Diabetic Macular Edema Responds Best to Frequent Ranibizumab

Laurie Barclay

October 12, 2012

October 12, 2012 — Aggressive treatment with ranibizumab during year 3 may be more effective for diabetic macular edema (DME) than less-intensive treatment, according to 3-year outcomes from an ongoing randomized clinical trial published online October 8 in the Archives of Ophthalmology.

Ranibizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), which promotes angiogenesis. The purpose of this prospective, interventional, multicenter follow-up study was to evaluate the benefit of increased follow-up and treatment with ranibizumab between months 24 and 36 in the Ranibizumab for Edema of the Macula in Diabetes (READ-2) Study.

"These data demonstrate that many patients with [DME] require very frequent (in many cases every month) intraocular injections of an anti-VEGF agent to control the edema and maximize visual acuity," senior author Peter A. Campochiaro, MD, the George and Dolores Eccles Professor of Ophthalmology and Neuroscience at Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape Medical News in an email interview. "[M]any DME patients currently being managed with as-needed injection protocols are being undertreated and have chronic edema. Over time, this chronic edema is likely to lead to permanent loss of vision."

The study sample consisted of patients enrolled in READ-2 who agreed to participate between months 24 and 36. There were 28 patients receiving ranibizumab treatment alone, 22 receiving laser therapy alone, and 24 receiving ranibizumab plus laser therapy. From months 24 to 36, these participants received ranibizumab, 0.5 mg, at monthly follow-up if foveal thickness (FTH, center subfield thickness) was at least 250 μm.

"In several large studies, the mean number of injections of anti-VEGF injections went down in year 2 and beyond when injections are given on an as-needed basis, but when one examines the mean central foveal thickness or percentage of patients with foveal thickness less than 250 μm with time domain optical coherence tomography, it is clear that many of the patients have substantial residual edema," Dr. Campochiaro said.

In the present analysis, the primary study endpoints were improvement in best-corrected visual acuity (BCVA) and reduction in FTH between months 24 and 36.

In the ranibizumab group, BCVA improved by a mean of 10.3 letters from baseline at month 36 compared with 7.2 letters at month 24 (change in BCVA letters, 3.1 letters; P = .009). At month 36, mean FTH was 282 μm compared with 352 μm at month 24 (change in FTH, 70 μm; P = .006).

Changes between months 24 and 36 in BCVA and FTH were not statistically significant in the laser group (−1.6 letters and −36 μm, respectively) or in the ranibizumab plus laser group (+2.0 letters and −24 μm, respectively).

The ranibizumab group had a significantly greater mean number of ranibizumab injections than the laser group (5.4 vs 2.3 injections; P = .008), but not compared with the ranibizumab plus laser group (3.3 injections; P = .11).

"This multicenter study demonstrated that ranibizumab was effective and safe for the treatment of DME," lead author Diana V. Do, MD, associate professor of ophthalmology at the Wilmer Eye Institute, Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape Medical News in an email interview. "In fact, ranibizumab was more effective than laser photocoagulation, which used to be the standard of care. The READ-2 study was one of the first studies to prove that intravitreal VEGF blockade is the most effective treatment for DME, and currently VEGF blockade is the new standard of care when treating patients with vision loss due to DME."

Strengths and Limitations

"The strengths of the study include that it is a prospective follow-up of a randomized clinical trial," Abdhish R. Bhavsar, MD, clinical correspondent, American Academy of Ophthalmology, and managing partner and director of clinical research, Retina Center of Minnesota, Minneapolis, told Medscape Medical News in an email interview. "The weaknesses of the study include that it is not masked, which introduces bias; that the primary outcome was at 6 months in the original study, and that is too short in DME studies; that the follow-up from 24 to 36 months does not seem to have been prospectively planned; and that the study involves relatively small numbers of subjects."

When asked about the clinical implications of this study, Dr. Bhavsar, who was not involved in the work, noted that "DME can be treated successfully with ranibizumab alone or ranibizumab plus focal laser, but focal laser appears to reduce the number of ranibizumab injections needed. The bottom line is that this adds to the evidence that anti-VEGF agents such as ranibizumab are useful in the treatment of DME."

In terms of additional research, Dr. Bhavsar recommends clinical trials with larger numbers of subjects, such as the Diabetic Retinopathy Clinical Research (DRCR) Laser-Ranibizumab-Triamcinolone trials.

According to Dr. Do, the DRCR network conducted a phase 3 trial to evaluate ranibizumab compared with laser photocoagulation and again with intravitreal steroids combined with prompt laser. This study confirmed that VEGF inhibition with ranibizumab was superior to laser and more effective than steroids combined with laser. She added that Genentech sponsored 2 phase 3 clinical trials, the RIDE and RISE studies, to evaluate 2 different doses of ranibizumab for DME. In both these studies, ranibizumab was more effective than sham treatment for DME.

"Therefore, there is robust level 1 evidence to demonstrate that intravitreal ranibizumab is currently the best treatment for DME," Dr. Do said.

Dr. Campochiaro pointed out that longer-acting VEGF antagonists are needed because monthly visits for intravitreal ranibizumab treatment are a strain on patients and their families.

"Frequent injections for many years is not a long-term solution, but until we develop longer-acting agents or good sustained delivery techniques, we are stuck with doing frequent injections to minimize edema, maximize vision for the present, and minimize gradual permanent loss of vision from chronic edema," Dr. Campochiaro concluded. "I stress to my DME patients that better solutions are coming, and thus it is critical to maintain as much visual potential as possible even if monthly injections are required to achieve that goal, so that they will still have good visual potential when those better solutions become available."

The Juvenile Diabetes Research Foundation and Genentech Inc funded this study. Dr. Campochiaro is a consultant for Genentech, Regeneron, and Aerpio, for which his institution receives remuneration, and he is on the data and safety monitoring committee for clinical trials sponsored by Advanced Cell Technology. His institution receives funding for clinical trials, for which he is principal investigator, from Genentech, Regeneron, Oxford Biomedica, Genzyme, and Aerpio. Dr. Do has received research funding from Genentech and Regeneron. Dr. Bhavsar has disclosed no relevant financial relationships.

Arch Ophthalmol. Published online October 8, 2012. Abstract