Short-Term Safety and Efficacy of Intravitreal Brolucizumab Injections for Neovascular Age-Related Macular Degeneration: A Multicenter Retrospective Real-World Study.

INTRODUCTION: The aim of the study was to determine the short-term real-world safety and efficacy of intravitreal brolucizumab injections in Korean patients with neovascular age-related macular degeneration (nAMD). METHODS: This multicenter retrospective study involved 294 eyes (treatment naïve 20 eye [6.8%] and nontreatment naïve 274 eyes [93.2%]) of 290 patients from 13 hospitals or retinal centers in South Korea. Patients with nAMD who received brolucizumab injection(s) between April 1 and November 30, 2021, with a follow-up ≥1 month, were included. Primary outcomes were safety, incidence of intraocular inflammation (IOI), and potential risk factors. The secondary outcome was efficacy, i.e., change in best-corrected visual acuity (BCVA) and optical coherence tomography-measured macular thickness and retinal fluid. RESULTS: The mean age was 71.63 ± 8.66. The follow-up period was 2.38 ± 0.79 months. The mean number of brolucizumab injections during the follow-up was 1.52 ± 0.58. The overall incidence of IOI was 13.9% (n = 41 eyes). Most IOI cases were of anterior uveitis (8.8%, 26 eyes), followed by retinal vasculitis (2.4%, seven eyes) and occlusive retinal vasculitis (0.3%, one eye). Most eyes showed IOI resolution (n = 40, 97.5%) and BCVA restoration (n = 39, 95.1%) with or without corticosteroid treatment during the follow-up. Age, sex, IOI history, or other anti-vascular endothelial growth factor injection histories were not associated with the occurrence of IOI. However, only thin subfoveal choroidal thickness (SFCT) was associated with the occurrence of IOI (odds ratio = 0.995, p = 0.020). BCVA at 1 month improved from baseline (baseline 0.518 ± 0.356 vs. 1 month 0.503 ± 0.383, p = 0.023), but the improvement was not maintained. Anatomical improvement was significant after 3 months. CONCLUSION: In Korean patients with nAMD, the incidence of IOI following brolucizumab injections was 13.9%. IOI was well-controlled with or without steroid treatment. Most IOI eyes (95.1%) were restored to the level of vision before. IOI occurrence and occlusive vasculitis was rare. In the short term, brolucizumab injection effectively improved vision at 1 month and dried retinal fluid for 3 months.

Choroidal vascular alterations evaluated by ultra-widefield indocyanine green angiography in central serous chorioretinopathy.

PURPOSE: This study aims to evaluate choroidal vascular alterations in patients with central serous chorioretinopathy (CSC) using ultra-widefield (UWF) indocyanine green angiography (ICGA). METHODS: This was a retrospective case-control study conducted at a single tertiary eye center. In total, 36 eyes in patients with either unilateral (24 patients) or bilateral (six patients) treatment-naïve CSC and 30 eyes in 24 age-matched controls were evaluated. The number of quadrants with vortex vein engorgement on UWF ICGA was evaluated. Dilated choroidal vessels affecting the macula were regarded as extended vortex vein engorgement. Choroidal vascular hyperpermeability (CVH) area on late-phase ICGA was quantified using stereographic projection. The parameters were compared with clinical and optical coherence tomographic findings. RESULTS: Eyes with CSC had larger CVH area, thicker choroid, and more quadrants with vortex vein engorgement and extended vortex vein engorgement compared with control eyes (all P < 0.001). In patients with unilateral CSC, affected eyes had larger CVH area, thicker choroid, and more extended vortex vein engorgements compared with unaffected fellow eyes (all P < 0.001), but vortex vein engorgement did not significantly differ. CVH was significantly correlated with extended vortex vein engorgement (P < 0.001) and subfoveal choroidal thickness (P = 0.007). CONCLUSIONS: The increased number and binocular symmetry of engorged vortex veins suggest an anatomical predisposition for CSC. CVH area and extended vortex vein engorgement were indicators of choroidal outflow congestion. These parameters may serve as diagnostic clues or predictors of disease development in eyes with CSC.

MULTIMODAL IMAGING FEATURES AND TREATMENT RESPONSES OF CHOROIDAL NEOVASCULARIZATION SECONDARY TO CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To investigate features of central serous chorioretinopathy with choroidal neovascularization (CNV) on multimodal imaging and analyze their association with treatment response. METHODS: A total of 37 patients with chronic central serous chorioretinopathy complicated by CNV were divided into bevacizumab and photodynamic therapy groups, and each group was subdivided into responders and nonresponders according to subretinal fluid status at 3 months. We assessed multimodal imaging parameters (subfoveal choroidal thickness; vortex vein engorgement; choroidal vascular hyperpermeability; and CNV morphologic pattern, area, and vessel density) and analyzed their association with treatment responses. RESULTS: Responders in the bevacizumab group showed thinner subfoveal choroidal thickness (384.0 ± 103.2 vs. 398.3 ± 87.1 µm, P = 0.042), smaller CNV area (0.512 ± 0.267 vs. 1.323 ± 0.481 mm2, P = 0.007), open-circuit pattern (84.6% vs. 12.5%, P < 0.001), and capillary fringe (69.2% vs. 37.5%, P = 0.001) than nonresponders. Responders in the photodynamic therapy group had thicker subfoveal choroidal thickness (420.1 ± 93.5 vs. 395.7 ± 6.5 µm, P = 0.021), more quadrants with engorged vortex veins extending to the macula (P = 0.012), and intense choroidal vascular hyperpermeability (57.1% vs. 50.0%, P = 0.026) than nonresponders. Choroidal neovascularization showing closed-circuit pattern (85.7% vs. 0%, P = 0.001) and peripheral loop (64.3% vs. 0%, P = 0.001) demonstrated a good response to photodynamic therapy. CONCLUSION: Heterogeneous features of choroidal hyperpermeability, thickness, and CNV morphology in CNV accompanying central serous chorioretinopathy are associated with different therapeutic responses to bevacizumab and photodynamic therapy treatments.

Topographic analysis of retinal and choroidal microvasculature according to diabetic retinopathy severity using optical coherence tomography angiography.

PURPOSE: To investigate the topographic changes in the retinal capillary plexus and the choriocapillaris according to the severity of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA). METHODS: Subjects were recruited and classified into one of the following four groups: normal controls (n = 52), diabetes without DR (n = 49), non-proliferative DR (n = 51) and proliferative DR (n = 38). Using OCTA, the superficial capillary plexus (SCP), deep capillary plexus (DCP) and the choriocapillaris vessel densities were measured and compared in different macular areas: the fovea (1-mm diameter circular area), parafovea (1-3-mm diameter ring) and perifovea (3-6-mm ring). RESULTS: With DR progression, vessel densities in the SCP and DCP as well as the choriocapillaris decreased, while the foveal avascular zone area increased (p < 0.001 for all). Compared with controls, the SCP and DCP vessel densities of the diabetes without DR group were decreased in all areas of the macula (p < 0.020 for all), while the choriocapillaris vessel density was decreased only in the perifoveal area (p = 0.823 for the foveal area; p = 0.631 for the parafoveal area; p = 0.039 for the perifoveal area). Multivariate linear regression analyses revealed that all retinal and choroidal microvascular indices were significantly associated with the DR severity. CONCLUSION: The morphological changes in the macular microvasculature were associated with DR severity. Also, the changes were found to be more vulnerable in the retinal capillary plexuses than the choriocapillaris.

Prospective trial of treat-and-extend regimen with aflibercept for branch retinal vein occlusion: 1-year results of the PLATON trial.

PURPOSE: To evaluate the functional and anatomical outcomes of a treat-and-extend (TAE) regimen with aflibercept for treatment-naive macular edema (ME) secondary to branch retinal vein occlusion (BRVO). METHODS: This was a prospective, multicenter, noncomparative, open-label clinical trial. Forty-eight eyes of 48 patients received three monthly intravitreal aflibercept injections prior to the TAE regimen. However, if the best-corrected visual acuity (BCVA) was ≥ 20/20 and the central macular thickness (CMT) was < 250 µm during the loading phase, the patient immediately proceeded to the TAE regimen. The treatment interval was adjusted by 4 weeks based on changes in CMT. The primary outcome was the mean change in BCVA from baseline to 52 weeks. RESULTS: The mean change in BCVA was 23.6 ± 14.2 letters. The proportion of patients with BCVA gain ≥ 15 letters was 77.1% at 24 weeks and 72.9% at 52 weeks. The mean reduction in CMT was 326.2 ± 235.6 µm at 24 weeks and 324.2 ± 238.0 µm at 52 weeks. The mean number of injections was 6.7 ± 1.2 (range: 6-11, all patients received three monthly intravitreal aflibercept injections) over 52 weeks, and 34 patients (70.8%) reached the maximal extension interval of 16 weeks at 52 weeks. CONCLUSIONS: The TAE regimen using aflibercept for ME secondary to BRVO, which has a treatment interval of up to 16 weeks, showed comparable efficacy to the fixed-dosing regimen along with reduced treatment burden.

Effects of refractive power on quantification using ultra-widefield retinal imaging.

BACKGROUND: Ultra-widefiled (UWF) retinal images include significant distortion when they are projected onto a two-dimensional surface for viewing. Therefore, many clinical studies that require quantitative analysis of fundus images have used stereographic projection algorithm, three-dimensional fundus image was mapped to a two-dimensional stereographic plane by projecting all relevant pixels onto a plane through the equator of the eye. However, even with this impressive algorithm, refractive error itself might affect the size and quality of images theoretically. The purpose of this study is to investigate the effects of refractive power on retinal area measurements (quantification) using UWF retinal imaging (Optos California; Dunfermline, Scotland, UK). METHODS: A prospective, interventional study comprised 50 healthy eyes. UWF images were acquired first without the use of a soft contact lens (CL) and then repeated with six CLs (+ 9D, +6D, +3D, -3D, -6D, and - 9D). Using stereographically projected UWF images, the optic disc was outlined by 15-17 points and quantified in metric units. We divided the subjects into three groups according to axial length: Groups A (22-24 mm), B (24-26 mm), and C (≥ 26 mm). The primary outcome was percentage change before and after use of the CLs. Secondary outcome was proportion of subjects with magnification effects, maximal changes > 10 %. RESULTS: The study population was 6, 28, and 16 eyes in each group. Overall changes for the measured area were not significantly different in the whole study population. Group C had a larger proportion of magnification effects compared to Groups A and B (50.0 %, 0 %, and 3.6 %, P = 0.020). Measured area with plus lenses was significantly higher in Group C (P < 0.001). CONCLUSIONS: The use of CLs might affect quantification of eyes with long axial length when using UWF images. Ophthalmologists should consider refractive error when measuring area in long eyes.

Title: efficacy of intravitreal dexamethasone implant on hard exudate in diabetic macular edema.

BACKGROUND: To investigate the effect of intravitreal dexamethasone implant (DEX implant) on hard exudate (HE) accompanying diabetic macular edema (DME). METHODS: This study was a non-comparative non-randomized 1-year prospective interventional study. Patients with DME and HE were treated using DEX implant two or three times. Color fundus photography and optical coherence tomography (OCT) were performed at every visit. HE area was measured semi-automatically from the fundus photographs. RESULTS: Thirty-five patients completed the study. Eleven patients (31.4%) received two injections, while the remaining received three times. HE area (primary outcome) significantly decreased from 1.404±2.094 mm2 (baseline) to 0.212±0.592 mm2 (last visit), which was 24% of the baseline HE area (P<0.001). HE1500 (HE within 1500 µm from the fovea) area also decreased significantly from 0.382±0.467 mm2 to 0.066±0.126 mm2 (P<0.001). Furthermore, anaverage best corrected visual acuity (BCVA) improvement of 4.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters was observed (from 49.9±18.3 to 54.3±20.4 letters) (P= 0.008). Central macular thickness (CMT) decreased from 455.8±23.6 µm to 366.8±31.1 µm (P=0.009). Repetitive measurements for entire study duration was analyzed using generalized estimating equations (GEE), where BCVA was related to age, CMT, and HE1500 area in multivariate analyses. CONCLUSION: DEX implant could reduce and suppress HE in DME for one year with two or three injections. And centrally located HE area (HE1500 area) is related to vision. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02399657 , Registered 26 March 2015.

SEVERITY OF DIABETIC MACULAR EDEMA CORRELATES WITH RETINAL VASCULAR BED AREA ON ULTRA-WIDE FIELD FLUORESCEIN ANGIOGRAPHY: DAVE Study.

PURPOSE: To quantify retinal nonperfusion area and retinal vascular bed area (RVBA) in mm on ultra-widefield fluorescein angiography in eyes with diabetic macular edema (DME) and explore their relationship with the severity of DME. METHODS: Prospective, observational case series. Baseline ultra-widefield fluorescein angiography images of 40 eyes from 29 patients with treatment-naive DME who participated in the DAVE study (NCT01552408) were stereographically projected at Doheny Image Reading Center. The retinal vasculature was automatically extracted to calculate RVBA. Nonperfusion area was manually delineated by two masked certified graders. Retinal vascular bed area and nonperfusion area were computed in mm automatically by adjusting for peripheral distortion and then correlated with the severity of DME. RESULTS: The global RVBA for the entire retina in eyes with DME was increased compared with healthy controls (54.7 ± 16.6 mm vs. 37.2 ± 9.9 mm, P < 0.001) and correlated with the severity of DME (P < 0.05). Retinal ischemia (nonperfusion area) was nonuniformly distributed and not related to DME extent (P > 0.05). CONCLUSION: Eyes with DME have an increased RVBA compared with healthy controls. The severity of DME appears to be related to global RVBA, but not to retinal ischemia.

One-Year Results of Treatment of Diabetic Macular Edema with Aflibercept Using the Treat-and-Extend Dosing Regimen: the VIBIM Study.

INTRODUCTION: The purpose of this study was to report the one-year results of treatment of diabetic macular edema (DME) with aflibercept using a treat-and-extend regimen (TER). METHODS: This was a prospective, multicenter, single-arm study planned for 2 years. The eyes received 5 consecutive intravitreal injections of 2 mg of aflibercept every 4 weeks, and the interval between injections was then adjusted by 2 weeks based on changes in the central subfield macular thickness (CSMT). If the CSMT was worse, stable, or better, the interval was shortened, extended, or maintained, respectively. The primary outcome measure was the change in best-corrected visual acuity (BCVA) from baseline to 104 weeks, and the secondary outcome was the change in BCVA from baseline to 52 weeks. RESULTS: Of the 48 patients enrolled, 46 completed a 1-year visit. BCVA improved significantly by 9.1 letters (95% confidence interval: 5.3-13.0 letters) from 56.2 letters at baseline (p < 0.001), and CSMT decreased by -171.7 µm from 489.4 to 317.7 µm (p < 0.001). The proportion of eyes having 20/40 or better vision increased from 17.4 to 41.3%, and the proportion of eyes that gained ≥15 letters was 28.3%. The mean number of injections was 8.5 times for 52 weeks. Worsening of macular edema did not occur in 76.1% of eyes during the extension period, and the interval between injections was extended to 12 weeks in 73.9% of eyes at 52 weeks. CONCLUSIONS: The TER showed 1-year efficacy comparable to that of the fixed dosing regimen of pivotal trials, and its flexible dosing would prevent overtreatment.

Impact of Early Anatomical and Functional Responses to Bevacizumab in Macular Edema Secondary to Branch Retinal Vein Occlusion.

PURPOSE: To evaluate whether early anatomical and visual acuity (VA) responses to intravitreal bevacizumab (IVB) in macular edema secondary to branch retinal vein occlusion (BRVO) are associated with 1-year follow-up outcomes. METHODS: Ninety-nine treatment-naïve patients (99 eyes) with macular edema after BRVO treated with IVB were analyzed retrospectively. All patients received single injection and were followed up with pro re nata regimen for at least 12 months. The relationship between early (1 month) and late (12 months) anatomical (presence/absence of fluid) and functional response (an improvement of <1, 1 to <3, or ≥3 logMAR lines from baseline in best corrected VA, BCVA) was explored. RESULTS: Fifty-eight eyes (58.6%) had absence of fluid at 1 month after the first injection, but 41 eyes (41.4%) did not. Those with absence of fluid at 1 month were more likely to be fluid-free at 12 months (p = 0.010). Thirty-seven (37.4%), 24 (24.2%), and 38 (38.4%) eyes showed an improvement of <1, 1 to <3, and ≥3 lines, respectively, at 1 month after the first injection. Intercohort differences across three response categories in BCVA change from baseline were statistically significant throughout the follow-up. Each group maintained stable VA changes within 1 line during the follow-up after 1 month. CONCLUSION: The early anatomical and functional response was associated with anatomical and functional improvement at 12 months.

Efficacy of intravitreal bevacizumab for macular edema following branch retinal vein occlusion stratified by baseline visual acuity.

PURPOSE: To compare the clinical features and bevacizumab efficacy for macular edema (ME) following branch retinal vein occlusion (BRVO) stratified by baseline visual acuity. METHODS: This retrospective study included a total 117 eyes from 117 consecutive patients with ME following BRVO, who received PRN intravitreal bevacizumab injection and were followed for more than 6 months. The eyes were categorized into three groups according to baseline best-corrected visual acuity (BCVA) (group A, BCVA <20/200; group B, BCVA ≥20/200 and ≤20/40; group C, BCVA >20/40). Baseline demographics, clinical features, BCVA, and central retinal thickness (CRT) at 1, 3, 6, and 12 months after injection and the number of injections were compared. RESULTS: Groups A-C included 11, 83, and 23 eyes, respectively. The mean baseline CRT was thickest in group A (810.1, 580.8, and 473.5 µm in groups A-C, respectively; p < 0.001) and the percentage of eyes with macular ischemia increased in the worst BCVA group (45.5, 25.0, and 4.3 % in groups A-C, respectively; p = 0.005). The mean BCVA and CRT improved at 1, 3, 6, and 12 months after treatment compared to baseline values in all groups (all, p < 0.001). The number of injections for 6 months was greater in the worst BCVA group (3.2, 2.3, and 1.9 injections in groups A-C, respectively; p = 0.009). CONCLUSION: In ME following BRVO, baseline visual acuity correlates with macular ischemia and baseline CRT. Intravitreal bevacizumab treatment results in significant anatomical and functional improvement regardless of baseline visual acuity.

COMPARISON OF THE LAMINA CRIBROSA THICKNESS OF PATIENTS WITH UNILATERAL BRANCH RETINAL VEIN OCCLUSION AND HEALTHY SUBJECTS.

PURPOSE: To compare the lamina cribrosa (LC) thickness of healthy subjects and patients with unilateral branch retinal vein occlusion (BRVO), and to determine possible correlations between the LC thickness and the BRVO subtypes. METHODS: This prospective, cross-sectional study included a total of 46 patients with naive, untreated, unilateral BRVO and 31 healthy control subjects. The occlusion site was divided into two BRVO types: arteriovenous crossing BRVO (AV-BRVO) and optic nerve BRVO (ON-BRVO). The optic nerve head was scanned using enhanced-depth imaging with the Spectralis optical coherence tomography system. RESULTS: The mean LC thickness of both eyes in patients with BRVO was thinner than that of eyes (274.0 µm) of the healthy subjects (both, P < 0.001). Although the LC thickness of the BRVO-affected eyes was slightly thinner than that of the fellow eyes (237.0 µm vs. 241.4 µm, respectively), there was no statistically significant difference. In addition, there were no significant differences in the LC thicknesses of both eyes according to the site of occlusion. CONCLUSION: A thinner LC was observed in both eyes of unilateral BRVO patients compared with those of healthy subjects. This finding suggests that thin LC may contribute to the pathogenesis of BRVO as a local mechanical factor in addition to systemic factors.

Acute angle closure attack after an intravitreal bevacizumab injection for branch retinal vein occlusion: a case report.

BACKGROUND: Intravitreal injection is widely used to treat retinal vein occlusion, and acute angle closure (AAC) is an exceptional complication of intravitreal injection. The authors report a case of AAC that occurred immediately after administering intravitreal bevacizumab to treat branch retinal vein occlusion (BRVO). CASE PRESENTATION: A 65-year-old woman was referred to the retina clinic of a tertiary referral center for the treatment of macular edema secondary to BRVO. On slit lamp examination, anterior chamber (AC) depth was shallow (3 corneal thicknesses centrally, 1/4 corneal thicknesses peripherally) in both eyes. Intraocular pressure (IOP) was 19 mmHg in both eyes, and refractive error was +1.00 diopter sphere in both eyes. A gonioscopy exam demonstrated narrow angle of over 180° in both eyes. To treat the macular edema, bevacizumab was injected into her right eye intravitreally. After two bevacizumab injections, the macular edema regressed but recurred 5 months later, and thus, a third injection was performed. The next day, she visited our emergency department complaining of persistent ocular pain in her right eye. The right pupil had dilated to 6 mm diameter and was fixed. Slit lamp exam revealed diffuse corneal edema in her right eye, which had an IOP of 56 mmHg. After administration of intravenous mannitol, the IOP fell to 14 mmHg and the corneal edema disappeared. Subsequently, a glaucoma specialist performed laser iridotomy on the right eye. CONCLUSIONS: Although AAC is a rare complication of intravitreal injection, it can occur in a patient with risk factors such as hyperopic eye or narrow angle.

Ultra-widefield Imaging of the Peripheral Retinal Vasculature in Normal Subjects.

PURPOSE: To establish the extent of the peripheral retinal vasculature in normal eyes using ultra-widefield (UWF) fluorescein angiography. DESIGN: Prospective, observational study. PARTICIPANTS: Fifty-nine eyes of 31 normal subjects, stratified by age, with no evidence of ocular disease in either eye by history and ophthalmoscopic examination. METHODS: Ultra-widefield fluorescein angiographic images were captured centrally and with peripheral steering using the Optos 200Tx (Optos, Dunfermline, United Kingdom). Images obtained at different gaze angles were montaged and corrected for peripheral distortion using a stereographic projection method to provide a single image for grading of the peripheral edge of the visible vasculature. The border of the vascularized retina was expressed as a radial surface distance from the center of the optic disc. The vascularized area was calculated based on this mean peripheral border position for each quadrant. MAIN OUTCOME MEASURES: Mean distance (mm) from the center of optic disc to the peripheral vascular border. RESULTS: In normal eyes, the mean radial surface distance from the center of the optic disc to the peripheral edge of the visible vasculature was 20.3±1.4 mm and the mean area of normal perfused retina was 977.0 mm(2). There was no significant difference between right and left eyes or between male and female participants. However, the distance to the periphery differed depending on the quadrant, with temporal (22.5±0.9 mm) being larger than inferior (20.4±1.7 mm) being larger than superior (19.2±1.5 mm) being larger than nasal (17.4±0.9 mm; P < 0.001) for all interquadrant comparisons. Interestingly, the distances to the perfused vascular border were significantly shorter in older individuals (≥60 years) than in younger subjects. CONCLUSIONS: Ultra-widefield fluorescein angiography is an important tool for studying the extent of peripheral retinal vasculature. With the increasing use of UWF imaging to evaluate and manage patients with retinal vascular disease, the normative data from this study may provide a useful reference when assessing the pathologic significance of findings in the setting of disease.

Short-Term Real-World Outcomes of Intensive Aflibercept Injection for Refractory Neovascular Age-Related Macular Degeneration.

Background: The aim of this study is to report short-term outcomes after the shortening of the treatment interval to 4 weeks with a treat-and-extend (TAE) regimen (Si4w) of aflibercept in patients with refractory neovascular age-related macular degeneration (nAMD). Methods: This retrospective study included 34 patients given aflibercept with a TAE regimen of a minimum of a 4-week interval when they had a limited response to bimonthly aflibercept. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) were compared before and after Si4w. The resolution of subretinal and intraretinal fluid before and after Si4w was also examined. The risk factors associated with persistent fluid were analyzed. Results: The average treatment duration until initiation of Si4w was 57.82 ± 28.59 months, with an average of 23.64 ± 12.40 injections administered. The BCVA was not significantly improved after Si4w. The CMT decreased significantly from 427.91 ± 125.74 µm to 336.38 ± 121.67 µm at the third visit (p < 0.001). Eighteen eyes (52.9%) showed complete resolution, and twenty-three eyes (67.6%) experienced complete resolution at least once during the three visits. The duration of fluid before Si4w was significantly associated with complete resolution (p = 0.011). Conclusions: Si4w of aflibercept showed satisfactory anatomical outcomes with complete resolution of fluid in patients with a limited response to bimonthly aflibercept injections, and should be considered as a useful treatment option.

Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: A review.

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars.

Prevalence and predictive value of sarcopenia in hospitalized patients with ischemic colitis.

Ischemic colitis (IC) and sarcopenia are associated with aging and multiple comorbidities. We aimed to investigate the prevalence and predictive role of sarcopenia in patients with IC. We retrospectively analyzed 225 hospitalized patients (median age, 72 years; women, 67.1%; severe IC, 34.2%) who were diagnosed with IC between January 2007 and February 2022. Sarcopenia was defined as the skeletal muscle index at the third lumbar vertebra determined by computed tomography. It was present in 49.3% (n = 111) of the patients and was significantly associated with severe IC compared to those without sarcopenia (48.6% vs. 20.2%, P < 0.001). Sarcopenia was associated with extended hospitalization (median: 8 vs. 6 days, P < 0.001) and fasting periods (4 vs. 3 days, P = 0.004), as well as prolonged antibiotic use (9 vs. 7 days, P = 0.039). Sarcopenia was linked to a higher risk of surgery or mortality (9.0% vs. 0%, P = 0.001) and independently predicted this outcome (odds ratio [OR], 11.17; 95% confidence interval [CI], 1.24‒1467.65, P = 0.027). It was prevalent among hospitalized patients with IC, potentially indicating severe IC and a worse prognosis. This underscores the importance of meticulous monitoring, immediate medical intervention, and timely surgical consideration.

Biosimilar candidate CT-P42 in diabetic macular edema: 24-week results from a randomized, active-controlled, Phase III study.

OBJECTIVE: To demonstrate the therapeutic similarity of CT-P42 compared to reference aflibercept (Eylea®) in adult patients with diabetic macular edema (DME). DESIGN: Randomized, active-controlled, double-masked, Phase III clinical trial PARTICIPANTS: Patients with a diagnosis of either type 1 or 2 diabetes mellitus (DM) with DME involving the center of the macula. METHODS: Patients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 mL) by intravitreal injection every 4 weeks (5 doses) then every 8 weeks (4 doses) in the main study period. Results up to Week 24 are reported herein. MAIN OUTCOME MEASURES: The primary endpoint was mean change from baseline at Week 8 in best corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the two-sided 95% confidence interval (CI) (global assumptions) and two-sided 90% CI (US Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set. RESULTS: Overall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). BCVA improved from baseline to Week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the pre-defined equivalence margin of ±3 letters (95% CI -0.73, 1.88 [global]; 90% CI -0.52, 1.67 [FDA]). Through Week 24, other efficacy results for the two groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing at least one treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups. CONCLUSIONS: This study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 mL) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles.

Long-term efficacy and safety of brolucizumab in neovascular age-related macular degeneration: A multicentre retrospective real-world study.

PURPOSE: To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups. RESULTS: Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes) and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution. CONCLUSION: Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management.

Pharmacogenetic association with early response to intravitreal ranibizumab for age-related macular degeneration in a Korean population.

PURPOSE: To determine whether genetic factors that influence age-related macular degeneration (AMD) have an early pharmacogenetic effect on treating exudative AMD with ranibizumab in a Korean population. METHODS: A retrospective study of 102 patients (70 with typical neovascular AMD and 32 with polypoidal choroidal vasculopathy) with exudative AMD treated with intravitreal ranibizumab monotherapy was conducted. Optical coherence tomography, fluorescein, and indocyanine green angiography were taken at the baseline. The best-corrected visual acuity (BCVA) and the central subfield macular thickness (CSMT) were recorded at the baseline and at each monthly visit. The genotypes of the polymorphisms in the known AMD susceptibility loci (CFH, AMRS2, HTRA1, VEGFA, and KDR) were determined, and association between their frequencies and the changes in the BCVA and the CSMT were evaluated. RESULTS: The mean baseline visual acuity was 0.96 ± 0.59 logMAR (approximately 20/200 in the Snellen equivalent), and the mean number of injections was 3.87 before the month 6 visit. No association was observed between the change in BCVA and each genotype. For the changes in the CSMT, a significant difference was observed only with the VEGF-A (rs833069) gene. The decrease in the CSMT at month 3 for the major allele homozygote AA genotype, the heterozygote AG genotype, and the risk allele homozygote GG genotype was 25.66 ± 85.40, 86.93 ± 92.31, and 85.30 ± 105.30 µm, respectively (p=0.012, p=0.044, and p=0.002 for AG, GG, and combined AG or GG genotype, respectively, compared to the AA genotype). This trend was maintained until month 6. CONCLUSIONS: The VEGF-A (rs833069) polymorphism showed a significant association with the anatomic response to intravitreal ranibizumab. No significant difference was found between the genotype of the potential risk polymorphism for development of AMD and the early visual improvement after intravitreal ranibizumab.