Volume 2, Number 6
June 2006



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: ONE-YEAR RESULTS OF PIER STUDY PRESENTED; PHASE II TRIAL OF siRNA THERAPY FOR AMD YIELDS POSITIVE RESULTS; AND MORE ITEMS OF INTEREST






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

Table of Contents










THE LATEST PUBLISHED RESEARCH

Optical coherence tomography at baseline, one week, and one month in a patient treated with bevacizumab for neovasuclar AMD. (Images courtesy of Philip Rosenfeld, MD, PhD).

Retrospective Review Adds to Data on Intravitreal Bevacizumab
A retrospective review demonstrated that off-label intravitreal bevacizumab (Avastin, Genentech) therapy for neovascular age-related macular degeneration improved visual acuity and OCT appearance of the macula while being well-tolerated over three months. Fifty-three eyes of 50 patients received bevacizumab between May and August 2005. All patients received an injection at baseline and were given additional monthly injections at the discretion of the treating physician. The average number of injections (including the three-month visit) was 2.3 out of a maximum of four.

No serious drug-related ocular or systemic adverse events occurred. Improvements in visual acuity and central retinal thickness were evident by week one and continued through month three. At month three, the mean visual acuity improved from 20/160 to 20/125 (p<0.001), and the mean central retinal thickness decreased by 99.6 µm (p<0.001). The researchers stated that while the long-term safety and efficacy of intravitreal bevacizumab remain unknown, these short-term results suggest that it may be the most cost-effective therapy for the treatment of neovascular AMD.

Source: Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495-511.

Study Tests Toxicity of Bevacizumab in Three Cell Types
The results of an in vitro study utilizing vascular endothelial growth factor, various concentrations of bevacizumab, and the trypan blue dye exclusion assay suggest that bevacizumab at concentrations at or above those normally used in clinical practice is not toxic to human retinal pigment epithelial (ARPE-19), rat neurosensory retinal (R28) or human microvascular endothelial (HMVECad) cells. ARPE-19 and R28 cells were exposed to 0.125 mg/mL, 0.25 mg/mL, 0.50 mg/mL and 1 mg/mL of bevacizumab for two, six and 24 hours. HMVECad cells were exposed to 5 mg/mL of VEGF and 0.125 mg/mL, 0.25 mg/mL, 0.50 mg/mL and 1 mg/mL of either bevacizumab for two, six and 24 hours or a nonspecific human purified immunoglobulin for 24 hours.

The viabilities of ARPE-19 cells, R28 cells and HMVECad cells treated with bevacizumab were not significantly different (p>0.05) from the viability of untreated controls. In addition, there was no significant difference (p>0.05) between viabilities of HMVECad cells treated with bevacizumab and immunoglobulin.

Sources: Luthra S, Narayanan R, Marques LEA, et al. Evaluation of in vitro effects of bevacizumab (Avastin) on retinal pigment epithelial, neurosensory retinal, and microvascular endothelial cells. Retina 2006;26:512-518.

Morphologic Effects of Triamcinolone on Rabbit Retina
In a study of pigmented rabbit eyes, a single intravitreal injection of 0.5 mg or 1 mg of triamcinolone acetonide did not produce morphologic retinal changes; however, injections of 4 mg, 8 mg and 20 mg produced toxic effects in the outer retina. Investigators administered 0.5 mg, 1 mg, 4 mg, 8 mg and 20 mg of triamcinolone (Kenalog-40, Bristol-Myers Squibb) in 0.1 mL in pigmented rabbits. For control, they injected 0.1 mL of vehicle and saline. On day 14, they euthanized the rabbits and used light and electron microscopy to analyze the retinas.

No changes were found on ophthalmoscopy. Eyes injected with 0.5 mg and 1 mg of triamcinolone had no morphologic abnormality. Eyes injected with 4 mg, 8 mg and 20 mg exhibited destruction of photoreceptor outer segments and migration of macrophage-like cells into the subretinal space. Eyes injected with 20 mg showed more extensive damage and increased pigment granules in the retinal pigment epithelium cells with large oil droplets in the cytoplasm. Electron microscopy also showed loss of photoreceptor/retinal pigment epithelium interdigitations. Eyes injected with vehicle and saline did not show morphologic changes.

Source: Yu SY, Damico FM, Viola F, et al. Retinal toxicity of intravitreal triamcinolone acetonide: a morphological study. Retina 2006;26:531-536.

Retinal Vascular Caliber Associated with Cardiovascular Risk Factors
Retinal arteriolar and venular caliber is associated with a range of cardiovascular risk factors, according to a cross-sectional study comprising 5,979 persons ages 45 to 84 residing in six multi-ethnic U.S. communities. In the multi-ethnic study of atherosclerosis (MESA), researchers used digital retinal photographs to measure and summarize retinal vascular caliber, and they assessed standard cardiovascular risk factors.

Mean retinal arteriolar caliber was 144.1 +/- 14.4 µm; mean venular caliber was 214.0 +/- 22.2 µm. In models controlling for age, gender, race-ethnicity and center, smaller retinal arteriolar caliber was related to higher systolic and diastolic blood pressure, hypertension status, current alcohol consumption, greater body mass index and higher levels of total homocysteine. Larger retinal arteriolar caliber was related to diabetes, current cigarette smoking and higher levels of plasma fibrinogen. Larger retinal venular caliber was related to diabetes, current cigarette smoking, greater body mass index and waist-hip ratio, higher levels of serum glucose, plasma triglyceride, plasma LDL-cholesterol, hsCRP, plasma fibrinogen, IL6, sICAM-1 and PAI-1 and lower levels of HDL-cholesterol. In multivariate analyses, blacks and Hispanics had larger retinal arteriolar and venular calibers than did whites and Chinese.

Source: Wong TY, Islam MA, Klein R, et al. Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA). Invest Ophthalmol Vis Sci 2006;47:2341-2350.

PDT for CNV Secondary to Reticular Pattern Dystrophy
Based on three-year results of its open-label, prospective, interventional case series involving 13 eyes, a group of researchers concluded that photodynamic therapy does not appear to guarantee long-term vision stabilization in patients with subfoveal choroidal neovascularization secondary to reticular pattern dystrophy of the retinal pigment epithelium. In the study, patients underwent complete ophthalmic examinations at baseline and at three-month intervals for three years. The primary outcome measure was the number of eyes losing <15 letters of visual acuity. At the three-year examination, seven eyes lost at least three lines of acuity. The median number of PDT treatments was two in year one, zero in year two, and zero in year three.

Source: Battaglia Parodi M, Liberali T, Pedio M, et al. Photodynamic therapy of subfoveal choroidal neovascularization secondary to reticular pattern dystrophy: three-year results of an uncontrolled, prospective case series. Am J Ophthalmol 2006;141:1152-1154.



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NOTEWORTHY: ONE-YEAR RESULTS OF PIER STUDY PRESENTED; PHASE II TRIAL OF siRNA THERAPY FOR AMD YIELDS POSITIVE RESULTS; AND MORE ITEMS OF INTEREST

One-Year Results of PIER Study Presented
Preliminary one-year results from the Phase IIIb PIER study show that quarterly dosing of ranibizumab (Lucentis, Genentech) for neovascular AMD provides a benefit compared with sham but suggest that treating patients on a quarterly basis may be less effective than monthly or individualized dosing. The study met its primary efficacy endpoint by preventing vision loss as measured by mean change in visual acuity from baseline to month 12. On average, patients treated with ranibizumab returned to baseline visual acuity by month 12, while patients in the sham group experienced significant vision loss.

Additional One-Year PIER Findings

0.3 mg 0.5 mg sham
Loss of less than 83% 90% 49%
15 letters compared
with baseline

Gain of greater than 12% 13% 10%
or equal to 15 letters
compared with baseline

20/40 at 12 months 30% 28% 11%

"The one-year PIER results demonstrate that even when ranibizumab is given less frequently, patients can maintain visual acuity," said David M. Brown, MD. "However, they also indicate that we need to tailor treatment regimens to individual patient’s responses or give the drug more frequently to achieve the marked visual acuity improvements seen in the ANCHOR and MARINA trials."

PIER is a two-year, multicenter, randomized, double-masked, sham injection-controlled study involving 184 patients with predominantly classic, minimally classic or occult with no classic lesions. Patients are randomized 1:1:1 to receive a 0.3-mg or 0.5-mg intravitreal injection of ranibizumab or sham injection once a month for the first three months followed by injections once every three months. (In the pivotal Phase III studies of ranibizumab, MARINA and ANCHOR, patients were dosed monthly.) Exclusion criteria included prior subfoveal laser treatment, PDT or experimental treatments for neovascular AMD. ETDRS refractions were taken at four meters.

At month three, on average, patients treated with the 0.3-mg dose of ranibizumab gained 2.9 letters in visual acuity, patients receiving the 0.5-mg dose gained 4.3 letters, and patients in the sham group lost 8.7 letters. At month 12, on average, patients treated with the 0.3-mg dose of ranibizumab lost 1.6 letters, patients receiving the 0.5-mg dose lost 0.2 letters, and patients in the sham group lost 16.3 letters (p<0.0001).

Common side effects that occurred more frequently in the ranibizumab groups than in the control group were mild to moderate and included conjunctival hemorrhage, eye pain and increased intraocular pressure. There were no reported cases of endophthalmitis, serious intraocular inflammation or other key ocular serious adverse events. There were no deaths, myocardial infarctions or cerebral vascular events.

"Data from ongoing Phase IIIb studies and emerging results from our Investigator Sponsored Trials should help us learn more about the optimal dosing regimen for patients," commented Hal Barron, MD, Genentech senior vice president, development, and chief medical officer.

Genentech submitted a Biologics License Application for ranibizumab to the U.S. Food and Drug Administration at the end of 2005 and was granted a Priority Review. The FDA has until the end of June to act on the filing.

Source: David M. Brown, MD, and Genentech, June 2006.

Phase II Trial of siRNA Therapy for AMD Yields Positive Results
Initial results from a Phase II trial of bevasiranib sodium (formerly known as Cand5) showed it to be safe and effective for the treatment of neovascular AMD. The findings represent the first-ever clinical proof-of-concept for a small interfering RNA-based therapy. Bevasiranib is designed to "turn off" the gene that produces vascular endothelial growth factor. The randomized, double-masked trial, called C.A.R.E., included three dose levels of bevasiranib tested in 129 patients at 28 sites nationwide. The study focused on patients with serious disease, including those who had rapidly degenerating retinal lesions or had failed previous treatments. It excluded patients with slow-growing occult lesions. Bevasiranib demonstrated signs of efficacy at all dose levels and was well-tolerated. A dose-related effect was evident across multiple endpoints including near vision, lesion size and time to rescue. Clinical data will be presented at the annual meeting of the American Society of Retinal Specialists in September. Phase III clinical trials are expected to begin next year.

Source: Acuity Pharmaceuticals, June 2006.

Pegaptanib for CRVO
Interim data from a Phase II, randomized, double-masked, multicenter study showed that intravitreal injections of pegaptanib sodium (Macugen, OSI/Eyetech and Pfizer) resulted in better visual acuity outcomes than sham injections in patients with macular edema due to central retinal vein occlusion. In the study, 98 patients were randomized to receive either 1.0 mg or 0.3 mg of pegaptanib or sham injection once every six weeks for 24 weeks.

At 30 weeks, more than 90 percent of patients treated with 0.3 mg or 1.0 mg of pegaptanib maintained or improved vision (loss of less than 15 letters in visual acuity) compared with approximately 69 percent of those in the control arm (p<0.05 for both doses). On average, mean visual acuity improved from baseline to week 30 by 7.5 letters in the 0.3-mg group and by 10.2 letters in the 1.0-mg group. Mean visual acuity declined by 1.9 letters in the control group. The proportion of patients gaining 15 letters or more was 36 percent in the 0.3-mg group, 39 percent in the 1.0 mg group, and 28 percent in the control group.

Final assessments will be performed at week 52. More complete trial results, including a summary of the safety analysis, will be presented at the annual meeting of the American Society of Retinal Specialists in September.

Source: OSI Pharmaceuticals, June 2006.

Data Show Ruboxistaurin Reduces Risk of Vision Loss in Diabetic Retinopathy
An analysis of pooled data from two Phase III trials showed that oral ruboxistaurin mesylate (Arxxant, Eli Lilly) reduced the risk of sustained moderate vision loss over three years by 41 percent (p=0.011) compared with placebo in patients with moderate-to-severe nonproliferative diabetic retinopathy. Vision loss, which was defined as a three-line decrease in visual acuity that was sustained for at least six months, occurred in 6.1 percent of patients treated with ruboxistaurin compared with 10.2 percent of patients receiving placebo. The beneficial effect of ruboxistaurin was not accompanied by a reduction in the progression from nonproliferative to proliferative diabetic retinopathy.

Comprising data from the PKC-DRS and PKC-DRS2 studies, the combined analysis included 813 patients treated with 32 mg per day of ruboxistaurin (n=412) or placebo (n=401). The two multicenter, randomized, placebo-controlled, double-masked trials were similar in design and implementation. The findings were part of the new drug application submitted to the FDA in February.

A separate analysis of data from 11 studies found 32 mg per day of ruboxistaurin to be well-tolerated in patients with at least one diabetic microvascular complication (including diabetic retinopathy).

Source: Eli Lilly, June 2006.
The PASCAL Photocoagulator treats retinal diseases using a single spot or a predetermined pattern array of up to 25 spots.
Experience with New Photocoagulation System
According to Harry Flynn Jr., MD, professor of ophthalmology at Bascom Palmer Eye Institute, treatment of the first 550 eyes with the Pattern Scan Laser (PASCAL) Photocoagulator resulted in reduced treatment time compared with single-spot photocoagulation. Patients were treated at six leading ophthalmic research institutes, including Bascom Palmer, Johns Hopkins University, the Jules Stein Eye Institute at UCLA, Stanford University, Associated Retinal Consultants in Detroit and the Asociacion Para Evitar La Ceguera (APEC) in Mexico.

The PASCAL Photocoagulator is a fully integrated pattern scan laser system designed to treat retinal diseases using a single spot or a predetermined pattern array of up to 25 spots. It is based on a proprietary, semi-automated pattern generation method employing 532-nm laser pulses with a typical duration of 20 ms. The pulses are delivered in a rapid predetermined sequence for improved precision, safety, patient comfort and treatment time.

For more information, visit optimedica.com.

Source: OptiMedica Corp., June 2005.

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