Vascular Endothelial Growth Factor C and D Signaling Pathways as Potential Targets for the Treatment of Neovascular Age-Related Macular Degeneration: A Narrative Review.

The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD.

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials.

BACKGROUND: Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy. METHODS: OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY). FINDINGS: Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean -0·41 mm2, 95% CI -0·64 to -0·18; p=0·0004) and 16% (-0·32 mm2, -0·54 to -0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (-0·23 mm2, -0·47 to 0·01; p=0·062) and 11% (-0·21 mm2, -0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (-0·90 mm2, -1·30 to -0·50; p<0·0001) and 18% (-0·74 mm2, -1·13 to -0·36; p=0·0002) in OAKS, and by 19% (-0·75 mm2, -1·15 to -0·34; p=0·0004) and 16% (-0·63 mm2, -1·05 to -0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. INTERPRETATION: Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile. FUNDING: Apellis Pharmaceuticals.

Intravitreal brolucizumab as treatment of early onset radiation retinopathy secondary to plaque brachytherapy for choroidal melanoma.

Purpose: To describe the efficacy and safety of brolucizumab (Beovu®, Novartis Pharmaceuticals) in a case of cystoid macular edema associated with radiation retinopathy as a result of iodine-125 plaque brachytherapy (PBT) for choroidal melanoma, resistant to treatment with other anti-vascular endothelial growth factor (VEGF) agents. Observations: A 67-year-old woman with choroidal melanoma in the right eye and best-corrected visual acuity (BCVA) of 20/20, underwent uncomplicated PBT. On post-operative month 7, the patient developed early onset radiation retinopathy. She failed to improve significantly with sub-tenon triamcinolone and 3 injections of intravitreal bevacizumab; BCVA was 20/200. Intravitreal brolucizumab was administered, and one month after, macular edema had resolved completely on optical coherence tomography, and BCVA improved to 20/50. At last follow up, 1 month after the third brolucizumab injection, BCVA was 20/60 and there was sustained resolution of intraretinal fluid. There were no signs of intraocular inflammation, progressive RR or optic neuropathy on exam or fluorescein angiography. Conclusions: This case suggests a positive effect of brolucizumab in the management of radiation retinopathy following PBT refractory to other anti-VEGF agents. However, one must consider the risk of severe vision loss associated with retinal vasculitis from use of brolucizumab.

Impact of Baseline Characteristics on Geographic Atrophy Progression in the FILLY Trial Evaluating the Complement C3 Inhibitor Pegcetacoplan.

PURPOSE: To evaluate the effect of select baseline characteristics on geographic atrophy (GA) progression in eyes receiving intravitreal pegcetacoplan or sham. DESIGN: Phase 2 multicenter, randomized, single-masked, sham-controlled trial. METHODS: Patients with GA received 15 mg pegcetacoplan monthly or every other month (EOM), or sham injection monthly or EOM for 12 months. Primary efficacy endpoint was change in GA lesion size (square root) from baseline. Post hoc analysis evaluated the effects of age; gender; lesion size, focality, and location (extrafoveal vs foveal); pseudodrusen status; best-corrected visual acuity (BCVA); and low-luminance deficit (LLD) on GA progression at Month 12. RESULTS: Of 246 randomized patients, 192 with 12-month data were included in this analysis. Overall mean (standard deviation) change in lesion size (mm) was 0.26 (0.17) (P < .01), 0.27 (0.27) (P < .05), and 0.36 (0.21) in the monthly pegcetacoplan (n = 67), EOM pegcetacoplan (n = 58), and sham (n = 67) groups, respectively. In univariate analysis, patients with extrafoveal lesions (P < .001), BCVA ≥20/60 (P = .001), and larger LLD (P = .002) had greater mean changes in lesion size. Multivariate analysis confirmed significant association of extrafoveal lesions (P = .001) and larger LLD (P = .023) with GA progression. Monthly and EOM pegcetacoplan significantly reduced progression (P < .05) when controlling for these risk factors. CONCLUSIONS: Extrafoveal lesions and larger LLD are potential risk factors for GA progression. Pegcetacoplan treatment significantly controlled GA progression even after accounting for these risk factors.

Outcomes by Baseline Choroidal Neovascularization Features in Age-Related Macular Degeneration: A Post Hoc Analysis of the VIEW Studies.

PURPOSE: To assess the influence of baseline choroidal neovascularization (CNV) features on visual change and fluid resolution after anti-vascular endothelial growth factor (VEGF) treatment of eyes with neovascular age-related macular degeneration (nAMD). DESIGN: Post hoc analysis of 52-week data from the phase 3 Vascular Endothelial Growth Factor VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD) Studies (VIEW) 1 and 2 clinical trials. PARTICIPANTS: One thousand eight hundred four patients with nAMD. METHODS: Integrated data from VIEW 1 and 2 of 1804 eyes receiving intravitreal aflibercept injections (IAIs) 2 mg every 4 weeks, IAIs 2 mg every 8 weeks after 3 initial monthly doses, and ranibizumab every 4 weeks with documented baseline CNV type, total area, and leakage area were analyzed. Time to an event and cumulative incidence were evaluated by Kaplan-Meier analysis, and relative risks were estimated using proportional hazards analysis. MAIN OUTCOMES MEASURES: Cumulative incidence of time to first sustained vision gain of 15 or more Early Treatment Diabetic Retinopathy Study letters, vision loss of more than 5 Early Treatment Diabetic Retinopathy Study letters from baseline, as well as first sustained absence of retinal fluid and intraretinal fluid as evaluated by OCT with respect to CNV type, total CNV, and leakage area. RESULTS: Eyes with predominantly classic CNV (mean best-corrected visual acuity [BCVA], 48.2 letters at baseline) showed a higher incidence rate of first sustained gain of 15 letters or more than eyes with occult CNV (mean BCVA, 57.9 letters at baseline; P < 0.01). Eyes with occult CNV at baseline showed higher incidence rates of first sustained absence of retinal fluid and of intraretinal fluid than eyes with predominantly classic CNV (both P < 0.01). With increasing baseline CNV total area and leakage area, the incidence rate of first sustained gain of 15 letters or more decreased. CONCLUSIONS: This post hoc analysis provided additional evidence for the role of baseline CNV features (CNV type, total area, and leakage area) in influencing visual and anatomic outcomes in eyes with nAMD after anti-VEGF treatment.

Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration.

PURPOSE: OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Open-label, dose escalation followed by a randomized dose expansion. PARTICIPANTS: Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). METHODS: In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. MAIN OUTCOME MEASURES: Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. RESULTS: Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0-18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4-17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3-7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were -119 µm (95% CI, -176 to -62 µm) and -54 µm (95% CI, -82 to -26 µm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. CONCLUSIONS: Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.

Protecting Vision in Patients With Diabetes With Ultra-Widefield Imaging: A Review of Current Literature.

Ultra-widefield fundus imaging (UWFI) is a relatively new technology capable of capturing 200° images of the retina. Since vision changes can be irreversible in diabetic retinopathy (DR), recognition of prognostic biomarkers in the peripheral retina may prove invaluable toward optimizing the management and reducing the societal burden of this blinding disease. Following a bibliographic review using Pubmed, OVID Medline, Embase, and the Cochrane Library, the current review systematically examined 13 studies that compared UWFI to conventional screening techniques such as seven standard field (7SF) Early Treatment In Diabetic Retinopathy Study (ETDRS) and non-mydriatic multifield fundus photography (NMFP), as well as their scientific level of evidence. Overall, UWFI had good agreement with 7SF ETDRS and NMFP, and moderate agreement with dilated fundus examination. Seven additional studies were examined that considered the significance of peripheral lesions found on UWFI. These studies demonstrated that UWFI captured additional DR pathology in the peripheral retina that may not be evident if evaluation is limited to the posterior pole and may be relevant to patient outcomes. Future directions include but are not limited to the potential of UWFI to track the progression of DR with treatment. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:639-648.].

LARGE SILICONE DROPLETS AFTER INTRAVITREAL BEVACIZUMAB (AVASTIN).

PURPOSE: Despite its off-label status, intravitreal bevacizumab is the most commonly used intraocular anti-vascular endothelial growth factor agent. Regulation of compounding pharmacies has recently increased to make compounded pharmaceuticals safer. Despite these changes, a marked increase in symptomatic, large silicone oil droplets following intravitreal bevacizumab injections was noticed. METHODS: Retrospective chart review was performed. Within a single private practice, patients who were noted to have large or symptomatic silicone oil bubbles after an intravitreal injection were reviewed. RESULTS: A recent, dramatic increase in the incidence of large or symptomatic silicone oil droplets was noted, with 23 cases noted in the past 5 months, compared with 1 in the previous decade. Patients frequently noted a circular floater consisting of a dark ring surrounding a bright central area immediately following an injection of intravitreal bevacizumab. All bevacizumab injections were from single-piece insulin syringes. B-scan ultrasonography produced a very characteristic reverberation pattern. No inflammation or visual acuity loss was noted because of the droplets; however, some patients were annoyed enough to consider vitrectomy. CONCLUSION: Patients should be carefully evaluated for this possibility, and the characteristic symptom of a round floater consisting of a dark ring surrounding a bright center, and the prominent reverberation pattern on B-scan ultrasonography may help increase detection. Changes in consent forms and discussion of this possibility are indicated while investigation into the cause of this increased incidence continues, especially if one is administering bevacizumab via the one-piece insulin syringes commonly used by compound pharmacies.

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. RESULTS: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. CONCLUSION: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

TREATMENT OF VITREOMACULAR TRACTION WITH INTRAVITREAL PERFLUOROPROPANE (C3F8) INJECTION.

PURPOSE: To assess the posterior vitreous release rates following a single, office-based intravitreal injection of expansile gas in treating vitreomacular traction. METHODS: Thirty eyes of 29 consecutive patients with symptomatic vitreomacular traction received a single, office-based intravitreal injection of up to 0.3 mL of 100% perfluoropropane (C3F8). RESULTS: Overall, vitreomacular traction release occurred in 25 of 30 eyes by the final follow-up visit (83% final release rate); furthermore, 90% (9 of 10 eyes) with diabetes mellitus released, 83% (5 of 6 eyes) with concurrent epiretinal membrane released, and 83% (5 of 6 eyes) previously treated with ocriplasmin released. Vitreomacular traction release occurred overnight in some patients and was documented on spectral domain optical coherence tomography at an average of 13 days (range, 1-62 days). The phakic release rate was 89% (16 of 18 eyes) versus a 75% pseudophakic release rate (9 of 12 eyes) (P = 0.3173). Ellipsoid zone changes on spectral domain optical coherence tomography occurred in 1 of 30 gas-treated eyes. One patient developed pupillary block. CONCLUSION: Office-based intravitreal injection of C3F8 offers an inexpensive and effective treatment for vitreomacular traction, including for patients who underwent previous ocriplasmin administration and in patients with diabetes mellitus or epiretinal membrane.

Outer retina reflectivity changes on sd-oct after intravitreal ocriplasmin for vitreomacular traction and macular hole.

PURPOSE: To report initial experience with intravitreal ocriplasmin (IVO) and to describe outer retina reflectivity changes observed on spectral domain optical coherence tomography (SD-OCT) after IVO injection in patients with vitreomacular traction (VMT) with or without macular holes (MHs). METHODS: A consecutive retrospective review of patients with VMT and MH who were treated with IVO was performed. Patients underwent complete ophthalmic evaluation, including nonstandardized Snellen visual acuity testing, and SD-OCT at baseline and follow-up visits. RESULTS: A total of 23 patients who received IVO for VMT and/or MH were included for analysis. Patient age ranged from 53 years to 93 years with a mean of 74 years. The mean follow-up was 174 days (range: 20-291 days). Vitreomacular traction release at Day 30 after IVO was achieved in 11 of 23 patients (47.82%), at an average of 14.54 days (range: 1-30 days) after treatment. The mean visual acuity improved from 0.50 to 0.38. At presentation, eight patients had MH associated with VMT. Closure of the MH with ocriplasmin was achieved in two patients, and six patients underwent pars plana vitrectomy for MH repair. Ten of 23 patients (43.47%) presented with changes in the outer retina reflectivity on SD-OCT after IVO, 4 patients of this group experienced a decrease in visual acuity. In 7 of these 10 patients (70%), VMT release was documented on OCT by Day 30 postinjection compared with 4 of 13 patients (30.76%) without outer retina changes post-IVO. Normalization of the outer retina reflectivity was achieved in all cases. CONCLUSION: In this case series of VMT/MH patients treated with ocriplasmin, changes in the SD-OCT outer retina reflectivity were relatively common. Within weeks, the outer retinal reflectivity on SD-OCT improved, as did the visual acuity. Further studies to investigate the association between outer retina reflectivity changes with the use of IVO and long-term visual acuity outcomes are warranted.

Retinal infiltrates secondary to metastatic squamous cell carcinoma masquerading as infectious retinitis.

PURPOSE: This report presents a case of metastatic carcinoma to the retina. METHODS: Retrospective chart review and systematic literature review. The patient was a 78-year-old man with history of small-cell lung cancer and with the development of metastatic carcinoma to the retina. RESULTS: The review of this case and previous literature reveals that the presentation of retinal metastases can occasionally be misinterpreted as infectious retinitis, which can delay the diagnosis of the disease. CONCLUSION: Metastatic carcinoma to the retina is a rare condition, which should be considered in patients who are suspected of having infectious retinopathy and who fail to respond to traditional antimicrobial therapies.

Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD.

BACKGROUND: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. METHODS: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. RESULTS: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. CONCLUSIONS: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. TRIAL REGISTRATION NUMBER: NCT02118831.

Rate of hypotony following 25-gauge pars plana vitrectomy.

BACKGROUND AND OBJECTIVE: To report the rates of hypotony after 25-gauge vitrectomy. PATIENTS AND METHODS: A retrospective review of 111 consecutive cases was performed in patients undergoing transconjunctival 25-gauge pars plans vitrectomy with either air or gas as a tamponade agent. The primary outcome measure was postoperative intraocular pressure less than 5 mm Hg. A Wilcoxon rank-sum test was conducted to determine the statistical significance of continuous variables in association with rates of hypotony. RESULTS: The overall incidence of hypotony on postoperative day 1 was found to be 8.1%. The rate of hypotony was 16.7% in uveitis cases and 0% in routine macular surgery. The rate of hypotony in cases in which sutures were used was 41.7%, compared to 4% in cases in which sutures were not used (P = .001). CONCLUSION: Hypotony rates were significantly higher after 25-gauge transconjunctival pars plana vitrectomy in uveitis and some other conditions.

Oral rifampin utilisation for the treatment of chronic multifocal central serous retinopathy.

Chronic central serous retinopathy (CSR) is characterised by frequent exacerbations and a poor visual prognosis. Very few therapies exist for chronic CSR, and the existing therapies are often ineffective. Thus, novel therapies to combat this frustrating disorder are needed. Presented here is a case detailing a patient with chronic CSR with persistent subfoveal fluid of 2 years' duration that completely resolved with 1 month of oral rifampin therapy. As a cytochrome P450, 3A4 inducer, rifampin is thought to favourably alter the metabolism of endogenous steroids, thereby leading to an improvement in CSR manifestations.