Childhood blindness, one of the most challenging disabilities to be contracted in early life, can be found all over the world. In underdeveloped countries, the predominant causes are infections and nutritional deficiencies, but in developed countries the situation is quite different. As healthcare levels improve, infant mortality rates have decreased, even among premature babies – a wonderful achievement, but one that can bring new risks for fragile infants.

To understand this growing problem, it is important to appreciate the exceptionally delicate condition of a premature baby. Born before their organs are mature, they are dependent on intensive life support to survive the critical first months of life.

As they are deprived of the maternal nutrition and oxygen provided by the placenta, premature infants must immediately adapt to processing food with an immature digestive system, eliminating waste using an immature renal system and, critically, gathering enough oxygen from the air through immature lungs.

However, supplemental oxygen treatment – which is vital to their survival – can jeopardize babies’ vision, presenting a major threat to their quality of life. Careful oxygen management is key: too little will decrease their chances of survival, but too much could blind them for life.

The higher levels of oxygen disturb the delicate development of the retinal circulation, which is dependent on mild ischemia to stimulate vascular growth. This explains why the heroic efforts to allow premature newborn babies to survive have become one of the main causes of childhood blindness in developed countries.

In recent years, researchers from across the life sciences have risen to the challenge of developing an innovative therapy that can save the child while sparing their sight.

Initial therapies and the quest for better outcomes[i] [ii]

Step 70 years back in time, when supplemental oxygen was liberally used to improve the survival of premature newborns, and one may find themselves at the center of the Retinopathy of Prematurity (ROP) epidemic. Rates of unfavorable anatomical outcomes were almost 50%.

These cases would progress to retinal detachment and require eye surgery in an often-unsuccessful effort to salvage minimal visual function. In 1990, a treatment for these cases was first established: cryotherapy almost halved the rate of unfavorable outcomes.

Still, approximately 25% of such cases showed unfavorable anatomical or visual outcomes. Even when successful, cryotherapy meant effectively destroying ischemic retina to stop the process.

This led to a reduction of the visual field and sometimes caused excessive scarring and loss of central vision. In the subsequent years, cryotherapy gradually gave way to laser, which provided a more precise method to ablate the avascular retina. Despite being a destructive treatment, laser remained the primary therapy for severe ROP for about two decades.

Introducing a non-surgical treatment option

After anti–vascular endothelial growth factor (anti-VEGF) agents became available for ophthalmological use, researchers compared anti-VEGF with laser in the treatment of ROP. A key study reported lower recurrence rates in the anti-VEGF treated eyes.[iii] Several clinical groups and investigators reported very encouraging outcomes in retinopathy of prematurity when using anti-VEGF agents[iv].

However, the discussion was hotter than ever with questions regarding the selection of the best compound, optimal treatment regimen, outcomes of visual function and possible long-term effects of anti-VEGF administration in this vulnerable population.

Bayer took up the challenge and started to evaluate ways to build on the existing evidence and to create a development program specifically designed to serve the needs of the premature infant population. The challenges were many: researchers had to determine the right dose, find a way to inject tiny amounts of drug into the eye of premature babies, and work with doctors and parents to design and conduct the clinical study in the most appropriate way. All with the goal of reducing one of the most important causes of childhood blindness.

The first baby was included in the pivotal clinical study (FIREFLY[v]) in September 2019, a few months before the start of the COVID-19 pandemic. Enrollment was successfully closed in August 2020 with the last young patient completing the 24 weeks observation period after initial treatment in February 2021.

Due to the medical importance of the disease under investigation, this clinical programme continued uninterrupted in 27 countries (64 hospitals) across Asia, Europe, and South America during the global COVID-19 pandemic. Overall, 118 pre-term infants with RoP requiring treatment in at least one eye were enrolled[vi]

Nearly all babies have been rolled over to a 5-year long-term follow-up study (FIREFLY NEXT[vii]) to observe long-term outcome. This study will end mid-2025.

Solving a technical challenge, together

Given the extremely low volume of 10 µl to be injected into the eye of the baby, Bayer partnered with a medical device company to develop a dosing device to be used with a prefilled syringe. A CE certificate for the dosing device was received in January 2023.

Subsequently, results of the clinical studies were used to file for an indication in countries across the globe. The new treatment option is approved and available in the European Union, the UK and Japan, and is awaiting approval in several other countries across different regions.

It has been a long road from the first treatments for ROP to the latest advances in care. It is a story of innovation and collaboration, as well as determination to solve a complex medical and scientific challenge in a highly vulnerable population.

[i] Bishnoi K, Prasad R, Upadhyay T, Mathurkar S. A Narrative Review on Managing Retinopathy of Prematurity: Insights Into Pathogenesis, Screening, and Treatment Strategies. Cureus. 2024 Mar 14;16(3):e56168. doi: 10.7759/cureus.56168. PMID: 38618439; PMCID: PMC11015904.

[ii] Tsai, A.S.H., Acaba-Berrocal, L., Sobhy, M. et al. Current Management of Retinopathy of Prematurity. Curr Treat Options Peds 8, 246–261 (2022). https://doi.org/10.1007/s40746-022-00249-8

[iii] Tan Q-Q, Christiansen SP, Wang J (2019) Development of refractive error in children treated for retinopathy of prematurity with anti-vascular endothelial growth factor (anti-VEGF) agents: A meta-analysis and systematic review. PLoS ONE 14(12): e0225643. https://doi.org/10.1371/journal.pone.0225643

[iv] Tan Q-Q, Christiansen SP, Wang J (2019) Development of refractive error in children treated for retinopathy of prematurity with anti-vascular endothelial growth factor (anti-VEGF) agents: A meta-analysis and systematic review. PLoS ONE 14(12): e0225643. https://doi.org/10.1371/journal.pone.0225643

[v] ClinicalTrials.gov ID NCT04004208

[vi] Stahl A, Sukgen EA, Wu WC, Lepore D, Nakanishi H, Mazela J, Moshfeghi DM, Vitti R, Athanikar A, Chu K, Iveli P, Zhao F, Schmelter T, Leal S, Köfüncü E, Azuma N; FIREFLEYE Study Group. Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial. JAMA. 2022 Jul 26;328(4):348-359. doi: 10.1001/jama.2022.10564. PMID: 35881122; PMCID: PMC9327573.

[vii] ClinicalTrials.gov ID NCT04015180