Volume 13, Number 2
February 2017

WELCOME to Review of Ophthalmology's Retina Online e-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.



GENENTECH COMPLETES ENROLLMENT IN PHASE III CHROMA AND SPECTRI TRIALS
Genentech completed enrollment in the Chroma and Spectri Phase III clinical trials, which are designed to investigate the efficacy and safety of lampalizumab in reducing the progression of geographic atrophy lesions secondary to AMD...


RESEARCHERS DEVELOP CELL CULTURE SYSTEM FOR AMD
An international research team from the University of Alabama at Birmingham, University College London and Queens University Belfast designed a cell culture model that could aid development of earlier treatment strategies for age-related macular degeneration...

And More...

 

Vancomycin-associated Hemorrhagic Occlusive Retinal Vasculitis

Researchers sought to expand knowledge about the presentation, diagnosis and outcomes of hemorrhagic occlusive retinal vasculitis, as part of a retrospective case series looking at 36 eyes of 23 patients.

Previous to the study series, the American Society of Cataract and Refractive Surgery and the American Society of Retina Specialists formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment and outcomes. They established an online registry, and e-mailed surveys to members of both societies, soliciting cases of suspected HORV. Researchers performed a literature search to uncover additional cases. Main outcome measures included historical data such as intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes.

Characteristic findings of HORV included unremarkable postoperative day one undilated exam, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), intravitreal injection (1/36) or through the irrigation bottle (2/36). Individuals sought treatment with HORV one to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61 percent) had 20/200 or worse visual acuity and eight of 36 eyes (22 percent) had no light perception. Neovascular glaucoma developed in 20 of 36 eyes (56 percent). Seven eyes received additional intravitreal vancomycin after surgery, five of which had no light perception visual acuity at the most recent exam. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70 and hand motion.

Researchers determined that all cases in this series were associated with intraocular vancomycin, and that disease course and findings suggested that HORV was caused by a delayed hypersensitivity reaction to vancomycin. They suggested that early treatment with corticosteroids likely was beneficial, and that later, anti-vascular endothelial growth factor injections and panretinal photocoagulation were important to prevent neovascular glaucoma. They recommended avoidance of additional intravitreal vancomycin if HORV is suspected.

SOURCE: Witkin AJ, Chang DF, Jumper M, et al. Vancomycin-associated hemorrhagic occlusive retinal vasculitis. Ophthalmology 2017; Jan 19. [Epub ahead of print].

 

 

Worsening PDR in Eyes Treated With PRP or Ranibizumab

Investigators compared rates and identified predictive factors for events that represented worsening of proliferative diabetic retinopathy in eyes treated with panretinal photocoagulation or ranibizumab, as part of a randomized clinical trial (55 U.S. sites).

They assessed 394 PDR eyes with visual acuity of 20/320 or better and no history of receiving PRP or intravitreous ranibizumab injections (0.5 mg/0.05 ml). Main outcome measures included time from randomization to a composite PDR-worsening result, defined as the first occurrence of vitreous hemorrhage, retinal detachment, anterior segment neovascularization or neovascular glaucoma.

Through two years, the cumulative probability of worsening PDR was 42 percent (PRP) vs. 34 percent (ranibizumab; HR=1.33; 99 percent CI, 0.90 to 1.98; p=0.063). Worse baseline levels of DR severity (Early Treatment Diabetic Retinopathy Study scale) were associated with increased risk of worsening PDR, regardless of treatment group (64 percent [high-risk PDR or worse] vs. 23 percent [moderate PDR or better]; HR=3.97; 99 percent CI, 2.48 to 6.36; p<0.001). In the PRP group, eyes receiving pattern scans vs. conventional, single-spot PRP also were at higher risk for worsening PDR (60 percent vs. 39 percent; HR=2.04; 99 percent CI, 1.02 to 4.08; p=0.008), regardless of the number of spots placed or the number of sittings to complete the initial PRP. Eyes in both groups with vision-impairing (VA 20/32 or worse), center-involved diabetic macular edema at baseline were required to receive ranibizumab for center-involved DME. Therefore, researchers compared the composite outcome by treatment in the subgroup of eyes that didn’t have vision-impairing, center-involved DME at baseline. For these eyes, the rate of PDR-worsening was greater with PRP than ranibizumab (45 percent vs. 31 percent; HR=1.62; 99 percent CI, 91.01 to 2.60; p=0.008).

Investigators determined that, in eyes with PDR, ranibizumab resulted in less PDR deterioration compared with PRP, especially in eyes not required to receive ranibizumab for center-involved DME. They added that these findings provide additional evidence supporting the use of ranibizumab as an alternative therapy to PRP for PDR, at least through two years.

SOURCE: Bressler SB, Beaulieu WT, Glassman AR, et al. Factors associated with worsening proliferative diabetic retinopathy in eyes treated with panretinal photocoagulation or ranibizumab. Ophthalmology 2017; Feb. 1. [Epub ahead of print].


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Baseline Choroidal Thickness as a Predictor for CRVO Treatment Outcomes

Scientists evaluated the association between initial subfoveal choroidal thickness and response to anti-vascular endothelial growth factor therapy in central retinal vein occlusion eyes, as part of a retrospective cohort study.

They included 43 eyes from 42 people with treatment-naïve CRVO. All individuals included were treated with a standard algorithm of three monthly anti-VEGF injections. Serial enhanced-depth-imaging optical coherence tomography scans helped measure subfoveal choroidal thickness and central macular thickness. Scientists assessed baseline predictors (particularly choroidal thickness) for functional response (best-corrected visual acuity gain ≥2 lines) at three months follow-up using univariate and multivariate analyses.

Initial choroidal thickness in CRVO eyes (246 ±102 μm) was greater than in fellow eyes (197 ±86 μm; p=0.023). In addition, mean choroidal thickness at baseline for functional responders (272.2 ±107.3 μm) was greater than that of nonresponders (209.6 ±85.8 μm; p=0.039). A higher baseline choroidal thickness (for every 100-µm increase in choroidal thickness) was found to be a positive predictor for functional response (regression coefficient: 0.7; p=0.04) on univariate analysis, whereas age (<70 years old) was the only positive predictor for functional response, with an odds ratio of 6.49 (CI, 1.11 to 38.1; p=0.03) on multivariate regression analysis.

Scientists found that baseline choroidal thickness and age could help predict which individuals with CRVO would have favorable visual outcomes following short-term anti-VEGF therapy.

SOURCE: Rayess N, Rahimy E, Ying GS, et al. Baseline choroidal thickness as a predictor for treatment outcomes in central retinal vein occlusion. Am J Ophthalmol 2016;171:47-52.




Treat-and-extend IVA Regimen for Polypoidal Choroidal Vasculopathy

Researchers evaluated the one-year treatment outcomes of intravitreal aflibercept injections using a treat-and-extend regimen for polypoidal choroidal vasculopathy, as part of a retrospective review. They included 37 eyes with treatment-naive PCV treated with IVA using a treat-and-extend regimen for one year. The main outcome measures were changes in best-corrected visual acuity and central retinal thickness, and the treatment interval at one year. They analyzed predictive factors for individuals who couldn’t continue to extend the treatment interval because of poor response to IVA or recurrence.

The mean logMAR BCVA improved from 0.37 (almost 20/50) at baseline to 0.21 (a little worse than 20/32) at one year (p<0.001). The mean CRT decreased from 342.3 μm at baseline to 196.6 μm at one year (p< 0.001). The mean treatment interval was: 9.7 weeks at one year (four weeks in 11 eyes [29.7 percent]; six weeks in one eye [2.7 percent]; eight weeks in two eyes [5.4 percent]; 10 weeks in one eye [2.7 percent]; and 12 weeks in 22 eyes [59.5 percent]). A larger number of polypoidal lesions at baseline was predictive of individuals who couldn’t continue to extend the treatment interval.

Researchers concluded that IVA using a treat-and-extend regimen was effective for improving BCVA and CRT in eyes with PCV.

SOURCE: Hosokawa M, Morizane Y, Hirano M, et al. One-year outcomes of a treat-and-extend regimen of intravitreal aflibercept for polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2016; Dec. 7. [Epub ahead of print].



Angiopoietin-Like 4 Correlates With Intravitreal Ranibizumab Response in nAMD

Investigators looked at whether the aqueous angiopoietin-like 4 level correlated with clinical features in neovascular age-related macular degeneration.

A control group consisted of all consecutive individuals who received senile cataract surgery, and the study group consisted of all consecutive individuals who received intravitreal ranibizumab injection for treatment-naïve neovascular AMD.

The AMD group received three monthly ranibizumab injections followed by monthly pro re nata injections for at least 12 months. Investigators measured aqueous ANGPTL4 and vascular endothelial growth factor at baseline and four weeks after the first injection. In the AMD group, investigators measured best-corrected visual acuity, lesion area by fluorescein angiography and central subfield thickness at baseline and 12 months.

The AMD group (30 eyes) had higher baseline aqueous ANGPTL4 and VEGF levels than those of the control group (32 eyes) (both p<0.001). Four weeks after the first injection, VEGF in individuals with AMD dropped significantly (p<0.001). Baseline ANGPTL4 correlated with the lesion area at baseline and 12 months (p<0.05, respectively), and correlated with the frequency of anti-VEGF injections during the 12 months (p=0.008).

Investigators determined that aqueous ANGPTL4 levels correlated with lesion area and anti-VEGF treatment frequency such that ANGPTL4 may be a potential diagnostic and/or therapeutic biomarker in the neovascular AMD.

SOURCE: Kim JH, Shin JP, Kim IT, et al. Angiopoietin-like 4 correlates with response to intravitreal ranibizumab injections in neovascular age-related macular degeneration. Retina 2017; Feb 1. [Epub ahead of print].




Oral Bisphosphonates & Risk of Wet AMD

Researchers examined the risk of age-related macular degeneration with oral bisphosphonates, as part of a disproportionality analysis, case-control study and self-controlled case series.

They collected data from the U.S. FDA Adverse Event Reporting System Database and cohorts from British Columbia. They included all FDA-reported cases of AMD using oral bisphosphoantes, individuals with wet AMD in British Columbia (between 2009 and 2013) and 1 million controls (between 2000 and 2007).

Main outcome measures included reports of AMD to the FDA and first diagnosis of wet AMD verified by a retina specialist in British Columbia.

Researchers found in the disproportionality analysis: 133 cases of AMD reported with alendronate; 20 with ibandronate; and 14 with risedronate. The reported odds ratios were: for alendronate: 3.82 (CI, 2.94 to 4.96); for ibandronate: 2.40 (CI, 1.49 to 3.86); and for risedronate: 2.87 (CI, 1.58 to 5.19). In the case-control analysis including 6,367 cases and 6,370 corresponding controls, the adjusted OR for wet AMD among regular users of bisphosphonates was: one year prior to the index date: 1.24 (1.12-1.38); two years prior to the index date: 1.38 (1.22 to 1.56); and the three years prior to the index date: 1.59 (1.38 to 1.82). In the SCCS analysis, with 198 cases of wet AMD on continuous bisphosphonate therapy, the rate ratio for wet AMD for continuous bisphosphonate use was 1.99 (CI, 1.41 to 2.79). Information on intravenous bisphosphonates was not available.

Researchers’ findings revealed that continuous users of oral bisphosphonates were at a higher risk of developing wet AMD. However, given the observational nature of the study and data limitations, researchers suggested that future studies were needed to confirm these findings.

SOURCE: Mammo Z, Guo M, Maberley D, et al. Oral bisphosphonates and risk of wet age-related macular degeneration. Am J Ophthalmol 2016;168:62-7.




Acute Posterior Multifocal Placoid Pigment Epitheliopathy on OCTA

Researchers investigated choroidal involvement in acute posterior multifocal placoid pigment epitheliopathy, as part of a retrospective, observational case series using optical coherence tomography angiography.

They included five cases with APMPPE. In most acute lesions, OCTA revealed outer retinal and retinal pigment epithelium hyperreflective lesions with attenuated OCT signal in the underlying choroid. However, researchers identified, upon careful examination, a single lesion with decreased choriocapillaris flow outside the signal attenuation. OCTA after healing of lesions revealed areas of hypointense circular flow voids clustered in groups surrounded by isointense or hyperintense signal background. Point-by-point evaluation revealed that the flow voids didn’t correspond to areas of RPE thickening or focal pigmentary changes. Researchers observed larger hypointense lesions that correlated with pigmentary changes.

The case series demonstrated choriocapillaris flow abnormalities in acute APMPPE extending beyond the OCT lesions and distinct residual vascular abnormalities in healed APMPPE lesions, on OCTA.

Researchers wrote that the findings supported a primary ischemic insult to the photoreceptors and RPE, although choriocapillaris flow abnormalities could be secondary to (OCT-invisible) retinal and RPE involvement. They suggested that a lack of understanding of the etiology, along with the inability to visualize most of the choroid in acute lesions, precluded definite conclusions about the true pathogenesis of APMPPE.

SOURCE: Heiferman MJ, Rahmani S, Jampol LM, et al. Acute posterior multifocal placoid pigment epitheliopathy on optical coherence tomography angiography. Retina 2017; Feb 1. [Epub ahead of print].




 



GENENTECH COMPLETES ENROLLMENT IN PHASE III CHROMA AND SPECTRI TRIALS

Genentech completed enrollment in the Chroma and Spectri Phase III clinical trials, which are designed to investigate the efficacy and safety of lampalizumab in reducing the progression of geographic atrophy lesions secondary to AMD. Lampalizumab is a monoclonal antibody fragment designed to inhibit complement factor D, a rate-limiting enzyme of the alternative complement pathway. This complement pathway is implicated in the development of age-related macular degeneration including GA. The two identical, double-masked, sham-controlled studies enrolled 1,881 individuals at nearly 300 study locations in more than 20 countries. The primary endpoint of both studies is the mean change in GA lesion area at one year, comparing treatment to sham, with a planned overall treatment duration of two years. Secondary endpoints assess visual function changes.

Source: Genentech, February 2017




RESEARCHERS DEVELOP CELL CULTURE SYSTEM FOR AMD

An international research team from the University of Alabama at Birmingham, University College London and Queens University Belfast designed a cell culture model that could aid development of earlier treatment strategies for age-related macular degeneration. In research published in Investigative Ophthalmology and Visual Science, researchers reported that retinal pigment epithelium cells removed from a pig eye can encompass all the major constituents of drusen and hydroxyapatite when the cells are grown on specific surfaces. This model confirms the hypothesis that RPE cells in early AMD are functional, and that the condition of Bruch’s membrane, where retinal pigment epithelium cells grow, is likely to be essential for drusen formation. The team expects that a reproducible and valid model system will be an important step in determining what drusen molecules, and what changes in RPE cells living over drusen, promote advancement to late stages of AMD. Read more.

Source: UAB News, February 2017




AGTC & Bionic Sight to Develop Optogenetic Therapy

Applied Genetic Technologies entered into a strategic research and development collaboration with Bionic Sight, a company in the emerging field of optogenetics and retinal coding. Using optogenetics to stimulate healthy cells in the retina and Bionic Sight's neuroprosthetic device to stimulate the cells with the retina's neural code, the companies seek to restore normal neural signaling to individuals with visual deficits or blindness due to retinal disease. Read more.

Source: AGTC, January 2017



MEIRAGTX GIVES UPDATES ON OCULAR GENE THERAPY PROGRAMS

MeiraGTx announced treatment at Moorfields Eye Hospital in London of the first patient in its clinical study for achromatopsia due to mutations in CNGB3 gene. The AAV-mediated gene therapy study design for CNGB3 deficiency is an open-label, multicenter, Phase I/II dose-escalation trial. In addition, the company successfully completed dosing of patients in the second cohort of its clinical trial for Leber's Congenital Amaurosis with RPE65 mutations, also at Moorfields. Read more.

Source: MeiraGTx, February 2017




GENSIGHT RECEIVES ORPHAN DRUG DESIGNATION FOR GS030 IN RETINITIS PIGMENTOSA

GenSight Biologics was granted orphan drug designation for the company’s product candidate GS030 for the treatment of retinitis pigmentosa. GS030 is currently undergoing a Good Laboratory Practices regulatory toxicity study and is expected to enter the clinic with a Phase I/II clinical trial in retinitis pigmentosa patients in the third quarter, subject to toxicity results and future regulatory review. The ODD status provides GenSight with incentives and benefits in the United States, including a seven-year period of market exclusivity if approved for the treatment of retinitis pigmentosa. Read more. 


Source: GenSight Biologics S.A., January 2017




ICONIC PRESENTS PHASE IIA EMERGE TRIAL RESULTS

The results of Iconic Therapeutics’ EMERGE trial, a Phase IIa- randomized, double-masked, multi-dose study of the drug candidate ICON-1 in wet age-related macular degeneration, were presented for the first time at the Angiogenesis, Exudation, and Degeneration meeting in Miami, on Feb.11. The trial design included assessment of outcomes to measure lesion growth and leakage. The six-month, active-controlled, multicenter study included 88 individuals with newly diagnosed disease. Read more.

Source: Iconic Therapeutics, February 2017




BIOTIME EXPANDS OPHTHALMOLOGY PORTFOLIO WITH UPMC AGREEMENT

BioTime acquired global rights to the University of Pittsburgh’s Medical Center Innovation Institute’s ophthalmology-related intellectual property assets. This includes technology developed in collaboration with BioTime scientists involving methodologies to develop three-dimensional retinal tissue derived from human pluripotent stem cells for implantation in individuals with advanced stages of retinal degeneration. Read more.

Source: BioTime, February 2017




ALIMERA’S ILUVIEN RECEIVES REIMBURSEMENT STATUS IN ITALY

Alimera Sciences announced Iluvien received a pricing and reimbursement decree for Agenzia Italiana del Farmaco in January. The decree changed the reimbursement status of the sustained-release intravitreal implant from Class C, in which the patient covers the cost of the treatment, to Class H, with a restriction to patients with an artificial lens implanted. In Italy, Iluvien will be hospital-administered and is expected to be fully reimbursed for patients who have previously undergone cataract surgery. Read more.

Source: Alimera Sciences, February 2017




SURGICAL EYE ROBOT PERFORMS PRECISION-INJECTION IN RVO PATIENT

Surgeons at the University Hospitals Leuven (Brussels, Belgium) were the first to operate using a surgical robot on a patient with retinal vein occlusion. The robot uses a needle of roughly 0.03 mm to inject a thrombolytic drug into the retinal vein of the patient. KU Leuven developed the robot and needle specifically for this procedure. The successful operation showed it was technically possible to safely dissolve a blood clot from the retinal vein with robotic support. A Phase II trial now must show the clinical effect. Researchers from the University Hospitals Leuven and KU Leuven are studying retinal vein cannulation, an experimental treatment that addresses the cause of RVO by removing the blood clot in the retinal vein. Read more.

Source: KU Leuven, January 2017




GROWTH FACTOR SHOWN TO PROTECT RETINA IN EARLY DIABETES

Researchers from the Schepens Eye Research Institute of Massachusetts Eye and Ear have shown that a slight increase in transforming growth factor beta, present in preclinical animal models with diabetic eye disease, protects retinal blood vessels from diabetic retinopathy. Their findings, published online in the American Journal of Pathology, may lead to targeted therapeutics that delay or prevent the development of the disease. In light of these findings, the study authors advise physicians to use caution when employing TGF-β blocking as a therapy for diabetes. Read more.

Source: Massachusetts Eye and Ear, February 2017




MALLICK JOINS SHIRE AS VP & GLOBAL DEVELOPMENT LEAD FOR CLINICAL DEVELOPMENT

Sushanta Mallick joined the Shire Ophthalmics team as vice president and global development lead for clinical development, Ophthalmics. Mallick has more than 20 years of experience in ophthalmology research and development and has made significant contributions in the development of drugs in the areas of wet AMD, dry eye and inherited retinal diseases. Mallick most recently worked at Aerie Pharmaceuticals as vice president of clinical research/glaucoma. Prior to that, he was vice president of research and development at QLT, where he led the company’s R&D activities and directed development of oral synthetic retinoid as an orphan drug in inherited retinal diseases LCA and RP. Mallick also spent 19 years at Alcon, where he held positions including senior clinical research scientist and associate director of development.

Source: Shire Ophthalmics, January 2016


 

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