Volume 4, Number 4
April 2008



Contents:
WELCOME
THE LATEST PUBLISHED RESEARCH
NOTEWORTHY: NOVARTIS PLANS TO ACQUIRE STAKE IN ALCON; OPKO EARNS ADDITIONAL PATENT FOR VEGF-TARGETING SIRNAS; 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

Table of Contents





THE LATEST PUBLISHED RESEARCH

Incidence of Acute Endophthalmitis after Intravitreal Bevacizumab
A retrospective review of 5,233 consecutive intravitreal injections of bevacizumab (Avastin) administered in a tertiary vitreoretinal group practice revealed one case of acute endophthalmitis. During the 23-month study period, the overall rate of postinjection endophthalmitis was 0.019 percent.

In the one case of endophthalmitis, cultures revealed the presence of coagulase-negative Staphylococcus. After treatment for the infection, two months after the initial bevacizumab injection, the patient's visual acuity improved from 4/400 to 20/400. The authors of the paper noted use of aseptic technique and povidone-iodine prophylaxis minimizes the risk of postinjection intraocular infection.

Source: Mason JO, White MF, Feist RM, et al. Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 2008;28:564-567.


Risk Factors for High IOP after Treatment with Triamcinolone
To determine risk factors for intraocular pressure (IOP) elevation to 24 mmHg or higher following treatment with triamcinolone acetonide, researchers in Japan conducted a multicenter retrospective interventional case-control study. In 427 patients, they measured IOP after sub-Tenon's capsule injection (12 mg, 20 mg or 40 mg), intravitreal injection (4 mg or 8 mg) and a combination of sub-Tenon's (20 mg) and intravitreal (4 mg) delivery. They also measured IOP after two triamcinolone treatments.

The combination of sub-Tenon's and intravitreal injection was a significant risk factor (hazard ratio 2.27, p=.003) compared with sub-Tenon's delivery alone. The following were also identified as risk factors: younger age (hazard ratio 0.96, p<.0001); intravitreal injection (hazard ratio 1.89, p<.0001); and higher baseline IOP (hazard ratio 1.15, p=.003). Risk factors for eyes receiving two treatments were intravitreal injection (hazard ratio 2.60, p=.010), higher IOP elevation after the first injection (hazard ratio 1.18, p=.011) and increased dosage of sub-Tenon's injection (hazard ratio, 1.07, p=.033). Dose dependency was shown in both sub-Tenon's (hazard ratio 1.07, p=.0006) and intravitreally treated (hazard ratio 1.64, p=.013) eyes.

Source: Inatani M, Iwao K, Kawaji T, et al. Intraocular pressure elevation after injection of triamcinolone acetonide: a multicenter retrospective case-control study. Am J Ophthalmol 2008;145:676-681.


Primary vs. Secondary Treatment with Triamcinolone for Macular Edema Due to BRVO
In a study comparing intravitreal triamcinolone acetonide (IVTA) as primary and secondary (following grid laser) treatment for macular edema due to branch retinal vein occlusion, IVTA significantly reduced edema in eyes with or without prior grid laser treatment. However, improvement in best-corrected visual acuity was more pronounced in eyes that received IVTA as primary therapy. In addition, the effects of IVTA were transient.

Eyes with macular edema secondary to BRVO and BCVA worse than 20/40 were included in the study (n=37). Twenty-five eyes received IVTA as primary treatment and 12 eyes received IVTA as secondary treatment. Mean follow-up time was 9.6 +/-4.5 months. Patients in the primary treatment group experienced a statistically significant gain in BCVA throughout follow-up (p<0.05). In the secondary treatment group, a small increase in BCVA was noted only at the month three visit (p=0.04). Pre-IVTA BCVA was the single statistically significant predictor of BCVA gain following injection. IOP increased to more than 25 mmHg in eight patients (21.6 percent).

Sources: Cakir M, Dogan M, Bayraktar Z, et al. Efficacy of intravitreal triamcinolone for the treatment of macular edema secondary t branch retinal vein occlusion in eyes with or without grid laser photocoagulation. Retina 2008;28:465-472.


Macular Edema Detection with FA and OCT -- Alone and Together
According to the results of a 12-month, single-center, retrospective study, conventional fluorescein angiography and Stratus optical coherence tomography are highly sensitive and correlate well for the detection of macular edema, but subtle edema can be missed when the tests are performed alone.

The study involved 1,272 eyes that underwent simultaneous FA and Stratus OCT testing to rule out macular edema. A subset of patients underwent additional examination with extremely high-resolution (6 µm), ultrahigh-speed spectral OCT/scanning laser ophthalmoscopy. In 1,208 (94.97 percent) of the eyes, both FA and OCT detected macular edema or subretinal fluid. In 15 eyes (1.17 percent), OCT showed intraretinal and subretinal fluid that FA missed. In 49 eyes (3.86 percent) FA showed dye leakage in the macular area and OCT showed normal foveal contour. Of 10 eyes in this group imaged with spectral OCT/scanning laser ophthalmoscopy, eight were shown to have subtle diffuse retinal lucencies.

Source: Kozak I, Morrison VL, Clark TM, et al. Discrepancy between fluorescein angiography and optical coherence tomography in detection of macular disease. Retina 2008;28:538-544.


Safety and Efficacy of a Second Sustained-Released Fluocinolone Implant
In a prospective, interventional study, replacing the fluocinolone-containing intraocular implant (Retisert) or implanting a second one after the drug was depleted and inflammation recurred was safe and effective. Retisert is indicated for treatment of chronic noninfectious uveitis of the posterior segment.

The study comprised 17 eyes of 14 consecutive patients who received a second implant at Duke Eye Center from March 2004 to July 2007. They were then followed for at least nine months; average follow-up was 17 months. Inflammation developed in only one eye during follow-up, three years after the second implantation. Adjunctive steroid use decreased significantly. Mean Snellen visual acuity 12 months after the second implantation was 20/78, compared with 20/400 at the time of the original implantation (p=.04). Compared with preoperative IOP, mean IOP was unchanged after insertion.

Mean time from original fluocinolone implantation to first recurrence of uveitis was 38 months. Mean time from first inflammation recurrence to second implantation was eight months.

Source: Jaffe GJ. Reimplantation of a fluocinolone acetonide sustained drug delivery implant for chronic uveitis. Am J Ophthalmol 2008;145(4):667-675.

Effects of the LOC387715 Polymorphism and Other Factors on AMD Risk
A population-based case-control study was designed to assess the combined effects of the LOC387715 gene polymorphism with smoking and inflammatory or hemostatic factors on the risk of age-related macular degeneration. The study found no significant interaction between the genetic and inflammatory/hemostatic factors. However, combined effects were found for the genotypes and three inflammatory markers and plasminogen activator inhibitor 1 (PAI-1) on the risk of developing early and late AMD, and when current smoking was added, there was an increased risk of developing late AMD.

Drawn from the Blue Mountains Eye Study, 278 subjects with AMD (224 early, 54 late) and 557 controls were matched for age, gender and smoking. They were genotyped for the LOC387715 Ala69Ser polymorphism (rs# 10490924). They self-reported smoking and researchers measured serum high-sensitivity C-reactive protein (CRP), interleukin 6 (IL-6), soluble intercellular adhesion molecule 1 (sICAM-1), fibrinogen, homocysteine, PAI-1, von Willebrand factor, and white cell count. Logistic regression models, adjusted for age and smoking, were used to assess combined effects. Interaction was defined as the influence of two factors departing from the multiplicative scale, confirmed by a statistically significant interaction term.

Combined effects on the likelihood of developing early or late AMD were demonstrated for the LOC387715 Ala69Ser G/T and T/T genotypes and the following (odds ratios for the highest tertile alone, for G/T and T/T genotypes alone, and for both G/T and T/T genotypes plus the highest tertile compared with the G/G genotype with the two lower tertiles):
• high-sensitivity CRP (1.2, 1.6, 2.2)
• IL-6 (1.1, 1.6, 2.2)
• sICAM-1 (1.0, 1.5, 2.3)
• PAI-1 (1.3, 1.7, 2.3).

Combined effects were not demonstrated for white cell count, fibrinogen, homocysteine or von Willebrand factor. Findings were similar for early and late AMD separately.

Current smokers with G/T and T/T genotypes had strong combined effects on risk for late AMD compared with those who never smoked or past smokers with the G/G genotype (odds ratios 1.2 for current smokers alone, 1.8 for G/T and T/T genotypes alone, and 6.1 for current smokers plus G/T and T/T genotypes).

Source: Wang JJ, Ross RJ, Tuo J, et al. The LOC387715 polymorphism, inflammatory markers, smoking, and age-related macular degeneration: a population-based case-control study. Ophthalmology 2008;115:693-699.

Further Study of Phacoemulsification and AMD Progression
Results from a retrospective case-control study indicated that phacoemulsification for cataract surgery does not cause early AMD to progress to neovascular AMD. The study included 1,152 eyes of 696 consecutive patients diagnosed with early AMD who underwent phacoemulsification from January 2000 to February 2006 at the Recklinghausen Eye Centre in Germany. They were followed for at least one year after surgery. The control group (334 eyes of 202 patients) was made up of phakic patients diagnosed with early AMD in the same time period. They were also followed for at least a year.

At baseline, control eyes had significantly better visual acuity than those of patients who were undergoing cataract surgery (p<0.001). After one year, visual acuity in control group eyes was worse than in operated eyes (p<0.001). There was no significant difference between the two groups in the incidence of neovascular AMD (p=0.57, odds ratio 1.30, 95 percent confidence interval 0.52 to 3.24).

Source: Baatz H, Darawsha R, Ackermann H, et al. Phacoemulsification does not induce neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49:1079-1083.

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NOTEWORTHY: NOVARTIS PLANS TO ACQUIRE STAKE IN ALCON; OPKO EARNS ADDITIONAL PATENT FOR VEGF-TARGETING SIRNAS; AND OTHER ITEMS OF INTEREST

Novartis Plans to Acquire Stake in Alcon
Nestle S.A. and Novartis AG announced an agreement under which Nestle will sell 74 million of its shares of Alcon Inc. common stock to Novartis in a cash transaction priced at $143.18 per share (approximately $11 billion). Novartis would then own a 25 percent minority stake in Alcon, while Nestle would remain Alcon's majority shareholder with approximately 52 percent of outstanding shares. The agreement also outlines an optional second step in which Novartis has exclusive right to acquire Nestlé's remaining 52 percent for a fixed price of $181 per share (approximately $28 billion).

The agreement also provides for the expansion of the Alcon board of directors from eight to ten members, with one of the additional members designated by Nestle and one designated by Novartis. The nominees for the additional board seats are James Singh, Nestle's executive vice president and chief financial officer, and Daniel Vasella, M.D., chairman and chief executive officer of Novartis.

The transaction is subject to regulatory approvals.

Source: Nestle S.A., April 2008.


OPKO Earns Additional Patent for VEGF-Targeting siRNAs
OPKO Health has been issued a key patent by the U.S. Patent and Trademark Office for methods related to the use and administration of small interfering RNAs (siRNAs) for targeting vascular endothelial growth factor, including bevasiranib, which is currently in Phase III trials for the treatment of wet AMD. Bevasiranib is designed to silence the genes that produce VEGF. It is the first such therapy to advance to Phase III clinical trials. The patent covers a broad range of methods for use of a specific sequence of siRNA. This is the company's second patent related to bevasiranib.

For more information about the COBALT trial, visit opko.com/clinicaltrials.

Source: OPKO Health, March 2008.


OTI Receives FDA Warning Letter for Manufacturing Facilities
According to the latest Annual Report filed by Opko Health with the U.S. Securities and Exchange Commission, the FDA has issued a warning letter pertaining to the manufacturing facilities of Ophthalmic Technologies Inc. (OTI). Opko acquired OTI in November 2007.

OTI has an instrumentation manufacturing facility in Toronto, Canada, which predominantly performs high level assembly. Some of OTI's components and optical subsystems are produced by subcontracted vendors that specialize in optical device manufacturing. On March 25, OTI received a warning letter in connection with FDA inspections of its facilities conducted in 2007. The letter cited several deficiencies in quality, record keeping and reporting systems relating to OTI products, including the OTI Scan 1000, OTI Scan 2000 and OTI OCT/SLO combination imaging system. Based on the observations noted in the warning letter, OTI is not currently in compliance with cGMP. The FDA indicated that it has issued an Import Alert and may refuse admission of these products. As a result, the company will not be permitted to sell these devices in the United States, and the pre-market approval application for the OCT/SLO product will be delayed until the violations have been corrected.

The Annual Report also stated that Opko plans to cooperate fully with the FDA and began to take corrective action upon receipt of the warning letter to remedy the deficiencies and implement updated and improved quality systems and concepts throughout the OTI organization.

Source: Opko Health Annual Report (Form 10-K filed March 31 for the period ending Dec. 31, 2007).


DSMB Says FAME Trials Can Continue as Planned
An independent Data Safety Monitoring Board has recommended that two pivotal Phase III clinical trials evaluating a fluocinolone-releasing ocular implant (Medidur) for the treatment of diabetic macular edema continue as planned. The studies, known collectively as FAME, are duplicate, double-masked, randomized, multicenter trials following 956 patients in the United States, Canada, Europe and India for 36 months. Enrollment was completed in October 2007; safety and efficacy will be assessed after two years of follow-up. The technology underlying Medidur for diabetic macular edema is licensed to Alimera Sciences.

Source: pSivida Limited, March 2008.

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