Chicago—The FDA has approved ISTA Pharmaceuticals’ supplemental new drug application for bromfenac ophthalmic solution 0.09% (Bromday) as a once-daily prescription eye drop for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract extraction.

 “[The eye drop] is the only once-daily ophthalmic nonsteroidal anti-inflammatory drug for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract extraction,” said Vicente Anido Jr., PhD, president and chief executive officer of ISTA. “We believe the convenience of a once-daily eye drop will help with treatment compliance and benefit patients recovering from cataract surgery.

“Since the . . . approval process required additional clinical investigations beyond those conducted for the original approval of bromfenac 0.09% [Xibrom],” Dr. Anido said, “we are seeking a 3-year exclusivity period under the Drug Price Competition and Patent Term Restoration Act, commonly known as the Hatch-Waxman Act.”

ISTA expects to launch the once-daily eye drop (formerly referred to as XiDay) before the end of the year. In addition, ISTA said that it expects to discontinue the twice-daily eye drop in early 2011.

Chicago—Retinopathy of prematurity (ROP) is the result of two phases: induction of ischemia and reactive secretion of growth factors. Jonathan Sears, MD, associate professor of ophthalmology, Cole Eye Institute, Cleveland, OH, described strategies to intervene in these processes during the first phase to sidetrack ROP development.

Because of the implication of increased levels of oxygen being associated with ROP, a recent study performed by Dr. Sears and colleagues controlled oxygen saturation levels by targeting them to 85% to 92% in infants with a corrected gestational age of 34 weeks and less and then later increased the oxygen saturation levels to 92% to 97% after 34 weeks corrected gestational age. This strategy allowed the retinas to follow the normal developmental course and prevent ROP.

“Gentle ‘physiologic’ hypoxia is required to induce retinal growth,” Dr. Sears said. These oxygen levels better approximate those that are found in the developing fetus and resulted in a “drastic reduction in ROP” from 35% to 40% to 10%. In later years, he noted, it is rare to see any ROP. However, the downside is that there was a trend toward increased mortality in the affected infants.

The second step in the strategy of regulating oxygen saturation levels involves pharmaceutical preconditioning. In a murine model, one injection of the antagonist of prolyl hydroxylase protected the retina from oxygen-induced retinopathy.

An exciting finding for Dr. Sears was that the liver might be the controlling factor in ROP, not the retina.

“We are really at an exciting crossroads,” he said. “In the future, we may be able to go upstream and prevent ischemia in the first place.”

Chicago—Following dramatic improvements in vision in patients with Leber’s congenital amaurosis (LCA) who underwent gene therapy treatment, the next step is bilateral treatment with injections of a genetically engineered vector into the target tissue. Albert Maguire, MD, described the progress in this retinal disease and the future steps that will be undertaken soon.

Gene therapy in patients with LCA resulted in increased light sensitivity within days of administration. In the treated eyes, investigators found pupillary responses to light and visual acuity increases in about 50% of patients. The biggest changes were increased visual fields and retinal sensitivity that was best in younger patients with viable photoreceptors, said Dr. Maguire, associate professor of ophthalmology, University of Pennsylvania, Bryn Mawr, PA. Thus far, about 30 patients have been treated.

Functional magnetic resonance imaging studies indicated that activity in the visual cortex was correlated with areas of the retina treated and changes in the visual fields. The changes in visual acuity were dramatically evident in the post-treatment videos of patients negotiating mobility courses that previously had been impossible to navigate. Outside the clinic, patients can ambulate independently, read large print, and write normal script.

Treatment of both eyes requires evaluation of the safety of re-administration of the therapy. A phase III study of bilateral near-simultaneous injections will be undertaken.

“The number of clinical trials now recruiting patients with LCA attests to the enthusiasm for retinal gene therapy,” Dr. Maguire said.

Chicago—A few strategies are under study to restore sight, including implantation of retinal prostheses, gene therapy, and stem cell replacement therapy. All approaches are promising but there are substantial barriers to overcome.

Another approach is use of a small molecule, AAQ, a photoactivatable compound, to induce light sensitivity in retinal ganglion cells. Russell Van Gelder, MD, PhD, chairman of ophthalmology, University of Washington School of Medicine, Seattle, described this novel approach.

When the AAQ compound was applied to neurons, it blocked the potassium channel, with resultant cell depolarization. When irradiated with 390-nm light, the channel was unblocked. After irradiation with 500-nm light, blockage and cell depolarization again resulted with cell firing. Dr. Van Gelder and colleagues applied the AAQ compound to hippocampal brain slices in vitro, and the compound produced light-dependent firing activity.

In a blind mouse model with no detectable light responses, when 2 μl of 100 mM AAQ was injected, the pupils reacted to light, leading to the conclusion that AAQ confers light sensitivity on a large proportion of retinal ganglion cells without short-term retinal toxicity. The question the investigators ultimately hope to answer is whether AAQ can be used to restore vision.

“AAQ confers light sensitivity to genetically blind mice,” Dr. Van Gelder concluded. “Ganglion cell firing can be controlled by different wavelength light. AAQ is responsible for partial restoration of the pupillary light response.”

Chicago—The questions surrounding idiopathic macular telangiectasia type 2 (MacTel) are slowly being answered as a result of the ongoing MacTel Project, but information about disease pathogenesis remains elusive. Mark Gillies, MD, PhD, speaking for the MacTel Project Study Group, reported the status of the study.

The 5-year MacTel Project, which is under way in 26 centers around the world, set out to observe the natural disease course, follow the progression, and conduct a genetic study of patients and families in order to identify genes and genetic variants. An eye donor program also was initiated to collect and study the disease pathology. About 500 patients have been enrolled, according to Dr. Gillies.

He reported that MacTel has been found to occur more commonly than previously thought and may be as or more common than retinitis pigmentosa.  The disease also is worse than previously suspected with loss of cones and dense central scotomas with patients have visual acuity levels similar to patients with age-related macular degeneration.  The study found that patients with MacTel have a higher prevalence of diabetes as well as hypertension and coronary artery disease. Familial transmission of the disease is recognized, but the gene has not been identified. MacTel remains untreatable, and the cause is unknown.

Dr. Gillies pointed out that study of subclinical disease likely will help determine the underlying disease mechanism. The project will conduct additional research to identify related gene defects, develop other animal models, use adaptive optics to study photoreceptor changes in the earliest clinical phenotype of the disease, and identify potential treatments, of which ciliary neurotrophic factor may be one. The hope is to conduct a phase III study of one or more candidate therapies.

Chicago—High rates of endothelial cell loss reported with Descemet’s stripping endothelial keratoplasty (DSEK) may spur a return to penetrating keratoplasty (PK) as the standard of care for vision loss from corneal edema, said Shahzad I. Mian, MD, assistant professor, Kellogg Eye Center, University of Michigan, Ann Arbor.

Although DSEK offers advantages such as a small-incision size, fewer sutures, reduced astigmatism, tectonic stability, and faster visual recovery, these pluses could be offset by higher rates of posterior graft dislocation and endothelial injury with primary graft failure. The paucity of long-term follow-up data also is problematic.

“There are factors that we just don’t know yet,” Dr. Mian said. “There’s increased primary graft failure, but we don’t know what’s going to happen in the long term regarding graft survival.”

The mean rate of posterior graft dislocation with DSEK is 14.5% (range 0% to 82%, indicating a large learning curve), while the mean rates of endothelial cell loss at 6 and 12 months are 37% and 42%, respectively, also with a wide range. The graft failure rate, measured by regraft rates, is a mean of 5% (range 0% to 29%). In addition, the rate of cell loss in the combined DSEK/cataract/IOL procedure has been reported to be 32% at 6 months.

Insertion techniques may be the Achilles’ heel of DSEK, Dr. Mian said. Studies have shown a cell loss rate of 32% to 34% at 6 months using the forceps technique, which has led to the introduction of many other techniques that may have fewer complications.

Dr. Mian also noted that DSEK procedures may be more expensive than PK because the higher failure rate and subsequent repeat procedures require more precut donor tissue from eye banks and additional preparation costs.

The proportion of endothelial keratoplasty corneal transplants has increased dramatically whereas that of PK has decreased in recent years. This trend may be reversed if data showing greater endothelial cell injury are verified by long-term data. Extensive experience with PK and solid prospective data may be factors in this change, Dr. Mian said, emphasizing the need for a prospective, randomized, multicenter trial to compare the outcomes of the two procedures.

Chicago—The quality of communication between ophthalmologists and their patients with glaucoma presently is imperfect, but easily can be improved with potential implications for improving patient behavior regarding medication compliance, said David S. Friedman, MD, MPH, PhD, the Alfred Sommer Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.

Dr. Friedman and colleagues developed a study to analyze interactions between ophthalmologists and their patients with glaucoma and to evaluate the effect of a simple intervention to improve the quality of the physician-patient communication. They recruited 23 practitioners who agreed to have their patients’ visits videotaped before and after the physicians participated in an educational program about improving their patient interactions.

The educational program was a 3-hour course with coaching on four basic steps for improving communication:

• Ask open-ended questions.

• Create a nonjudgmental environment.

• Ask about patient understanding of glaucoma.

• Ask about missed doses.

The behavioral intervention program significantly improved physician behavior in these areas, but also tripled the ability of the physicians to detect non-adherence. Whereas in the pre-intervention visits, the physicians identified only 25% of non-adherent patients, their detection rate increased to 78% in the post-intervention visits.

“Poor medication adherence is a failure of the system,” Dr. Friedman said. “It is partly our failure and partly our patients, but it almost certainly reduces the success of our treatments. While our study did not follow the patients to determine if they took more drops, I believe that changing the way we talk to patients can improve their outcomes.”

Chicago—Although prostaglandin analogue agents have remained the last new class of drugs approved for the treatment of glaucoma for almost 15 years, the situation is likely to change in the not-too-distant future considering the wide array of unique compounds in clinical development, said Richard A. Lewis, MD, a glaucoma specialist in private practice, Sacramento, CA.

Reviewing the current pipeline based on his review of publicly available information, Dr. Lewis noted that among potential new IOP-lowering agents, rho-kinase inhibitors are perhaps generating the most enthusiasm. Acting by rearranging the actin cytoskeleton to restore trabecular meshwork and enhance outflow, one investigational agent (Aerie Pharmaceuticals) showed a 28% reduction in IOP in a phase IIa clinical trial.

Other IOP-lowering agents in development include an EP2 receptor agonist (Pfizer) that targets uveoscleral outflow, an adenosine-1 receptor agonist (Inotek) that reduces IOP by clearing protein material from the trabecular meshwork, an oral selective adenosine-3 receptor agonist (Can-Fite) that is presumed to inhibit inflammatory cytokine production in the outflow system, and an RNA interfering agent that inhibits expression of beta-2 adrenergic receptors (Sylentis).

“Efficacy data on these new compounds is limited, but they are raising exciting potential for the future,” Dr. Lewis said. “And, while IOP lowering remains the goal, we can only wonder whether visual restoration is far off.”

Chicago—Approaches to wound modulation after filtration surgery have not changed much over the past 20 years, but new therapeutic agents and combination approaches are showing promise, said Malik Y. Kahook, MD.

Although current use of mitomycin-C and 5-fluorouracil helps to increase surgical success rates, the benefit occurs at the cost of increased short- and long-term complications, said Dr. Kahook, associate professor of ophthalmology, University of Colorado School of Medicine, Denver.

Combination therapy has not received much attention for modulating wound healing after filtration surgery, but has potential for improving efficacy and safety by possibly offering synergistic therapeutic activity while allowing the use of lower doses of each medication.

A pilot clinical trial conducted by Dr. Kahook yielded encouraging results about the potential for a combination approach adding the anti-vascular endothelial growth factor (VEGF) agent, ranibizumab (Lucentis, Genentech), to mitomycin-C. The study was an open-label, phase I/II safety trial enrolling 10 patients with primary open-angle glaucoma undergoing trabeculectomy. They were randomly assigned equally into two groups to receive topical mitomycin-C alone or combined with intravitreal ranibizumab. The primary endpoint was bleb morphology and vascularity scored using the Moorfields Bleb Grading System.

The two study groups were similar in their preoperative mean IOP and mean bleb scores on the first day after surgery. However, at the end of the 6-month postoperative follow-up, there were statistically significant differences favoring the combination group in three of the grading system categories: peripheral bleb area, peripheral bleb vascularity, and non-bleb-related peripheral conjunctiva vascularity.  There were no cases of bleb leaks, all patients remained off medications, and vision remained stable.

“Ranibizumab also has an anti-inflammatory effect, and I was struck by how quiet the eyes were that had been treated with this anti-VEGF agent,” Dr. Kahook said. “Further studies are needed to validate these findings and better understand the role of anti-VEGF treatment at the time of trabeculectomy. Now we are proceeding with another clinical trial that will include a third arm receiving ranibizumab only at the conclusion of surgery.”

Chicago—With rare exceptions, all patients with definite glaucoma should be treated and in a similar way, which is as aggressively as possible, said M. Roy Wilson, MD, professor of ophthalmology, University of Colorado School of Medicine, Denver.

Characterizing the treatment of glaucoma as still an art, rather than a science, Dr. Wilson advocated tailoring management based on follow-up and not on existing risk factors.

He supported his opinions with data on the natural history of untreated glaucoma from observational cohort studies in Olmsted County and St. Lucia and from the Early Manifest Glaucoma Trial showing that 1) the probability of blindness in untreated or suboptimally treated glaucoma was high, and 2) there is significant interpatient variability in rate of glaucoma progression.

The latter information suggests the potential utility of determining markers for identifying patients who are likely to progress faster than others, and certain risk factors for a faster rate of progression have been determined, including older age, bilaterality, presence of disc hemorrhages, and worse disease severity based on IOP level and extent of visual field damage. However, the predictive value from applying this information to the individual patient is poor, Dr. Wilson said.

“Treatment for glaucoma can be monitored based on data collected, and the treatment approach can be modified based on this information, but it should not be based a priority on risk factors that are looked at prior to initiating treatment,” he said.

Chicago—The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, was honored for excellence in the area of Best Research in Ophthalmology Times’ 2010 Best Programs Awards.

The institution was ranked first in the category in an Ophthalmology Times poll of chairmen and residency directors from the Association of University Professors of Ophthalmology and all Ophthalmology Times e-mail subscribers.

Peter J. McDonnell, MD, director and William Holland Wilmer Professor of Ophthalmology, accepted the honor. The award was presented by Ophthalmology Times during the Wilmer Eye Institute’s reception Saturday evening at the University Club of Chicago.

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