Ranibizumab Effective for Pigment Epithelial Detachment

Nicola M. Parry, DVM

September 30, 2016

According to a recent study, pigment epithelial detachments (PEDs) of any size can be effectively treated with monthly or pro re nata [PRN] injections of ranibizumab in patients with neovascular age-related macular degeneration (AMD).

David Sarraf, MD, from the University of California, Los Angeles, and colleagues performed a post hoc analysis of the HARBOR study and published the results in the October issue of Ophthalmology.

"Ranibizumab 0.5 mg given monthly or PRN effectively treated PEDs in patients with neovascular AMD, and significant vision gains resulted regardless of PED status and height at baseline," the authors write. "In this analysis, there was no additional vision benefit with a higher dose of ranibizumab (2.0 mg)."

Although their pathogenesis is not fully understood, PEDs arise in up to 62% of patients with advanced neovascular AMD and are important markers of disease severity. Without treatment, about half of patients with newly diagnosed PEDs will experience significant loss in visual acuity within 1 year.

The emergence of antivascular endothelial growth factor (anti-VEGF) agents has substantially improved treatment for neovascular AMD, but previous prospective studies and small retrospective trials have reported mixed results of anti-VEGF therapy for PEDs.

With this in mind, Dr Sarraf and colleagues conducted an exploratory subgroup analysis of the phase 3 HARBOR study to evaluate the effect of ranibizumab treatment on PEDs over 2 years. "This HARBOR subanalysis is the largest prospective study of neovascular AMD patients with PEDs treated with intravitreal ranibizumab injection," the authors say.

In HARBOR, 1097 treatment-naive patients with subfoveal AMD were randomly assigned to receive one of four intravitreal ranibizumab regimens: 0.5 mg monthly, 0.5 mg PRN, 2.0 mg monthly, or 2.0 mg PRN. Patients received three monthly doses of intravitreal ranibizumab 0.5 mg or 2.0 mg at the beginning of the study. Patients in the monthly groups then continued with monthly treatment, whereas the PRN groups were evaluated every month and re-treated as needed for the remaining 21 months on the basis of visual acuity and spectral domain optical coherence tomography (OCT).

In their post hoc analysis, Dr Sarraf and colleagues analyzed data from all 1097 patients and found that 598 (54.5%) had PEDs at study baseline. The investigators categorized PEDs according to vertical height: small (35 - 164 μm), medium (164.5 - 233 μm), large (233.25 - 351 μm), or extra-large (352 - 1395.5 μm).

At 24 months, they found that mean best-corrected visual acuity (BCVA) was improved in all treatment groups, and gains were comparable in patients with PED at baseline or without PED at baseline: ranibizumab 0.5 mg monthly (+9.0 letters vs +11.3 letters), ranibizumab 0.5 mg PRN (+8.4 letters vs +7.9 letters), ranibizumab 2.0 mg monthly (+7.1 letters vs +11.1 letters), ranibizumab 2.0 mg PRN (+7.2 letters vs +8.8 letters).

When they evaluated changes in mean BCVA according to PED height at baseline, the investigators also found comparable gains at 24 months in all treatment groups except for in patients with extra-large PEDs (≥352 μm) that received ranibizumab 2.0 mg monthly (mean BCVA change, −0.8 letters).

Although the anatomic response in terms of mean change in PED height from baseline to 24 months was slightly better in patients who received ranibizumab 2.0 mg (monthly, −191.1 μm; PRN, −201.6 μm) than in those who received ranibizumab 0.5 mg (monthly, −155.9 μm; PRN, −165.8 μm), this did not translate into an additional benefit in visual acuity.

From baseline to 24 months, patients who received ranibizumab 2.0 mg monthly or PRN also had higher rates of PED resolution than those who received ranibizumab 0.5 mg monthly or PRN (70.4% or 57.3% vs 53.2% or 44.5%); however, they did not experience greater increases in visual acuity (approximately 7 letters vs 8 - 9 letters), the authors note.

"These data suggest that complete resolution of the PED is not necessary for visual acuity gains," the authors say. "In fact, patients with an extra-large PED who received ranibizumab 2.0 mg monthly had a mean decrease in vision at 24 months, although there was a lot of variability in BCVA change from baseline at month 24 in these patients (range, −62 to 30 letters)."

However, Dr Sarraf and colleagues also acknowledge the limitations of this study. In particular, because this was an exploratory post hoc subgroup analysis, the findings may be a result of chance and should therefore be interpreted with caution, they explain. In addition, because PED type at baseline was not evaluated, the effect of PED type on outcomes could not be determined.

"Despite these limitations, this subanalysis still provides previously unavailable data on the efficacy of ranibizumab therapy in approximately 600 patients with PEDs," the authors conclude.

In an interview with Medscape Medical News, Michael W. Stewart, MD, the chair of ophthalmology at Mayo Clinic, Jacksonville, Florida, notes that the impetus for this post hoc analysis was probably to show that ranibizumab effectively flattens PEDs, and that flattening of PEDs may not be necessary to produce optimal visual acuity benefits.

"The results of this analysis could be used to combat the perception that aflibercept is superior to ranibizumab at flattening PEDs," he explained.

"Of course this trial did not include an aflibercept arm, so direct comparison between the results of this trial and those of the VIEW trials (which directly compared aflibercept with ranibizumab) needs to be made with caution, since these represented different studies with different cohorts. Additionally, HARBOR showed that flattening of PEDs is associated with RPE atrophy, a major worry in the long-term treatment of patients with AMD."

Although this analysis was post hoc, Dr Stewart notes that treatment of residual PED elevation was mandated in the PRN groups, so it does not appear that changing the re-treatment criteria in any obvious way would have changed the success of PED flattening. He adds that, as PED changes are morphologic (measured by OCT), the results of this article would therefore appear to be reliable, because the methodology leaves little room for human interpretation.

According to Dr Stewart, "[a]n argument can be made from these data that treatment of AMD should be done until the retina is dry, but that flattening of the PED does not improve visual acuity and may be harmful in the long run by promoting RPE atrophy."

"This argument could be indirectly used to prevent patients from being switched to aflibercept," he concludes.

Several coauthors have reported various financial relationships with various companies: Aerpio, Alcon, Alimera, Allergan, Genentech Inc, Novartis, Optovue, and Regeneron. Dr Stewart has reported serving on an advisory board for Regeneron.

Ophthalmology. 2016;123:2213-2224. Full text

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