A new research study, published in the journal JAMA Ophthalmology, suggests that a dose of 0.004mg bevacizumab may be the lowest dose effective for retinopathy of prematurity (ROP). Previously, intravitreous bevacizumab (0.25mg to 0.625mg) was commonly used to treat type 1 ROP however, there may be adverse events on systemic toxicity, specifically in the context of risks for neurodevelopmental delay in preterm infants. The current research indicates that a dose as low as 0.004 mg met criteria for successful outcome at 4 weeks in 9 of 10 study eyes (1 per infant), and, according to the authors, “0.004mg may be the lower limit of bevacizumab dose effectiveness for ROP”.
ROP has been a significant challenge for managing preterm infant care since the 1940s. A number of research reports has steadily progressed on clinical ROP research to protect vision and minimise any adverse effects of anti-VEGF treatment. Previous research has shown that intravitreal bevacizumab injection may enter the systemic circulation, escaping the eye, lowering the serum level of VEGF. Such earlier studies have shown that levels of serum bevacizumab 8 weeks after an intravitreal injection could still prevent VEGF in circulation. This impact on bevacizumab of preterm infants can then negatively harm the development of kidneys, lungs, brain, and other organs. In commenting on the literature, Dr. David Wallace, Indiana University, stated that, “as a faster and easier treatment option, anti-VEGF eye injections were a welcomed alternative to laser therapy for treating severe ROP, but we know that anti-VEGF agents injected into the eye also get into the bloodstream, and doctors worry that inhibiting VEGF systemically could interfere with normal development of brain, lung, bone, and kidney tissues”. To minimise any toxicities for developmental organogenesis, further research has been conducted for their current research work.
For the clinical research work, carried out by multiple authors and by the Pediatric Eye Disease Investigator Group, premature infants with type 1 ROP in 1 or both eyes were previously enrolled in a masked, multi-center, dose de-escalation study. Cohorts of 10 to 14 infants (with a mean [SD] birthweight of 664[258] grams) received 0.016mg, 0.008mg, 0.004mg, or 0.002mg of bevacizumab. Following the study, fifty-five of fifty-nine infants were enrolled (93%). The research results found that a dose as low as 0.004 mg bevacizumab met criteria for successful outcomes at 4weeks in 9 of 10 study eyes (1 per infant). Commenting on the research, the lead PI stated that, “at the lower dose of 0.002 mg, a short-term successful outcome was achieved in only 74% of 23 eyes, suggesting that 0.004mg may be the lower limit of bevacizumab dose effectiveness for ROP”. Finally, while the study was limited because of the small sample size and the shorter timeframe, researchers aim to follow up these infants and report recurrence rates and 2-year outcomes in due course.