Benefits of Ranibizumab for AMD Outweigh Risk of MA Development

SriniVas R. Sadda, MD

The benefits of long-term treatment—24 months—of neovascular (or wet) age-related macular degeneration (AMD) with anti-vascular endothelial growth factor (anti-VEGF) agent ranibizumab (Lucentis, Genentech) outweigh the risk of macular atrophy (MA) in patients.

New study data revealed that ranibizumab was not associated with MA development, and that use of ranibizumab was associated with clinically significant gains in best corrected visual acuity (BVCA) in study patients.

Led by SriniVas R. Sadda, MD, the president and chief scientific officer of UCLA's Doheny Eye Institute, he and colleagues performed a post-hoc analysis of data on 1095 study eyes from the HARBOR study, a 2-year phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial focused on safety and efficacy of intraviteral ranibizumab on a monthly or pro re nata (PRN) treatment regimen for patients with choroidal neovascularization (CNV) secondary to wet AMD.

Inclusion in the HARBOR study, Sadda wrote, required patient be ≥50 years of age, with a BCVA of 20/40 to 20/320 (Snellen equivalent) using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts, active subfoveal CNV lesions of <12-disc areas or 30.48 mm², and "total CNV area >50% of the total lesion area. Patients in the HARBOR study were randomized 1:1:1:1 to receive intraviteral ranibizumab at 0.5 mg monthly (n = 275), 0.5 mg PRN (n = 275), 2.0 mg monthly (n = 274), or 2.0 mg PRN (n = 273).

Using the HARBOR data, Sadda and colleagues retrospectively analyzed fluorescein angiograms (FAs) and color fundus photographs taken at baseline, 3-, 12-, and 24- months in order to grade those images for MA and compared the rate of MA incidence over the 24-month period to BCVA under monthly and PRN ranibizumab treatment.

Data showed that MA was detected at baseline in 123 study eyes (11.2%), the number of study eyes with MA increased by an additional 229 study eyes (29.4%) at 24-months. Sadda wrote that study eyes “with and without baseline MA had significant mean BCVA gains from baseline at month 24” and eyes with baseline MA averaged an increase of +6.7 (95% CI) EDTRS letters, while eyes without baseline MA experienced an increase of +9.1 (95% CI) EDTRS letters.

Sadda reported that the mean BCVA was comparable in eyes with and without concurrent MA at baseline (54.1 and 53.9 [95% CI], respectively), 3 months (60.8 and 62.9 [95% CI]), 12 months (62.9 and 65.0 [95% CI]) and 24 months (62.0 and 64.7 [95% CI]).

The study data showed that there were increased risk of MA development associated with some features of “baseline retinal anatomy or patient characteristics,” according to the authors, including the presence of baseline intraretinal cysts (hazard ratio [HR], 2.45), the presence of fellow eye atrophy (HR, 2.02) and heightened patient age (HR, 1.09). Sadda reported that the presence of baseline subretinal fluid was associated with a decreased risk of developing MA (HR, 0.50), and that other factors such as baseline “BCVA, cardiovascular history, gender, intraretinal fluid presence, PED [pigment epithelial detachment], PED height, CNV lesion size, CNV lesion type (predominantly classic, minimally classic, occult), and subretinal fluid thickness” were not associated with any increased risk factors.

Although monthly treatment regimens with ranibizumab versus PNR treatment regimens were associated with a slightly greater risk (HR, 1.29) of MA development, the authors noted that “injection frequency in the PRN arms did not appear to be associated with MA presence at month 24” and there were “no meaningful differences in new MA rates by injection frequency.” In fact, the rates of new MA reported among PRN injection patients were higher among those who received the fewest number of treatments—42% of patients receiving 1-6 injections were diagnosed with new MA compared with 19% of patients receiving more than 18 injections.

Sadda wrote that “evidence to date suggests that there is not a straightforward link between treatment exposure and atrophy development.” Although there were increased risk factors associated with some baseline anatomic characteristics, the increased risk of MA for monthly ranibizumab injections versus PRN ranibizumab injections does not appear to be statistically significant.

The authors stated that the likelihood of MA development differs among individuals with wet AMD and suggested that the study results reinforced the need for individualized, or tailored, treatment that takes into account heightened risk factors for MA.

Ultimately, they concluded that the benefits of ranibizumab therapy for wet AMD in terms of BCVA gains “far outweigh the risk of developing new MA.”

The study, “Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration,” was published in Ophthalmology.