Anti-VEGF for DME durable to 3 years

Take-Home

Patients who receive intravitreal ranibizumab (Lucentis, Genentech) for treatment of diabetic macular edema over a 3-year period achieved rapid improvements in vision and edema.

By Cheryl Guttman Krader; Reviewed by Leonard Feiner, MD, PhD

Teaneck, NJ-Monthly injections of intravitreal ranibizumab (Lucentis, Genentech) for diabetic macular edema (DME) result in functional and anatomic improvements that are maintained for at least 3 years and without the emergence of new safety signals, recent research has found.

Findings from 36 months of follow-up in the phase III RISE and RIDE trials also indicated a physiologic benefit of the anti-vascular endothelial growth factor (VEGF) treatment, said Leonard Feiner, MD, PhD, who is in private practice, Retina Associates of New Jersey, Teaneck, NJ.

The trials showed reduction in area of leakage on fluorescein angiography, which continued to increase over time.

Earlier treatment initiation may result in better outcomes as well.

“Laser photocoagulation is beneficial for the treatment of DME and reduces the risk of vision loss by about 50%,” Dr. Feiner said. “However, few patients experience visual benefit.

“As in age-related macular degeneration and retinal vein occlusion, ranibizumab redefines the standard of care for patients with DME,” he said.

About the trials

RISE and RIDE enrolled about 750 patients with best-corrected visual acuity (BCVA) of 20/40 to 20/320 and optical coherence tomography central subfield thickness ≥275 µm.

They were randomly assigned 1:1:1 to monthly intravitreal injection with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham. All patients could receive laser photocoagulation beginning at month 3 if their vision or macular edema was not improving.

The primary endpoint was at 24 months, and thereafter, patients in the sham arm were eligible to be crossed over to ranibizumab.

More than 80% of patients in each treatment arm completed follow-up to 24 months, and retention at 36 months ranged from 73% in the sham arm to about 78.5% in the ranibizumab arms.

Trial results

Patients originally treated with ranibizumab experienced rapid improvement in BCVA, with notable vision gain seen as early as 7 days, on average.

At 24 months, BCVA had improved by slightly more than 2 lines across all ranibizumab arms and the gains persisted at 36 months.

After crossover to ranibizumab, patients in the sham arm also had an improvement in vision. However, the gain from BCVA at 24 months was only about 2 letters based on an intent-to-treat analysis, with last observation carried forward.

Only about 3 letters in an analysis included only the sham patients who received at least one ranibizumab injection after month 24.

“Findings from subgroup analyses showed that the benefits of ranibizumab treatment for improving vision were consistent-whether patients had been previously treated for their DME, …were treatment naïve, and whether their diabetes was well-controlled,” Dr. Feiner said. “However, as expected, patients whose central foveal thickness was 450 µm

 or greater at baseline had more BCVA improvement than their counterparts with less edema at enrollment.”

Analyses of changes in central foveal thickness showing early reductions were maintained with continued ranibizumab treatment.

The crossover to ranibizumab among sham patients resulted in drying of macular edema despite the limited vision benefit.

Analyses

Evaluation of changes in area of fluorescein angiogram leakage provided evidence of the physiologic benefit of ranibizumab and showed a steady incremental increase over time in the proportion of patients with complete absence of leakage.

“This effect of the anti-VEGF treatment does not seem to have peaked yet at 36 months,” Dr. Feiner said.

Patients who were also treated with ranibizumab had less progression (by 2 or 3 steps on the ETDRS retinopathy severity scale) of their background diabetic retinopathy than those who were in the sham group.

Patients in the ranibizumab groups also had higher rates of improvement in diabetic retinopathy than those in the sham group.

“This suggested that treatment with ranibizumab may lead to some disease-modifying effects in the eyes of patients with DME and warrants further study,” Dr. Feiner said.

While the phase III studies are not powered to evaluate safety, Dr. Feiner said he found that adverse event data showed ocular safety was generally balanced between groups.

The few cases of endophthalmitis occurred only among ranibizumab-treated patients and the rate of vitreous hemorrhage was higher in sham-treated patients.

Rates of arterial thrombotic events and death at 36 months were also slightly higher in the ranibizumab arms versus the sham-treated control, as were rates of serious adverse events potentially related to systemic VEGF inhibition.

“The latter events occurred at a higher rate with the 0.5-mg dose of ranibizumab compared with the 0.3-mg arm,” Dr. Feiner said. “Along with the finding of similar efficacy between doses, (these events) were some of the primary motivations for Genentech choosing to file the 0.3-mg dose for FDA approval.

 “Overall, the rates of these serious adverse events with ranibizumab treatment were low, but a relationship to VEGF inhibition cannot be excluded,” he said.

Leonard Feiner, MD, PhD

E: feinerl@yahoo.com

Dr. Feiner is a consultant to and serves on the speakers’ bureau for Genentech.

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