DME TREATMENT

Patients with diabetic macular oedema (DME) receiving intravitreal aflibercept (Eylea, Regeneron) every four or every eight weeks have superior visual acuity outcomes compared to patients treated with laser photocoagulation. These findings come from the recently announced primary efficacy analysis conducted at week 52 in the Phase 3 VISTA-DME trial. The study has a planned duration of 148 weeks, but a recent topline analysis of data from ongoing follow-up show the functional treatment benefit of aflibercept is sustained at two years. VISTA-DME is one of three double-masked Phase 3 studies comparing aflibercept against laser photocoagulation for the treatment of DME. Eligible eyes had centre-involved disease, BCVA of 20/40 to 20/320, no active proliferative diabetic retinopathy, and no history of vitreoretinal surgery in the study eye.

A total of 461 patients were randomised into the three treatment groups, of which 43 per cent had a history of prior anti-VEGF treatment in the study eye (not within 90 days). In the primary efficacy analysis at week 52, mean change from baseline BCVA was 12.5 letters in patients treated with aflibercept every four weeks, 10.7 letters in those receiving aflibercept every eight weeks and only 0.2 letters in the laser group. At two years, mean change from baseline BCVA in the aflibercept four week, aflibercept eight week groups, and laser groups was 11.5, 11.1 and 0.9 letters, respectively. No important safety signals have emerged. Rates of serious ocular and non-ocular adverse events, arterial thromboembolic adverse events, and deaths were similar comparing the aflibercept and laser treatment groups.

Speaking to EuroTimes, Pravin U Dugel MD, managing partner, Retinal Consultants of Arizona, Phoenix, and investigator in the VISTA-DME trial, commented that the two-year results are not surprising and reaffirm that aflibercept is an excellent anti-VEGF agent. However, he was careful to point out that in looking for take-home messages from the study about the use of aflibercept in clinical practice, there are a number of issues and unanswered questions to consider.

COMPARISONS
First, VISTA-DME compared aflibercept to laser photocoagulation. How aflibercept measures up against ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech) is of greater interest because those agents represent the current standard of care. In seeking an answer to that question, however, cross-trial comparisons of outcomes in VISTADME and the pivotal ranibizumab trials (RISE and RIDE) should not be made considering differences between the studies in their patient populations and design, said Dr Dugel.

He also pointed out that the results achieved with aflibercept in VISTA-DME or with ranibizumab in its pivotal trials or DRCR.net Protocol I may not translate into the real world where patients may not receive the same rigorous care with four weekly treatment group follow-up. “Compliance with such an intensive visit schedule is very difficult to duplicate in clinical practice and particularly in the population of patients with DME who are younger on average and more likely to be working than patients with age-related macular degeneration,” he explained.

Clinicians should also not assume that real world patients treated with aflibercept every eight weeks will achieve the same benefit as their counterparts in VISTA-DME if they are seen only at their injection visits. “Outcomes are influenced not just by the frequency of treatment, but also by how often the patient is evaluated,” Dr Dugel said.

SUBGROUP ANALYSIS
He noted he would like to see a subgroup analysis of outcomes for the patients with a history of anti-VEGF therapy. However, he cautioned that the information still cannot be used to reach any conclusions about the efficacy of aflibercept in patients who respond suboptimally to another anti-VEGF agent in the absence of details to determine the quality of their previous anti-VEGF treatment. “All studies of anti-VEGF treatment for DME have shown a direct correlation between the number of injections and outcome. We know that in VISTA-DME, patients were followed and treated on a regular basis. However, we do not know how thoroughly they were treated previously,” he explained.

Dr Dugel is also looking forward to more information on systemic safety because he believes that the available anti-VEGF agents are similarly efficacious in the various indications where they are used but will be differentiated based on safety profiles. This insight will likely come from post-marketing data.

In addition, looking ahead to an expanded portfolio of DME treatment options, including extended-release steroid delivery devices and more sophisticated, targeted laser systems, and considering that DME is a dynamic, evolving condition, Dr Dugel emphasised the need for research to define optimal mono- and combination therapy approaches for the different presentations of the disease. “There is no reason to believe that one single agent will be best for every stage and more likely we will find that different agents and different combinations are preferred,” he concluded.