Volume 2, Number 2
February 2006



Contents:
WELCOME
THE LATEST RESEARCH
NOTEWORTHY: RHEOPHERESIS TRIAL FAILS TO MEET PRIMARY ENDPOINT; FDA REQUESTS BSS RECALL; 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 information to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

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

Table of Contents











THE LATEST RESEARCH

Phase I Trial Shows AdPEDF Therapy to be Safe
A Phase I, multicenter, open-label, dose-escalation clinical trial to evaluate intravitreal injection of an adenoviral-based vector containing the gene for human pigment epithelium-derived factor (AdPEDF) for neovascular wet age-related macular degeneration showed the treatment to be safe. By 12 months of follow-up, no serious adverse events occurred, and no dose-limiting toxicities were found. Mild, transient intraocular inflammation occurred in 25 percent of patients, and six patients experienced increased intraocular pressure, which was controlled with topical medication. All adenoviral cultures were negative.

Fundus photographs of an eye with wet AMD at baseline and after a single, high-dose injection of AdPEDF.

Twenty-eight patients with AMD and leaking subfoveal choroidal neovascularization less than or equal to 12 MPS disc areas in the study eye and best-corrected visual acuity of 20/200 or worse were given a single intravitreal injection of AdPEDF. Eight doses, ranging from 106 to 109.5 particle units (PU), were investigated.

Although the study was not designed to evaluate efficacy, the authors wrote that the data suggested the possibility of anti-angiogenic activity that may last for several months after one injection of doses greater than 108. At six months after injection, 50 percent of patients treated with a 106 to 107.5 PU dose and 71 percent treated with a 108 to 109.5 PU dose had no change or improvement in lesion size from baseline. The median increase in lesion size at six and 12 months was 0.5 and 1.0 disc areas in the low-dose group compared with 0 and 0 disc areas in the high-dose group.

Source: Campochiaro PA, Nguyen QD, Shah SM, et al. Adenoviral vector-delivered pigment epithelial-derived factor for neovascular age-related macular degeneration: a phase I clinical trial. Hum Gene Ther 2006;17:167-176.

A: A patient with wet AMD prior to a single intravitreal injection of bevacizumab. B: Lack of leakage five months after the injection. C. Optical coherence tomography scans pre-injection, one month later, and five months later. (Images courtesy of Robert L. Avery, MD.)

Intravitreal Bevacizumab for Wet AMD
In an interventional, retrospective, consecutive case series of 81 eyes with subfoveal neovascular AMD, intravitreal injections of bevacizumab (Avastin, Genentech Inc.) were well-tolerated and associated with improvement in visual acuity, decreased retinal thickness, and reduction in angiographic leakage. Patients received 1.25-mg injections of bevacizumab monthly until macular edema, subretinal fluid and/or pigment epithelial detachment (PED) resolved. The majority of patients had been treated previously with photodynamic therapy and/or pegaptanib sodium.

No significant ocular or systemic side effects were observed. Short-term results showed that 55 percent of patients had a >10 percent reduction in retinal thickness at one week after injection. At four weeks after injection, 30 of the 81 eyes demonstrated complete resolution of retinal edema, subretinal fluid and PED. Of the eyes (n=51) with eight weeks of follow-up, 25 had complete resolution of retinal thickening, subretinal fluid and PED.

At four and eight weeks, mean visual acuity (not standardized) improved from 20/200 to 20/125 (p<0.0001). Median visual acuity improved from 20/200 to 20/80 at four weeks and from 20/200 to 20/80 at eight weeks. Mean retinal thickness of the central 1 mm was reduced by 67 µm at 12 weeks (p<0.01).

Throughout the study, patients who had complete resolution of subretinal fluid, macular edema and PEDs were not re-injected until the conditions recurred. In some patients, the conditions had not recurred at 15 weeks after a single injection. In cases with recurrence, patients responded to re-injections without loss of vision.

Source: Avery RL, Pieramici DJ, Rabena MD, et al. February 3, 2006. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology DOI: 10.1016/j.ophtha.2005.11.019.

Intravitreal Bevacizumab for Proliferative Diabetic Retinopathy
At this year’s Masters of the American Society of Retina Specialists meeting, in Rio Grande, Puerto Rico, Robert L. Avery, MD, presented early results from a study of intravitreal bevacizumab in 45 eyes of 32 patients with proliferative diabetic retinopathy. In the Institutional Review Board-approved retrospective review, patients had received bevacizumab doses ranging from 6.2 µg to 1.25 mg. Mean follow-up was five weeks (range one to 14 weeks). Dr. Avery reported that all 45 eyes demonstrated at least partial resolution of leakage on angiography, and many showed complete resolution. In addition, he pointed out that in some cases, the biologic effects were noted following the injection of 6.2 µg, which is 1/200th of the usual dose of bevacizumab. He also cited several potential uses for bevacizumab in PDR: rubeosis, persistent neovascularization despite panretinal photocoagulation, vitreous hemorrhage that precludes panretinal photocoagulation, PDR with macular edema, and prior to vitrectomy for PDR to reduce intraoperative bleeding.

Reduction in caliber of abnormal disc vessels after injection of bevacizumab in a patient with proliferative diabetic retinopathy. (Images courtesy of Robert L. Avery, MD.) Regression of new vessels on the optic disc (top) and resolution of leakage (center and bottom) in a patient receiving intravitreal bevacizumab for proliferative diabetic retinopathy. (Images courtesy of Robert L. Avery, MD.)

Source: Intravitreal bevacizumab (Avastin) in the treatment of PDR, Avery RL, 2006 Masters of the American Society of Retina Specialists meeting paper presentation, Rio Grande Puerto Rico.

VISION Subgroup Analyses Suggest Benefit of Early CNV Treatment
Recent analyses of data from two patient subgroups in the VISION clinical trials suggested that using pegaptanib sodium (Macugen) to treat early subfoveal CNV due to AMD may produce better outcomes than were observed more generally in the clinical trials. The study authors emphasized that the analyses were exploratory and designed to assist in the generation of a hypothesis that treatment of early disease yields superior vision outcomes. They concluded that the hypothesis is convincing and deserving of more rigorous testing.

The authors analyzed 54-week outcomes in two patient subgroups treated with the 0.3-mg dose of pegaptanib. They defined early disease differently in each subgroup. For Group 1 (n=34), early disease was defined as lesion size of <2 disk areas, baseline visual acuity of greater than or equal to 54 ETDRS letters, no prior PDT or thermal laser photocoagulation to the lesion, and absence of scarring or atrophy within the lesion. For Group 2 (n=30) early disease was defined as occult with no classic CNV, absence of lipid, and better visual acuity at baseline in the fellow eye.

The proportion of patients in treatment Group 1 that lost fewer than 15 letters of visual acuity was 76 percent. The proportion of patients in usual care Group 1 that lost fewer than 15 letters of visual acuity was 50 percent (p=0.03). The proportion of patients in treatment Group 2 that lost fewer than 15 letters of visual acuity was 80 percent. The proportion of patients in usual care Group 2 that lost fewer than 15 letters of visual acuity was 57 percent (p=0.05). In addition, patients in usual care Group 1 and Group 2 lost 11.1 letters and 12.7 letters more on average than patients in treatment Group 1 and Group 2 (p< 0.01, p< 0.006).

Patients in usual care Group 1 were approximately 10 times more likely to have severe vision loss (greater than or equal to 30 ETDRS letters) than subjects treated with pegaptanib. Patients in usual care Group 2 were more than two times more likely to have severe vision loss than those treated with pegaptanib.

In treatment Group 1, 12 percent of patients gained 15 letters or more of visual acuity compared with 4 percent in usual care Group 1. In treatment Group 2, 20 percent of patients gained 15 letters or more compared with none in usual care Group 2.

In Group 1, 24 percent of pegaptanib-treated patients and 32 percent of usual care patients were treated with PDT at baseline or during the study. In Group 2, 3 percent of pegaptanib-treated patients and 9 percent of usual care patients were treated with PDT at baseline or during the study.

Source: Gonzales CR, Adamis AP, Cunningham ET, et al. on behalf of the VISION Clinical Trial Group. Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis. Retina 2005;25:815-827.

Candidate Gene Study Implicates VEGF, VLDLR, and LRP6 in AMD
Based on a candidate gene study, researchers at Vanderbilt and Duke Universities concluded that LRP6, VEGF and VLDLR may play a role in the risk of developing AMD. They used two independent datasets: a family-based association dataset that included 162 families and an independent case-control dataset that included 399 cases and 159 fully evaluated controls. They tested eight genes for genetic linkage and allelic association: 2-macroglobulin (A2M), creatine kinase (CKB), angiotensin-converting enzyme (DCP1), interleukin-1 (IL1A), low-density lipoprotein receptor–related protein 6 (LRP6), microsomal glutathione-S-transferase 1 (MGST1), vascular endothelial growth factor (VEGF), and very low density lipoprotein receptor (VLDLR).

Results indicated that genetic variation in IL1A, CKB, A2M, MGST1 or DCP1 is unlikely to explain a significant portion of the risk for developing AMD. However, LRP6 showed evidence of linkage in the family-based dataset and for association in the case-control dataset. VEGF showed evidence of linkage and demonstrated significant independent allelic association in both datasets. In addition, VLDLR showed evidence of association in both datasets.

Source:
Haines JL, Schnetz-Boutaud N, Schmidt s, et al. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci 2006;47:329-335.

Transplanted Iris Pigment Epithelial Cells Well-Tolerated after Three Years
A study involving removal of CNV and transplantation of autologous iris pigment epithelial cells indicated that the cells could serve as a substitute for retinal pigment epithelial cells in patients with wet AMD. After three years of follow-up, the iris cells were well-tolerated in the study’s 20 patients. No macular edema or recurrent choroidal neovascularization was apparent at any time during follow-up. Visual acuity improved in one patient, remained stable in 13 patients, and declined in three patients. The study authors wrote that further clinical observation and additional research are needed to determine whether the iris cells will be of any value in restoring vision or preventing recurrence of neovascularization over a longer period of time.

Source:
Aisenbrey S, Lafaut BA, Szurman P, et al. Iris pigment epithelial translocation in the treatment of exudative macular degeneration: a 3-year follow-up. Arch Ophthalmol 2006;124:183-188.

Panretinal Laser and Triamcinolone for Diabetic Retinopathy and Edema
Combining intravitreal triamcinolone acetonide with panretinal photocoagulation in patients with proliferative diabetic retinopathy and clinically significant macular edema produced promising results in a study of 35 eyes. The study authors treated the eyes with PRP and a single 4-mg injection of triamcinolone. They retrospectively compared the data on those eyes with the data from 35 other eyes that underwent grid laser treatment to the macula followed by PRP two weeks later (laser group). Mean follow-up was 9.6 months for the triamcinolone group and 11.9 months for the laser group.

At nine months, visual acuity improved from 20/286 to 20/80 in the triamcinolone group and from 20/282 to 20/156 in the laser group (p=0.007). Thirty-four percent of eyes in the triamcinolone group had final vision of 20/40 or better compared with 11 percent of the laser group (p=0.044). In addition, at nine months follow-up, macular edema completely resolved in 84 percent of triamcinolone eyes compared with 46 percent of laser eyes (p=0.002).

Macular edema recurred in three of the triamcinolone eyes after six months and required re-injection. Also in the triamcinolone group, eight eyes had elevated intraocular pressure that was responsive to medical therapy, and cataracts progressed in nine eyes.

Source:
Zein WA, Dih M, Noureddin B, et al. Panretinal photocoagulation and intravitreal triamcinolone acetonide for the management of proliferative diabetic retinopathy with macular edema. Retina 2006;26(2):137-142.


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NOTEWORTHY: RHEOPHERESIS TRIAL FAILS TO MEET PRIMARY ENDPOINT; FDA REQUESTS BSS RECALL; AND MORE ITEMS OF INTEREST

Rheopheresis Trial Fails to Meet Primary Endpoint
OccuLogix Inc. announced that its MIRA-1 Phase III clinical trial of rheopheresis for the treatment of dry AMD did not meet its primary endpoint. The treatment group demonstrated a positive response, but the trial did not demonstrate a statistically significant difference in mean change in BCVA between the treated and control groups at 12 months. The company said an anomalous response of the control group is the principal reason that the primary efficacy endpoint was not met. Treated subgroups did demonstrate statistical significance in mean change in BCVA vs. controls, and further data analyses are under way.

Source: OccuLogix Inc., February 2006.

FDA Requests BSS Recall
The U.S. Food and Drug Administration asked Cytosol Laboratories Inc., of Braintree, Mass., to recall all brands and sizes of Balanced Salt Solution that Cytosol manufactures. Product lots were found to have elevated levels of endotoxin. The FDA has received complaints relating to injuries in more than 300 patients who were given BSS manufactured by Cytosol. Approximately 1 million units of the BSS products were distributed between December 2003 and December 2005 under three labels: AMO Endosol (Advanced Medical Optics Inc.), Cytosol Ophthalmics (Cytosol Ophthalmics), and Akorn (Akorn Inc.).

Physicians can direct questions to the FDA at 1 (888) 463-6332 and should report any adverse reactions associated with these products to the MedWatch Program at www.fda.gov/medwatch/report.htm or 1 (800) FDA-1088.

Source: U.S. Food and Drug Administration, February 2006.

Pegaptanib Receives Approval in Europe; Companies Collaborate on Sustained Release Delivery
The European Commission has granted regulatory approval to pegaptanib sodium for the treatment of neovascular AMD. Pegaptanib had already been approved in the United States, Canada, Brazil, Argentina, Peru, Pakistan and the Philippines, and is awaiting approval in 15 other countries, including Australia, Switzerland and Mexico. It was also recently announced that PR Pharmaceuticals Inc. (PRP) has entered into an agreement with OSI Pharmaceuticals to collaborate on the development of a sustained release formulation of pegaptanib sodium injection for wet AMD. The agreement grants OSI an exclusive license to use PRP’s proprietary ProPhase encapsulation technology with respect to pegaptanib in the treatment of eye diseases.

Source: OSI Pharmaceuticals, February 2006, and PR Pharmaceuticals Inc., January 2006.

Preliminary Phase I VEGF Trap Results Presented
At the Bascom Palmer Eye Institute’s Angiogenesis 2006 symposium in Miami, Regeneron Pharmaceuticals Inc. presented preliminary results from its ongoing Phase 1, dose-escalation study of VEGF Trap for the treatment of wet AMD. The protein-based VEGF Trap binds all forms of VEGF-A and the related Placental Growth Factor, preventing their interaction with cell-surface receptors and the subsequent formation of new blood vessels. Eighteen patients have received a single intravitreal dose of the VEGF Trap at levels up to 2 mg. A maximum tolerated dose has not been reached, and no evidence of ocular inflammation has been observed. The company reported that patients have shown rapid and substantial reductions in retinal thickness lasting up to at least four weeks. A 4-mg dose is now being tested.

Source: Regeneron Pharmaceuticals Inc., February 2006.

Company Discontinues Macular Edema Trials
Inspire Pharmaceuticals decided to discontinue two Phase II pilot clinical trials that were designed to evaluate denufosol tetrasodium intravitreal injection in patients with macular edema. The first trial was scheduled to enroll 15 patients with persistent macular edema associated with uveitis. The treatment and evaluation of 12 patients showed no significant safety problems, but did not show reduction of retinal thickness or improvement in visual acuity. The second trial was to evaluate denufosol in patients with persistent macular edema following cataract surgery. No patients had been enrolled. The company has stopped enrollment in both trials but will continue to follow the treated patients for one year, as specified in the protocol.

Source: Inspire Pharmaceuticals Inc., January 2006.

Collaboration to Focus on Combination Therapies
CombinatoRx Inc. and Fovea Pharmaceuticals SA reported that they will collaborate to develop and commercialize combination drugs to treat ophthalmic diseases. The agreement unites CombinatoRx’s leadership in the discovery of novel combination drug candidates with Fovea’s drug development resources and expertise in the field of ophthalmic therapeutics, retinal pathologies in particular. For more information about each of the companies, visit www.fovea-pharma.com and www.combinatorx.com.

Source: CombinatoRx Inc., January 2006.

Novartis to Co-Promote Fluocinolone Implant
Bausch & Lomb and Novartis Ophthalmics have agreed that Novartis will co-promote B&L’s fluocinolone acetonide intravitreal implant (Retisert) for the treatment of chronic noninfectious posterior segment uveitis. The Novartis retinal sales team will supplement the efforts of B&L’s U.S. pharmaceutical sales representatives. B&L remains responsible for marketing and product strategy.

Source: Bausch & Lomb, February 2006.

Phase II Trials of RNAi Therapy for AMD and DME Progress
Acuity Pharmaceuticals completed the patient dosing component of its Phase II CARE trial of Cand5 for the treatment of wet AMD. Results from the randomized, double-masked trial, which involves 129 patients and three dose levels, are expected by mid-year. CARE is the first-ever Phase II efficacy trial of a small interfering RNA therapy that targets the genes responsible for production of vascular endothelial growth factor.

Acuity also reported that it has begun dosing patients in a pilot Phase II trial (RACE) of Cand5 for diabetic macular edema. RACE is 48-patient, multicenter, double-masked, randomized trial evaluating the safety and preliminary efficacy of three dose levels. Completion is expected by the end of 2006.

Source: Acuity Pharmaceuticals, February 2006.



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