The vascularization that presents in premature babies with retinopathy of prematurity (ROP) requires prompt treatment to prevent retinal detachments and blindness. Currently, ROP is treated by conventional laser therapy, with vitrectomy required when disease fails to regress. But what about using anti-VEGF agents, such as bevacizumab, to dampen down neovascularization? David K Wallace of Indiana University School of Medicine, Indianapolis, USA, performed a dose de-escalation study and discovered that less is more.
“Bevacizumab, when injected intravitreally, can reach the systemic circulation and cause large and persistent reductions in serum VEGF levels,” said Wallace (1). “This is important because developing infants need VEGF for vascular growth in important structures like the brain and lungs for example.” Bevacizumab has been investigated previously for ROP, with 0.625 mg – half the adult dose – being administered in the BEAT-ROP study (2). However, this is likely still too high: “It has been estimated that this may be as much as 10,000 times the drug we need to bind VEGF in the vitreous,” said Wallace.
To determine a lower dose of bevacizumab that is effective and could be tested in future larger studies, they performed a multi-center dose de-escalation study in which successive cohorts of infants with ROP received lower concentrations of bevacizumab. Study eyes were administered investigational (reduced) doses, whilst fellow eyes received the last dose to be found effective in the study; progression to the next lower dose was based on achieving successful results with the previous dose. Dosing schedules in the cohorts was as follows (study eye, fellow eye):
- Cohort 1: 0.250 mg, 0.625 mg
- Cohort 2: 0.125 mg, 0.250 mg
- Cohort 3: 0.063 mg, 0.125 mg
- Cohort 4: 0.031 mg, 0.063 mg.
In total, 61 infants were treated (mean gestational age, 24.9 weeks), with 58 completing examinations at four weeks. All type 1 ROP study eyes treated with 0.25 mg (11/11), 0.125 mg (14/14) and 0.031 mg (9/9) bevacizumab showed successful treatment at four weeks; of the 24 infants treated with 0.063 mg, 21 showed success. Of all 61-treated infants, three had early failure (5 percent) and 11 (18 percent) were re-treated for a late recurrence of ROP. At ≥6 months, 54 patients had regressed ROP, and one infant each had progressed to retinal detachment stage 4a and stage 5. “Doses of bevacizumab as low as 5 percent of that which was administered, and considered the standard dose, in the BEAT-ROP study were effective in treating ROP” said Wallace. In terms of adverse events, he reported that mild vitreous hemorrhage occurred in one study eye, and that five infants died from pre-existing conditions that were not related to treatment.
Referring to the suppression of serum VEGF – which was found to be reduced at both 2- and 4-weeks after injection – Wallace said: “We’d like to see less effect on VEGF levels as we go to lower doses, as all the doses tested so far still suppress VEGF and give us concern about the possible systemic side effects.” Their next steps? “We are going lower in terms of dose, as well as following these babies forwards to 24 months to obtain neurodevelopmental tests.”
- DK Wallace, “Lower dose intravitreal bevacizumab for ROP”. Presentation at the American Academy of Ophthalmology annual meeting, November 13, 2017; New Orleans, USA.
- HA Mintz-Hittner et al., “Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity”, N Engl J Med, 364, 603–615 (2011). PMID: 21323540.
