Intraocular drugs: pharmacokinetic strategies and the influence on efficacy and durability.

INTRODUCTION: The modern treatment of chorioretinal vascular diseases follows the recent development and rapid adoption of drugs that inhibit vascular endothelial growth factor (VEGF). All anti-VEGF drugs are delivered intravitreally, with clinical behavior, including efficacy, durability, and safety, largely determined by their pharmacokinetic properties. AREAS COVERED: Properties of these new drugs include additional binding targets (placental growth factor (PlGF) and angiopoietin 2 (Ang 2)), binding affinity, potency, intravitreal half-life, and increased molar dose. A PubMed search for 'pharmacokinetics of anti-VEGF drugs' was performed from 2000 to 2023. Relevant studies were reviewed and referred to in the manuscript. EXPERT OPINION: Early developers concentrated on improving efficacy, but since maximum efficacy with VEGF inhibition has been reached, development has pivoted to extending the duration of action. Durability strategies include inhibiting additional pathways (faricimab), increasing molar dose (abicipar, brolucizumab, faricimab, and aflibercept 8 mg), and prolonging the intravitreal half-life (abicipar and KSI-301). Recent phase 3 trials demonstrated modest improvements in durability, but failures that might be attributed to these strategies (conjugation and manufacturing processes) have occurred. Future drug development focuses on extending duration of action with implantable reservoirs (ranibizumab port delivery system), sustained release devices (tyrosine kinase inhibitors), and gene therapy.

Anatomic Characteristics of Eyes With Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The purpose of this study was to evaluate and compare the anatomic characteristics of eyes with Fuchs endothelial corneal dystrophy (FECD) with eyes without FECD. METHODS: This study was a retrospective chart review performed at an academic medical center. Patients with FECD were identified through a search of the electronic medical records. Eligible patients underwent Scheimpflug imaging and optical biometry and were compared with age and sex-matched control subjects who underwent similar testing in preparation for cataract surgery. Several measurements of the cornea, anterior chamber, and eyes were evaluated using multivariable linear regression models and multivariable logistic regression models. RESULTS: A total of 404 eyes (202 eyes with FECD and 202 control eyes) were included in this study. Compared with controls, eyes with FECD had shallower AC depths, lower AC volumes, and narrower angles. Conversely, the spherical equivalent before cataract surgery, corneal pachymetry, and corneal volume were higher in eyes with FECD. On Scheimpflug imaging analysis, these anatomical differences were present in FECD eyes with and without corneal edema. After adjusting for sex, these differences remained statistically significant. Shorter axial length was found to be statistically significant in male eyes but not in female eyes with FECD. CONCLUSIONS: This study reports new ocular characteristics in FECD eyes with and without edema. Optical biometry and Scheimpflug imaging established that the anatomic findings in eyes with FECD were not simply due to the larger volume of an edematous cornea but rather unique to eyes with FECD. These findings will provide reliable, normative data for future studies examining surgical, medical, and anatomical factors in FECD.

Macular neovascularization.

Neovascularization of the macula, a common complication of many chorioretinal diseases such as neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and pathologic myopia results from increased synthesis of vascular endothelial growth factor (VEGF) by the retinal pigment epithelium and/or Müller cells because of localized ischemia and inflammation. The Consensus on Neovascular AMD Nomenclature (CONAN) study group acknowledged that these vessels may originate from either the choriocapillaris or the retinal microvasculature, prompting them to propose the term 'macular neovascularization' (MNV) to include intraretinal, subretinal, and sub-pigment epithelial neovascularization localized to the macula. MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition. Multimodal imaging with optical coherence tomography (OCT), OCT angiography, dye-based angiographies, fundus autofluorescence, and multiwavelength photography help establish the diagnosis and aid in selecting an appropriate treatment. The standard of care for MNV is usually intravitreal anti-VEGF injections, though thermal laser photocoagulation, verteporfin photodynamic therapy, and vitreoretinal surgery are occasionally used. This current review discusses the etiology and clinical features of MNV, the role of multimodal imaging in establishing the diagnosis, and the available therapeutic options.

The Role of Widefield Optical Coherence Tomography Angiography in Assessing the Severity of Diabetic Retinopathy.

INTRODUCTION: Physicians need an accurate understanding of diabetic retinopathy (DR) severity to optimally manage patients. The aim of this prospective study is to correlate the severity of macular and peripheral retinal vascular abnormalities seen on widefield (WF) optical coherence tomography angiography (OCTA) with DR grading based on WF fundus photography. METHODS: The study included 150 eyes from 82 patients with treatment-naïve DR. All patients were imaged with WF fundus photography and swept-source WF OCTA. Quantitative and qualitative analyses of the foveal avascular zone (FAZ) size and shape, and measurement of capillary nonperfusion (CNP) areas, were performed from the OCTA images. The mixed-effects model was used to compare the DR grading from WF photography with the vascular changes seen on WF-OCTA, and Bonferroni correction was applied to the gradings. RESULTS: The mean [± standard deviation (SD)] age of patients was 55.5 (± 9.4) years. The WF-OCTA showed that an increasing size of the FAZ (from 0.442 (± 0.059) µm to 0.933 (± 0.086) µm) correlated with increasing severity of the DR (as determined with WF photography). The deep capillary plexus, FAZ size, and CNP areas in eyes with proliferative diabetic retinopathy (PDR) differed from those with mild nonproliferative diabetic retinopathy (NPDR) (p < 0.001). Most eyes with severe nonproliferative DR were found to have CNP in four quadrants [superficial capillary plexus (SCP) 60%, deep capillary plexus (DCP) 50%]. The WF-OCTA detected subtle neovascularization of the disc (NVD) in 7 eyes (10%) and neovascularization elsewhere (NVE) in 13 eyes (18%) that had been diagnosed with only moderate NPDR on WF photography. CONCLUSIONS: FAZ and CNP areas as measured by WF-OCTA correlate with DR severity. WF-OCTA can also detect subtle NVE and NVD that cannot be seen with fundus photography.

Recent Updates on the Diagnosis and Management of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the Western world, with a higher prevalence among Europeans and North Americans than that in Africans, Hispanics, and Asians. Advanced AMD is categorized as atrophic (dry) or exudative (wet/neovascular age-related macular degeneration [nAMD]). Dry AMD is characterized by progressive geographic atrophy of the retinal pigment epithelium and outer retinal layers, whereas nAMD is characterized by new vessels that invade the subretinal and/or subretinal pigment epithelium spaces. Existing treatments delay the onset of advanced AMD and reverses vision loss for a couple of years before atrophy usually decreases central visual acuity. We searched PubMed and Medline databases from January 1, 1980, to December 1, 2023, using the following search terms: macular degeneration, choroidal neovascularization, geographic atrophy, drusen, age-related maculopathy, AMD, ARMD, and anti-VEGF. Relevant articles in English (or English translations) were retrieved and reviewed. Bibliographies of the identified manuscripts were also reviewed to identify relevant studies. Age-related macular degeneration most commonly affects people older than 55 years. Visual prognosis varies, with advanced lesions (nAMD and geographic atrophy) leading to rapid, progressive loss of central vision and contrast sensitivity. Although AMD is not a life-threatening disease, reduced vision profoundly compromises quality of life and necessitates living assistance for many patients. Over the past 2 decades, advances in prevention (vitamin supplementation) and therapy (antivascular endothelial growth factor and complement inhibitor drugs) have reduced vision loss and blindness. Further research is needed to decrease the incidence of blindness in patients with advanced disease.

Fatal Presentation of Susac Syndrome in a Congenitally Deaf Patient With a Cochlear Implant.

OBJECTIVE: To report a fatal case of Susac syndrome in a congenitally deaf patient with a cochlear implant and a history of migraines, emphasizing the diagnostic challenges in patients with preexisting conditions. PATIENT: A 33-year-old male with congenital hearing loss, a cochlear implant, and chronic migraines who presented with mild subacute auditory disturbance and headaches that later progressed to severe encephalopathy. INTERVENTION: Explantation of a non-magnetic resonance imaging (MRI) compatible cochlear implant followed by MRI, fundoscopy, and the administration of immunosuppressive medications. MAIN OUTCOME MEASURES: Diagnosis was confirmed by characteristic MRI appearance and the presence of a hemi-retinal artery occlusion. RESULTS: After weeks of immunosuppressive treatment, the patient died of a global cerebral ischemic event of unknown origin. CONCLUSIONS: For patients with preexisting sensorineural hearing loss and cochlear implants, Susac syndrome poses a diagnostic challenge. Auditory disturbances in the absence of cochlear implant failure should prompt further evaluation for visual disturbances and encephalopathy. MRI and fundoscopy should be performed to detect other features of the disease.

Real-world experience of full-thickness traumatic macular hole among young patients.

OBJECTIVE: To describe the demographics, clinical, and imaging characteristics, and visual outcomes in young patients with full-thickness traumatic macular hole (TMH). METHODS: This retrospective hospital-based study included patients with full-thickness TMH who presented between August 2010 and June 2021. Demographic data, clinical findings, and imaging characteristics were extracted from an electronic medical record system. Regression analyses were performed to determine significant associations among variables and to identify predictors of visual outcomes. RESULTS: 144 (0.005%) patients among 2,834,616 were diagnosed with Full thickness TMH. The majority of them were male (89.58%; odds ratio [OR] = 6.71) and the holes were unilateral. The mean age at presentation was 23.37 ± 8.19 years. Ball were the most common cause of injuries (22.22%), followed by stick (14.58%) and firecracker (12.50%). The mean LogMAR visual acuity (VA) at presentation was 1.18 ± 0.72, with 25.69% of eyes having VA < 20/400. The mean minimum hole diameter was 619.34 ± 336.16 µm. Sub-retinal fluid was present in 44.44%, followed by intraretinal fluid in 34.03% of eyes. Macular holes closed after vitrectomy in 66.67% of eyes, with mean final VA of 1.07 ± 0.85. Baseline VA was a strong predictor of final VA (R2 = 0.677; p = 0.000168). CONCLUSION: Traumatic macular hole is a unilateral condition with significant visual impairment that is mainly seen in males during the third decade of life. Surgery is successful in most cases but improvements in VA are modest.

Hyperviscosity Syndrome Induced Bilateral Visual and Auditory Impairment in Therapy Resistant Waldenström Macroglobulinemia with MYD88 and CXCR4 Mutations.

Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton's tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.

Recent Advancements in Glaucoma Surgery-A Review.

Surgery has long been an important treatment for limiting optic nerve damage and minimising visual loss in patients with glaucoma. Numerous improvements, modifications, and innovations in glaucoma surgery over recent decades have improved surgical safety, and have led to earlier and more frequent surgical intervention in glaucoma patients at risk of vision loss. This review summarises the latest advancements in trabeculectomy surgery, glaucoma drainage device (GDD) implantation, and minimally invasive glaucoma surgery (MIGS). A comprehensive search of MEDLINE, EMBASE, and CENTRAL databases, alongside subsequent hand searches-limited to the past 10 years for trabeculectomy and GDDs, and the past 5 years for MIGS-yielded 2283 results, 58 of which were included in the final review (8 trabeculectomy, 27 GDD, and 23 MIGS). Advancements in trabeculectomy are described in terms of adjunctive incisions, Tenon's layer management, and novel suturing techniques. Advancements in GDD implantation pertain to modifications of surgical techniques and devices, novel methods to deal with postoperative complications and surgical failure, and the invention of new GDDs. Finally, the popularity of MIGS has recently promoted modifications to current surgical techniques and the development of novel MIGS devices.

Evaluating Access to Laser Eye Surgery by Driving Times Using Medicare Data and Geographical Mapping.

Importance: Recently, several states have granted optometrists privileges to perform select laser procedures (laser peripheral iridotomy, selective laser trabeculoplasty, and YAG laser capsulotomy) with the aim of increasing access. However, whether these changes are associated with increased access to these procedures among each state's Medicare population has not been evaluated. Objective: To compare patient access to laser surgery eye care by estimated travel time and 30-minute proximity to an optometrist or ophthalmologist. Design, Setting, and Participants: This retrospective cohort database study used Medicare Part B claims data from 2016 through 2020 for patients accessing new patient or laser eye care (laser peripheral iridotomy, selective laser trabeculoplasty, YAG) from optometrists or ophthalmologists in Oklahoma, Kentucky, Louisiana, Arkansas, and Missouri. Analysis took place between December 2021 and March 2023. Main Outcome and Measures: Percentage of each state's Medicare population within a 30-minute travel time (isochrone) of an optometrist or ophthalmologist based on US census block group population and estimated travel time from patient to health care professional. Results: The analytic cohort consisted of 1 564 307 individual claims. Isochrones show that optometrists performing laser eye surgery cover a geographic area similar to that covered by ophthalmologists. Less than 5% of the population had only optometrists (no ophthalmologists) within a 30-minute drive in every state except for Oklahoma for YAG (301 470 [7.6%]) and selective laser trabeculoplasty (371 097 [9.4%]). Patients had a longer travel time to receive all laser procedures from optometrists than ophthalmologists in Kentucky: the shortest median (IQR) drive time for an optometrist-performed procedure was 49.0 (18.4-71.7) minutes for YAG, and the the longest median (IQR) drive time for an ophthalmologist-performed procedure was 22.8 (12.1-41.4) minutes, also for YAG. The median (IQR) driving time for YAG in Oklahoma was 26.6 (12.2-56.9) for optometrists vs 22.0 (11.2-40.8) minutes for ophthalmologists, and in Arkansas it was 90.0 (16.2-93.2) for optometrists vs 26.5 (11.8-51.6) minutes for ophthalmologists. In Louisiana, the longest median (IQR) travel time to receive laser procedures from optometrists was for YAG at 18.5 (7.6-32.6) minutes and the shortest drive to receive procedures from ophthalmologists was for YAG at 20.5 (11.7-39.7) minutes. Conclusions and Relevance: Although this study did not assess impact on quality of care, expansion of laser eye surgery privileges to optometrists was not found to lead to shorter travel times to receive care or to a meaningful increase in the percentage of the population with nearby health care professionals.

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study.

BACKGROUND: Age-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA. OBJECTIVE: To compare the prevalence of CAA in patients with or without AMD matched for age. METHODS: We conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD). RESULTS: Our analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669). CONCLUSIONS: AMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.

Medical Therapy for Large Idiopathic Full-Thickness Macular Holes.

PURPOSE: To describe the characteristics and outcomes of eyes with idiopathic full-thickness macular holes (FTMH) that underwent initial medical management. METHODS: This retrospective study included eyes with FTMH that were initially managed with one month of topical therapy. Eligible subjects were treated with dorzolamide 2% three times a day, nepafenac 0.1% twice a day, and prednisolone acetate 1% four times a day. The primary endpoints was hole closure at one month and secondary endpoint was change in best-corrected visual acuity (BCVA). RESULTS: Ten subjects (mean age: 62.80 years; female: 50%) with unilateral FTMH were studied. The mean basal diameter of the entire cohort at baseline was 824.1 µm (median 828 µm). Four (40%) of the smaller holes (mean 698 µm; median 698.50 µm) closed after one month of topical therapy, whereas larger holes (mean 908.17µm; median 889.50 µm) did not close. In one eye, the hole reopened 4 months after stopping the medication, but closed again at one month after re-starting the topical treatment. Median BCVA improved from 0.35 logMAR at baseline to 0.05 logMAR in eyes that closed but remained at 0.70 logMAR at one month in eyes that did not close. CONCLUSION: Topical corticosteroid, non-steroidal anti-inflammatory, and carbonic anhydrase inhibitor therapy may promote closure of small FTMHs, but large holes are less likely to respond. One month of topical therapy might avoid subjecting some patients to complex vitreo-retinal surgery without compromising visual outcomes. Macular hole may re-open after stopping the topical therapy.

Updates on the Diagnosis and Management of Glaucoma.

Glaucoma is the leading cause of blindness throughout the world (after cataracts); therefore, general physicians should be familiar with the diagnosis and management of affected patients. Glaucomas are usually categorized by the anatomy of the anterior chamber angle (open vs narrow/closed), rapidity of onset (acute vs chronic), and major etiology (primary vs secondary). Most glaucomas are primary (ie, without a contributing comorbidity); however, several coexisting ophthalmic conditions may serve as the underlying etiologies of secondary glaucomas. Chronic glaucoma occurs most commonly; thus, regular eye examinations should be performed in at-risk patients to prevent the insidious loss of vision that can develop before diagnosis. Glaucoma damages the optic nerve and retinal nerve fiber layer, leading to peripheral and central visual field defects. Elevated intraocular pressure (IOP), a crucial determinant of disease progression, remains the only modifiable risk factor; thus, all current treatments (medications, lasers, and operations) aim to reduce the IOP. Pharmacotherapy is the usual first-line therapy, but noncompliance, undesirable adverse effects, and cost limit effectiveness. Laser and surgical treatments may lower IOP significantly over long periods and may be more cost effective than pharmacotherapy, but they are plagued by greater procedural risks and frequent treatment failures. Traditional incisional procedures have recently been replaced by several novel, minimally invasive glaucoma surgeries with improved safety profiles and only minimal decreases in efficacy. Minimally invasive glaucoma surgeries have dramatically transformed the surgical management of glaucoma; nevertheless, large, randomized trials are required to assess their long-term efficacy.

Macular Telangiectasia Type 2: A Comprehensive Review.

Macular telangiectasia Type 2 (MacTel) is a gradually progressive disease that affects the quality of life by impairing both distant and near vision. It had previously been considered a vascular condition, but recent evidence suggests a neurodegenerative etiology, with primary involvement of Muller cells. Retinal pigment epithelium (RPE) hyperplasia and subretinal neovascularization (SNV) are responsible for most of the vision loss in advanced cases. Neurotrophic factors in the non-proliferative phase and intravitreal anti-Vascular Endothelial growth factor (VEGF) in the proliferative phase have shown to retard the progression of the disease. This review will discuss the pathophysiology, clinical features, important diagnostic imaging studies and available treatment options for MacTel.

SAFETY AND THERAPEUTIC EFFECTS OF ORALLY ADMINISTERED AKST4290 IN NEWLY DIAGNOSED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the safety and therapeutic effects of orally administered AKST4290 (formerly BI 144807 and ALK4290) in treatment-naive patients with neovascular age-related macular degeneration. METHODS: In this prospective, multicenter, open-label Phase 2a pilot clinical study, 30 patients with newly diagnosed neovascular age-related macular degeneration self-administered AKST4290 (400 mg) orally twice daily for 6 weeks. Patients were examined weekly for safety, to measure best-corrected visual acuity (BCVA), and to perform exploratory morphologic assessments. The primary endpoint was the mean change in BCVA from baseline to end of treatment, and the secondary endpoint was safety. Exploratory endpoints investigated potential changes in macular morphology. RESULTS: Mean BCVA improved by +7.0 letters (95% CI, 2.2-11.7); 24 patients (82.8%) had stable or improved BCVA, with 6 (20.7%) gaining ≥15 letters. No patients experienced severe or serious adverse events. CONCLUSION: In this 6-week study, AKST4290 treatment was associated with improved BCVA scores in patients with treatment-naive neovascular age-related macular degeneration. All adverse events were mild or moderate in severity and no safety issues were identified. Treatment of neovascular age-related macular degeneration with AKST4290 warrants further investigation in randomized, placebo-controlled trials.

Doctor I Have an Iodine Allergy.

Ophthalmologists frequently face patients who refuse asepsis protocols involving povidone-iodine (PI) due to claims of an allergy to iodine. Such patients usually base this claim on previous reactions to shellfish consumption or to imaging procedures that used iodine-based contrast agents. Allergy to iodine, however, is biologically impossible, and iodine deficiency causes severe developmental problems, including mental retardation. Furthermore, shellfish allergy is due to tropomyosins in muscle tissue, and reactions to intravascular contrast dyes are due to hyperosmolar solutions; neither "allergy" is due to iodine. PI, which contains 9-12% iodine, is the preferred antiseptic for ophthalmic procedures. Experience shows that PI can be administered safely to patients claiming iodine allergy. True allergy to PI is rare and, if indicated, skin patch testing can be performed prior to surgery. Patients who react adversely to highly concentrated (5-10%) PI usually experience toxicity to the corneal and conjunctival epithelium after topical administration. Dilute (0.1-0.25%) PI kills microbes quicker than higher concentrations but for shorter periods of time because the total dose of iodine is smaller. Repeated administration (every 20-30 s) of dilute PI effectively kills microbes for as long as necessary with little risk of epithelial toxicity.

IMPACT OF FLUID COMPARTMENTS ON FUNCTIONAL OUTCOMES FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Systematic Literature Review.

PURPOSE: Understanding the impact of fluid in different retinal compartments is critical to developing treatment paradigms that optimize visual acuity and reduce treatment burden in neovascular age-related macular degeneration. This systematic review aimed to determine the impact of persistent/new subretinal fluid, intraretinal fluid, and subretinal pigment epithelial fluid on visual acuity over 1 year of treatment. METHODS: Publication eligibility and data extraction were conducted according to Cochrane methods: 27 of the 1,797 screened records were eligible. RESULTS: Intraretinal fluid negatively affected visual acuity at baseline and throughout treatment, with foveal intraretinal fluid associated with lower visual acuity than extrafoveal intraretinal fluid. Some studies found that subretinal fluid (particularly subfoveal) was associated with higher visual acuity at Year 1 and longer term, and others suggested subretinal fluid did not affect visual acuity at Years 1 and 2. Data on the effects of subretinal pigment epithelial fluid were scarce, and consensus was not reached. Few studies reported numbers of injections associated with fluid status. CONCLUSION: To optimally manage neovascular age-related macular degeneration, clinicians should understand the impact of fluid compartments on visual acuity. After initial treatment, antivascular endothelial growth factor regimens that tolerate stable subretinal fluid (if visual acuity is stable/improved) but not intraretinal fluid may enable patients to achieve their best possible visual acuity. Confirmatory studies are required to validate these findings.

Durability of VEGF Suppression With Intravitreal Aflibercept and Brolucizumab: Using Pharmacokinetic Modeling to Understand Clinical Outcomes.

Purpose: To investigate whether vascular endothelial growth factor (VEGF)-suppression durations contribute to our understanding of clinical trial outcomes by simulating vitreous molar concentrations (Cvm) of intravitreal aflibercept (IVT-AFL) and brolucizumab (IVT-BRO) using pharmacokinetic (PK) modeling. Methods: A PK model simulated Cvm after single-dose IVT-AFL, IVT-BRO, and ranibizumab (IVT-RAN), and extrapolated intraocular VEGF-suppression thresholds and durations. Vitreous PK after multidose regimens used in studies of IVT-AFL versus IVT-BRO were simulated and compared with best-corrected visual acuity (BCVA) data. Results: Cvm peaked higher (Cmax) and decreased more quickly to the VEGF-suppression threshold and minimum (Cmin) levels with IVT-BRO than with IVT-AFL, consistent with their molar doses calculated using molecular weights and vitreous half-lives (26 kDa and 115 kDa; 4.4-5.1 and 9.1-11 days, respectively). The mean VEGF suppression durations were 71 days for IVT-AFL 2 mg and 51 (48-59) days for IVT-BRO 6 mg. Based on dosing in OSPREY (matched dosing to week [w]32 for both agents; thereafter, IVT-AFL every eight weeks [q8w] and IVT-BRO q12w for the last two doses [w32→w44 and w44→w56]), IVT-BRO showed wider Cmax-Cmin fluctuations than IVT-AFL. The IVT-BRO Cmin fell below the VEGF-suppression threshold at timepoints near w56, when decreases in BCVA were also observed. The IVT-AFL vitreous Cmin remained above the suppression threshold through w56, where BCVA gains were maintained. Conclusions: The PK-modeled mean VEGF-suppression duration for IVT-BRO was substantially shorter than that published for IVT-AFL and may not be sufficient to effectively suppress VEGF throughout q12w dosing. Translational Relevance: The PK modeling suggests that more patients may be maintained on ≥q12w dosing with IVT-AFL than with IVT-BRO.

Real-World Safety Outcomes of Intravitreal Ranibizumab Biosimilar (Razumab) Therapy for Chorioretinal Diseases.

INTRODUCTION: To assess the safety profile of the intravitreal ranibizumab biosimilar molecule, Razumab® (Intas Pharmaceuticals, Ahmedabad, India) in chorioretinal disorders under real-world conditions. METHODS: This was a multicenter, retrospective chart review which included patients from 15 centers receiving intravitreal Razumab (IVRz) injections from 2016 to 2020. Patient demographics, ocular examination data, and detailed safety information regarding serious adverse events (SAE) or serious adverse drug reactions (sADR), and non-serious AEs (nsAE) or non-serious ADRs (nsADR) occurring within 1 month of IVRz injections were compiled. RESULTS: A total of 6404 eyes of 6404 patients received 9406 IVRz injections [mean (± SD) = 1.49 (± 0.63)] during 4.25 years. Adverse events were reported after 1978 injections (21.03%): 64.16% nsAE, 32.96% nsADR, 2.37% sADR, and 0.51% SAE. The most frequent adverse events were subconjunctival hemorrhage (8.2% of total injections), transient blurring of vision (6.5% of total injections), and mild ocular pain (5.27% of total injections). Serious ocular (31 cases with retinal pigment epithelial tears [0.33%], two cases of non-infectious vitritis [0.02%], and one case of endophthalmitis [0.01%]) and systemic (seven patients with non-fatal myocardial infarction [0.12%] and six patients with non-fatal cerebrovascular accident [0.09%]) adverse events were infrequent. CONCLUSION: The study reports the largest pooled safety data on IVRz use in a real-world scenario. The results did not raise any new ocular or systemic safety concerns for the biosimilar agent, with the incidence and spectrum of adverse reactions similar to those reported with other anti-vascular endothelial growth factor (anti-VEGF) drugs. The real-world evidence suggests that IVRz is a safe anti-VEGF agent in the management of chorioretinal disorders.