Pharmacological evidence for the role of RAR in axon guidance and embryonic development of a protostome species.

Retinoic acid (RA), the active metabolite of vitamin A, functions through nuclear receptors, one of which is the retinoic acid receptor (RAR). Though the RAR is essential for various aspects of vertebrate development, little is known about the role of RAR in nonchordate invertebrates. Here, we examined the potential role of an invertebrate RAR in mediating chemotropic effects of retinoic acid. The RAR of the protostome Lymnaea stagnalis is present in the growth cones of regenerating cultured motorneurons, and a synthetic RAR agonist (EC23), was able to mimic the effects of retinoic acid in inducing growth cone turning. We also examined the ability of the natural retinoids, all-trans RA and 9-cis RA, as well as the synthetic RAR agonists, to disrupt embryonic development in Lymnaea. Developmental defects included delays in embryo hatching, arrested eye, and shell development, as well as more severe abnormalities such as halted development. Developmental defects induced by some (but not all) synthetic RAR agonists were found to mimic those induced by addition of high concentrations of the natural retinoid isomers. These pharmacological data support a possible physiological role for the RAR in axon guidance and embryonic development of an invertebrate protostome species.

The Effect of a Head-mounted Low Vision Device on Visual Function.

SIGNIFICANCE: Head-mounted low vision devices have received considerable attention in recent years owing to rapidly developing technology, facilitating ease of use and functionality. Systematic clinical evaluations of such devices remain rare but are needed to steer future device development. PURPOSE: The purpose of this study was to investigate, in a multicenter prospective trial, the short- and medium-term effects of a head-worn vision enhancement device (eSight Eyewear). METHODS: Participants aged 13 to 75 years with stable vision (distance acuity, 20/60 to 20/400; visual field diameter >20°) were recruited across six sites. Data were collected at baseline (no device), at fitting (with device), and after 3 months of everyday use. Outcome measures were visual ability measured by the Veterans Affairs Low Vision Visual Functioning Questionnaire 48, distance acuity (Early Treatment Diabetic Retinopathy Study), reading performance (MNREAD chart), contrast sensitivity (MARS chart), face recognition, and a modified version of the Melbourne Low Vision Activities of Daily Living (ADL) Index. RESULTS: Among the 51 participants, eSight introduction immediately improved distance acuity (0.74 ± 0.28 logMAR), contrast sensitivity (0.57 ± 0.53 log units), and critical print size (0.52 ± 0.43 logMAR), all P < .001, without any further change after 3 months; reading acuity improved at fitting (0.56 ± 0.35 logMAR) and by one additional line after 3 months, whereas reading speed only slightly increased across all three time points. The Melbourne ADL score and face recognition improved at fitting (P < .01) with trends toward further improvement at 3 months. After 3 months of use, Veterans Affairs Low Vision Visual Functioning Questionnaire 48 person measures (in logits) improved: overall, 0.84, P < .001; reading, 2.75, P < .001; mobility, 0.04, not statistically significant; visual information, 1.08, P < .001; and visual motor, 0.48, P = .02. CONCLUSIONS: eSight introduction yields immediate improvements in visual ability, with face recognition and ADLs showing a tentative benefit of further use. Overall, visual ability, reading, and visual information showed greatest benefit with device use. Further studies need to examine benefits of practice and training and possible differential effects of underlying pathology or baseline vision.

Results of the 2-Year Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) Randomized Trial.

PURPOSE: The Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) trial was designed to evaluate the long-term efficacy and safety profile of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA)/vitreomacular traction, including full-thickness macular hole (FTMH). DESIGN: Phase 3b, randomized, sham-controlled, double-masked, multicenter clinical trial. PARTICIPANTS: Sample size was 220 subjects (146 ocriplasmin, 74 sham) randomized in a 2:1 ratio to receive intravitreal ocriplasmin 0.125 mg or sham injection. METHODS: The trial involved 12 visits over 24-months. Inclusion criteria included presence of VMA and best-corrected visual acuity (BCVA) of 20/32 or worse in the study eye. Exclusion criteria included FTMH >400 µm, presence of epiretinal membrane (ERM), and aphakia in the study eye. MAIN OUTCOME MEASURES: The primary efficacy end point was the proportion of subjects with pharmacologic VMA resolution at day 28. Secondary efficacy end points were assessed at month 24 and included proportion of subjects with BCVA gain from baseline, nonsurgical FTMH closure, vitrectomy, and Visual Function Questionnaire 25 (VFQ-25) outcomes. RESULTS: The OASIS trial met its primary end point with pharmacologic VMA resolution at day 28 being significantly higher in the ocriplasmin group (41.7%) compared with the sham group (6.2%). The treatment effect was maintained until study end. In the ocriplasmin group, pharmacologic VMA resolution at day 28 was higher in subgroups with the following baseline characteristics compared with the complementary subgroups without them: presence of focal VMA, presence of FTMH, absence of ERM, and phakic lens status. In the ocriplasmin group, 50.5% of subjects had a ≥2-line improvement in BCVA from baseline compared with 39.1% of subjects in the sham group. The nonsurgical FTMH closure rate was 30.0% for the ocriplasmin group compared with 15.4% for the sham group. All other secondary end points also favored ocriplasmin over sham. Regarding safety, most adverse events were mild to moderate, had a short onset time, and were transient, with no new safety signals identified. CONCLUSIONS: The OASIS trial demonstrates the long-term efficacy and safety of ocriplasmin, providing improved resolution of symptomatic VMA compared with previous phase 3 trials with no additional safety signals identified.

Safety of intravitreal ocriplasmin for focal vitreomacular adhesion in patients with exudative age-related macular degeneration.

PURPOSE: The evaluation of the safety and preliminary efficacy of 125 µg ocriplasmin intravitreal injection in patients with focal vitreomacular adhesion (VMA) and exudative age-related macular degeneration (AMD). DESIGN: Randomized, sham-injection controlled, double-masked, multicenter, phase II trial. PARTICIPANTS: A total of 100 patients with VMA and wet AMD were randomized 3:1 to receive 125 µg ocriplasmin intravitreal injection or sham injection. METHODS: Study treatment was administered in the mid-vitreous cavity by injection. Post-treatment safety and efficacy assessments were made at baseline and on days 7, 14, and 28 and months 3, 6, and 12 after injection. Secondary efficacy end points were exploratory in nature. MAIN OUTCOME MEASURES: The safety and tolerability of ocriplasmin were evaluated. The primary efficacy end point was the proportion of patients with VMA release at day 28 after injection. Secondary end points reported included VMA release over time, total posterior vitreous detachment (PVD), change in visual acuity from baseline, and number of anti-vascular endothelial growth factor (VEGF) injections. RESULTS: The safety of ocriplasmin in patients with VMA and wet AMD was shown to be comparable to the known safety profile, with the majority of adverse events in the study eye occurring in the first 7 days after study treatment. A greater proportion of patients achieved VMA resolution and total PVD at month 12 with ocriplasmin compared with sham treatment. There was a decrease in the number of anti-VEGF injections with ocriplasmin at month 12 compared with the sham group, although no differences in visual acuity were observed. CONCLUSIONS: Ocriplasmin treatment in this population seems to be generally safe and well tolerated and resulted in more patients achieving VMA resolution and PVD with less anti-VEGF use compared with sham treatment.

Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie2.

PURPOSE: AKB-9778 is a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP) that promotes Tie2 activation and reduces vascular leakage and neovascularization in mouse models. The purpose of this study was to test the safety, tolerability, pharmacokinetics, and biological activity of AKB-9778 in patients with diabetic macular edema (DME). DESIGN: Open-label, dose-escalation clinical trial. PARTICIPANTS: Four dose cohorts of 6 patients with DME self-administered subcutaneous injections of 5 mg, 15 mg, 22.5 mg, or 30 mg AKB-9778 twice daily for 4 weeks. METHODS: Patients were seen weekly during a 4-week treatment period for safety assessments, best-corrected visual acuity (BCVA) assessment by Early Treatment Diabetic Retinopathy Study protocol, and measurement of central subfield thickness (CST) by spectral-domain optical coherence tomography. Additional safety assessments were performed at 6, 8, and 12 weeks. MAIN OUTCOME MEASURES: Safety assessments, change from baseline BCVA, and change from baseline CST. RESULTS: All doses were well tolerated. A modest, transient reduction in blood pressure and adverse events consistent with vasodilatory activity of AKB-9778 emerged at doses of 22.5 mg or more twice daily. At the week 4 primary end point, BCVA improved 5 letters or more from baseline in 13 of the 18 patients receiving 15 mg or more twice daily; 1 patient improved by 10 to 15 letters, and 2 patients improved by more than 15 letters. Among 18 patients receiving 15 mg or more twice daily, CST decreased by more than 100 µm in 5 patients and by 50 to 100 µm in 2 patients. There was a significant correlation between reduction in CST and improvement in BCVA. CONCLUSIONS: No safety concerns were identified after systemic administration of AKB-9778 for 4 weeks in patients with DME, and doses of 15 mg or more twice daily reduced macular edema and improved vision in some patients. This is a preliminary demonstration of clinical safety and efficacy of a VE-PTP inhibitor and Tie2 activator.

PolySialic Acid Nanoparticles Actuate Complement-Factor-H-Mediated Inhibition of the Alternative Complement Pathway: A Safer Potential Therapy for Age-Related Macular Degeneration.

The alternative pathway of the complement system is implicated in the etiology of age-related macular degeneration (AMD). Complement depletion with pegcetacoplan and avacincaptad pegol are FDA-approved treatments for geographic atrophy in AMD that, while effective, have clinically observed risks of choroidal neovascular (CNV) conversion, optic neuritis, and retinal vasculitis, leaving room for other equally efficacious but safer therapeutics, including Poly Sialic acid (PSA) nanoparticle (PolySia-NP)-actuated complement factor H (CFH) alternative pathway inhibition. Our previous paper demonstrated that PolySia-NP inhibits pro-inflammatory polarization and cytokine release. Here, we extend these findings by investigating the therapeutic potential of PolySia-NP to attenuate the alternative complement pathway. First, we show that PolySia-NP binds CFH and enhances affinity to C3b. Next, we demonstrate that PolySia-NP treatment of human serum suppresses alternative pathway hemolytic activity and C3b deposition. Further, we show that treating human macrophages with PolySia-NP is non-toxic and reduces markers of complement activity. Finally, we describe PolySia-NP-treatment-induced decreases in neovascularization and inflammatory response in a laser-induced CNV mouse model of neovascular AMD. In conclusion, PolySia-NP suppresses alternative pathway complement activity in human serum, human macrophage, and mouse CNV without increasing neovascularization.

Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials.

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte-derived macrophages (PBMDMs) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring glyco-immune checkpoint control with a sialic acid mimetic agonist targeting microglial/macrophage Siglecs to regain retinal para-inflammatory and inflammatory homeostasis is a promising therapeutic that could halt the progression of and improve visual function in all stages of macular degeneration.

PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration.

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1ß, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Investigational drugs in clinical trials for macular degeneration.

INTRODUCTION: Intravitreal anti-vascular endothelial growth factor (VEGF) injections for exudative age-related macular degeneration (eAMD) are effective and safe but require frequent injections and have nonresponding patients. Geographic atrophy/dry AMD (gaAMD) remains an unmet medical need. New therapies are needed to address this leading cause of blindness in the increasing aged population. AREAS COVERED: This paper reviews the pathogenesis of macular degeneration, current and failed therapeutics, therapies undergoing clinical trials and a rationale for why certain AMD therapies may succeed or fail. EXPERT OPINION: VEGF-inhibitors reduce both vascular leakage and neovascularization. Experimental therapies that only address neovascularization or leakage will unlikely supplant anti-VEGF therapies. The most promising future therapies for eAMD, are those that target, more potently inhibit and have a more sustained effect on the VEGF pathway such as KSI-301, RGX-314, CLS-AX, EYEP-1901, OTX-TKI. GaAMD is a phenotype of phagocytic retinal cell loss. Inhibiting phagocytic activity of retinal microglial/macrophages at the border of geographic atrophy and reducing complement derived activators of microglial/macrophage is the most promising strategy. Complement inhibitors (Pegcetacoplan and Avacincaptad pegol) will likely obtain FDA approval but will serve to pave the way for combined complement and direct phagocytic inhibitors such as AVD-104.

SCORE Study report #11: incidences of neovascular events in eyes with retinal vein occlusion.

PURPOSE: To investigate in The Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study: (1) incidences of neovascular events and retinal capillary nonperfusion (abbreviated as "nonperfusion"), and their relationship with treatment groups; (2) neovascular incidences by nonperfusion status; and (3) pertinent baseline factors for their potential risk for neovascular events. DESIGN: Two multicenter, randomized clinical trials, 1 evaluating participants with central retinal vein occlusion (CRVO) and the other evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS: At 36 months, data were available for 81 participants with CRVO and 128 with BRVO. INTERVENTION: Standard care (observation or grid photocoagulation) versus 1 or 4 mg intravitreal triamcinolone. MAIN OUTCOME MEASURES: Neovascularization of the iris (NVI), neovascular glaucoma (NVG), disc or retinal neovascularization (NVD/NVE), preretinal or vitreous hemorrhage (PRH/VH), and nonperfusion. RESULTS: The cumulative 36-month incidences for CRVO and BRVO eyes, respectively, were 8.5% and 2.4% for NVI or NVG; 8.8% and 7.6% for NVD/NVE or PRH/VH. There were no differences in incidences of neovascular events or risk of nonperfusion when comparing the 3 treatment groups within diseases. For CRVO at 36 months, 16.6% of eyes with ≥5.5 disc areas of nonperfusion versus 4.0% of eyes with <5.5 disc areas of nonperfusion developed NVG (P = 0.0003); for BRVO at 36 months, 14.6% versus 2.4% developed NVD/NVE (P<0.0001). Similar results were noted for most other neovascular events. Nonperfusion was the only significant baseline factor for neovascularization in BRVO, with the risk of a neovascular event increasing with greater disc areas of nonperfusion, and the highest risk noted at ≥5.5 disc areas. CONCLUSIONS: In the SCORE Study, triamcinolone treatment was not associated with lower incidences of neovascular events or nonperfusion status compared with observation or grid photocoagulation. Cumulative 36-month incidences for most neovascular events were significantly higher for nonperfused than perfused eyes. Greater baseline disc areas of nonperfusion increased the risk of neovascularization in BRVO but not CRVO eyes, possibly owing to obscuration of retinal capillary details caused by dense hemorrhage at baseline for CRVO eyes. Increased risk of neovascularization was noted below the historical threshold of 10 disc areas of nonperfusion for retinal vein occlusion.

Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema.

OBJECTIVE: To assess the efficacy and safety of intravitreal inserts releasing 0.2 µg/day (low dose) or 0.5 µg/day (high dose) fluocinolone acetonide (FA) in patients with diabetic macular edema (DME). DESIGN: Two parallel, prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Subjects with persistent DME despite at least 1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393). METHODS: Subjects received study drug or sham injection at baseline and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year. MAIN OUTCOME MEASURES: The primary outcome was the percentage of patients with improvement from baseline best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Trial (ETDRS) letter score of 15 or more at month 24. Secondary outcomes included other parameters of visual function and foveal thickness (FTH). RESULTS: The percentage of patients with improvement from baseline ETDRS letter score of 15 or more at month 24 was 28.7 and 28.6 in the low- and high-dose insert groups, respectively, compared with 16.2 in the sham group (P = 0.002 for each). Benefit occurred for both doses compared with sham at 3 weeks and all subsequent time points. The mean improvement in BCVA letter score between baseline and month 24 was 4.4 and 5.4 in the low- and high-dose groups, respectively, compared with 1.7 in the sham group (P = 0.02 and P = 0.016). At all time points compared with sham, there was significantly more improvement in FTH. Subjects requiring cataract surgery were more frequent in the insert groups, and their visual benefit was similar to that of subjects who were pseudophakic at baseline. Glaucoma requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the low-dose, high-dose, and sham groups, respectively. CONCLUSIONS: Both low- and high-dose FA inserts significantly improved BCVA in patients with DME over 2 years, and the risk-to-benefit ratio was superior for the low-dose insert. This is the first pharmacologic treatment that can be administered by an outpatient injection to provide substantial benefit in patients with DME for at least 2 years.

The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema.

PURPOSE: To determine whether different doses and dosing regimens of intravitreal vascular endothelial growth factor (VEGF) Trap-Eye are superior to focal/grid photocoagulation in eyes with diabetic macular edema (DME). DESIGN: Multicenter, randomized, double-masked, phase 2 clinical trial. PARTICIPANTS: A total of 221 diabetic patients with clinically significant macular edema involving the central macula. METHODS: Patients were assigned to 1 of 5 treatment regimens: 0.5 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye every 4 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then every 8 weeks; 2 mg VEGF Trap-Eye for 3 initial monthly doses and then on an as-needed (PRN) basis; or macular laser photocoagulation. Assessments were completed at baseline and every 4 weeks thereafter. MAIN OUTCOME MEASURES: Mean change in visual acuity and central retinal thickness (CRT) at 24 weeks. RESULTS: Patients in the 4 VEGF Trap-Eye groups experienced mean visual acuity benefits ranging from +8.5 to +11.4 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters versus only +2.5 letters in the laser group (P ≤ 0.0085 for each VEGF Trap-Eye group vs. laser). Gains from baseline of 0+, 10+, and 15+ letters were seen in up to 93%, 64%, and 34% of VEGF Trap-Eye groups versus up to 68%, 32%, and 21% in the laser group, respectively. Mean reductions in CRT in the 4 VEGF Trap-Eye groups ranged from -127.3 to -194.5 µm compared with only -67.9 µm in the laser group (P = 0.0066 for each VEGF Trap-Eye group vs. laser). VEGF Trap-Eye was generally well tolerated. Ocular adverse events in patients treated with VEGF Trap-Eye were generally consistent with those seen with other intravitreal anti-VEGF agents. CONCLUSIONS: Intravitreal VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in visual acuity when compared with macular laser photocoagulation in patients with DME.

Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration.

PURPOSE: To assess outcomes for patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) treated with verteporfin photodynamic therapy (PDT) and bevacizumab. DESIGN: Retrospective, case series database study (registry). PARTICIPANTS: We included 1196 patients with CNV due to AMD who received > or =1 combination treatment of 1.25 mg intravitreal bevacizumab within 14 days of verteporfin PDT. METHODS: Retrospective analysis of baseline data with ongoing follow-up. Physicians from 45 clinical centers entered patient data at baseline and follow-up examinations, including subsequent treatments, into a secure, Web-accessed database. Snellen visual acuity (VA) was converted to logarithm of the minimum angle of resolution (logMAR) for statistical analyses. MAIN OUTCOME MEASURES: Change from baseline in VA and retreatment rates of any therapy after the initial combination treatment. RESULTS: Of 1196 patients, 1073 patients had > or =6 months of follow-up. For these 1073 patients, mean baseline VA was 0.967 logMAR (approximate Snellen 20/185) and 56.3% of patients (604/1073) were treatment naïve. After their baseline combination treatment, patients received a mean of 0.6 additional verteporfin PDT retreatments and 2.0 bevacizumab retreatments over a mean follow-up period of 15.0 months. By 12 months, 82% of patients (578/701) had stable or improved vision (loss of <3 lines or a gain in VA), 36% (255/701) improved by > or =3 lines, and 17% (121/701) improved by > or =6 lines. By 12 months, patients gained approximately 1.2 lines (6 letters) of VA from baseline. Patients who were treatment naïve gained significantly more VA by month 12 (+8.4 letters) compared with those who had been previously treated (+2.4 letters; P<0.01). Most serious adverse events (26/30) were judged by investigators as not related to any study treatment, although 3 ocular events were judged related to bevacizumab alone, and 1 ocular event was judged related to both bevacizumab and PDT. CONCLUSIONS: Combination therapy with PDT and bevacizumab led to vision benefit for most patients, particularly those who were treatment naïve at baseline. The number of retreatments was lower than published reports with either treatment delivered as monotherapy. Randomized clinical trials are underway to confirm these findings.

Assessing Appropriateness of CT and MRI Referrals for Headache and Lumbar: A Canadian Perspective on Patient-Centered Referrals.

BACKGROUND: Inappropriate diagnostic imaging is a burgeoning problem within the Canadian healthcare system and imposes considerable burdens to efficiency and timeliness of care. Low back pain and headaches affect an immense portion of the general population and have become exceedingly common complaints from patients seeking diagnostic imaging from primary care physicians. METHODS: A total of 399 magnetic resonance imaging (MRI) and computed tomography (CT) requisitions for lumbar and head scans were reviewed and assessed for appropriateness in concordance with published Choosing Wisely guidelines for head and lumbar diagnostic imaging. Requisitions were classified as appropriate, inappropriate, or incomplete. Baseline data collection showed 51.6% appropriateness, 12.0% inappropriateness, and 36.3% incompleteness. New patient-centered referral forms containing evidence-based red flags by Choosing Wisely Canada were created for head and lumbar MRI and CT. The aim was to increase awareness and consideration of the guidelines during the referral process. The new referrals were distributed among 149 local family physicians in addition to information pamphlets summarizing the need to reduce unnecessary diagnostic imaging for head and lower back pain. RESULTS AND CONCLUSION: After collection and review of 251 requisitions in the postintervention period, incomplete referrals dropped from 36.3% to 13.15%. Despite insignificant changes in appropriateness, it is promising that the intervention educated local physicians on the information required to complete the CT or MRI forms as further evidence is provided showing the efficacy of the patient-centered referrals. This study provides insight on the importance of appropriate diagnostic imaging and what methods can be used at the primary care level.

Intravitreal bevacizumab for macular edema from idiopathic juxtafoveal retinal telangiectasis.

To assess the potential visual benefit of intravitreal bevacizumab in a patient with idiopathic juxtafoveal retinal telangiectasis refractory to focal laser treatment, an intravitreal injection of bevacizumab (1.25 mg) was given. Within 1 week, visual acuity improved from 20/50 to 20/25 and optical coherence tomography demonstrated complete resolution of macular edema. There was no adverse effect. The macular edema recurred after 3 months, requiring a repeat injection of bevacizumab with subsequent resolution of macular edema. An intravitreal injection of bevacizumab may provide potential short-term visual benefit in patients with macular edema from idiopathic juxtafoveal retinal telangiectasis.

Baseline Factors Associated With 6-Month Visual Acuity and Retinal Thickness Outcomes in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Study Report 4.

Importance: Macular edema (ME) is the leading cause of decreased visual acuity (VA) associated with retinal vein occlusion (RVO). Identifying factors associated with better outcomes in RVO eyes treated with anti-vascular endothelial growth factor (VEGF) therapy may provide information useful in counseling patients. Objective: To investigate baseline characteristics associated with 6-month VA and central subfield thickness (CST) outcomes in participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2). Design, Setting, and Participants: A total of 362 patients with central RVO or hemi-RVO were enrolled between September 17, 2014, and November 18, 2015, and randomized 1:1 in a masked fashion to receive bevacizumab or aflibercept. At month 6, 348 participants (96%) had VA outcomes measured and 335 participants (93%) had spectral domain optical coherence tomography outcomes measured. The current data analysis was conducted from February 27, 2017, to April 7, 2017. Interventions: Eyes were randomly assigned to receive an intravitreal injection of bevacizumab, 1.25 mg, or aflibercept, 2.0 mg, at baseline and every 4 weeks, with the primary outcome measured at 6 months. Main Outcomes and Measures: Change from baseline in VA letter score (VALS), VALS gain of 15 or more, change from baseline in CST, CST less than 300 µm, and resolution of ME. Baseline factors associated with 6-month outcome at the 0.05 level in univariate regressions were included in multivariate regressions, with those significant after multiplicity control by the Hochberg method reported. Results: The mean (SD) age of patients was 69 (12) years, and 43% were women. Younger patient age (odds ratio [OR], 0.95 per year of age; 95% CI, 0.93-0.98; P = .007) and lower baseline VALS (OR, 0.96 per letter; 95% CI, 0.94-0.98; P < .001) were associated with a 6-month VALS gain of 15 or greater. Compared with bevacizumab, aflibercept treatment was associated with a higher odds of ME resolution (OR, 3.59; 95% CI, 2.22-5.80; P < .001) and CST less than 300 µm (OR, 5.30; 95% CI, 2.40-11.67; P = .001), but not with a better VA outcome. Macular edema was less likely to resolve in eyes that received anti-VEGF treatment prior to study participation (OR, 0.33; 95% CI, 0.17-0.64; P = .03). Conclusions and Relevance: In eyes treated with bevacizumab or aflibercept, younger age and worse baseline VALS were associated with better 6-month VA outcomes. Aflibercept treatment was associated with more favorable spectral domain optical coherence tomography outcomes but not VA outcomes. These findings may be useful in assessing expected response at month 6 after monthly injection of anti-VEGF agents for treating ME due to CRVO and HRVO. Trial Registration: clinicaltrials.gov Identifier: NCT01969708.

Long-term Safety and Visual Outcome of Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: VIEW 1 Extension Study.

PURPOSE: To assess the long-term safety and vision change in patients who received intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration in an extension study after completing VIEW 1 trial. DESIGN: Prospective, open-label, multicenter, extension study. PARTICIPANTS: Three hundred twenty-three patients. METHODS: In VIEW 1, 1217 patients were randomized to receive fixed dosing of 0.5 mg IAI every 4 weeks (0.5q4), 2 mg IAI every 4 weeks (2q4), 2 mg IAI every 8 weeks after 3 initial monthly dosing (2q8), or 0.5 mg ranibizumab every 4 weeks (Rq4) from baseline through week 52, followed by modified quarterly injections of the same dose of anti-vascular endothelial growth factor agent from weeks 52 to 96. After completing VIEW 1 at week 96, patients (n = 323) enrolled in an extension study and received 2 mg IAI on a modified quarterly injection schedule followed by at least an every 8-week dosing through week 212. MAIN OUTCOME MEASURES: Long-term safety and vision change in patients followed for a median duration of 116 weeks in the extension study (total follow-up time of 212 weeks from the VIEW 1 baseline). RESULTS: Patients enrolled in the extension study gained a mean of 10.2 letters from the VIEW 1 baseline at week 96. These patients largely maintained vision over the extension study with a mean gain of 7.1 letters from the VIEW 1 baseline to week 212. The proportion of patients who lost ≥15 letters from the VIEW 1 extension baseline was 8.2% at week 212. Mean number of injections was 12.9 (range, 1-41) in the extension study. The most common serious ocular adverse event was endophthalmitis (0.9%). The overall incidence of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events was 6.2%. CONCLUSIONS: Vision gains achieved with anti-vascular endothelial growth factor therapy in VIEW 1 were largely maintained by continued treatment with IAI 2 mg in the extension study. Anti-vascular endothelial growth factor injections (including 4 years of IAI 2 mg) were well-tolerated with no new safety signals compared with the known profile of IAI.

Interference RNA technology in the treatment of CNV.

RNA interference is a new technology that allows the production of therapeutic double-stranded RNA molecules (siRNA) that can specifically prevent the production of a particular gene product in a potent and efficient manner. It accomplishes this task by activating a native cellular defense mechanism, which when triggered results in the prevention of gene product production before the protein is made. Because of this amplification, only small quantities of siRNA are required to produce a silencing of gene production. siRNA designed to reduce production of angiogenic molecules provides potent therapies for ocular neovascularization in patients with age-related macular degeneration or diabetic retinopathy.

Current and investigational drugs for the treatment of diabetic retinopathy.

INTRODUCTION: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are the two complications of diabetes that cause visual loss and blindness. Laser photo-coagulation in the past was used to prevent progression of disease to these advanced stages. Advances in pathophysiologic understanding of DME and PDR have ushered the development of effective targeted therapy that given intravitreally improves vision and prevents blindness. While effective, these therapies require frequent administration and are not universally effective. AREAS COVERED: This purpose of this paper is to review the current pathophysiologic understanding and treatments for DME and PDR as well as the novel treatments currently being developed. The treatments will be juxtaposed to the factor in the disease cascade being targeted. The potential role of these novel treatment in the clinical armamentarium are postulated. EXPERT OPINION: Mono-therapy, single category targeting is the current strategy being utilized clinically. However, diabetic retinopathy needs combination therapy. Therapies that will prove successful will address multiple factors involved in the pathogenesis of diabetic retinopathy.