State of the Science in Retinal Disorders: Latest Advances in the Treatment of DME, AMD, and BRVO

Course Director

Carl Regillo, MD

Carl Regillo, MD
Thomas Jefferson University
Wills Eye Hospital
Philadelphia, Pennsylvania


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Part 1 of a 2-part series

Dr. Regillo provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

In the past few years, a number of novel treatments, including vascular endothelial growth factor (VEGF)–targeted therapies, have either become available or continue to be evaluated for the management of retinal diseases in order to improve patient outcomes and allow for better therapeutic individualization. However, rapid advances make it difficult for clinicians to remain current on the latest evidence and implications for clinical practice. In this activity, Dr. Carl Regillo explores recent data for various retinal diseases and elaborates on the roles these therapies may play in everyday patient care.


Disclosures

This activity is supported by an educational grant from Regeneron Pharmaceuticals.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Carl Regillo, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Allergan, Inc.; Genentech, Inc.; GlaxoSmithKline; Novartis Corporation; and Regeneron Pharmaceuticals, Inc.
Grant/Research Support from Allergan, Inc.; Genentech, Inc.; GlaxoSmithKline; and Regeneron Pharmaceuticals, Inc.
Speakers Bureau participant with Genentech, Inc. and Regeneron Pharmaceuticals, Inc.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, currently has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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How should we interpret the latest clinical trial findings on treatments for diabetic macular edema (DME)? And how should we use these data to guide clinical decision-making for individual patients (eg, considering the location of the edema, duration of DME, timing of initiation of therapy, dosing)?

Dr. Regillo: The latest clinical trials for diabetic macular edema suggest that we should be initiating treatment with pharmacotherapy, namely anti-VEGF therapy, for patients who present with clinically significant diabetic macular edema that involves the foveal center and decreases the visual acuity—so that's center-involving DME. These are the types of patients that were enrolled in the major clinical studies that looked at using anti-VEGF agents, such as ranibizumab or even bevacizumab,1-10 and current studies using aflibercept.11-16 All three pan-VEGF blockers are known to work well in clinical studies to reduce the edema and improve the visual outcomes.17,18

Narrator: In 2012, the US FDA approved a 0.3-mg intravitreal dose of ranibizumab for the treatment of diabetic macular edema. Consequently, intravitreal pharmacotherapy with ranibizumab is currently often the initial treatment of choice, but the precise interrelation between this treatment and other modalities is not yet conclusively defined. Recently presented data from VIVID and VISTA, two parallel studies testing separate regimens of aflibercept injections against laser photocoagulation, showed that patients randomized to either dosing regimen of aflibercept had superior visual acuity outcomes compared with laser-treated patients.19 On average, those receiving aflibercept gained 10.5 to 12.5 letters of acuity at one year. Among aflibercept-treated patients, 32% to 41% gained 15 or more letters of acuity compared with 8% to 9% of those treated with laser. In addition, there were no systemic safety signals associated with aflibercept through the one year of treatment.

A meta-analysis of trials evaluating the VEGF inhibitors showed that, compared with grid laser photocoagulation, the anti-angiogenic agents bevacizumab, ranibizumab, or aflibercept increased the chance of gaining three or more lines of vision and decreased the risk of losing three or more lines (RR 0.13, 95% CI, 0.05 to 0.34).20 Compared with laser alone, the combination of ranibizumab plus photocoagulation approximately doubled the chances of gaining three or more lines of vision and decreased the chance of losing three or more lines.

Adverse events associated with intravitreal injections of anti-VEGF drugs that threaten patients’ sight are very rare and include endophthalmitis and retinal detachment.21 For example, larger studies have shown an approximate rate of 0.1% for endophthalmitis in patients receiving intravitreal injections of VEGF inhibitors.22,23

Dr. Regillo: So a patient who presents with some visual symptoms and decreased acuity and has center-involving DME should have treatment initiated with anti-VEGF therapy.

Narrator: In addition to treatment with anti-VEGF agents, laser photocoagulation continues to be a reasonable choice in many clinical scenarios.

Dr. Regillo: When the DME is not involving the foveal center—and the visual acuity is likely to be very good—standard laser photocoagulation is still a good choice. It's a proven therapy, based on ETDRS [Early Treatment Diabetic Retinopathy Study] results, and it can, indeed, control the edema and prevent vision loss and may be the better way to go in patients who have non–foveal-involving DME and relatively good visual acuity.24,25 So laser is still utilized both as primary therapy and [it] can be utilized later, of course, for any clinically significant diabetic macular edema in conjunction with anti-VEGF therapy as adjunctive therapy.

Lastly, corticosteroids injected intravitreally as an off-label form of therapy have shown some benefits.26-31 It's just that there are side effects with steroids in the eye, such as cataract progression and elevated intraocular pressure.31 And these side effects often put steroids in the second position for treating DME.

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Can you provide some evidence-based guidance on the potential role of alternative anti-VEGF dosing regimens for age-related macular degeneration (AMD)?

Dr. Regillo: The original major, prospective clinical studies using anti-VEGF agents for AMD, such as using ranibizumab in the MARINA and ANCHOR studies or aflibercept in the VIEW studies, were, of course, fixed regimens with the drugs administered intravitreally, dosed monthly or, as in the aflibercept VIEW study, dosed every other month during the maintenance phase after a loading dose.32-35 And we know that this fixed, continuous regimen over one or two years works very well.36

But based anecdotally on our experience and now with some solid Level I evidence using alternative treatments such as PRN [pro re nata; as needed]-style therapy, we know that not every patient with wet AMD needs a fixed and frequent regimen to have a good visual outcome.36 So it certainly seems reasonable to consider an alternative, less frequent dosing arrangement—in particular, dosing that allows for individualization of therapy with a given anti-VEGF agent. And your choices for individualizing therapy include what we commonly refer to as PRN, treating for signs of recurrent exudation, or the even more common approach now, which is the treat-and-extend approach, in which you're treating at every visit but adjusting the treatment interval according to the response of a given patient to the given treatment.37

Although it's important to recognize that a patient who is not responding well may need to do something more frequent and more fixed, the treat-and-extend approach is very appealing in many ways: It's highly cost-effective; it helps to minimize the burden of therapy; and it's a continuous form of therapy, so it tends to minimize the recurrences and possibly the setbacks with decreased acuity that could occur with less frequent types of injections over time in our patients with wet AMD. The evidence is mounting and the publications thus far do suggest very good visual results with using the treat-and-extend approach.38-41 And these results do appear to be comparable to the original anti-VEGF clinical studies using a fixed-frequent regimen. There will be additional evidence with the treat-and-extend approach forthcoming within the next year or two, so hopefully this will help to confirm our impressions in the field that the treat-and-extend approach is a good alternative anti-VEGF dosing to a fixed, continuous regimen.42

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What are the latest clinically relevant treatment advances and clinical trial findings with anti-VEGF agents and steroids for the management of branch retinal vein occlusion (BRVO)?

Dr. Regillo: The latest clinical trials regarding the management of branch retinal vein occlusion mainly surround the use of anti-VEGF agents to treat BRVO-related macular edema—which [the edema] is, of course, the main source for decreased vision in patients with branch retinal vein occlusions—and these trials would include major phase 3 studies such as BRAVO for ranibizumab43,44 and additional information should be coming in [VIBRANT] a phase 3 study with aflibercept for BRVO macular edema treatment. At this time, aflibercept is FDA-approved to treat central retinal vein occlusion edema,45 not branch retinal vein occlusion edema, but it's highly likely to work well in this setting. We know that with ranibizumab as an FDA-approved drug for the treatment of BRVO-related macular edema46 we can effectively reduce the edema and improve the vision in most of our patients.

Narrator: In the six-month BRAVO trial, more patients receiving low- and high-dose ranibizumab versus sham had improvements in visual acuity of at least 15 letters and achieved visual acuity of 20/40 or better. A 12-month update of the BRAVO trial has confirmed longer-term benefits, as more patients receiving low- and high-dose ranibizumab had improvements in visual acuity of at least 15 letters compared with sham: 56% and 60% versus 44%, respectively. As well, more patients achieved visual acuity of 20/40 or better: 68% and 66% versus 57%, respectively.43,44 Recently reported results from the VIBRANT trial showed that, at 24 weeks, 53% of the patients in the intravitreal aflibercept arm gained at least 15 letters of visual acuity compared with 27% of the patients receiving laser to treat macular edema secondary to BRVO.47

Dr. Regillo: So anti-VEGF agents have been shown in both the short- and now long-run to control the edema and improve the visual outcomes. And it's probably the most effective and safest way to do that.

That being said, of course, steroids also can play a role in the setting of branch retinal vein occlusion, just like with diabetic macular edema. And the GENEVA study, using the dexamethasone implant, definitively showed visual benefits with the use of this implantable steroid in terms of reducing the edema and improving the vision.48

We don't have comparative clinical studies, however, to know if anti-VEGF therapy works better than steroid therapy in the setting of BRVO. That being said, looking at all the studies, and with all the caveats of cross-trial comparisons, the effectiveness of anti-VEGF therapy coupled with the lack of significant ocular side effects tends to put anti-VEGF therapy as the primary therapy for treating BRVO-related macular edema. Steroids can certainly be very useful if anti-VEGF therapies are not effectively controlling the edema or if anti-VEGF therapies need to be administered very frequently as a way to reduce the burden of therapy. Of course, bear in mind that steroids do have side effects, namely the possibility of promoting cataract or raising intraocular pressure, which will need to be managed.49

Lastly, grid laser photocoagulation—although not likely to be primary therapy for most BRVO macular edema—is a known, proven, effective therapy and may be utilized in the course of managing patients with BRVO edema.50-53 It could be initial therapy in milder cases, or as backup or adjunct therapy after initiation of pharmacotherapy.

So in a patient with a BRVO and significant macular edema, one may find that you start with one type of therapy, such as anti-VEGF therapy, move to another to get a better or more long-lasting effect, such as steroids, and then even consider utilizing grid laser therapy in hopes of providing a more long-lasting decrease in the macular edema over time.

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References

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This activity is supported by an educational grant from Regeneron Pharmaceuticals.
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