The Treatment Patterns with Brolucizumab in Germany (REALIZE) Study: A Retrospective Cohort Study Based on Longitudinal Prescription Data.

INTRODUCTION: This study describes real-world treatment patterns in Germany for brolucizumab, an anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD). METHODS: This single-arm retrospective cohort study used German patient-level prescription data. Patients aged ≥ 50 years, who received ≥ 1 brolucizumab prescription in one eye only (unilateral) and had a minimum of 12 months follow-up were included. Three cohorts were defined from the overall population: anti-VEGF treatment-naive patients ("treatment-naive"); anti-VEGF treatment-experienced patients ("treatment-experienced"); and of the treatment-experienced cohort, patients persistent on brolucizumab for 12 months ("treatment-experienced persistent"), i.e. who received ≥ 2 brolucizumab injections and did not discontinue or use other anti-VEGF agents in that period. Descriptive statistics were used to analyse patient characteristics and injection intervals. RESULTS: A total of 2089 patients with at least 12 months follow-up and one brolucizumab injection were analysed. Most were female (58.1%), aged 80+ years (54.7%). A total of 539 (25.8%) were treatment-naive, 1550 (74.2%) treatment-experienced and, of those, 787 (50.8%) were persistent. Overall, the median (interquartile range, IQR) number of brolucizumab injections during the 12 months follow-up was 5.0 (3.0-8.0). In the treatment-naive and treatment-experienced sub-cohorts it was 5.0 (3.0-8.0) and 5.0 (3.0-9.0) injections, respectively. In the treatment-experienced persistent cohort the median (IQR) number of injections was 8.0 (5.0-10.0). In this same cohort, the median (IQR) treatment interval between anti-VEGF injections before switch to brolucizumab was 5.1 (4.0-8.0) weeks, whilst the brolucizumab interval at 12 months after switch was 8.0 (6.0-11.9) weeks. Of treatment-experienced patients, 67% extended their treatment interval and those with pre-switch intervals less than 6 weeks (< q6w), in particular, had meaningful treatment interval extensions. CONCLUSION: Patients who switched to brolucizumab had a median treatment interval extension of about 3 weeks at 12 months. These results show that treatment with brolucizumab has the potential to reduce treatment burden in patients with nAMD in routine clinical practice.

Axitinib modulates hypoxia-induced blood-retina barrier permeability and expression of growth factors.

This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor (VEGF) receptors 1/2 (VEGFR-1/2) and platelet-derived growth factor (PDGF) receptor beta (PDGFR-ß), hypoxia-induced increased tissue permeability, occludin, zonula occludens protein 1 (ZO-1), VEGF-A, and PDGF expression of human retinal pigment epithelial (RPE) cells and human umbilical vein endothelial cells (HUVECs). Primary human RPE cells and HUVECs were exposed to hypoxia and axitinib. Viability of cells, tissue permeability, and expression of occludin, ZO-1, VEGF, PDGF, VEGFR-1/2 and PDGFR-ß, and their mRNAs, were investigated by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunohistochemistry. Treatment with axitinib reduced expression of VEGFR-1/2 and PDGFR-ß. Hypoxia decreased cell viability, occludin, and ZO-1 expression and increased tissue permeability, expression, and secretion of VEGF and PDGF. Axitinib significantly reduced hypoxia-induced effects on HUVEC and RPE cells. Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema.

The national comprehensive cancer network distress thermometer as a screening tool for the evaluation of quality of life in uveal melanoma patients.

PURPOSE: To assess quality of life (QoL) status via the National Comprehensive Cancer Network (NCCN) distress thermometer as a psychooncological screening tool in uveal melanoma patients. METHODS: One hundred and six consecutive patients suffering from uveal melanoma completed the distress thermometer between 04/2018 and 12/2018. Practical, emotional, family concerned, spiritual, physical and overall distress levels, distribution of distress and subgroup analyses defining groups of potential high distress levels in need of intervention were assessed. Descriptive statistics, cross-tabulations, chi-square and Fisher's exact test as well as correlation coefficients (Spearman's rho) and receiver operating characteristic (ROC) were used for analysis. RESULTS: Patients with higher T-category had significantly more emotional problems and spiritual concerns (p = 0.046 and p = 0.023, respectively). Female patients accounted for higher rates of physical issues (p = 0.034). Lower best corrected visual acuity (BCVA) was correlated with higher distress levels (p = 0.037). Patients resulting in loss of BCVA of ≥3 lines reported higher distress levels (p = 0.029). A distress threshold of 5 on the basis of ROC analysis showed a corresponding sensitivity of 100% and specificity of 76%. CONCLUSION: The NCCN distress thermometer could be integrated well into our clinical routine and proved to be a rapid, yet sensible screening tool for emotional and physical distress in patients with uveal melanoma. Special attention should be paid to patients with higher T-category and patients resulting in lower levels of BCVA. As in patients with different tumour entities, the established distress threshold of ≥5 proposing intervention proved to be adequate for uveal melanoma patients.

Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis.

Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)α agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs). While ω-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ω-3 and ω-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ω-3 LCPUFA (and ω-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPARα-/-mice and augmented ω-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ω-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPARα. Fenofibrate augmented the overall protective effects of ω-3 LCPUFAs on neovascular eye diseases.

Pain and accuracy of focal laser treatment for diabetic macular edema using a retinal navigated laser (Navilas).

AIM: To investigate treatment-related pain and the accuracy of navigated laser photocoagulation in the treatment of clinically significant macular edema. METHODS: Focal laser treatment of diabetic macular edema in 54 consecutive patients was digitally planned on fundus images and performed using the navigated laser photocoagulation system Navilas(®) (OD-OS GmbH, Teltow, Germany). Treatment-related pain was quantified on a visual analog scale directly after treatment and compared with a matched control group who received conventional laser treatment (n = 46). In addition, for Navilas-treated patients, the accuracy of spot placement on color images was analyzed 1 month after treatment. RESULTS: In total, 5423 laser spots (mean 100 per eye) were analyzed. With navigated treatment, 90% of laser spots were visible on color images, of which 96% were within 100 µm from the target. Eighty percent of the laser spots were placed and visible within the 100 µm target on an intention-to-treat basis for color imaging. Optical coherence topography confirmed that laser effects were limited to the outer retina. Treatment-related pain following navigated laser photocoagulation was significantly lower than that of conventional laser treatment (1.6 vs 4.4 on a visual analog scale, P < 0.001). CONCLUSION: Navigated laser effects could be visualized to a high percentage on post-treatment color images, and their location showed a high concordance to targeted areas. Patients reported that treatment-related pain following Navilas laser photocoagulation was significantly lower than pain following conventional laser treatment.

Intracameral moxifloxacin: in vitro safety on human ocular cells.

PURPOSE: The fourth-generation fluoroquinolone, moxifloxacin, covers most gram-positive and gram-negative isolates causing endophthalmitis. It is safe and effective for systemic and topical use, but only limited data are available on prophylactic intracameral administration to prevent endophthalmitis. This study uses a cell culture model to investigate the safety of moxifloxacin for intracameral application. METHODS: Endothelial toxicity of moxifloxacin was evaluated in cultured human corneas. Possible toxic effects of moxifloxacin (10-750 microg/mL) in corneal endothelial cells (CEC), primary human trabecular meshwork cells (TMC), and primary human retinal pigment epithelial (RPE) cells were evaluated after 24 hours and under conditions of oxidative and inflammatory stress by treatment with tumor necrosis factor alpha, lipopolysaccharides, or interleukin-6. Toxicity was evaluated by tetrazolium dye reduction assay, and cell viability was quantified by a microscopic live-dead assay. RESULTS: No corneal endothelial toxicity could be detected after 30 days of treatment with 500 microg/mL moxifloxacin. Concentrations up to 150 microg/mL had no influence on CEC, TMC, or RPE cell proliferation or on cell viability when administered for 24 hours. After preincubation with tumor necrosis factor alpha, lipopolysaccharides, or interleukin-6 for 24 hours and subsequent treatment with moxifloxacin at concentrations from 10 to 150 microg/mL for 24 hours, no significant decrease in proliferation or viability was observed. Hydrogen peroxide exposure did not increase cellular toxicity. CONCLUSIONS: This study showed no significant toxicity for moxifloxacin on CEC, TMC, RPE cells, or human corneal endothelium for concentrations up to 150 microg/mL. The minimum inhibitory concentration of moxifloxacin to inhibit 90% of pathogens commonly encountered in endophthalmitis is known to be in the range of 0.25-2.5 microg/mL. Therefore, prophylactic intracameral use of moxifloxacin at concentrations up to 150 microg/mL may be safely used to prevent endophthalmitis after intraocular surgery.