prematurity (BIOS-ROP Study). Clin Ophthalmol. 2024;18:61-68. doi:10.2147/OPTH.S443104

23. Jung EE, Lee TC, Nagiel A. Initial experience with biosimilar bevacizumab-bvzr for intravitreal use in children: a case series and literature review. Ophthalmic Surg Lasers Imaging Retina. 2023;54(2):84-88. doi:10.3928/23258160-20230130-01