Review of Ophthalmology's Retina Online

Volume 1, Number 2

June 2005

Contents:

		EDITORIAL: WELCOME

		THE LATEST RESEARCH

		NOTEWORTHY: TRIAL OF RANIBIZUMAB PLUS PDT MEETS PRIMARY ENDPOINT, AND MORE ITEMS OF INTEREST

EDITORIAL: 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:

	Summaries of the latest research presented at scientific meetings and in peer-reviewed journals
	Noteworthy, items of interest
	Don’t miss this article in the June issue of Review of Ophthalmology: Retinal Insider covers the management of globe injuries

THE LATEST RESEARCH

Original Amsler Grid Outperforms Modified Version
In a study of 182 patients with wet and dry AMD and a history of metamorphopsia, the original version of the Amsler grid (white lines on a black background) produced better results than the widely used modified version (black lines on a white background). Patients in the study had never used an Amsler grid. If disease was present in both eyes, the study eye was chosen randomly. Both grid types were used, and the order of presentation of the grids was randomized. Patients were divided into seven groups according to level of visual acuity (0.1-0.7). The paired Wilcoxon rank sum test was used for statistical evaluation. In the overall study population, results with the original grid were significantly better (P<0.05). The benefit was most pronounced among patients with visual acuities of 0.5 or better, suggesting that the original grid rather than the modified grid should be used for patients with early-stage macular disease, and that either grid type may be suitable for patients with advanced disease.

Source: Augustin AJ, Offermann I, Lutz J, Schmidt-Erfurth U, Tornambe P. Comparison of the original Amsler grid with the modified Amsler grid. Retina 2005;25:443-445.

OCT for Early Detection of AMD Progression
Based on a study of 30 patients with dry AMD in one eye and wet AMD in the fellow eye, researchers in Illinois concluded that optical coherence tomography (OCT3, Carl Zeiss Meditec) may be a useful tool for early detection of progression from dry AMD to wet AMD. The researchers monitored the dry AMD eye of these patients every three months with a dilated exam and OCT3. Early signs of disease progression visible on OCT were drusen increasing in height, subretinal fluid, sub-RPE fluid, RPE breaks, and outer retinal disorganization. Five of the patients showed definite or suspicious signs of disease progression in their dry AMD eye. OCT showed pathological changes in all five patients, but in three of them, dilated ophthalmoscopy and fluorescein angiography results were normal.

Source: The use of serial optical coherence tomography in the early detection of wet age-related macular degeneration, Padnick-Silver L, Macsai-Kaplan MS, LaFranco FP, Beck JL, 2005 ARVO poster presentation 233/B207.

PDT Instead of Photocoagulation for Non-Subfoveal AMD Lesions
Based on their six-month study of 10 eyes of 10 patients, researchers in France concluded that limited-size PDT may be a safe and effective alternative to laser photocoagulation for juxtafoveal and extrafoveal predominantly classic choroidal neovascularization (CNV) in AMD. The 10 patients underwent PDT instead of laser photocoagulation. PDT spot diameter for each eye was matched to CNV area as determined by angiography or OCT. Lesions in two eyes were juxtafoveal; lesions in eight eyes were extrafoveal. Initial visual acuity ranged from 20/125 to 20/32. Angiography or OCT and visual acuity tests were performed at weeks three, six, 12 and 24. At 24 weeks, the visual acuity range was 20/200 to 20/25. Vision was maintained or improved in eight eyes; in six, the CNV network was closed; in two, CNV remained perfused but did not increase. Two eyes required re-treatment for subfoveal extension.

Source: Photodynamic therapy for juxtafoveal or extrafoveal choroidal neovascularization in ARMD: results of pilot study, Francais C, Devin F, El Maftouhi A, et al., 2005 ARVO poster presentation 308/B282.

Tamoxifen Does Not Appear to Increase Risk for Retinal Vascular Occlusive Disease
According to a review of adverse effects data from the Breast Cancer Prevention Trial (BCPT), patients treated with the estrogen receptor modulator tamoxifen did not show an increased incidence of retinal vascular occlusive disease compared with the control group. Based on previous studies, tamoxifen has been associated with an increased risk of cataract and an increased risk of systemic large vessel thromboembolic disease. A total of 13,204 patients participated in the BCPT. Mean follow-up was 47.7 months. No formal ophthalmic evaluation was part of the study design, but participants were encouraged to have regular eye care, and during follow-up 10,758 participants reported more than 30,000 eye exams. In this latest review of the data, eight different types of retinal vascular occlusive disease were found. Eleven cases were found in the tamoxifen-treated group; eight cases were found in the control group. The average annual rates per 1,000 of retinal vascular occlusive lesion were 0.29 and 0.40 respectively. The relative risk of a vascular occlusive event associated with tamoxifen was 1.37 with a 95 percent confidence interval of 0.50 to 3.93.

Source: Gorin MB, Costantino JP, Kulacoglu DN, et al. Is tamoxifen a risk factor for retinal vaso-occlusive disease? Retina 2005;25:523-526.

NSAID Fails to Retard Diabetic Macular Edema
In a pilot study of nine eyes of five patients, the COX-2 inhibitor rofecoxib (Vioxx, Merck) did not reverse or prevent diabetic macular edema. Patients were treated daily with 50 mg of rofecoxib and followed for six months. Testing included ETDRS visual acuity, dilated fundus exam, optical coherence tomography and fluorescein angiography. No clinical or statistically significant improvement in visual acuity or decrease in macular edema was seen. The study coordinators said the lack of effect could be explained by the dosage, differences in inflammatory mechanisms in an animal model vs. in humans, or the lack of a direct inhibitory effect of COX-2 inhibitors on vascular endothelial growth factor activity.

Source: Medical treatment of diabetic macular edema with rofecoxib, Christoforidis JB, Adamis AP, D’Amico DJ, 2005 ARVO poster presentation 391/B365.

Effects of Triamcinolone Differ for CME and CSDME
According to a retrospective chart review on 35 eyes of 31 patients, cystoid macular edema (CME) is more responsive to sub-Tenon’s injections of triamcinolone acetonide than clinically significant diabetic macular edema (CSDME). Patients whose charts were reviewed were treated between Jan. 1, 2002 and Dec. 31, 2003. Only eyes that had two or more optical coherence tomography measurements of central foveal thickness, one on the day of treatment and another at follow-up, were included. Thirty-seven injections were performed. For those injections, the mean decrease in central foveal thickness was 20.8 percent (SD +/-24.7 percent). Twenty of the 37 injections were for CSDME. The mean response in that group was a 9.6-percent decrease. Seventeen of the 37 injections were for CME. Mean response in that group was a 33-percent decrease. Statistical analysis showed equivalent variances by F test, but a two-sample t test showed a statistically significant difference in mean thickness decrease between the two groups (P=0.0011).

Source: The effect of subtenon’s steroid injection on macular edema as measured by OCT, Hamilton R, Kim JE, Patel CC, 2005 ARVO poster presentation 286/B260.

A new non-trocar system for 25-ga. transconjunctival pars plana vitrectomy.

New System for 25-Ga. Transconjunctival Pars Plana Vitrectomy
In the June issue of the American Journal of Ophthalmology, surgeons using a new non-trocar system for 25-ga. transconjunctival pars plana vitrectomy reported no intraoperative or postoperative complications in a series of 14 patients. The system (NIDEK Corp.) consists of a contact lens ring with four projections containing 1-mm holes (located 3 mm from the ring’s edge), a wedge-shaped 25-ga. infusion cannula, and two plugs. The ring is fixed with 7-0 silk sutures at the 3- and 9-o’clock positions on the limbus. Using the 25-ga. needle, the surgeon creates three conjunctival and scleral incisions at the projection holes located inferotemporally, superonasally and superotemporally. Suturing of the sclerotomies is not required.

Source: Tei M, Shimamoto T, Yasuhara T, Komori H, Oda H, Kinoshita S. A new non-trocar system for 25-gauge transconjunctival pars plana vitrectomy. Am J Ophthalmol 2005;139:1130-3.

OCT Imaging May Help Predict Success of Macular Translocation Surgery
To determine whether lesion morphology, as imaged by presurgical OCT, can predict visual outcomes following 360-degree macular translocation surgery (MTS360), researchers at Duke University obtained preoperative OCT and pre- and postoperative visual acuity measurements from 73 eyes of patients with vision loss from subfoveal neovascular AMD. The only significant correlations at one year were subretinal fluid thickness with reading speed (P<0.0072); the sum of retina and lesion thickness with reading speed (P<0.011); presence of vitreomacular attachment with reading speed (P<0.0054); and for a subgroup of patients with poor preoperative vision, lesion thickness and near acuity (P<0.024). In a secondary analysis, the sum of retina thickness and subretinal fluid correlated with both near acuity (P<0.029) and reading speed (P<0.012). The researchers said that the correlation between increasing subretinal fluid under the fovea and better MTS360 outcomes suggests that the presence of subretinal fluid might prevent foveal photoreceptor injury when the retina is separated from the retinal pigment epithelium during the procedure.

Source: Presurgical OCT lesion analysis predicts visual outcomes for patients undergoing MT360 for subfoveal CNV, Ramchandran RS, Stinnett S, Winter K, Toth C, 2005 ARVO poster presentation 214/B188.

PPV Fares Better Than IMT for Treatment of Pars Planitis
In a recent Massachusetts Eye & Ear Infirmary study comparing pars plana vitrectomy (PPV) with immunomodulatory therapy (IMT) for pars planitis, a higher percentage of the vitrectomy patients had resolution of uveitis at 18 months. Twenty eyes of 16 patients were randomized to receive either PPV or IMT. The condition had degraded vision and persisted despite regional steroid injections. Eleven eyes had PPV; nine had IMT. Of the PPV eyes, 82 percent showed resolution of inflammation by the end of follow-up. Of the IMT eyes, 55 percent had persistent inflammation and required subsequent PPV. PPV eyes showed greater improvement in Snellen lines of visual acuity, intraocular pressure and vitreous cell reduction, although no data point was statistically significant at P=0.05. Four (36 percent) PPV eyes and four (44 percent) IMT eyes had cataract progression.

Source: Pars plana vitrectomy versus immunomodulatory therapy in a prospective randomized trial for treatment of pars planitis, Choi JY, Kafkala C, Foster CS, 2005 ARVO poster presentation 2830/b383.

Work Explores Utility of Ultrawide-Field Angiography System
Several presentations at this year’s annual meeting of the Association for Research in Vision and Ophthalmology pertained to a new ultrawide-field fluorescein angiography system (Panoramic200A, Optos), which is expected to be commercially available in the United States this fall. At the Jules Stein Eye Institute in Los Angeles, the system was used to simultaneously image the posterior pole and retinal periphery in many conditions, including asteroid hyalosis, Coats’ disease, diabetic retinopathy, central retinal vein occlusion, branch retinal vein occlusion, retinal detachment, traumatic macular hole, retinoschisis, retinal vasculitis, idiopathic polypoidal choroidal vasculopathy, AMD, peripheral disciform degeneration, sarcoidosis, angioid streaks in pseudoxanthoma elasitcum, coloboma, presumed ocular histoplasmosis syndrome, punctate inner choroidopathy, congenital hypertrophy of the retinal pigment epithelium, and choroidal melanoma. According to the physicians analyzing the images, previously unrecognized, rarely appreciated, and/or clinically meaningful peripheral angiographic findings were obtained in a number of cases and used as the basis for treatment decisions. A pilot study conducted at the University of Pittsburgh Medical Center Eye Center indicated that clinically significant diabetic macular edema appears to be associated with measurable capillary dropout outside of the macular arcades, which, the researchers said, could have important treatment implications. Seventeen eyes of 11 patients underwent ultrawide-field fluorescein angiograms. An overlay of a digital grid of 12 concentric circles divided into 45-degree sectors facilitated evaluation of the images. Each grid was adjusted to reflect the disc diameter of each eye. Among the 17 eyes, the percentage of extramacular sectors showing ischemia ranged from 36 percent to 88 percent with a mean of 71 percent +/-12 percent. Another study of this system, also conducted at the University of Pittsburgh, compared montaged seven-field angiography imaging obtained using a 50-degree fundus camera with 200-degree angiography imaging obtained with the Panoramic200A. The overlaid digital grid described above was used in image evaluation. The peripheral limit of the images was measured in each sector, and the number of sectors containing neovascularization and/or ischemia was determined by a masked retinal specialist and tabulated. For the seven-field montage, the mean extent of the outermost edge of the imaged field was 6.843 +/-0.71 disc diameters (DD). For the ultrawide-field imaging, the mean extent was 9.56 +/-0.93 DD. The mean number of sectors containing ischemia was 14.6 +/-10.4 for the montage and 22.7 +/-14.9 for the ultrawide-field system. The mean number of sectors containing neovascularization for the montage was 1.19 +/-1.87 and 3.18 +/-2.52 for the ultrawide-field system. The differences between the three sets of values were statistically significant (P<0.05).

Sources: Peripheral angiographic evaluation of vitreoretinal diseases using the Optos Panoramic200A imaging system, Gonzales CR, Gupa A, Young TA, et al., 2005 ARVO poster presentation 2576/B129. Detection of capillary drop out in ultra wide angle (Optos P200A) fluorescein angiograms in patients with clinically significant diabetic macular edema, Reznick LG, Friberg TR, 2005 ARVO poster presentation 1555/B324. Ultra wide angle fluorescein angiography (Optos Panoramic200A) compared to 7-field fluorescein angiographic imaging of pre-proliferative diabetic retinopathy, Huang L, Friberg TR, Eller AW, 2005 ARVO poster presentation 369/B343.

NOTEWORTHY: TRIAL OF RANIBIZUMAB PLUS PDT MEETS PRIMARY ENDPOINT, AND MORE ITEMS OF INTEREST

Trial of Ranibizumab Plus PDT Meets Primary Endpoint.
Genentech Inc. reported that the FOCUS clinical study of ranibizumab (Lucentis) in combination with verteporfin (Visudyne, Novartis Ophthalmics) photodynamic therapy met its primary endpoint as well as a key secondary endpoint. According to the company, the combination of ranibizumab and PDT maintained or improved vision in approximately 90 percent of patients, while PDT alone maintained or improved vision in 68 percent of patients (P=0.0003). Also, at 12 months, the group treated with both therapies had an increase in mean visual acuity from baseline, while the group treated with PDT alone had a decrease in mean visual acuity. Patients treated with the two therapies were at increased risk of uveitis compared with those treated with only PDT. Based on the preliminary analysis of that data, the study protocol was amended. Endophthalmitis was the second most common ocular serious adverse event occurring in patients treated with ranibizumab. FOCUS is a Phase I/II, randomized, single-masked study evaluating the safety, tolerability and efficacy of ranibizumab in combination with PDT in 162 patients with predominantly classic subfoveal wet AMD. Patients are randomized 2:1 to receive PDT followed by either 0.5-mg injections of ranibizumab or sham injections for 23 months. One-year data from the trial will be presented at the annual meeting of the American Society of Retina Specialists in July. [Genentech Inc., May 2005]

Pegaptanib sodium (Macugen) has received regulatory approval in Canada and Brazil.

Eyetech Announces International Approvals, Provides Update on Research.
Eyetech Pharmaceuticals Inc.’s anti-VEGF therapy for wet AMD, pegaptanib sodium (Macugen), has received regulatory approval in Canada and Brazil. In both countries, as in the United States, pegaptanib is the first therapy indicated for wet AMD regardless of lesion size or subtype. In a recent conference call, CEO David Guyer, MD, reiterated the company’s confidence in its continued success and provided an update on its research and development activity. He reported that first-quarter gross product revenue was $25.4 million, and that, as of the end of March, 99 of the company’s top 100 accounts had already reordered pegaptanib. "We strongly believe there is room for multiple anti-VEGF agents in this large and growing AMD market much like the industry has already experienced in multiple sclerosis and oncology," Dr. Guyer said. "Our first mover advantage with Macugen, our partnership with Pfizer, our advantage in dosing schedule and our proven safety make us especially confident of our continued success in the AMD market." Also during the call, Dr. Guyer said the company anticipates beginning a Phase I study of an anti-PDGF-B (platelet-derived growth factor-B) aptamer in mid-2006. Pre-clinical proof of concept is complete, and laboratory studies have shown the compound to be synergistic with pegaptanib. With partner Archemix Corp., Eyetech will study the aptamer both as a single agent and in combination with pegaptanib for neovascular AMD. In addition, Eyetech and Pfizer plan to start a pivotal Phase II/III trial of pegaptanib for the treatment of diabetic macular edema in the second half of this year, and had already initiated a Phase II trial in 2004 to determine the safety, efficacy and pharmacokinetics of pegaptanib in patients with central retinal vein occlusion. The companies also expect to complete enrollment in the Phase IIIb/IV trial of pegaptanib in combination with photodynamic therapy for wet AMD by the second half of 2006. Additional research focuses on a sustained-release drug delivery system for pegaptanib. In another announcement in June, Eyetech executives said the company has revised its expectation for net product revenue from the sale of pegaptanib. It now expects $175 to $190 million in net product revenue for the full fiscal year ending December 31, 2005. [Eyetech Pharmaceuticals Inc., May and June 2005]

Study Finds Retinopathy in Pre-Diabetic Patients.
A recent study funded by the National Eye Institute reinforces the recommendation that patients with newly diagnosed type 2 diabetes should be screened for retinopathy. Diabetic retinopathy was found in nearly 8 percent of pre-diabetic patients in the Diabetes Prevention Program (DPP), a major clinical trial involving 3,234 people with impaired glucose tolerance. The DPP’s main results were announced in 2001 and reported in the Feb. 7, 2002 issue of the New England Journal of Medicine.* "Previous studies have not accurately defined when type 2 diabetes begins, so our understanding of the onset of diabetic eye disease has been limited," said Richard Hamman, MD, DrPH, vice chairman of the DPP. "Now we know that diabetic retinopathy does occur in pre-diabetes." [*Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2005;346:393-403.] [American Diabetes Association, June 2005]

A patient receives an injection of an siRNA-based drug from physicians at Retina Associates of Cleveland.

Companies Collaborate on RNA Interference Therapies.
Acuity Pharmaceuticals and Intradigm Corp., a pioneer in RNA interference therapy, have agreed to a strategic collaboration. The agreement gives Acuity exclusive rights to Intradigm’s technology for topical and systemic drug delivery for ophthalmic uses. It licenses to Acuity exclusive rights to Intradigm’s siRNA ophthalmic drug discovery platform and portfolio and the intellectual property associated with the ophthalmic drug discovery and delivery programs. The companies also will collaborate to develop a topical formulation of Acuity’s RNAi compound, Cand5. Acuity intends to begin Phase II trials of Cand5 for wet age-related macular degeneration later this year. Cand5 is currently administered by intravitreal injection. Acuity says the availability of alternative delivery modes will make development of prophylactic and early treatment options more feasible. For more information on Acuity and Intradigm, visit intradigm.com and acuitypharma.com. [Acuity Pharmaceuticals, June 2005]

FDA, Pfizer Address Possible Link Between NAION and Viagra.
In response to reports that sildenafil (Viagra) may be linked to vision loss from nonarteritic anterior ischemic optic neuropathy (NAION), Pfizer Inc. reviewed 103 clinical trials involving 13,000 patients and issued a statement that, "There is no evidence showing that NAION occurred more frequently in men taking Viagra than men of similar age and health who did not take Viagra." The company and the FDA are discussing potential updates to the drug’s labeling to reflect the rare occurrence of NAION. The possibility that Viagra might lead to NAION was first suggested by Howard Pomeranz, MD, in 2002. In a study published in the Journal of Neuro-Ophthalmology this March*, Dr. Pomeranz noted seven new cases in which men developed NAION, possibly because of Viagra. On May 26, CBS News reported that the FDA was investigating similar reports in nearly 50 men. In the March Pomeranz study, seven patients between the ages of 50 and 69 had typical features of NAION within 36 hours of ingesting Viagra for erectile dysfunction. Six patients had vision loss within 24 hours after use of the drug. Final visual acuity in the affected eye ranged from 20/20 to light perception. [*Pomeranz, HD, Bhavsar, AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 2005;25(1):9-13.]

The architect’s rendering of the planned new wing at the Bausch & Lomb Rochester facility. Image courtesy of Flad & Associates.

Bausch & Lomb Plans Major Expansion of R&D Facility.
Bausch & Lomb has announced a $35-million expansion plan that will nearly double the size of its main research and development center in Rochester, N.Y. The expansion includes a new two-story 75,000-square-foot, glass-and-brick wing that will house laboratories and offices and allow room for a future 25,000-square-foot addition. The company also plans to add up to 200 research jobs over the next two years. [Bausch & Lomb, June 2005]

Squalamine Trial Reaches Target Enrollment.
Genaera Corp. has reached the target enrollment for the third U.S. Phase II clinical trial of squalamine lactate (Envizon) for the treatment of wet AMD. The trial, MSI-1256F-209, is multicenter, randomized, controlled and double-masked and involves 100 patients. It will evaluate the safety and efficacy of two different systemically delivered doses in all subtypes of wet AMD over a two-year period and will run concurrently with Phase III trials. Patients will be treated once a week for four weeks followed by maintenance doses once every four weeks until week 48. At the end of 48 weeks, each patient will be followed for an additional 12 months. The company expects to initiate Phase III trials this quarter. [Genaera Corp., June 2005]

Vitreous comes out from under the lateral rectus muscle in a patient with a ruptured globe.

IN THE JUNE ISSUE OF REVIEW OF OPHTHALMOLOGY

Retinal Insider
Dante Pieramici, MD, shares his expertise on managing open globe injuries, with an emphasis on proper classification and diagnosis of the injury and treatment options.

The Retinal Insider article begins on page 93, or you can access the article online by going to to www.revophth.com and clicking on our Archive, or click here.

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