Retina drug therapies ever evolving


Medical advances run gamut from AMD to symptomatic vitreomacular adhesion


Pharmacologic treatments for retina diseases continued to made headlines in 2013, including the release of ocriplasmin and the AREDS2 Study.


Dr. Dugel

By Lynda Charters; Reviewed by Pravin U. Dugel, MD, Sharon Fekrat, MD, and Paul Hahn, MD, PhD

Thanks to drug therapy advances in 2013, retina patients can benefit from pharmacologic vitreolysis and improved monitoring of oral hydroxychloroquine use.

Likewise, clinical studies are testing new drugs to treat both dry and wet forms of age-related macular degeneration (AMD). Trials also hold the promise of combination therapies for AMD as well as diabetic macular edema (DME) and retinal vein occlusion (RVO).

However, the Age-Related Eye Disease 2 (AREDS2) Study proved to be inconclusive.

Pharmacologic vitreolysis

One highlight of drug delivery during the past year is the commercial availability of ocriplasmin (Jetrea, ThromboGenics) to induce vitreolysis pharmacologically.

“This is a revolutionary formulation in that it is the first of its kind that is designed to pharmacologically treat patients with symptomatic vitreomacular adhesion, which can lead ultimately to macular hole formation,” said Paul Hahn, MD, PhD, assistant professor of ophthalmology, Duke Eye Center, Duke University School of Medicine, Durham, NC.

“Before the availability of this drug, the only option was observation of the patients to evaluate for progression which might prompt the need for surgical intervention,” Dr. Hahn said. “Ocriplasmin can induce vitreomacular separation without surgery in some cases.”

Retinal protection

The AREDS2 Study found that the new supplement formulation that was proposed was not superior to the previous AREDS1 formulation.

However, the investigators did identify a benefit of the supplement among a subgroup of patients who received the AREDS2 formulation. Removing beta-carotene and adding lutein and zeaxanthin resulted in an additional 18% decrease in the risk of progression to advanced AMD, Dr. Hahn noted.

“This vitamin formulation is probably helpful to some degree,” Dr. Hahn said. “The optimal formulation still remains to be determined. In the AREDS2 study, supplementing the formulation with the additional components did not result in any significant benefit.”

Pravin U. Dugel, MD, found the clinical interpretation of the AREDS2 study challenging.

“This was a fantastic study and very difficult to perform,” said Dr. Dugel, clinical associate professor of ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles.

“This study showed that when considering the entire self-selected study population, the components of the formulation-such as the antioxidants and fish oil-that were thought to be helpful were not helpful,” Dr. Dugel said.

Patients who are apt to enroll in such a study are those who are motivated to take better care of themselves.

One concern, Dr. Dugel noted, is generalizing the results from that subset of motivated patients to the entire population of patients that ophthalmologists see on a daily basis.

“The AREDS results should be taken in perspective,” he said. “They may apply to that group of people seen in the study, but may not be generalizable.”

Dr. Dugel also commented on an interesting study performed by Carl Awh, MD, and colleagues showing that-depending on individual genetic factors-certain nutrients might be more beneficial or harmful to patients. The investigators published their findings in Ophthalmology (2013;11:2317-2323).

“This is highly controversial and a great deal more study needs to be done, he said. “However, this is the first time that we have the possibility of individualized nutritional medicine.”

This study was not definitive, but is an exciting concept to consider, Dr. Dugel added.


Wet and dry AMD and RVO

Generally, there is a bigger disconnect between clinical trials and real patient experience in AMD, DME and BVO, in the opinion of Dr. Dugel.

“Many of the trial protocols simply are not sustainable,” he said. “We are also seeing that the number of treatments [which] patients actually receive are less than what they should have been receiving. Therefore, the outcomes must be much worse than those that are expected in randomized clinical trials.”

Sustained as well as effective therapy may be attainable with the introduction of combination therapies, which seems to be the future trend.

“As good as anti-vascular endothelial growth factor [VEGF] treatment is, . . . we may have reached a ceiling with anti-VEGF monotherapy,” Dr. Dugel said. “Combination therapy may be the logical evolutionary strategy when treating wet AMD.”

A novel anti-platelet-derived growth factor combination agent (Fovista, Ophthotech) may be the next important therapy for wet AMD, he continued. Clinical trials are currently under way.

“This will be the most exciting combination treatment,” he said.

For the treatment of diabetes and RVO, Dr. Dugel sees a strong role for steroid delivery devices, two in particular: dexamethasone (Ozurdex, Allergan) and fluocinolone acetonide (Iluvien, Alimera Sciences).

The steroid devices have different pharmacokinetic profiles from each other, he said.

Dexamethasone provides an initially high-dose increase and a slow decrease and can last 3 to 5 months, whereas fluocinolone acetonide has a near zero-order kinetics with release that may last for 3 years, Dr. Dugel explained.

The choice is not one or the other. We need both to achieve the best treatment, Dr. Dugel said.

“We also will see a trend toward combination treatment in DME and RVO,” he said.

Progress for dry AMD also continues to be made in clinical trials.

 For instance, a study involving an oral visual cycle modulator, emixustat hydrochloride (Acucela), is currently under way.

“The drug slows the visual cycle and decreases toxic by product accumulation,” Dr. Dugel said. “It has the potential to be an effective and sustainable strategy to decrease progression to dry AMD.”

Anti-factor D (Genentech) is an injectable drug recently studied in a phase II trial for the treatment of geography atrophy. In patients with complement factor I, results show a 44% reduction in the progression to geographic atrophy (GA) with monthly injections. This is the first study to demonstrate a positive treatment effect with a complement inhibitor in GA, he noted.

“All of these drugs are exciting,” Dr. Dugel said. “Even within the same drug category, these drugs can complement each other.

“The goal is to individualize therapy,” he added. “Therefore, the more drugs we have at our disposal, the better . . . for our patients.”

Detection of ophthalmic toxicity

Guidelines for detecting ophthalmic toxicity in the form of retinal pigment epithelial and retinal injury in patients receiving hydroxychloroquine (Plaquenil, Sanofi-Synthelabo) have changed. The American Academy of Ophthalmology recently updated guidelines for detecting toxicity resulting from the drug using newer imaging technologies.

Hydroxychloroquine is used to treat inflammatory diseases, such as rheumatoid arthritis and lupus. However, the drug is associated with corneal changes and irreversible retinal toxicity, so early detection is advised.

In the retina, bilateral pigmentary retinopathy can develop that manifests late in disease as a bull’s eye maculopathy with paracentral and central scotomas.

Ultimately, extensive retinal and retinal pigment epithelial atrophy develops that affects the central and peripheral vision, which emphasizes the need for early screening to prevent profound visual loss, according to Sharon Fekrat, MD, associate professor of ophthalmology, Duke Eye Center, Duke University School of Medicine, Durham, NC, and chief of ophthalmology at the Durham Veterans Affairs Medical Center.

The recommended screening modalities for detecting hydroxychloroquine side effects include biomicroscopy, Humphrey visual field testing, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, or multifocal electroretinography.

When Dr. Fekrat performs screening, she prefers 10-2 Humphrey visual field white-on-white.

“We are standardizing our protocol at the Durham VA and have decided on this approach after collaborative discussion,” she said.


Pravin U. Dugel, MD

Dr. Dugel is a consultant for Alimera, Allergan, Bausch + Lomb, Genentech, Novartis, Regeneron, and ThromboGenics. He is also a minor shareholder of Ophthotech.


Sharon Fekrat, MD

Dr. Fekrat has no financial interest in the subject matter.


Paul Hahn, MD, PhD

Dr. Hahn has no financial interest in the subject matter.



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