Sustained-release and combination therapies may be future of retinal treatment

The availability of sustained-release drug delivery systems for the treatment of retinal disease may lead to a paradigm shift in coming years. As treatment options continue to accumulate, retina specialists may choose to adhere to the growing trend of individualizing patient care through combination therapy.

Expert viewpoints always vary regarding the future of a given specialty, and the presence of new anti-VEGF agents and steroids in the ophthalmic armamentarium has supplied clinicians with an array of predictions.

“I think everybody is sorting out exactly which patient is better suited to which drug and where combinations may be effective,” Julia A. Haller, MD, OSN Retina/Vitreous Board Member, said. “Targeting therapies to the exact profile of the disease process in the individual patient is one of the most exciting areas in our field’s development.”

While corticosteroid use declined in recent years as anti-VEGF therapies made their entrance onto the ophthalmic stage, physicians are beginning to take advantage of the benefits of multiple therapies.

Cataract may be an eventual consequence of effective steroid therapy, according to Julia A. Haller, MD. Image: Roger Barone/Wills Eye Institute

“Combination therapy is useful, because there are components [in retinal diseases] of both inflammation, which the steroids hit, and also components of high VEGF levels, which the anti-VEGF therapies hit,” Seenu M. Hariprasad, MD, OSN Retina/Vitreous Board Member, said.

Additionally, new longer-acting steroid implants hold promise for decreasing treatment burden. Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan), which is on-label for macular edema secondary to central or branch retinal vein occlusion and posterior segment uveitis, and Iluvien (sustained-release fluocinolone acetonide, Alimera Sciences), which is currently being evaluated in phase 3 clinical trials collectively known as FAME, are two such implants.

“There are two paradigm shifts that have come about and are continuing to form, which are combination therapy and sustained release. … We are beginning to use sustained-release formulation system treatments in order to decrease the burden on the patient, on the physician and on the health care system,” Szilard Kiss, MD, said.

Sustained-release systems enable steady release of a given drug over an extended period of time, allowing for longer duration between treatments. Clinicians hope that these systems may reduce overall complication rates for retinal disease therapy.

Corticosteroids for retina applications

“The steroid is kind of like a shotgun, whereas the anti-VEGFs, Lucentis and Avastin, are like sniper bullets,” Dr. Haller said, noting that corticosteroids target numerous components of retinal diseases. “That is appealing, because we know that many of these disease processes are quite multifactorial in terms of their pathogenesis.”

Corticosteroids affect different chemical modulators of vascular permeability and retinal edema and stabilize the tight junctions between endothelial cells, in addition to having anti-inflammatory and anti-VEGF effects, she said.

According to Dr. Kiss, steroids activate genes within specific cells, either by turning them off or on, and while considerable overlap exists among all steroids, each affects some of its own specific genes.

“Experimental evidence shows that you have a different gene expression profile depending on what steroid is injected in the eye. Now clinical evidence is also suggesting that this may be true, because steroids have very different side effect profiles,” Dr. Kiss said.

In the realm of corticosteroids for retina applications, there are three chief contenders: triamcinolone acetonide, dexamethasone and fluocinolone acetonide.

Triamcinolone exists in two formulations, as Kenalog (triamcinolone acetonide, Bristol-Myers Squibb), which the U.S. Food and Drug Administration has classified as against-label for intraocular use, and Triesence (triamcinolone acetonide, Alcon); both are available in 1-mg and 4-mg formulations. Triesence is approved by the FDA for visualization during vitrectomy and for treating sympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions that are unresponsive to topical corticosteroids. Off-label indications extend to various retinal vascular uses.

Dexamethasone is available as sustained-release, biodegradable Ozurdex and, in addition to its on-label indications, is currently being evaluated for diabetic macular edema.

Fluocinolone comes as the non-biodegradable Retisert (fluocinolone intravitreal implant, Bausch + Lomb), which is approved for noninfectious posterior uveitis, and the not-yet-approved Iluvien, which is a non-erodible reservoir of fluocinolone acetonide that is being studied for diabetic macular edema. It is injected through a 25-gauge needle and left in the vitreous cavity.

While most surgeons agree that sustained-release implants are going to change the treatment paradigm for retinal disease, some view older corticosteroids as outdated in light of anti-VEGF therapies.

“When we started to use corticosteroids, the only thing we had for retinal vascular diseases was laser photocoagulation. In contrast to laser, the greater improvement that we saw with the corticosteroids and the rapidity of the response, often measured in days rather than months or years, was so significant that the ophthalmology community was extremely excited. … [However,] I would say that corticosteroids, either as monotherapy or as part of combination therapy, have really fallen out of favor over the last 5 to 10 years,” Michael S. Ip, MD, said.

Michael S. Ip

Shortly after initial enthusiasm died down, evidence-based medicine in the form of clinical trials suggested that corticosteroids were not superior to laser photocoagulation, Dr. Ip said. For instance, in a DRCR.net study evaluating intravitreal triamcinolone vs. laser photocoagulation for diabetic macular edema, it was found that laser photocoagulation was superior to triamcinolone at 2 years, with most eyes in the triamcinolone group requiring cataract surgery.

Additionally, while the central retinal vein occlusion (CRVO) analysis in the SCORE studies showed triamcinolone to be more efficacious than observation, the standard of care at that time, the branch retinal vein occlusion (BRVO) analysis suggested equivalent efficacy for triamcinolone and laser, with more adverse events for triamcinolone.

“With respect to central vein occlusion, because there was no treatment for central retinal vein occlusion, we compared corticosteroids to observation, and compared to observation, the corticosteroids were better. … So for some time, people used corticosteroids for CRVO. But again, as with AMD, the advent of anti-VEGF therapy really caused the use of corticosteroids for CRVO, for BRVO and even DME to taper off significantly,” Dr. Ip said.

Sustained visual and anatomical benefits observed at 12 months in the CRUISE and BRAVO studies assessing the use of Lucentis (ranibizumab, Genentech) for macular edema secondary to CRVO and BRVO may further encourage clinicians who prefer anti-VEGFs.

Safety profiles

According to David S. Boyer, MD, who begins many of his retinal treatments with anti-VEGF therapy and then adds steroids if patients are not achieving desired outcomes, the safety profile of a steroid goes beyond the amount delivered, type of administration and individual potency and extends to location of delivery.

“A lot of these differences may be related to sustained release, where you have chronic, low-grade release, or they may be related to the position that the drugs are actually placed,” he said.

The distance between the location of administration and the lens, ciliary body or other components of the eye plays a significant role in determining side effect profiles, Dr. Boyer noted.

“As an example, you have a safer side effect profile using Iluvien, the fluocinolone extended-release implant, than you would using the same medicine put in an insert, in Retisert. … And that’s not necessarily because you’re getting an extended release of a small amount of medication. It may be because you’re also putting the release mechanism away from the front of the eye,” he said.

For patients with severe glaucoma, surgeons typically avoid steroids and stick with anti-VEGFs or other therapies, because pressure elevation is one of the two most common complications of steroids; the other is cataracts. Rates of IOP elevation vary, but to date, there is little clinical evidence to establish one steroid as safer than another due to the lack of head-to-head comparisons.

Dr. Haller said that data from the prospective, multicenter, phase 3 GENEVA trials have suggested that dexamethasone has a better safety profile than triamcinolone, specifically a lower rate of IOP elevation, cataract progression and glaucoma, but she also acknowledged that the drug is not without adverse effects.

“Patients are starting to get some cataracts after they get two doses of the Ozurdex implant, after a year or two or more. There may not so far be a statistical difference in cataract surgery rates compared to the control group, but it is starting to trend upward. … I think it is unlikely that there is any steroid that is going to work that is not going to eventually give you a cataract,” she said.

However, she said there is a decreased treatment burden associated with sustained-release implants. In addition to enhancing convenience, sustained-release systems might reduce certain safety issues associated with frequent intravitreal injections.

“A key appealing aspect of the dexamethasone implant is that it is far more potent a steroid than triamcinolone. It lasts a long time, so you don’t have to re-inject as frequently as you do with anti-VEGF drugs,” Dr. Haller said.

Acknowledging a lack of definitive evidence, Dr. Kiss said dexamethasone may be the safest of the three steroids. He cited Iluvien’s relatively high association with glaucoma surgery, as demonstrated in the prospective, randomized, double-masked, multicenter FAME trials. These analyses showed a 3.7% rate for the low-dose 0.2 µg/day group and a 7.6% rate for the high-dose 0.5 µg/day group.

Dr. Kiss believes that triamcinolone’s safety profile may sit somewhere in between, as injections generate an initial bolus of steroid that may not cause many problems in the long term. Regardless of such variations, he emphasized the advantages of local administration of all three steroids.

“If you are looking at a locally delivered steroid, I think very little gets into the system. People can tolerate higher doses of steroids given locally than they can of those given systemically,” he said.

Varying indications, informed consent

While intrigue over newer sustained-release implants remains high, and while many advocate combination therapy, there remains some debate over steroid indications.

Dr. Kiss considers steroids the standard of care for uveitis and prefers dexamethasone for long-term treatment. In the case of inflammation after cataract or Irvine-Gass syndrome, he performs one sub-Tenon’s injection of triamcinolone and does not typically repeat. He prefers combination therapy for CRVO and BRVO patients, administering anti-VEGFs initially for immediate benefit and then dexamethasone for long-term durability.

“I am looking forward to using something like Iluvien for my diabetic patients. For patients who have this chronic, long-term systemic problem that is causing sort of chronic retinal dysfunction, I think Iluvien will definitely play a role,” he said.

Dr. Boyer is an advocate of laser for diabetic patients who have leaks away from the fovea and no central involvement. He prefers combination therapy for central involvement, using anti-VEGFs first, and believes that longer-acting steroids will be crucial for patients after vitrectomy.

Dr. Ip shares widespread enthusiasm for sustained-release systems and thinks they are the future of treating retinal diseases, but he does not use traditional steroids unless other options have been exhausted.

“I think the use of anti-VEGF therapy is so widespread that it is nearly a standard-of-care therapy for most of the macular diseases that you encounter today. … My main use of corticosteroids is as a second-line rescue therapy,” he said.

Socioeconomic status also plays a role in determining which treatments patients receive, because on-label and off-label therapies tend to have drastically different costs. According to Dr. Hariprasad, the dexamethasone implant is roughly $1,200, while Kenalog is only $16. Moreover, it is well-known that there is a large price difference between anti-VEGFs such as ranibizumab and Avastin (bevacizumab, Genentech).

Seenu M. Hariprasad

“There are some patients who have Medicare only or Medicaid only, so they have a huge co-pay. If we did not have off-label therapy, these patients might go blind. … But in the setting of these options, we have to provide appropriate informed consent,” Dr. Hariprasad said. “We cannot be paternalistic and make the decision for the patient.”

The future

With so many treatment options available and so many studies ongoing to assess anti-VEGFs, steroids, combination therapies and other emerging technologies, deciding upon a course of action may be confusing for clinicians and patients alike.

“The question is: How do you put combinations in effect to really help your patients? There are some patients where steroids work better; there are some patients where anti-VEGFs work better. How do you make these decisions?” Dr. Hariprasad said.

Dr. Boyer suggested that, going forward, retina specialists may be able to predict which patients need anti-VEGFs, steroids or combination therapy by evaluating vitreous specimens and other factors. Widefield angiography may also help to pinpoint areas of non-perfusion, he said.

Pharmacogenetics, or the study of how genetic variations give rise to different drug reactions, may play a role as well, Dr. Haller noted. She said that assessing patients’ underlying genetic predispositions may help to determine which treatments fit which patients.

For instance, in a study published in Investigative Ophthalmology & Visual Science, anti-VEGF treatment outcomes for wet AMD were shown to be associated with variations in the apolipoprotein E gene. On a related note, clinicians recently used longitudinal data from the AREDS to generate a risk assessment model for predicting development of neovascular AMD.

As far as the outlook for corticosteroids is concerned, retina specialists await long-term outcomes for different combination treatments and sustained-release systems.

“I do not think steroids are dead at this point. We just have to figure out their place. … I think we are going to have longer-acting, chronic release mechanisms for anti-VEGFs and steroids with refillables that will allow us to go 3 to 6 months between filling the reservoir,” Dr. Boyer said.

For now, sustained-release implants are viewed by many as a welcome relief from the burden of frequent anti-VEGF injections.

“Repeated intravitreal injections are great, and they are definitely a revolution and a leap forward compared to older treatments, but now we need to do better. We have not done a service to our patients if we say that seven to eight injections a year is acceptable long-term treatment for these chronic retinal disorders,” Dr. Kiss said. – by Michelle Pagnani

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References:

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• David S. Boyer, MD, can be reached at Retina-Vitreous Associates Medical Group, 1127 Wilshire Blvd., Suite 1620, Los Angeles, CA 90017; 213-483-8810; fax: 213-481-1503; email: vitdoc@aol.com.
• Julia A. Haller, MD, can be reached at Wills Eye Institute, 840 Walnut St., Philadelphia, PA 19107; 215-928-3073; fax: 215-928-3853; email: jhaller@willseye.org.
• Seenu M. Hariprasad, MD, can be reached at University of Chicago, Department of Surgery, Section of Ophthalmology and Visual Science, 5841 S. Maryland Ave., MC2114, Chicago, IL 60637; 773-795-1326; email: retina@uchicago.edu.
• Michael S. Ip, MD, can be reached at the University of Wisconsin, Fundus Photograph Reading Center, Park West One, 406 Science Drive, Suite 400, Madison, WI 53711-1068; 608-263-2853; fax: 608-262-1899; email: msip@wisc.edu.
• Szilard Kiss, MD, can be reached at the Weill Cornell Medical College, New York-Presbyterian Hospital, 1305 York Ave, 11th Floor, New York, New York 10021; 646-962-2217; email: szk7001@med.cornell.edu.
• Disclosures: Dr. Boyer is a consultant for Alcon, Allergan, Genentech, Regeneron, Bayer and Novartis. Dr. Haller is a consultant for Allergan, Genentech and Regeneron. Dr. Hariprasad is a consultant for Alcon, Bayer, Allergan, Genentech, OD-OS, Optos and Regeneron. Dr. Ip is a consultant for Genentech, iTech, NicOx and Alimera and receives research support from Allergan. Dr. Kiss serves on the advisory boards of Alimera and Allergan and receives research support from Genentech and Regeneron.