Low-dose ranibizumab effective for retinopathy of prematurity

A low dose of ranibizumab (Lucentis, Genentech/Roche) works well as a treatment for retinopathy of prematurity (ROP), researchers say.

A 0.12-mg dose of the anti-vascular endothelial growth factor (VEGF) drug prevented the need for laser photocoagulation or retreatment for at least 24 weeks without suppressing plasma VEGF levels, reported Dr Andreas Stahl of the University of Freiburg in Germany, and colleagues, in JAMA Pediatrics.

The treatment could offer an attractive alternative to bevacizumab (Avastin, Genentech/Roche), which has been shown to halt the progression of severe ROP but suppresses VEGF plasma levels below the limit of detection for weeks, the researchers wrote.

Bilateral blindness

In retinopathy of prematurity, the growth of disturbed blood vessels can lead to bilateral blindness in early infancy. Treatments aim to prevent the growth of these vessels while fostering the expansion of physiologic retinal vasculature into the retinal periphery.

Unlike bevacizumab, ranibizumab is an anti-VEGF antibody fragment with a systemic half-life of hours rather than days. Dr Stahl and his colleagues wanted to know if it could stop the growth of the disturbed blood vessels without interfering with the growth of physiologic vessels, especially at a lower dose than the standard adult doses.

So they enrolled 19 patients from nine academic centres in Germany. The patients all had bilateral retinopathy of prematurity in zone I (stages 1 with plus disease, 2 with plus disease, 3 with or without plus disease, and aggressive posterior ROP) or posterior zone II (stage 3 with plus disease or aggressive posterior ROP).

Since gestational age at birth is a major risk factor for ROP, the researchers divided the patients into a group of 11 who were up to 25 weeks in age and a group of eight who were older than that.

They randomly assigned six patients in the younger group and four patients in the older group to receive 0.12 mg of ranibizumab (20 µl of 6 mg/mL, which is 24% of the standard adult dose). The other patients received 0.20 mg of ranibizumab (20 µl of 10 mg/mL, which is 40% of the standard adult dose). The researchers did not include a control group.

The patients’ average gestational age at birth and postmenstrual age at first treatment were comparable for the two doses. Occurrence of ROP in zone I was more prevalent among patients receiving the 0.12 mg dose.

The researchers defined their primary endpoint as reaching 24 weeks after treatment without needing either photocoagulation or a reinjection of 0.20-mg ranibizumab as rescue therapies.

One infant receiving 0.12 mg and two infants receiving 0.20 mg died without reaching that endpoint. All three died at least 101 days after the treatment, so the researchers did not think they were killed by the ranibizumab.

Eight infants in the 0.12 mg group (88.9% not including those who died) and six infants in the 0.20-mg group (85.7%) met the primary endpoint.

Looking at the results by eye, 94.4% of the eyes receiving the low dose and 92.9% of those receiving the high dose reached the primary endpoint. There were no statistically significant differences between the doses in the proportion who reached the primary endpoint, whether or not the infants who died were included in the analysis.

No infant older than 25 weeks gestational age required rescue therapy.

Twelve of 20 eyes in the 0.12-mg group (60%) and 10 of 18 eyes in the 0.20-mg group (55.6%) had no ROP in the final visit. All the remaining eyes had ROP stage 1.

Resolution

The researchers observed resolution of plus disease and the disappearance of active proliferations soon after treatment. They noted resolution of the ridge and complete resolution of ROP much later.

Two eyes required rescue therapy, one at 14 and one at 17 days. Both these eyes responded well to rescue therapy and had fully resolved ROP at the final visit.

Two infants in each dosage group had recurrences after the 24-day period that were severe enough to warrant retreatment, at a mean of 87 days after the initial treatment for the 0.12-mg dose and 53 days for the 0.20-mg dose. The researchers considered these retreatments as  “different in nature” from the rescue treatments because the retreatments were part of a planned anti-VEGF dose titration.

Physiologic vascularisation progressed faster and complete vascularisation was achieved more often with the lower dose.

Mean VEGF levels were not reduced with either dose, and vital signs and growth values were comparable. The number and type of serious adverse events were not different.

“The implications of such-long term systemic VEGF suppression on organ development are unknown,” the researchers wrote. “We hypothesised that ranibizumab may be advantageous in this regard because ranibizumab has a systemic half-life of hours vs. days for bevacizumab.”

They acknowledged limitations to their study, including the small number of patients, a relatively early primary endpoint, and the failure to evaluate lower doses than 0.12 mg.