Anti-VEGF drugs: Safe and effective for treating DME

Take-Home Message: Data from large randomized trials indicate that diabetic macular edema can be treated safely and effectively with anti-vascular endothelial growth factor therapies.

By Lynda Charters; Reviewed by Dante J. Pieramici, MD

Santa Barbara, CA-In recent years, there has been a great deal of interest focused on the efficacy of various anti-vascular endothelial growth factor (VEGF) agents for treating diabetic macular edema (DME). The data from large randomized clinical trials indicate that anti-VEGF drugs should be the first-line therapy for treating center-involved DME and most of the drugs are considered safe within the confines of the clinical trials.

Efficacy of anti-VEGF agents

Perhaps the most important phase III trials are those that have evaluated ranibizumab (Lucentis, Genentech Inc.) (Protocol I, RESTORE, and RISE and RIDE), aflibercept (Eylea, Regeneron Pharmaceuticals) (VIVID and VISTA), and bevacizumab (Avastin, Genentech Inc.) (BOLT). Comparisons of the various levels of efficacy among these agents, which is the bottom line of the trials, can be difficult because of differing enrollment criteria and study protocols among the trial, according to Dante Pieramici, MD.

Differences in dosing frequencies ranged from pro ra nata (PRN) administration in the Protocol I, RESTORE, and BOLT studies; monthly in the RIDE and RISE trials; and monthly and every other month in the VIVID and VISTA trials.

In the Protocol I study, most gains in vision occurred during the first year, after which the vision stabilized. Similar results also occurred in the RESTORE trial. The RISE and RIDE trials, Dr. Pieramici pointed out, had slightly better visual outcomes, with most gains during the first year. The VIVID and VISTA trials showed similar results and there was no difference in the results between aflibercept administered every 4 or 8 weeks. Finally, the BOLT study data also showed results with PRN bevacizumab.

Dr. Pieramici, who is in private practice in Santa Barbara, CA, pointed out that clinicians evaluating these results might be tempted to conclude that PRN dosing can result in inferior visual outcomes compared to fixed dosing. However, he suggested that a ceiling effect may explain what appears to be inferior results in the PRN trials.

“When the baseline visual acuity levels are evaluated in all the studies under discussion, the patients in the PRN-dosing studies had higher baseline visual acuity levels, and thus potentially less room for improvement (ceiling effect). Over the first year, we see a ceiling effect with patients on average gaining to the level of 70 letter in all the ranibizumab and aflibercept trials,” he said.

He explained that when he and his colleagues evaluated a number of studies of aflibercept and ranibizumab, the finding was that worse baseline visual acuity was correlated strongly with better chances for improved vision.

A recent meta-analysis of ranibizumab and aflibercept that included eight randomized clinical trials in which 1,978 patients were enrolled found that after adjusting for the baseline visual acuity, both drugs were “far superior” to laser treatment and that ranibizumab was numerically but not significantly superior to aflibercept, Dr. Pieramici recounted.

Regarding efficacy, these three drugs work well against VEGF and reducing diabetic macular edema Most of the visual improvement occurs early during the first treatment year, and there appears to be similar levels of improvement when PRN and fixed dosing are compared after adjusting for the baseline vision.

Treatment burden

Another consideration is the treatment burden for patients treated with anti-VEGF drugs. When considering the various study protocols, the number of injections administered decreased markedly during the second year of treatment and further decreased during the third year and subsequent years, Dr. Pieramici commented. A similar decrease in number of injections was apparent with aflibercept dosed every other month. Analysis of the RISE and RIDE Extension study data demonstrated that the visual acuity levels were maintained after patients were switched to PRN dosing with fewer injections; a quarter of patients did not require any additional treatment.

The Diabetic Retinopathy Clinical Research Trial (DRCR) study data, which compared ranibizumab and prompt laser application with ranibizumab with deferred laser application, also showed that 4 and 5 years after the start of treatment, both groups needed very few injections. The patients who received ranibizumab and prompt laser application required about four fewer injections compared with the deferred-laser group over the course of the study. However, he noted, in the deferred-laser group, 56% of patients did not require laser treatment during the trial; another difference was that at the end of 5 years, the patients in the ranibizumab and prompt laser group had a mean increase of +7.2 letters compared with +9.8 letters in the ranibizumab and deferred laser group.

Regarding treatment burden, the key points are that far fewer injections can be administered with PRN dosing and after 2 years, patients require few injections. The role of focal laser in treatment remains unclear in that laser application can reduce the treatment burden but the visual acuity may suffer.

Refractoriness to anti-VEGF therapy

Patients with less than a 10% reduction in the central foveal thickness after three or six injections of anti-VEGF therapy are considered nonresponders. Fortunately, these patients are rare, according to Dr. Pieramici. In the RIDE and RISE studies, 10% of patients were non-responders after three injections of 0.3 mg of ranibizumab; after six such injections, the percentage dropped to 7%. With the 0.5-mg injection of ranibizumab, the respective percentages of nonresponders were 9% and 3%.

After 2 years of monthly injections, these nonresponders had an anatomic response to therapy that was not as great as the early responders but surpassed the response in the sham-treated group. Interestingly, despite the paltry anatomic response, the visual outcomes among the three groups were similar. The 10-letter gain on average, in the initial nonresponders, suggested that continued treatment is reasonable approach for a patient who does not show a robust initial anatomic response.

There may be factors besides reduction of retinal edema that lead to the anti-VEGF’s positive effect on visual acuity. One such benefit may be a reduction in the severity of the retinopathy. Many of the anti-VEGF trials suggest that these agents can reduce the level of diabetic retinopathy and progression of the retinopathy in some patients, Dr. Pieramici said. In addition, it was recently reported that anti-VEGF agents reduce the incidence of posterior retinal nonperfusion in some of patients.

Safety

The initial concern regarding patients with DME who were treated with anti-VEGF drugs was that they might be at increased risk of heart attack and stroke

“Overall, the data from all studies seem to indicate that use of these drugs is safe in these patients. The rates of APTC and deaths are similar in the treatment and control groups. However, further observation over extended time is needed,” Dr. Pieramici said.

“Anti-VEGF drugs have clearly become the first-line therapy for patients with center-involved DME. Most of these drugs are safe, at least for the populations of patients, in the clinical trials, which did not include the most severely ill patients. Clinical trials are guidelines for treatment and therapy should be customized for treating individual patients,” he summarized.

Dante J. Pieramici, MD

E: dpieramici@yahoo.com

Dr. Pieramici is a consultant for Genentech, Alimera, ThromboGenics, Allergan, QLT, and Santen Pharmaceuticals.