Retinopathy in Premature Infants: Low Dose Ranibizumab May Be Effective Without Systemic Side Effects Interview with:

Prof. Dr. Andreas Stahl
Geschäftsführender Oberarzt
Leiter Arbeitsgruppe Angiogenese
Universitätsaugenklinik Freiburg | University Eye Hospital Freiburg
Freiburg, Germany What is the background for this study?

Response: Retinopathy of prematurity (ROP) is a sight-threatening disease and one of the main reasons for irrreversible bilateral blindness in children. Particularly infants born at very early gestational ages or with very low birth weight are affected. In these infants, vascularization of the retina is unfinished at the time of birth. Severeal weeks into the life of these very prematuerly born infants, angiogenic growth factors, mainly vascular endothelial growth factor (VEGF), become upregulated in the avascular parts of the retina, leading to a re-activation of physiologic vascular growth. If all goes well, these re-activated retinal blood vessels progress towards the periphery and lead to a fully vascularized and functional retina. If, however, the vascular activation by VEGF is too strong, then vascular growth becomes disorganized and vessels are redirected away from the retina and into the vitreous. If left untreated, these eyes can then proceed towards tractional retinal detachment and blindness.

Since the 1990s, the standard method of treating ROP has been laser photocoagulation of avascular parts of the retina. This treatment is sensible because VEGF as the main angiogenic driver of pathologic blood vessel growth is expressed in these avascular parts of the retina. The downside of laser treatment, however, is that treated retinal areas are turned into functionless scar tissue and are lost for visual function. In addition, infants treated with laser need to be under general anesthesia for hours during treatment which can be troublesome in very young and fragile preterm infants. And in the long run, infants treated with laser have a high risk of developing high myopia in later life.

A sensible alternative to laser treatment is the injection of anti-VEGF compunds directly into the vitreous of the affected eye. This approach targets the excessively produced VEGF molecule directly and neutralizes it before it can lead to overactivation and misdirected growth of retinal blood vessels. The advantage of this approach is that – different from laser treatment – physiologic vascular growth can continue after anti-VEGF treatment and peripheral retinal areas can become vascularized instead of being turned into functionless scar tissue. In addition, anti-VEGF treatment takes minutes instead of hours. It also significantly reduces the risk of myopia in later life.

One of the major downsides of the pharmacologic anti-VEGF approach, however, is that – different from laser treatment – systemic effects have to be taken into account. It is well established that intravitreally injected drugs exit the eye and enter the systemic circulation where they can have significant off-target effects. This is particularly true for bevacizumab, a full-size anti-VEGF antibody that is the current standard for off-label anti-VEGF treatment in ROP. A single bevacizumab injection suppresses systemic VEGF levels over weeks below the limit of detection – both in adults and in premature infants. The particular concern in infants is that other organs, in particular brain and lung, are still undergoing profound developmental stages at the time of anti-VEGF treatment of ROP. And it is currently unknown what side effects a sustained suppression of systemic VEGF levels after bevacizumab treatment might have on a developing organism at this stage. In addition, the current standard dose of bevacizumab in ROP treatment is half the adult dose. Selection of this anti-VEGF dosage has been purely empiric and recent studies suggest that very likely much lower anti-VEGF doses are sufficient to control ROP.

The goal of the CARE-ROP study therefore was to investigate with ranibizumab an anti-VEGF compound that is similarly effective intraocularly as bevacizumab but has a systemic half life of only hours vs. days for bevacizumab. We hypothesized that we could achieve similarly good results in controlling acute ROP with ranibizumab as was previously described for bevacizumab but with the decisive advantage that systemic VEGF levels would very likely remain unaffected – thus significantly limiting the risk for negative off-target effects in other organs. In addition, we investigated in CARE-ROP two lower doses of ranibizumab in a randomized, double blind fashion in order to evaluate whether the amount of anti-VEGF agent can be reduced from the current standard half-adult dose without losing efficacy in treating ROP. What are the main findings?

Response: Both ranibizumab doses investigated in CARE-ROP (24 vs. 40% of the adult dose) were equally effective in treating ROP (94 vs. 93% success in per protocol treated eyes). Only one eye in each arm required rescue therapy with laser coagulation. Four eyes in each arm required re-injection of the study drug several weeks after initial treatment. Systemic VEGF levels were not suppressed following ranibizumab treatment. This is very different from bevacizumab therapy and potentially the biggest advantage of using ranibizumab instead of bevacizumab from a systemic safety point of view. There was a trend for superior vascularization of the peripheral retina with the lower ranibizumab dose indicating that lower anti-VEGF doses may be sufficient to suppress pathologic angiogenesis while at the same time still allowing physiologic vascular growth. What should clinicians and patients take away from your report?

Response: Using anti-VEGF agents for treating defined stages of ROP is a sensible approach. However, open questions relating to choice of the ideal drug and dose as well as to long-term ocular and systemic safety have to be considered. The CARE-ROP study identified ranibizumab as an effective anti-VEGF alternative to bevacizumab, the current standard anti-VEGF agent in ROP. While both anti-VEGF agents successfully suppress pathologic vascular growth in ROP eyes, ranibizumab does not suppress systemic VEGF levels, thus limiting unwanted effects on organs like brain and lung that are still undergoing development at the time of ROP treatment. What recommendations do you have for future research as a result of this study?

Response: While ranibizumab may have significant advantages regarding systemic drug exposure over bevacizumab, the search for the ideal dosage is still unfinished for both agents. The recent PEDIG trial has found that very low doses of bevacizumab are still effective in treating ROP – however with still unknown effects on other organs outside the eye. Ranibizumab with its superior systemic safety profile should be investigated further at even lower doses than was done in the CARE-ROP study. In addition, trials with direct comparison of ranibizumab to laser treatment are required. Is there anything else you would like to add?

Response: CARE-ROP is an investigator-initiated trial (IIT) conducted at nine academic centers in Germany. Novartis Germany supplied study medication and funding for the project. Novartis had, however, no influence on trial design, data acquisition or interpretation of the data. The University Medical Center Freiburg, Germany, is sponsor of the CARE-ROP clinical trial and owns all data. Most of the currently available data is published open-accesss as supplementary material in JAMA Pediatrics. The follow-up study period of CARE-ROP is ongoing and comprises 1, 2 and 5 year follow-up visits with standardized pediatric and ophthalmologic examinations. Thank you for your contribution to the community.


JAMA Pediatr. 2018 Jan 8. doi: 10.1001/jamapediatrics.2017.4838. [Epub ahead of print]

Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.

Stahl A1, Krohne TU2, Eter N3, Oberacher-Velten I4, Guthoff R5, Meltendorf S6, Ehrt O7, Aisenbrey S8, Roider J9, Gerding H10, Jandeck C11, Smith LEH12, Walz JM1,13; Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.


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