Volume 3, Number 10
October 2007



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: GENENTECH CHANGES ITS BEVACIZUMAB DISTRIBUTION POLICY; FDA ISSUES APPROVABLE LETTER FOR ANECORTAVE ACETATE; AND OTHER 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

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THE LATEST PUBLISHED RESEARCH

Angiography and OCT Outcomes in the MARINA Study
Prespecified and ad hoc retrospective analyses of 24-month data from the MARINA study of ranibizumab (Lucentis) showed that the treatment consistently improved visual acuity, fluorescein angiography and optical coherence tomography outcomes in patients with minimally classic or occult with no classic neovascular age-related macular degeneration. The analyses also showed that the improvement was superior to that in sham-treated patients.

At 12 and 24 months, ranibizumab demonstrated statistically significant benefits compared with sham treatment for mean change from baseline in areas of choroidal neovascularization, total CNV, leakage from CNV, serous sensory retinal detachment and disciform scar/subretinal fibrosis. At 12 months (final OCT), the mean change in foveal center point thickness on OCT was a significant decrease in the ranibizumab group compared with the sham group.

In the MARINA study, 716 patients were randomized to receive either 0.3-mg ranibizumab (n=238), 0.5-mg ranibizumab (n=240) or sham injection (n=238). Stereoscopic fundus photography and FA were performed at baseline and months three, six, 12 and 24. OCT was performed in 46 patients at a subset of investigative sites at baseline and day seven and months one and 12.

Source: Kaiser PK, Blodi BA, Shapiro H, Acharya NR. Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007;114:1868-1875.


Visual Acuity Effects of Ranibizumab Following Treatment with Bevacizumab
In addition to the effects of ranibizumab on visual acuity and central macular thickness in patients with neovascular AMD, a retrospective review evaluated the treatment's effects in eyes previously treated with bevacizumab (Avastin). The review included 231 consecutive eyes treated with ranibizumab from July 6 to July 31, 2006. Of those eyes, 153 (65.4 percent) had previously received bevacizumab.

Ranibizumab significantly improved visual acuity and central macular thickness, but eyes that had received bevacizumab treatment within three months before initiating ranibizumab treatment had stability of, but no improvement in, visual acuity. At three months, overall mean visual acuity improved to 20/126 from a baseline mean of 20/152. Mean visual acuity for the 98 available patients treated with bevacizumab within three months before ranibizumab injection was 20/100 at baseline and 20/98 at three months (p=0.35).

Mean baseline central macular thickness was 278 µm for all patients and improved to 211 µm at three months (p<0.001). Macular thickness decrease was noted irrespective of previous bevacizumab therapy.

Source: Bhatnagar P, Spaide RF, Takahashi BS, et al. Ranibizumab for the treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2007;27:846-850.


Researchers Examine Types of CNV in Newly Diagnosed AMD
Researchers in France reported that their prospective, multicenter, consecutive descriptive case series confirmed that newly diagnosed cases of neovascular AMD are mainly occult and subfoveal. Seven referral hospital-based or private centers recruited 207 consecutive cases of newly diagnosed neovascular AMD undergoing FA. The investigators also performed indocyanine green angiography in cases where they determined it was necessary. Two independent experts, and a third when the first two did not agree, classified lesion type and size.

The percentages of patients with the following classifications were: 17.6 percent, classic CNV only; 5.4 percent, predominantly classic; and 8.3 percent minimally classic. Occult CNV was classified as "without vascularized pigment epithelial detachment" in 32.7 percent of cases and "with vascularized PED" in 23.9 percent of cases. Hemorrhagic AMD was observed in 5.8 percent of cases, and 4.8 percent of cases had fibrovascular scars. Eighty percent of the lesions were subfoveal.

The researchers also reported that retinal angiomatous proliferation (RAP) appeared as a common lesion in newly diagnosed neovascular AMD. They observed RAP in 15.1 percent of cases, and RAP accounted for 30 percent of vascularized PED.

Source: Cohen SY, Creuzot-Garcher C, Darmon J, et al. Types of choroidal neovascularisation in newly diagnosed neovascular age-related macular degeneration. Br J Ophthalmol 2007;91:1173-1176.


New View of RAP Using FD-OCT
Using Fourier-domain OCT to image the eyes of five patients who were clinically diagnosed with RAP, researchers reported that the technology provides unprecedented in vivo detail of the anatomy of RAP lesions that nearly resembles histologic specimens.

They captured a series of 100 raster-scanned B-scans centered over the macula, which were registered and presented as a three-dimensional volume. They were able to identify RAP lesions within the retina in all five cases.

Images of the first four cases revealed areas of intraretinal neovascularization in the deep retina adjacent to a PED. Neovascular proliferation was present anteriorly and posteriorly through a break in the retinal pigment epithelium. In three of the four cases, Bruch's membrane remained intact and there was no identifiable CNV. The fifth case exhibited both subretinal and sub-RPE neovascular membranes without a PED.

Source: Truong SN, Alam S, Zawadzki RJ, et al. High resolution fourier-domain optical coherence tomography of retinal angiomatous proliferation. Retina 2007;27:915-925.


Analysis of Pooled IOP Data from Fluocinolone Implant Trials
Pooled data from three double-masked, randomized Phase IIb/III clinical trials evaluating the fluocinolone acetonide intravitreal implant (Retisert) for the treatment of chronic noninfectious uveitis indicate that elevated intraocular pressure is a significant complication but that it can be controlled with medication and surgery. Follow-up in the studies was three years.

Among the eyes that received the implant, 71 percent had an IOP increase of 10 mmHg or more from baseline. Also, 55.1 percent reached an IOP of 30 mmHg or more, 24.7 percent reached 40 mmHg or more, and 6.2 percent reached 50 mmHg or more. Topical medication was administered for 74.8 percent of implanted eyes, and IOP-lowering surgeries were performed for 36.6 percent. Most of the surgeries, 76.2 percent, were trabeculectomies. Surgeries were considered a success if postoperative IOP was 6 to 21 mmHg with or without IOP-lowering medication, and the success rate at one year was 85.1 percent.

Source: Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthalmol 2007;125:(doi:10.1001/archopht.125.11.ecs70063).


Intravitreal ICG Toxicity: Review and Recommendations
Brazilian and German investigators conducted a literature search from 1998 through 2005 for information related to the toxicity of intravitreal indocyanine green (ICG) dye when used to improve the visualization of preretinal tissues during chromovitrectomy. They collated animal and clinical data to clarify the mechanisms of the risk of intravitreal ICG injection. More than 80 controversial in vitro, ex vivo and in vivo animal investigations, as well as clinical reports on intravitreal ICG staining, appeared in the literature.

The main postulated mechanisms of intravitreal ICG-related toxicity were: biochemical direct injury to the ganglion cells/neuroretinal cells, RPE cells, and superficial retinal vessels; apoptosis and gene expression alterations to either RPE cells or neuroretinal cells; osmolarity effect of ICG solution on the vitreoretinal interface; light-induced injury; and mechanical cleavage effect to the internal limiting membrane/inner retina. While the exact mechanism of intravitreal ICG-related damage remains to be determined, most animal experiments indicated that the dye has a dose-dependent toxic effect on retinal tissue. This hypothesis was supported by clinical data. Better functional outcomes were obtained when low dye concentrations and short incubation times were reported.

Given the body of evidence supporting that ICG dye has a dose-dependent toxic effect on the retina, the authors made these recommendations: injecting in concentrations as low as possible; avoiding repeated ICG injections onto bare retina; injecting dye far from a macular hole to prevent direct contact with the RPE; shortening incubation time of ICG in the vitreous cavity to diminish the concentration in contact with retinal tissue; and keeping the light pipe far from the retina throughout the surgical procedure.

Source: Rodrigues EB, Meyer CH, Mennel S, Farah ME. Mechanisms of intravitreal toxicity of indocyanine green dye: implications for chromovitrectomy. Retina 2007;27:958-70.


Use of Bone Marrow-Derived Cells to Replace Damaged Retinal Tissue
Opening new possibilities for cell replacement therapy in ophthalmology, it appears that bone marrow-dervied cells (BMCs) can be mobilized into the peripheral circulation, travel to focal areas of RPE damage and express cell markers of RPE lineage.

Investigators co-cultured adult RPE cells with green fluorescence protein (GFP)-labeled stem cell antigen-1 positive (Sca-1(+)) BMCs for one, two and three weeks. They studied the cell morphology and expression of RPE-specific markers and markers for other retinal cell types. Using a mouse model of sodium iodate-induced RPE degeneration, they mobilized BMCs into the peripheral circulation by granulocyte-colony stimulating factor, flt3 ligand or both and used immunocytochemistry to identify and characterize BMCs in the subretinal space.

In vitro, BMCs changed from round cells to flattened, polygonal cells and expressed cytokeratin, RPE65, and microphthalmia transcription factor (MITF) when co-cultured in direct cell-cell contact with RPE. In vivo, BMCs were identified in the subretinal space as Sca-1(+) or c-kit(+) cells. They were also double-labeled for GFP and RPE65 or MITF. These cells formed a monolayer on the Bruch's membrane in focal areas of RPE damage.

Source: Li Y, Atmaca-Sonmez P, Schanie CL, et al. Endogenous bone marrow derived cells express retinal pigment epithelium cell markers and migrate to focal areas of RPE damage. Invest Ophthalmol Vis Sci 2007;48:4321-4327.


Multiuse Drops Found to Have High Rate of Bacterial Contamination in Long-Term Care Setting
An analysis of ophthalmic solutions used for patient treatment in a long-term care facility led researchers to question whether single-use solutions would be a safer option in this setting. Out of the 123 ophthalmic solutions they cultured for bacteria, 8 percent were contaminated. Neither the length of time the solutions had been in use nor the appearance of the bottle predicted contamination. Only 30 percent of the contaminated bottles were classified as "dirty" upon visual inspection.

Proteus mirabilis was the bacteria most frequently found (80 percent of the contaminated solutions). Steroid solutions were 5.8 times more likely to be contaminated than solutions not containing steroids (RR=5.84, 95% CI: 2.42 to 14.10, p<0.002). No mydriatic, miotic or noncombination antimicrobial solution was found to be contaminated.

Source: Kauffmann-Jokl DH, Wormser GP, Nichols NS, et al. Bacterial contamination of ophthalmic solutions used in an extended care facility. Br J Ophthalmol 2007;91:1308-1310.

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NOTEWORTHY: GENENTECH CHANGES ITS BEVACIZUMAB DISTRIBUTION POLICY; FDA ISSUES APPROVABLE LETTER FOR ANECORTAVE ACETATE; AND OTHER ITEMS OF INTEREST

Genentech Changes its Bevacizumab Distribution Policy
On Oct. 11, Genentech issued a letter notifying physicians that as of Nov. 30, the company will no longer allow compounding pharmacies to purchase bevacizumab directly from wholesale distributors. The change does not otherwise effect the distribution of the product, and physicians can still order it directly from authorized wholesale distributors.

The letter stated that a series of events led to the company's decision: "Most important among these events is the FDA approval and broad availability of Lucentis for patients with wet AMD. Subsequent to the approval of Lucentis, the FDA raised concerns related to the sterility and repacking of Avastin for ocular use in a Warning Letter to a compounding pharmacy and, separately, during a routine FDA inspection of our South San Francisco manufacturing facility, concerns were raised by inspectors related to the ongoing ocular use of Avastin because it is not designed, manufactured or approved for this use. In addition, we note that Avastin has not undergone any formal, randomized, controlled clinical trials for ocular use."

Physicians with questions or comments regarding this distribution change can send them to [email protected].

Source: Genentech, October 2007.

FDA Issues Approvable Letter for Anecortave Acetate
Alcon received an approvable letter from the U.S. Food and Drug Administration for anecortave acetate (Retaane) for the treatment of neovascular AMD. The letter advised the company that approval will require an additional clinical study. The company has no immediate plans to conduct a new study due to the difficulty of recruiting patients in light of other currently available treatments.

However, the company continues to believe that anecortave acetate could play a role in the treatment of neovascular AMD. As a result, it will continue to support the Anecortave Acetate Risk-Reduction Trial (AART), which is studying the ability of the treatment to reduce the risk of progression from the dry to the wet form of AMD. AART, which is fully enrolled with more than 2,500 patients, is expected to be completed within three years.

In addition, Alcon is conducting clinical studies of anecortave acetate for the treatment of glaucoma and continues to pursue other potential treatments for wet AMD in its pipeline. Anecortave acetate remains commercially available in several countries outside the United States.

Source: Alcon, September 2007.

Editorial Urges Continuation of Anticoagulant Therapy Surrounding Intravitreal Injections
The physician-authors of an editorial in the journal Retina urged vitreoretinal specialists not to discontinue patients' anticoagulant therapies prior to treating them with intravitreal injections of anti-VEGF agents. Discontinuing anticoagulation, they said, may put patients at a higher risk of thromboembolic events and possible death. "Currently, the literature does not provide compelling evidence to suggest that discontinuation of anticoagulation before cataract surgery, vitreoretinal surgery or intravitreal injection is either necessary or safe," the editorial stated.

The authors cited unpublished data from the Phase III MARINA and ANCHOR trials of ranibizumab for the treatment of neovascular AMD, which suggest that an intraocular injection in a patient being treated with warfarin (Coumadin) is unlikely to cause ocular hemorrhage. In both trials, an overall average total of 1,852 injections were given to patients taking warfarin without ocular bleeding diathesis attributable to anticoagulation. They also pointed out that the increasing popularity of small-incision techniques and other advances in vitreoretinal surgical management may lessen the potential hemorrhagic ocular risks of retinal surgery for anticoagulated patients.

The authors also wrote about the importance of determining whether anticoagulation therapy was stopped in patients participating in the SAILOR study of ranibizumab. A preliminary data analysis in SAILOR suggested that the risk of stroke is possibly higher for patients receiving the 0.5-mg dose. Furthermore, they wrote, it is possible that the stroke risk could have been exacerbated by the as-needed dosing regimen used in SAILOR because warfarin therapy would be stopped and restarted less predictably compared with a monthly dosing regimen.

Source: Charles S, Rosenfeld PJ, Gayer S. Medical consequences of stopping anticoagulant therapy before intraocular surgery or intravitreal injections. Retina 2007;27:813-815.

VEGF 164 Implicated in Diabetic Retinopathy Inflammation
Scientists in the United Kingdom determined that vascular endothelial growth factor isoform 164 not only plays a role in the neovascularization and vascular permeability associated with ocular diseases such as diabetic retinopathy, but also drives an undesirable inflammatory reaction. As such, VEGF 164 could become a target for novel therapies, according to Prof. David T. Shima, group leader at the University College of London, Institute of Ophthalmology.

Prof. Shima announced these research results at the European Meeting on Vascular Biology and Medicine, held in conjunction with the Fourth Annual Meeting of the European Vascular Genomics Network. "When this form [VEGF 164] is genetically or pharmaceutically inhibited the pathological neovascularization is inhibited as well, and blood vessels sprout normally," he said. Prof. Shima added, "However there is one problem to solve: VEGF has a second, beneficial role as it protects neurons from ischemic death. Its complete elimination would trigger unwanted consequences and further research is needed to understand this apparent contradiction."

Source: European Vascular Genomics Network, September 2007.

NEI Awards Grant for Study of Potential Diabetic Retinopathy Therapy
Arteriocyte, a Cleveland-based clinical stage biotechnology company developing cellular therapies for ischemic diseases, announced the award of a $310,000 National Institute of Health grant to evaluate its cellular therapy product (ACY001) as a potential treatment for diabetic retinopathies. The effort will be in collaboration with researchers at the Cleveland Clinic Cole Eye Institute. The award was made by the National Eye Institute as part of the Small Business Technology Transfer program. The planned research is aimed at treating one of the underlying causes of diabetic retinopathy: hypoxia resulting from vaso-obliteration.

Source: Arteriocyte, October 2007.

Positive Primary Endpoint Results from Phase II Study of VEGF Trap
Regeneron Pharmaceuticals and development partner Bayer HealthCare AG announced positive results from the full analysis of the primary 12-week endpoint of a Phase II study evaluating the VEGF Trap-Eye for the treatment of neovascular AMD. The VEGF Trap-eye met the primary study endpoint of a statistically significant reduction in retinal thickness after 12 weeks of treatment compared with baseline (all five dose groups combined, mean decrease of 119 µm, p<0.0001).

The mean change from baseline in visual acuity, a key secondary endpoint of the study, also demonstrated statistically significant improvement (all groups combined, increase of 5.7 letters, p<0.0001). Preliminary analyses at 16 weeks showed that the treatment, dosed monthly, led to a mean gain in visual acuity of 9.3 to 10 letters for the 0.5 and 2-mg dose groups, respectively.

In the double-masked, prospective, randomized, multicenter trial, 157 patients were randomized to five groups and treated in one eye. Two groups received monthly doses of 0.5 or 2.0 mg of the VEGF Trap-Eye, and three groups received quarterly doses of 0.5, 2.0, or 4.0 mg (at baseline and week 12). No drug-related ocular or systemic serious adverse events were observed.

"These results reaffirm the decision to study both the 0.5-mg and 2-mg monthly doses in the Phase III program," said Jeffrey Heier, MD, a primary investigator in the Phase II study. "The quarterly dosing arms seemed to sustain their effect on visual acuity out to eight weeks, providing the rationale for exploring an eight-week dosing schedule in the Phase III program."

Source: Regeneron Pharmaceuticals, October 2007.

Phase III Trial of Fluocinolone Implant Fully Enrolled
Alimera Sciences and pSivida Limited announced that enrollment is complete for the FAME (Fluocinolone Acetonide in Diabetic Macular Edema) study of the Medidur FA intravitreal implant. FAME is a double-masked, randomized, multicenter study that is following more than 900 patients in the United States, Canada, Europe and India for 36 months with safety and efficacy assessed at two years.

Source: Alimera Sciences, October 2007.

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