Factors That Can Prolong Ocular Treatment Duration in Age-Related Macular Degeneration.

Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are used to treat wet age-related macular degeneration (wAMD); however, they are associated with a considerable treatment burden and poor real-world outcomes. The molecular size and charge of anti-VEGF agents influence drug pharmacokinetics in the vitreous and peak drug efficacy. This article reviews the established and novel strategies to prolong drug action, in the vitreal cavity, and thus reduce dosing frequency. Increased ocular residency can be attained by increasing drug size as with large molecules, such as KSI-301; adding polyethylene glycol to pegcetacoplan (APL-2) or avacincaptad pegol to increase molecular size; or binding to other targets that increase molecular size, such as vitreal albumin in the case of BI-X. Faricimab is a bispecific antibody in which the fragment crystallizable portion is engineered to prolong ocular residency and reduce systemic exposure. Conversely, small VEGF-binding molecules, such as brolucizumab, can be administered at higher clinical doses, with the potential for prolonged clinical activity versus larger molecules. Other important considerations include sustained drug delivery routes, such as the ranibizumab port delivery system or subconjunctival or suprachoroidal injection. More effective and longer-lasting treatments are needed for wAMD to prolong drug action and reduce dosing frequency. Several strategies are under investigation and the prevention of vision loss in patients with AMD or other retinal diseases may be attainable in the near future.

Progression to Surgery for Patients With Idiopathic Epiretinal Membranes and Good Vision.

BACKROUND AND OBJECTIVE: Patients with idiopathic epiretinal membranes (ERMs) and visual acuity of 20/40 or better are often monitored until vision or associated symptoms worsen to affect everyday living. This study looks at the rate of progression to surgery and the characteristics associated with progression. PATIENTS AND METHODS: This study was a retrospective, consecutive case series of patients with newly diagnosed idiopathic ERMs who were referred to the Retina Service at the Ophthalmic Consultants of Boston between January 2009 and May 2015 with 20/40 or better visual acuity. Surgical membrane peel was typically offered when vision worsened to 20/50 or beyond and/or when patients could not tolerate symptoms attributable to the ERM. All eligible eyes were categorized by baseline optical coherence tomography (OCT) morphology into normal, mild or incomplete, or complete loss of foveal contour. Visual acuities were averaged through conversion to logMAR. Kaplan-Meier survival curves for progression to surgical membrane peel were calculated. The main outcome measure was progression to surgical intervention. RESULTS: The study included 201 eyes from 170 patients; 29.8% had normal, 18.9% had mild loss, and 51.2% had complete loss of foveal contour on baseline OCT. Overall, 13% of eyes progressed to surgery at 7 years. However, only 5% of eyes with normal foveal contour progressed to surgery by 5.5 years, whereas 17% with incomplete and 16% with complete loss of foveal contour progressed to surgery at 6 and 7 years, respectively. Eyes with worse foveal contours progressed to surgery more rapidly. CONCLUSION: A minority of patients with newly diagnosed ERMs who did not need surgical intervention progressed to needing surgery at 7 years with the rate and speed of progression dependent on baseline OCT morphology. These statistics can be useful in counseling patients who are deciding between watchful waiting and surgical intervention. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:S18-S22.].

Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: One hundred twenty-six patients with DME. METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ. MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24. RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 µm, 286 µm, and 258 µm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 µm or less was 36%, 47%, and 68%, respectively. CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Topical mecamylamine for diabetic macular edema.

PURPOSE: Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema. DESIGN: A multicenter phase I/II clinical trial. METHODS: Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks. RESULTS: Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine. CONCLUSIONS: This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.

Primary End Point (Six Months) Results of the Ranibizumab for Edema of the mAcula in diabetes (READ-2) study.

OBJECTIVES: To compare ranibizumab with focal/grid laser or a combination of both in diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: A total of 126 patients with DME. METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg of ranibizumab at baseline and months 1, 3, and 5 (group 1, 42 patients), focal/grid laser photocoagulation at baseline and month 3 if needed (group 2, 42 patients), or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 (group 3, 42 patients). MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at month 6. RESULTS: At month 6, the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, P = 0.01, analysis of variance) compared with group 2 (-0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. For patients with data available at 6 months, improvement of 3 lines or more occurred in 8 of 37 (22%) in group 1 compared with 0 of 38 (0%) in group 2 (P = 0.002, Fisher exact test) and 3 of 40 (8%) in group 3. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively. CONCLUSIONS: During a span of 6 months, ranibizumab injections by the current protocol had a significantly better visual outcome than focal/grid laser treatment in patients with DME.

Multiple repeated intravitreal triamcinolone treatments for radiation-induced macular edema.

BACKGROUND AND PURPOSE: This report discusses a patient with a predictably and repetitively favorable anatomic and functional response to intravitreal triamcinolone for radiation-induced macular edema. The purpose of this report is to demonstrate a situation where this treatment may have a favorable outcome over time. METHOD: Retrospective interventional case study. RESULT: Restoration of normal macular contour as well as maintenance of good vision after several treatments with intravitreal triamcinolone. CONCLUSION: Intravitreal triamcinolone is a well-established treatment for macular edema. In the vast majority of cases, its effect is transient, and additional treatments are necessary. It is important to realize that, in certain cases which are effectively treated with this modality, it may allow for preservation of good vision over time. One must be vigilant for the known complications of intravitreal triamcinolone, especially increased intraocular pressure and cataract progression.

Future pharmacological treatment options for nonexudative and exudative age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the industrialised world. Within the past decade, researchers have introduced many promising prevention and treatment options in an attempt to minimise the central vision loss imparted from AMD. Based on large-scale, randomised, prospective, placebo-controlled trials, a specially formulated combination of the antioxidants vitamin C, vitamin E, beta-carotene, copper and zinc is the only proven means of AMD prophylaxis. Thermal laser photocoagulation and photodynamic therapy with verteporfin are the only standard treatment options. However, efficacy is limited and treatment is only applicable to a minority of AMD patients. Thus, alternative pharmacological interventions are in all phases of clinical development. Researchers are guardedly optimistic that these advances may change the entire approach to AMD management in the near future. This review article will detail the currently accepted treatment options, as well as describe several of the more promising investigational pharmacological approaches to AMD.