Volume 3, Number 5
May 2007



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: EARLY TRIAL RESULTS: VEGF TRAP FOR AMD AND DME; PHASE II TRIAL OF AMD EYE DROP THERAPY BEGINS






WELCOME

Welcome to Review of Ophthalmology’s Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

In this edition:
The latest published research
Noteworthy, items of interest

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THE LATEST PUBLISHED RESEARCH

Dexamethasone Implant for Macular Edema
In a six-month study evaluating a dexamethasone drug delivery system (DDS) for the treatment of macular edema, a single implant significantly improved best-corrected visual acuity (BCVA) by 90 days and was well-tolerated for 180 days.

A total of 315 patients were randomized to observation or a single treatment with either a 350-mcg or a 700-mcg dexamethasone DDS. All patients had persistent macular edema (greater than or equal to 90 days despite treatment) and BCVA of 20/40 to 20/200 in the study eye.

At 90 days, which was the primary endpoint, a greater proportion of patients treated with dexamethasone DDS achieved an improvement in BCVA of 10 letters or more (35 percent of the 700-mcg group, 24 percent of the 350-mcg group, and 13 percent of the observation group). An improvement of 15 letters or more was achieved in 18 percent of the 700-mcg group compared with 6 percent of the observation group.

During three months of observation, 11 percent of treated patients and 2 percent of observed patients had intraocular pressure increases of 10 mmHg or higher. Study results were similar in patients with diabetic retinopathy, vein occlusion, uveitis or Irvine-Gass syndrome.

Source: Kuppermann BD, Blumenkranz MS, Haller JA, et al. (Dexamethasone DDS Phase II Study Group). Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 2007;125(3):309-17.

Using OCT to Predict Treatment Outcome in DME
Based on its analysis of 25 controls and 93 patients with diabetic macular edema (DME) treated with intravitreal triamcinolone, a group of researchers hypothesized that optical coherence tomography (OCT) findings may be predictive of visual outcome.

Two independent masked observers retrospectively examined pre-treatment OCTs from 93 eyes of 93 patients who were given a single injection (4 mg/0.1 mL) of triamcinolone for DME. Eyes were categorized into two groups. Group One showed high reflectivity of inner retinal layers on OCT. Group Two showed low reflectivity of inner retinal layers.

All patients completed three months of follow-up, and macular thickness decreased significantly after treatment in both groups. However, in Group One, 44 of 51 eyes (86 percent) experienced visual acuity improvement of two or more lines at three months. In Group Two, 18 of 42 eyes (43 percent) experienced visual acuity improvement of one or more lines. Acuity remained unchanged in the remainder of eyes.

The authors of the study paper concluded that low reflectivity of inner retinal layers may be related to their atrophy, thus resulting in a failure of visual acuity recovery.

Source: Gibran SK, Khan K, Jungkim S, Cleary PE. Optical coherence tomographic pattern may predict visual outcome after intravitreal triamcinolone for diabetic macular edema. Ophthalmology 2007;114(5):890-894.

Bevacizumab for Macular Edema Associated with BRVO
A retrospective review of 27 consecutive patients who received intravitreal injections of bevacizumab (Avastin) for macular edema secondary to branch retinal vein occlusion (BRVO) suggested that the treatment can be safe and effective in this setting. Patients received an average of two injections (1.25 mg/0.05 mL); mean follow-up time was 5.3 months.

Mean visual acuity improved from 20/200- at baseline to 20/100+ at last follow-up (p<0.001). Mean central macular thickness improved from 478 µm at baseline to 332 µm at last follow-up (p<0.001). No adverse events occurred.

Source: Rabena MD, Pieramici DJ, Castellarin AA, et al. Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion. Retina 27(4):419-425.

Three Cases of Rebound Macular Edema after Treatment with Bevacizumab
A recent report in the journal Retina describes three cases of macular edema secondary to retinal vein occlusion that initially responded to treatment with intravitreal bevacizumab but subsequently recurred. In all three patients, the rebound edema was more pronounced than it had been before treatment.

The authors of the report wrote that the cases illustrate a potential limitation of using relatively short-acting anti-vascular endothelial growth factor (VEGF) agents in chronic retinal vascular diseases. Frequent injections may be required to prevent a rebound effect with no clearly defined endpoint. They recommended caution in using this treatment strategy until the long-term safety of multiple injections is established.

Source: Matsumoto Y, Freund KB, Peiretti, et al. Rebound macular edema following bevacizumab (Avastin) therapy for retinal venous occlusive disease. Retina 2007;27(4):426-431.

Pharmacokinetics of Bevacizumab in the Rabbit Eye
An experimental animal study found the half-life of 1.25 mg of intravitreally administered bevacizumab to be 4.32 days in the vitreous of rabbit eyes. Researchers injected bevacizumab into one eye of 20 Dutch-belted rabbits. They enucleated both eyes of each of four rabbits at days one, three, eight, 15 and 29 and measured the concentration of bevacizumab in aqueous fluid, whole vitreous and serum.

Concentrations of >10 µg/mL bevacizumab were maintained in the vitreous humor for 30 days. Three days after drug administration, concentrations in the aqueous humor of the injected eyes reached a peak of 37.7 µg/mL. A maximum serum concentration of 3.3 µg/mL was achieved eight days after injection and fell below 1 µg/mL 29 days after injection. Elimination from the aqueous humor and serum paralleled elimination from the vitreous humor, with half-life values of 4.88 days and 6.86 days, respectively.

Concentrations in the vitreous of the fellow eyes varied incrementally, from 0.35 ng/mL at one day to 11.17 ng/mL at four weeks. Concentrations in the aqueous humor of the fellow eyes reached a peak of 29.4 ng/mL at one week and declined to 4.56 ng/mL at four weeks.

Source: Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114(5):855-859.

Tacrolimus for Uveitis
In a retrospective case series evaluating the immunosuppressive agent tacrolimus for the treatment of noninfectious uveitis, treatment outcomes were maintained long-term and the cardiovascular risk profile was favorable. In the series, 62 consecutive patients were treated at a single academic referral center between April 2000 and April 2004.

Patients successfully tapered their oral prednisone use to 10 mg daily at an average rate of 1.62 per patient-year. They had an 85 percent probability of achieving 10 mg or less after one year and two months of treatment. Tacrolimus was discontinued because of intolerance at a rate of 0.13 per patient year. The paper authors reported that discontinuations were predominantly due to noncardiovascular adverse events. In addition, rates of introducing or increasing concomitant treatment for hypertension, hypercholesterolemia and diabetes mellitus were all below 0.05 per patient year. Creatinine increases of greater than or equal to 30 percent were low, occurring at a rate of 0.05 per patient year.

Source: Hogan AC, McAvoy CE, Dick AD, Lee RWJ. Long-term efficacy and tolerance of tacrolimus for the treatment of uveitis. Ophthalmology 2007;114(5):1000-1006.


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NOTEWORTHY: EARLY TRIAL RESULTS: VEGF TRAP FOR AMD AND DME; PHASE II TRIAL OF AMD EYE DROP THERAPY BEGINS

Early Trial Results: VEGF Trap for AMD and DME
Regeneron Pharmaceuticals announced positive early results from studies evaluating its VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration (AMD) and DME. VEGF Trap-Eye is a fully human, soluble VEGF receptor fusion protein that binds all forms of VEGF-A and related placental growth factor.

Data from a planned interim analysis of the first 78 patients who completed 12 weeks of the Phase II AMD study showed that the most intense dosing regimen studied (2 mg delivered by intravitreal injection every four weeks) resulted in an average gain of more than 10 letters after 12 weeks of treatment. After a single dose of VEGF Trap-Eye, patients on average improved in the number of letters read at eight and 12 weeks. The multicenter trial involves 150 patients who were randomized to five groups and treated with VEGF Trap-Eye in one eye. Two groups received either 0.5 or 2.0 mg of VEGF Trap-Eye administered every four weeks, and three groups received a single dose of 0.5, 2.0, or 4.0 mg.

The study met its primary endpoint of a statistically significant reduction in retinal thickness after 12 weeks compared with baseline (all groups combined, decrease of 135 µm, p<0.0001). Mean change in visual acuity, a key secondary endpoint, also demonstrated a statistically significant improvement (all groups combined, increase of 5.9 letters, p<0.0001). There were no drug-related serious adverse events.

In the open-label Phase I safety study of VEGF Trap-Eye for the treatment of DME, the drug was administered as a single 4-mg intravitreal injection to five patients with longstanding diabetes and multiple prior treatments for DME. The single injection resulted in a marked decrease in mean central retinal thickness and mean macular volume throughout the six-week observation period. Mean BCVA improved (range 2.6 to 6.8 letters) compared to baseline at all time points. The treatment was well-tolerated; no drug-related serious adverse events occurred.

Regeneron and Bayer HealthCare AG plan to initiate the VEGF Trap-Eye Phase III program in wet AMD in the third quarter of this year .

Source: Regeneron Pharmaceuticals, March 2007.

Phase II Trial of AMD Eye Drop Therapy Begins
CoMentis (formerly Athenagen) announced the initiation of a Phase II clinical study of ATG3, the company's topical eye drop therapy for neovascular AMD. A proprietary ophthalmic formulation of mecamylamine, ATG3 is an antagonist of the nicotinic acetylcholine (nACh) receptor pathway that mediates angiogenesis. The drug was developed to penetrate into the retina and choroid following topical administration.

The Phase II study is a double-masked, randomized, placebo-controlled clinical trial designed to evaluate the safety and efficacy of ATG3 in approximately 330 patients. Patients will be randomized to one of three treatment groups: two different doses of ATG3 twice daily or placebo. One eye per patient will receive the study treatment. Patients will be treated for up to 48 weeks during which time change in visual acuity and macular thickness will be assessed.

Interim six-month data are expected by mid-2008.

Source: CoMentis, April 2007.



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