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News in Review
A Look at Today's Ideas and Trends
New AMD Target, Potential New Therapy
In recent years, antiangiogenic agents that inhibit vascular endothelial growth factor have been at the forefront of therapeutic approaches for neovascular age-related macular degeneration.
But now an antiangiogenic agent that targets a different place in the angiogenic cascade is under investigation. Specifically, the experimental agent JSM6427 exerts its effect by blocking the fibronectin receptor, integrin .
Integrins are a family of transmembrane proteins involved in cell survival, adhesion and proliferation; is critical for the growth and stabilization of blood vessels. It binds fibronectin, a glycoprotein in the extracellular matrix. Integrin receptors are upregulated on the surface of activated endothelial cells involved in neovascularization.
“If you block the binding of fibronectin to the integrin receptor, then you can prevent neovascularization from progressing and developing,” said principal investigator Jack Wells, MD, a retina specialist in private practice in Columbia, S.C. “This is a totally new target.”
In addition, is upregulated on fibroblasts, activated retinal pigment epithelial cells and macrophages, all of which are associated with neovascular AMD. Inhibition of fibronectin binding to integrin with JSM6427 may therefore interfere with other key processes in the pathogenesis of AMD, namely fibrosis and inflammation.
“The ultimate hope is that JSM6427 will not only stop progression of neovascularization but also cause regression,” said Dr. Wells. “The large trials of anti-VEGF agents such as ranibizumab (Lucentis) didn’t show much regression of neovascular tissue, just a reduction in leakage and edema and prevention of further growth. That may be a major difference between JSM6427 and current anti-VEGF drugs.”
This phase 1 trial is the first involving humans. Because it is designed to demonstrate safety, patients were enrolled with quite advanced disease. The mean duration of AMD prior to entering the trial, for example, was 27 months; the mean number of prior treatments with intravitreal anti-VEGF injections was six.
Among the 16 patients included in the escalating single-dose phase, there have been no signs of toxicity or serious adverse effects to date, said Dr. Wells. After reaching the maximum single dose of 1.5 mg without toxicity, the trial is now testing repeated injections. Given the very short half-life of JSM6427 in its current formulation, four injections given at weekly intervals at several doses are planned in this phase of the study.
Visual results of the single-dose cohorts were not expected to be good because of the severity of AMD among subjects, said Dr. Wells. Yet in early follow- up, Dr. Wells reported, vision is stable or improved in all patients, with a mean increase of 5 ETDRS letters, and OCTs are stable.
The success of JSM6427 could give retina specialists a welcome new weapon in the fight against AMD. Moreover, because JSM6427 works by a new mechanism, there is hope that it could be used in combination with anti-VEGF drugs to improve anatomic and visual outcomes. Of course the current findings are only early phase 1 results. “We still have a long way to go,” emphasized Dr. Wells.
JSM6427 is being developed by Jerini Ophthalmic Inc. Dr. Wells has no financial interest in Jerini.
New Use for Avastin: Pseudophakic CME TX
Looking at factors that may play a key etiological role in clinically significant pseudophakic cystoid macular edema, including vitreous traction, vascular instability, relative ocular hypotony, ultraviolet radiation and inflammation, one group of researchers determined that the last factor was most worth investigating.
“Inflammation is probably the key etiological factor,” said J. Fernando Arevalo, MD, FACS, director of the Clinica Oftalmologica Centro Caracas in Venezuela. “Previous experimental studies have demonstrated elevated levels of cytokines, including interleukin-6, and many times it is associated with the upregulation of VEGF.”
Choosing their favored theory—inflammation with upregulation of VEGF—Dr. Arevalo and co-investigators studied the feasibility, safety and clinical effectiveness of intravitreal bevacizumab (Avastin) in an interventional, retrospective, multicenter study. Reviewing the clinical records of cataract patients with refractory CME who had not responded after three or four months of conventional treatments, such as systemic, periocular, intravitreal and topical corticosteroids or topical NSAIDS, the investigators hoped to demonstrate results similar to those obtained using bevacizumab in patients with primary CME after cataract surgery.1
Both visual acuity and anatomic status improved significantly, and with no serious ocular or systemic short-term complications, said Dr. Arevalo. Of the 36 eyes (31 patients) with refractory CME, 26 (72.2 percent) had improvement of best-corrected visual acuity of ETDRS lines—a result almost identical to that of the previous study.1 At 12 months, no eyes had worsening of BCVA. As demonstrated by optical coherence tomography, mean central macular thickness also decreased—from 499.9 µm at baseline to 286.1 µm at the end of follow-up (P < 0.0001), which ranged from 48 to 104 weeks.
Although a dosing regimen similar to that used with age-related macular degeneration might be more effective, said Dr. Arevalo, the physicians used a conservative approach, starting with one injection of 1.25 mg or 2.5 mg of bevacizumab, and re-treating only if the patient had a recurrence. This was defined as a decrease of BCVA of two or more ETDRS lines, along with an increase in intraretinal fluid of 50 µm or more due to macular edema, following complete or partial previous resolution. Almost three out of four patients required reinjections.
Because of the invasiveness of intravitreal injections, Dr. Arevalo doubts Avastin will become a first-line therapy for CME. But he predicts it will be added to the specialists’ armamentarium for the treatment of refractory macular edema, especially if future prospective, controlled studies duplicate these initial findings. “I think bevacizumab modifies the natural history of macular edema,” said Dr. Arevalo. Because fluid is under the macula for less time, he added, complications of chronic CME can be reduced or avoided.
1 Arevalo, J. F. et al. J Cataract Refract Surg 2007;33:2098–2105.
Dr. Arevalo reports no related financial interests.
Keratoconus and LASIK: Mapping Out Who’s Eligible
Despite the presence of topographical forme fruste or suspect keratoconus, epithelial thickness mapping may enable refractive surgeons to safely perform LASIK in patients formerly considered ineligible for the procedure, according to Dan Z. Reinstein, MD, medical director of the London Vision Clinic, and his colleagues.
Performing LASIK on eyes with forme fruste keratoconus or undiagnosed keratoconus is a chief concern among refractive surgeons because it is the leading cause of ectasia after laser refractive surgery. The procedure is therefore generally contraindicated in patients with an abnormal corneal topography—a condition detected in up to 10 percent of patients during preoperative screening.
“Although corneal topography is the current standard for keratoconus screening, it cannot definitively identify early or mild cases of keratoconus,” said Dr. Reinstein. “Instead, surgeons must exclude patients with suspicious topographies even though some are suitable candidates. Conversely, there are cases in which the topography appears normal, but the patient indeed has keratoconus. The result is that surgeons err on the side of caution and exclude some patients, while simultaneously approving others who are at risk for ectasia. The ideal solution is a diagnostic technique that renders a definitive diagnosis of keratoconus. If keratoconus is present, surgery would not be performed; but, if keratoconus is excluded, either PRK or LASIK can be done.”
Dr. Reinstein has scanned thousands of eyes throughout his career and may have discovered a solution to this quandary. “I noticed that the epithelial thickness profile varied between patients and diagnoses. Patients with advanced keratoconus have a very distinct epithelial thickness profile with epithelial thinning over the region of topographic steepening, surrounded by an annulus of epithelial thickening.
“I also noticed that sometimes this pattern was present in mild topographic asymmetry of the sort that wouldn’t normally be of concern to a surgeon screening for LASIK candidacy. Conversely, there were eyes in which the topography looked like possible keratoconus, but the pattern of thin surrounded by an annulus of thick epithelium was absent; in fact, the epithelium was thicker in the region of topographic steepening. In other words, sometimes it is the asymmetry of epithelial thickness that produces inferior steepening on topography, mimicking keratoconus.
“This inspired me to investigate whether the epithelial thickness profile could be used to exclude keratoconus in cases that I would have otherwise rejected for LASIK due to suspicious topography,” he said.
Dr. Reinstein and his colleagues conducted a controlled prospective study of LASIK stability in eyes with topographically suspected keratoconus classified as nonkeratoconic by epithelial thickness mapping.
In the study, 104 of 1,352 consecutive myopic eyes in patients who presented for refractive surgery had topographic forme fruste or suspect keratoconus. Epithelial thickness mapping excluded keratoconus in 90 of these eyes and confirmed keratoconus in 14 eyes. LASIK was performed on the 90 eyes. Stability of spherical equivalent and cylinder were followed for one year, and the researchers found that the control and study groups were statistically identical.
“We found that epithelial thickness mapping may provide a tool that enables us to distinguish whether surgery can be performed in equivocal cases,” said Dr. Reinstein. “Surgeons can identify patients in whom corneal ablative procedures are contraindicated, but they can also identify patients who are suitable for surgery despite topographic findings suggestive of keratoconus,” he said.
“Our next step is to study the differences in the epithelial thickness profile between normal and keratoconic eyes and define parameters with which to classify normal corneas from early keratoconus,” said Dr. Reinstein
Update on New Glide Insertion Device for DSAEK
Last year, three ophthalmologists from Singapore reported on a device they had developed to minimize endothelial cell damage during Descemet’s stripping automated endothelial keratoplasty (DSAEK). This year, they describe an improved version of the device (Network Medical Products), which potentially offers even better results.
“We have developed a specially designed disposable inserter,” said Donald Tan, MD, medical director of the Singapore National Eye Center. “The actual technique of gliding and pulling the donor tissue through the scleral wound is more efficient with our new device and should result in even less endothelial damage.”
Dr. Tan calls the disposable device a lot easier to use than the flexible, clear plastic, modified standard anterior chamber sheet glide that he reported on last year during the Annual Meeting’s Cornea Papers session. The 2008 version is, he said, “a delivery system that’s shaped like a plastic airplane cockpit.” Where last year’s model required trimming or cutting the flexible plastic sheet to size, this year’s design requires a simple two-step procedure. The donor tissue is preloaded into the disposable inserter in much the same way an IOL is loaded into a cartridge. Then, the unit is inserted into the scleral wound, and using intraocular forceps introduced from a nasal paracentesis, the surgeon grasps the corneal tissue and slides it into the eye.
“The key concept in our new device is that we obviate contact between plastic and the endothelial surface of the donor, and also avoid endothelium-to-endothelium contact to significantly reduce cell loss,” he said.
“Cell loss with the older glide was 29.8 percent. With our new glide, we hope to cut that down to well below 20 percent. Especially important is the fact that, like with our previous method, the donor tissue does not require folding with forceps and unfolding within the anterior chamber, which has been shown to be damaging to the corneal endothelium.”
The team’s prospective clinical evaluation, to be presented at this year’s Meeting, compared 70 cases of the improved glide’s insertion with 20 cases of conventional donor-folding insertion. Mean postoperative endothelial cell loss was 61.4 percent in the folding group and 29.8 percent in the glide insertion group. The donor dislocation rates were 5 percent and 1.43 percent, respectively. The Singapore National Eye Center, home to a large database of cornea transplants, will provide comprehensive clinical data over the next few months as clinical trials begin using the new capsule inserter.
“Corneas are frequently wasted if they’re damaged when inserted using the more conventional folding insertion techniques. We’re trying to make the technique safer and easier by manufacturing the disposable inserter as cost-effectively as possible,” said Dr. Tan.
Dr. Tan has a patent pending and will receive royalty fees from Network Medical Products.
Drug in a Plug May Lower Pressure
It’s an oft-quoted statistic: Fifty percent of patients with chronic health conditions don’t take their prescribed medication. The same is true of glaucoma patients—many don’t use or even obtain the very medication that could alleviate their condition.
Now scientists are testing a new punctal plug device for delivery of glaucoma medication into the eye, which may provide a solution.
Since punctal plugs are already in use for dry eye and are fairly comfortable, they might be an ideal device for delivering glaucoma medication in slow release—and could help resolve noncompliance among glaucoma patients, said lead author Richard A. Lewis, MD, a glaucoma consultant based in Sacramento, Calif. Other devices for delivering glaucoma medication into the eye have been tried with little success. For instance, contact lenses or ocular inserts placed in the cul-de-sac can be used to deliver glaucoma medications, but they tend to be poorly tolerated, he said.
In the study, the investigators fitted 10 eyes that had elevated IOP (five patients) with a latanoprost-eluting punctal plug delivery system (QLT Inc.). This pilot trial was designed to test whether the punctal plug technology could lead to a reduction in IOP over 90 days. The primary efficacy endpoint was measurement of IOP.
At baseline, the mean IOP was 23mmHg for the 10 eyes treated. However, at 90-day follow-up, the mean IOP was reduced to 17mmHg for the six eyes that remained—a 28 percent decrease from baseline. Data from two patients were excluded due to loss of a plug. No significant adverse events were reported.
“This is a preliminary study, but it showed us that punctal plugs can be comfortable and can decrease IOP,” Dr. Lewis said, adding that the plugs did not cause any discomfort, and there was little initial redness. Questions remain about how to ensure retention of the plugs and what dose of latanoprost can achieve efficacy while minimizing side effects, and the investigators also want to determine whether the concentration of latanoprost will induce side effects, he said.
The next step is a phase 2 randomized study involving up to 60 patients with primary open-angle glaucoma or ocular hypertension. The punctal plug delivery system in this study will contain different concentrations of latanoprost.
Although the current study contained only a small series of patients, the idea of delivering glaucoma medication through punctal plugs may be a promising one. According to Kuldev Singh, MD, MPH, professor of ophthalmology and director of the glaucoma service at Stanford University, “Any safe and effective method of delivering glaucoma medications without the patient having to instill eyedrops would be a significant advance in how we care for our glaucoma patients, he said.
While some physicians may have concerns about punctal plugs falling out or getting “lost” in the lacrimal duct, Dr. Singh, who was not involved in the study, said, “Only time will tell if this scenario is problematic.” He noted that patient noncompliance and nonpersistence with glaucoma medications is a significant problem and is due to a number of factors, including difficulty with instillations, poor memory, lack of affordability and other difficulties in obtaining medications.
“If a system could be found that provided glaucoma drugs via slow release into the eye, and could do so over a length of time that would allow appropriate IOP lowering throughout the period between physician visits, the result could contribute significantly toward caring for glaucoma patients,” Dr. Singh said.
Dr. Lewis is a consultant to QLT. Dr. Singh reports no financial interest in QLT. The trial was underwritten by QLT.