Focke Ziemssen

Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn

Purpose:  That vascular endothelial growth factor (VEGF) plays a major role in inflammatory angiogenesis has been well established. This pilot study was designed to evaluate experimental treatment with bevacizumab eyedrops in corneal neovascularization induced by alkali burn. The feasibility of topical administration, corneal cell viability and corneal penetration were investigated in an animal model.

Vitreous Levels of Bevacizumab and Vascular Endothelial Growth Factor-A in Patients with Choroidal Neovascularization

PURPOSE To investigate the vitreous levels of bevacizumab and vascular endothelial growth factor-A (VEGF-A) after intravitreal injection of the drug in patients with choroidal neovascularization (CNV). DESIGN Interventional case series. PARTICIPANTS Eleven eyes of 11 patients with submacular hemorrhage and CNV due to age-related macular degeneration (n = 10) or angioid streaks (n = 1). METHODS All patients were treatment naïve except for a single dose of intravitreal injection of bevacizumab (1.25 mg/50 muL dose) and subsequent vitrectomy after various intervals (1-101 days) because of active and progressive lesion. Intravitreal free bevacizumab and VEGF-A levels were measured using enzyme-linked immunosorbent assay and microsphere-based immunoassay, respectively. Vitreous VEGF-A isoforms were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting. MAIN OUTCOME MEASURES Intravitreal bevacizumab and VEGF-A levels were measured and pharmacokinetic parameters were calculated. RESULTS Pharmacokinetics of intravitreal bevacizumab followed a 2-compartment model with initial and terminal half-lives of 0.5 and 6.7 days, respectively. Bevacizumab could be detected in all cases, ranging from 2.63 ng/ml to 165 microg/ml. The peak concentration was observed on the second day after intravitreal bevacizumab injection. Vitreous free VEGF-A levels ranged from 0.2 to 33.9 pg/ml and showed a negative correlation with the bevacizumab concentration (P<0.001; r = -0.955) and a positive correlation with time (P<0.001; r = 0.964). However, the percentage expression of VEGF-A(165) exhibited a positive correlation with the bevacizumab concentration (P = 0.032, r = 0.645) and a negative correlation with time (P = 0.007, r = -0.755). A time-dependent increase was found for the percentage expression of VEGF-A(189) (P = 0.023, r = 0.673). Neither bevacizumab- nor time-related alterations were found for VEGF-A(121). CONCLUSIONS Based on pharmacokinetics, the interval of 6-7 weeks would be appropriate for efficacy, although clinical trials should guide dosing recommendations. Vitreous levels of free VEGF-A showed a negative correlation with the bevacizumab concentration, which confirmed the in vivo binding affinity of bevacizumab to VEGF-A. The analysis of the VEGF-A isoforms suggests differences of interaction between bevacizumab and individual VEGF-A isoforms.

Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema

PURPOSE: To describe the efficacy of intravitreal bevacizumab (Avastin) in patients with cystoid macular edema (CME) after cataract surgery (Irvine‐Gass syndrome). METHODS: This retrospective case series comprised 16 eyes of 16 patients with CME after cataract surgery refractory to current standard treatment who received an injection of 1.25 mg intravitreal Avastin. The main outcome measures were visual acuity, retinal thickness on optical coherence tomography (OCT), and complications related to treatment. RESULTS: The median duration of CME before treatment with intravitreal Avastin was 14 weeks (range 3 to 84 weeks). Although the mean retinal thickness decreased slightly after intravitreal Avastin, the mean visual acuity remained unchanged. Visual acuity improved by 2 Early Treatment Diabetic Retinopathy Study lines in 1 patient, remained unchanged in 12 patients, and decreased by 2 lines in 2 patients. Repeated Avastin injections did not result in a better outcome. Other than mild ocular irritation, there were no adverse effects of the intravitreal injections. CONCLUSIONS: Intravitreal injection of Avastin, although safe, did not result in improved visual function in patients with postoperative CME. In contrast to findings in a previous case report, the beneficial effect of vascular endothelial growth factor inhibition in Irvine‐Gass syndrome was not observed.

Effects of bevacizumab on retinal function in isolated vertebrate retina.

Background: Bevacizumab (Avastin) is a recombinant protein that targets vascular endothelial growth factor (VEGF). In vitro, bevacizumab inhibits VEGF induced cell proliferation and tissue factor production. Abnormal angiogenesis involving VEGF is a central event during the development of choroidal neovascularisation (CNV). The present study was designed to evaluate the short term toxic effects of bevacizumab on retinal function for a therapeutic intraocular application. Methods: Isolated bovine retinas were perfused with an oxygen pre-incubated nutrient solution. The electroretinogram (ERG) was recorded as a transretinal potential using silver/silver chloride electrodes. Bevacizumab was added in different concentrations to the nutrient solution for 45 minutes. Thereafter the retina was reperfused for 60 minutes with normal nutrient solution. The percentage of a-wave and b-wave reduction during the application of bevacizumab was calculated and compared to control recordings. Results: During the application of three different concentrations of bevacizumab (0.08 mg/ml, 0.25 mg/ml, 0.8 mg/ml) no significant reduction of the a-wave and b-wave amplitude was observed. During the washout, the ERG amplitudes were unchanged. Conclusion: The present study suggests that an intraocular application of 0.25 mg/ml bevacizumab for the treatment of CNV is reasonable. No significant short term effects of bevacizumab on retinal function were detected, but long term effects cannot be excluded.

Intravitreal Bevacizumab in Inflammatory Ocular Neovascularization

PURPOSE To assess the role of bevacizumab in inflammatory ocular neovascularization. DESIGN Retrospective, multicenter, consecutive case series of inflammatory ocular neovascularization. METHODS Patients with inflammatory ocular neovascularization of varying causes for whom standard therapy failed were treated with intravitreal injection of bevacizumab. Main outcome measures included improvement of best-corrected visual acuity (BCVA) expressed in logarithm of minimum angle of resolution units, response of inflammatory ocular neovascularization by funduscopy and angiography, and decrease in central foveal thickness as measured by optical coherence tomography at the three-month follow-up. RESULTS At the three-month follow-up, 84 eyes of 79 patients had been treated with a mean of 1.3 injections (range, one to three). Thirty-four eyes showed juxtafoveal choroidal neovascularization (CNV), 34 eyes showed subfoveal CNV, eight eyes showed peripapillary CNV, and 11 eyes showed neovascularization of the disc (NVD) or neovascularization elsewhere (NVE). BCVA improved 2.4 lines from 0.68 (6/28 or 20/94) to 0.44 (6/17 or 20/55) (P < .001). BCVA improved by one to three lines in 34.5% of the eyes, by four to six lines in 16.7% of the eyes, and by more than six lines in 14.2% of the eyes. Function was unchanged in 23.8% of the eyes. BCVA worsened in 10.7% (zero to three lines in 7.1%, more than four lines in 3.6%). Central foveal thickness decreased from baseline 346 to 252 microm (P < .001). For CNV, 32 eyes (43.2%) had complete regression after the injection, 27 (36.5%) had partial regression, five (6.8%) had no response, and 10 eyes (13.5%) were not evaluated by the contributors. For NVD or NVE, seven eyes (63.6%) had complete regression of new vessels and four eyes (36.4%) had partial regression after the injection. CONCLUSIONS Intravitreal bevacizumab led to short-term significant visual improvement and regression of inflammatory ocular neovascularization in a wide variety of inflammatory ocular diseases.

INTRAVITREAL BEVACIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION

ZusammenfassungDie Wirksamkeit des Anti-VEGF-Therapiekonzepts bei der neovaskulären altersabhängigen Makuladegeneration (AMD) konnte bereits für Pegaptanib und Ranibizumab gezeigt werden. Mit Bevacizumab steht ein Antikörper gegen den vaskulären endothelialen Wachstumsfaktor (VEGF) zur Verfügung, der ursprünglich für onkologische Anwendungsgebiete mit intravenöser Applikation entwickelt wurde. Im „Off-label use“ von Bevacizumab zeigte sich in ersten Fallberichten auch ein Therapieeffekt nach intravitrealer Applikation bei der neovaskulären AMD. Weltweit wurden mittlerweile auf diese Weise, auch aufgrund der mitunter erstaunlich positiven morphologischen und funktionellen Effekte, schon mehrere Tausend Patienten behandelt. Allerdings fehlen kontrollierte, prospektive Studien zur Sicherheit und Wirksamkeit von Bevacizumab bei der neovaskulären AMD. Hier sollen aktuelle Daten zusammengefasst und diskutiert werden. Mit dem Pooling von Daten und einer dafür eigens eingerichteten webbasierten Datenbank sollen bald aussagekräftigere Ergebnisse zur Verfügung stehen. Insbesondere gibt es noch offene Fragen hinsichtlich Dosierung, Applikationsintervall, Gesamtdauer der Applikation, biologischer Halbwertszeit und Langzeitsicherheit des Medikaments.AbstractThe efficacy and safety of the therapeutic anti-VEGF concept has already been demonstrated for pegaptanib and ranibizumab. Bevacizumab acts as an antibody against all VEGF-A isoforms and has been developed for oncological indications with intravenous application. Initial reports on intravitreal administration in patients with neovascular age-related macular disease (AMD) have shown beneficial morphological and functional effects. In the meantime, bevacizumab has been used off-label in thousands of patients with AMD. However, data from prospective, controlled, randomized trials on both safety and efficacy are lacking. Herein recent experiences with bevacizumab are summarized and discussed. Furthermore, a web-based platform for online data registration and pooled analyses is presented.

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

BACKGROUND The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. METHODS This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. FINDINGS The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. INTERPRETATION Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. FUNDING Biogen.

Retinal pigment epithelial tears after single administration of intravitreal bevacizumab for neovascular age-related macular degeneration

PurposeTo analyse retinal pigment epithelial (RPE) tears following single administration of intravitreal bevacizumab for neovascular age-related macular degeneration (AMD) during early follow-up.MethodsInterventional, retrospective, non-comparative case series included 397 patients (409 eyes) of the 746 consecutive patients that met the eligibility criteria. Standardized visual acuity testing, fluorescein angiography, and optical coherence tomography were performed. Data collected included status of the fellow eye, previous treatment, subtypes of choroidal neovascularization (CNV), size and composition of the lesion. Multiple linear regression modelling was used to explore the effect of baseline parameters on the RPE tears. Primary end point was occurrence of RPE tears within 6 weeks after therapy.ResultsFifteen of the 409 eyes (3.6%) developed RPE tear (95% confidence interval: 2.2–6.0, odds ratio: 26.3). The statistical modelling showed significant association between RPE tear and occult without classic CNV/predominantly haemorrhage vspredominantly/minimal classic CNV (P=0.019), as well as medium or large (>4 disc area) vssmall size of the total lesion (P=0.038). Previous treatment and status of the fellow eye did not statistically influence the risk of RPE tears.ConclusionsAn RPE tear can develop in up to 3.6% of eyes with neovascular AMD following single administration of intravitreal bevacizumab in a short-term follow-up. Medium and large lesion size and occult without classic and predominantly haemorrhagic subtype of CNV were important predictive factors. Preoperative assessment of the lesion characteristics may help in identifying the risk of individual patients with neovascular AMD before intravitreal bevacizumab treatment.

Antipermeability and antiproliferative effects of standard and frozen bevacizumab on choroidal endothelial cells

Background: Bevacizumab is an antiangiogenic compound developed to target tumour vessels. Its off-label use in ophthalmology requires in vitro testing on ocular cells. Aim: To quantify the antipermeability and antiproliferative effects of bevacizumab on cultured choroidal endothelial cells (CECs). It was examined whether deep-freezing of bevacizumab attenuates its antiangiogenic activity. Methods: Porcine CECs were cultured in permeable insert systems. Permeability of the cell monolayers was quantified by a fluorescent isothiocyanate-dextran assay after treatment with vascular endothelial growth factor (VEGF; 20–100 ng/ml) alone and in combination with bevacizumab (0.1–1 mg/ml). Proliferation of the CECs was tested using a “wound scratch” assay. The experiments were repeated with bevacizumab after freezing at −20°C for 5 days. Results: Bevacizumab significantly reduced VEGF-induced permeability in a dose-dependant manner. A molar ratio of 2.6:1 of bevacizumab to VEGF was required for complete blocking of VEGF-induced rise in permeability. CEC proliferation was significantly blocked by bevacizumab (0.5 mg/ml). Thawed bevacizumab after deep freezing showed a moderate, but not statistically significant loss in activity. Conclusion: Bevacizumab significantly reduces VEGF-induced permeability and proliferation of CECs. Freezing and thawing of bevacizumab will affect its biological activity.

Weak transient response of chronic uveitic macular edema to intravitreal bevacizumab (Avastin)

Dear Editor: We want to report on our experiences with bevacizumab (Avastin; Genentech, Inc., San Francisco, CA, USA) in chronic cystoid macular edema (CME), which is the most common cause of irreversible visual loss in chronic uveitis [1, 2]. Anti-VEGF treatment has been reported to be a powerful treatment modality in reducing macular edema of different origin [3, 4]. Additionally, there is a rationale that VEGF-antagonists may also have anti-inflammatory capabilities. VEGF can induce chemotaxis and migration of monocytes [5]. Other pro-inflammatory effects are the induction of Band Tlymphocytes [6, 7]. Therefore, VEGF-inhibitors have also been considered to be effective in inflammatory autoimmune disorders such as rheumatoid arthritis. Intraocular administration of triamcinolone acetonide frequently causes a harmful increase in intraocular pressure—especially in uveitis [8]. Limited efficacy of other topical agents in otherwise systemically controlled inflammation led us to think about the use of bevacizumab in chronic CME. Six patients with chronic macular edema due to uveitis were treated with an intravitreal injection of bevacizumab 1.25 mg in 0.05 ml. Extensive evaluation had previously been performed to determine the cause of the uveitis. Offlabel bevacizumab therapy was only considered if inflammatory activity was judged completely quiet for more than 6 months, steroid-induced increase in IOP was in the history, or no response was seen to other immunosuppressive agents. All patients underwent Snellen chart visual acuity testing, ophthalmoscopic examination, flare measurement (FC-2000, Kowa Co. Ltd, Tokyo, Japan) and ocular coherence tomography at baseline, 1-week and 4-week intervals. The subjects opted for the injection, signing for informed consent after being given detailed information about the limited experience and the “off-label” nature of the treatment in compliance with IRB approval. Two patients showed a marked, but temporary decrease in the height of the edema and experienced transient improvement of visual acuity at the 1-week examination. One month after the injection, none of the patients had either significant improvement in visual acuity or decrease in central retinal thickness (CRT, Table 1). Apart from the rupture of a retinal cyst, no other adverse events were observed in any patient up to 12 months after the injection. Non-parametric Fisher–Pitman test (small sample procedure) revealed no significant difference in flare (p=0.369). CRT after 4 weeks did not differ significantly from the baseline (Wilcoxon matched pairs test, p=0.599). Thus, in this group of severe, chronic uveitis-associated CME, resistant to established therapies, bevacizumab has shown only minor and transient effects, but good tolerability. The full-length antibody was well-tolerated in the vitreous, in spite of present autoimmune disorders. The disrupted boundary of an intraretinal cyst could be explained by a coincidental and spontaneous event. However, with respect to pigment epithelium tears seen after anti-VEGF treatment [9] mechanical stress has also been thought to occur in desiccating CME. Graefe’s Arch Clin Exp Ophthalmol (2007) 245:917–918 DOI 10.1007/s00417-006-0512-2