Anti-VEGF therapy is on the horizon for APROP

Key Points

Auburn Hills, MI-Anti-angiogenic therapy for aggressive posterior retinopathy of prematurity (APROP) may be a feasible therapy for the children with this form of ROP, which develops in profoundly immature neonates, according to Antonio Capone Jr., MD.

The BLOCK-ROP study, which began in the second quarter of 2008, will add to the limited knowledge of the safety and efficacy of an anti-vascular endothelial growth factor (VEGF) drug in treating posterior ROP, said Dr. Capone, clinical associate professor of ophthalmology, Oakland University, Auburn Hills, MI.

"With the advent of FDA-approved drugs for anti-VEGF treatment, treating eyes off-label with an anti-VEGF drug has become possible," he said. The rationale for this treatment approach is based on the mechanistic importance of VEGF in the pathogenesis of ROP. The normal biochemistry of the developing eye changes, normal production of VEGF decreases, and retinal maturity is delayed, he said.

"As a result, VEGF production is dysregulated, the peripheral retina remains avascular, and tissue hypoxia ensues. Subsequent up-regulation of VEGF leads to the pathologic vascularization seen in ROP," he said.

A study conducted by Dr. Capone and colleagues in human infant eyes elucidated the activity of ROP. Samples of vitreous were obtained during vitrectomy for stage 4A ROP from infants 37 to 45 weeks postmenstrual age. The study included 12 eyes with vascularly active stage 4A ROP and 10 eyes with vascularly quiet stage 4A ROP. The study also included five control eyes of five children who were undergoing vitrectomy in association with surgery for congenital cataract. All VEGF isoforms were measured. The VEGF levels in the vitreous fluid were found to be elevated in all eyes with ROP; however, there was a significant difference in the VEGF levels in eyes with vascularly active ROP.

"Our findings confirmed that up-regulation of VEGF occurs in ROP and that particularly high levels are seen in eyes with increased vascular activity. These eyes are potential candidates for anti-VEGF therapy," he said.

Because VEGF is needed in developing eyes for normal angiogenesis, the goal of therapy is not to penetrate tissue but to block excessive VEGF in the overlying vitreous, which is presumed to be responsible for the abnormal vasculature of ROP. It is possible that one or perhaps two injections of anti-VEGF drugs would be necessary because VEGF normally down-regulates.

Clinical experience

The largest known experience to date with anti-VEGF therapy for ROP was carried out in Mexico, Portugal, and New York by Quiroz-Mercado and colleagues. In this study, 53 eyes were treated with one injection of bevacizumab (Avastin, Genentech) and followed for a mean of 6 months. The study, which started in September 2005, included patients who received the standard of care for ROP, eyes that were untreated because of poor visualization, and eyes with high-risk pre-threshold ROP in an institution where laser was unavailable, Dr. Capone recounted.

"All eyes responded favorably to treatment regarding neovascularization; five eyes with ROP worsened. There were no serious systemic adverse events. The authors concluded that further studies were needed to determine the safety and long-term efficacy of the treatment," Dr. Capone said.

BLOCK-ROP study

The BLOCK-ROP study, a phase I prospective multicenter trial, is being carried out in the United States and Canada and is evaluating the safety of one injection of bevacizumab (0.75 mg) into the vitreous cavity as rescue therapy in 22 patients with APROP unresponsive to retinal ablation whose conditions are highly likely to progress to retinal detachment and blindness. Enrollment is expected to be complete by the fourth quarter this year.

Dr. Capone said that bevacizumab was chosen as therapy because the full antibody has less retinal penetration and is theoretically less likely to have a negative impact on VEGF homeostasis in the developing retina. Ranibizumab (Lucentis, Genentech) is designed specifically to penetrate the retina. The volume of drug used in the study is three-fifths that of the adult dose, i.e., 0.75 mg in 0.03 ml. The risk of a substantial increase in IOP is expected to be reduced with this volume and eliminate the need for paracentesis.

"The scientific rationale for using anti-VEGF therapy for ROP is compelling. This is an exciting time in the history of ROP therapy. Accrual of standard phase I and II data is appropriate considering the vulnerability of the target population. In the interim, caution is warranted with use of anti-VEGF drugs outside of a clinical trial in premature neonates," Dr. Capone concluded.